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Advanced Organic Chemistry FOURTH EDITION Part B: Reactions and Synthesis FRANCIS A. CAREY and RICHARD J. SUNDBERG University of …...

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Advanced Organic Chemistry

FOURTH EDITION

Part B: Reactions and Synthesis

Advanced Organic Chemistry PART A: Structure and Mechanisms PART B: Reactions and Synthesis

Advanced Organic FOURTH Chemistry EDITION Part B: Reactions and Synthesis FRANCIS A. CAREY and RICHARD J. SUNDBERG University of Virginia Charlottesville, Virginia

Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow

eBook ISBN: Print ISBN:

0-306-47380-1 0-306-46244-3

©2002 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's eBookstore at:

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Preface to the Fourth Edition Part B emphasizes the most important reactions used in organic synthesis. The material is organized by reaction type. Chapters 1 and 2 discuss the alkylation, conjugate addition and carbonyl addition=condensation reactions of enolates and other carbon nucleophiles. Chapter 3 covers the use of nucleophilic substitution, both at saturated carbon and at carbonyl groups, in functional group of interconversions. Chapter 4 discusses electrophilic additions to alkenes and alkynes, including hydroboration. Chapter 5 discusses reduction reactions, emphasizing alkene and carbonyl-group reductions. Concerted reactions, especially Diels±Alder and other cycloadditions and sigmatropic rearrangements, are considered in Chapter 6. Chapters 7, 8, and 9 cover organometallic reagents and intermediates in synthesis. The main-group elements lithium and magnesium as well as zinc are covered in Chapter 7. Chapter 8 deals with the transition metals, especially copper, palladium, and nickel. Chapter 9 discusses synthetic reactions involving boranes, silanes, and stannanes. Synthetic reactions which involve highly reactive intermediatesÐcarbocations, carbenes, and radicalsÐare discussed in Chapter 10. Aromatic substitution by both electrophilic and nucleophilic reagents is the topic of Chapter 11. Chapter 12 discusses the most important synthetic procedures for oxidizing organic compounds. In each of these chapters, the most widely used reactions are illustrated by a number of speci®c examples of typical procedures. Chapter 13 introduces the concept of synthetic planning, including the use of protective groups and synthetic equivalents. Multistep syntheses are illustrated with several syntheses of juvabione, longifolene, Prelog±Djerassi lactone, Taxol, and epothilone. The chapter concludes with a discussion of solid-phase synthesis and its application in the synthesis of polypeptides and oligonucleotides, as well as to combinatorial synthesis. The control of reactivity to achieve speci®c syntheses is one of the overarching goals of organic chemistry. In the decade since the publication of the third edition, major advances have been made in the development of ef®cient new methods, particularly catalytic processes, and in means for control of reaction stereochemistry. For example, the scope and ef®ciency of palladium- catalyzed cross coupling have been greatly improved by optimization of catalysts by ligand modi®cation. Among the developments in stereocontrol are catalysts for enantioselective reduction of ketones, improved methods for control of the

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vi PREFACE TO THE FOURTH EDITION

stereoselectivity of Diels±Alder reactions, and improved catalysts for enantioselective hydroxylation and epoxidation of alkenes. This volume assumes a level of familiarity with structural and mechanistic concepts comparable to that in the companion volume, Part A, Structure and Mechanisms. Together, the two volumes are intended to provide the advanced undergraduate or beginning graduate student in chemistry a suf®cient foundation to comprehend and use the research literature in organic chemistry.

Contents of Part B Chapter 1. Alkylation of Nucleophilic Carbon Intermediates . . . . . . . . . . . 1.1. 1.2. 1.3. 1.4. 1.5. 1.6. 1.7. 1.8. 1.9.

Generation of Carbanions by Deprotonation . . . . . . . . . . . . . . . . . Regioselectivity and Stereoselectivity in Enolate Formation. . . . . . . Other Means of Generating Enolates . . . . . . . . . . . . . . . . . . . . . . Alkylation of Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Generation and Alkylation of Dianions . . . . . . . . . . . . . . . . . . . . Medium Effects in the Alkylation of Enolates. . . . . . . . . . . . . . . . Oxygen versus Carbon as the Site of Alkylation . . . . . . . . . . . . . . Alkylation of Aldehydes, Esters, Amides, and Nitriles . . . . . . . . . . The Nitrogen Analogs of Enols and EnolatesÐEnamines and Imine Anions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.10. Alkylation of Carbon Nucleophiles by Conjugate Addition . . . . . . . General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 2. Reaction of Carbon Nucleophiles with Carbonyl Groups . . . . . .

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Aldol 2.1.1. 2.1.2. 2.1.3.

Addition and Condensation Reactions. . . . . . . . . . . . . . . . . . . . The General Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . Mixed Aldol Condensations with Aromatic Aldehydes . . . . . . . Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehydes and Ketones . . . . . . . . . . . . 2.1.4. Intramolecular Aldol Reactions and the Robinson Annulation . . 2.2. Addition Reactions of Imines and Iminium Ions . . . . . . . . . . . . . . . . . 2.2.1. The Mannich Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Amine-Catalyzed Condensation Reactions . . . . . . . . . . . . . . . . 2.3. Acylation of Carbanions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2.4.

The Wittig and Related Reactions of Phosphorus-Stabilized Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Reactions of Carbonyl Compounds with a-Trimethylsilylcarbanions. 2.6. Sulfur Ylides and Related Nucleophiles . . . . . . . . . . . . . . . . . . . 2.7. Nucleophilic Addition±Cyclization . . . . . . . . . . . . . . . . . . . . . . . General References ............................... Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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111 120 122 127 128 128

Chapter 3. Functional Group Interconversion by Nucleophilic Substitution . . 141 3.1.

Conversion of Alcohols to Alkylating Agents . . . . . . . . . . . . . . . . . 3.1.1. Sulfonate Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Introduction of Functional Groups by Nucleophilic Substitution at Saturated Carbon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. General Solvent Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Nitriles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.5. Nitrogen Nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.6. Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.7. Phosphorus Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.8. Summary of Nucleophilic Substitution at Saturated Carbon . . . 3.3. Nucleophilic Cleavage of Carbon±Oxygen Bonds in Ethers and Esters. 3.4. Interconversion of Carboxylic Acid Derivatives . . . . . . . . . . . . . . . . 3.4.1. Preparation of Reactive Reagents for Acylation . . . . . . . . . . . 3.4.2. Preparation of Esters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Preparation of Amides. . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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147 147 150 150 152 155 158 158 159 159 164 166 172 172 180

Chapter 4. Electrophilic Additions to Carbon±Carbon Multiple Bonds . . . . . 191 4.1. 4.2. 4.3. 4.4. 4.5. 4.6. 4.7. 4.8. 4.9.

Addition of Hydrogen Halides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydration and Other Acid-Catalyzed Additions of Oxygen Nucleophiles Oxymercuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Halogens to Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Sulfur and Selenium Reagents. . . . . . . . . . . . . . . . . . . . Addition of Other Electrophilic Reagents . . . . . . . . . . . . . . . . . . . . . Electrophilic Substitution Alpha to Carbonyl Groups. . . . . . . . . . . . . . Additions to Allenes and Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . Addition at Double Bonds via Organoborane Intermediates . . . . . . . . . 4.9.1. Hydroboration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9.2. Reactions of Organoboranes. . . . . . . . . . . . . . . . . . . . . . . . . 4.9.3. Enantioselective Hydroboration. . . . . . . . . . . . . . . . . . . . . . . 4.9.4. Hydroboration of Alkynes . . . . . . . . . . . . . . . . . . . . . . . . . .

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191 195 196 200 209 216 216 222 226 226 232 236 239

General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 5. Reduction of Carbonyl and Other Functional Groups . . . . . . . .

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249 249 262 262 262 273 280 286 288 290 292 296 299 307 310 315 316

Chapter 6. Cycloadditions, Unimolecular Rearrangements, and Thermal Eliminations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

331

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5.3. 5.4. 5.5.

5.6. 5.7.

6.1.

6.2. 6.3. 6.4. 6.5. 6.6. 6.7. 6.8.

Addition of Hydrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Catalytic Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Other Hydrogen-Transfer Reagents . . . . . . . . . . . . . . . . Group III Hydride-Donor Reagents . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . 5.2.2. Stereoselectivity of Hydride Reduction . . . . . . . . . . . . . . 5.2.3. Reduction of Other Functional Groups by Hydride Donors Group IV Hydride Donors. . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrogen-Atom Donors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dissolving-Metal Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.1. Addition of Hydrogen . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.2. Reductive Removal of Functional Groups . . . . . . . . . . . . 5.5.3. Reductive Carbon±Carbon Bond Formation . . . . . . . . . . . Reductive Deoxygenation of Carbonyl Groups . . . . . . . . . . . . . . Reductive Elimination and Fragmentation . . . . . . . . . . . . . . . . . General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. The Diels±Alder Reaction: General Features . . . . . . . . . . . . 6.1.2. The Diels±Alder Reaction: Dienophiles . . . . . . . . . . . . . . . 6.1.3. The Diels±Alder Reaction: Dienes . . . . . . . . . . . . . . . . . . . 6.1.4. Asymmetric Diels±Alder Reactions . . . . . . . . . . . . . . . . . . 6.1.5. Intramolecular Diels±Alder Reactions . . . . . . . . . . . . . . . . . Dipolar Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . [2 ‡ 2] Cycloadditions and Other Reactions Leading to Cyclobutanes Photochemical Cycloaddition Reactions. . . . . . . . . . . . . . . . . . . . . [3,3] Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . 6.5.1. Cope Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5.2. Claisen Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . [2,3] Sigmatropic Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Unimolecular Thermal Elimination Reactions . . . . . . . . . . . . . . . . . 6.8.1. Cheletropic Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . 6.8.2. Decomposition of Cyclic Azo Compounds . . . . . . . . . . . . . 6.8.3. b Eliminations Involving Cyclic Transition States. . . . . . . . . General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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ix CONTENTS OF PART B

x CONTENTS OF PART B

Chapter 7. Organometallic Compounds of the Group I, II, and III Metals . . 433 7.1. 7.2.

Preparation and Properties . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions of Organomagnesium and Organolithium Compounds . 7.2.1. Reactions with Alkylating Agents . . . . . . . . . . . . . . . . 7.2.2. Reactions with Carbonyl Compounds . . . . . . . . . . . . . 7.3. Organic Derivatives of Group IIB and Group IIIB Metals . . . . . 7.3.1. Organozinc Compounds . . . . . . . . . . . . . . . . . . . . . . 7.3.2. Organocadmium Compounds . . . . . . . . . . . . . . . . . . . 7.3.3. Organomercury Compounds. . . . . . . . . . . . . . . . . . . . 7.3.4. Organoindium Reagents . . . . . . . . . . . . . . . . . . . . . . 7.4. Organolanthanide Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . General References ............................. Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 8. Reactions Involving the Transition Metals . . . . . . . . . . . . . . . . . 477 8.1. 8.2.

8.3. 8.4. 8.5.

Organocopper Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1.1. Preparation and Structure of Organocopper Reagents ...... 8.1.2. Reactions Involving Organocopper Reagents and Intermediates Reactions Involving Organopalladium Intermediates . . . . . . . . . . . . . 8.2.1. Palladium-Catalyzed Nucleophilic Substitution and Alkylation . 8.2.2. The Heck Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.3. Palladium-Catalyzed Cross Coupling . . . . . . . . . . . . . . . . . . 8.2.4. Carbonylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions Involving Organonickel Compounds. . . . . . . . . . . . . . . . . Reactions Involving Rhodium and Cobalt . . . . . . . . . . . . . . . . . . . . Organometallic Compounds with p Bonding . . . . . . . . . . . . . . . . . . General References ................................. Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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477 477 481 499 501 503 507 521 525 529 531 535 536

Chapter 9. Carbon±Carbon Bond-Forming Reactions of Compounds of Boron, Silicon, and Tin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 547 9.1.

Organoboron Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.1. Synthesis of Organoboranes . . . . . . . . . . . . . . . . . . . . . . 9.1.2. Carbon±Carbon Bond-Forming Reactions of Organoboranes 9.2. Organosilicon Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.1. Synthesis of Organosilanes . . . . . . . . . . . . . . . . . . . . . . 9.2.2. Carbon±Carbon Bond-Forming Reactions . . . . . . . . . . . . . 9.3. Organotin Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.3.1. Synthesis of Organostannanes. . . . . . . . . . . . . . . . . . . . . 9.3.2. Carbon±Carbon Bond-Forming Reactions . . . . . . . . . . . . . General References ............................... Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 10. Reactions Involving Carbocations, Carbenes, and Radicals as Reactive Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Reactions Involving Carbocation Intermediates . . . . . . . . . . . . . . . . . . . 10.1.1. Carbon±Carbon Bond Formation Involving Carbocations . . . . . . 10.1.2. Rearrangement of Carbocations . . . . . . . . . . . . . . . . . . . . . . . 10.1.3. Related Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1.4. Fragmentation Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. Reactions Involving Carbenes and Nitrenes . . . . . . . . . . . . . . . . . . . . . 10.2.1. Structure and Reactivity of Carbenes . . . . . . . . . . . . . . . . . . . 10.2.2. Generation of Carbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.3. Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.4. Insertion Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.5. Generation and Reactions of Ylides by Carbenoid Decomposition 10.2.6. Rearrangement Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.7. Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.8. Nitrenes and Related Intermediates. . . . . . . . . . . . . . . . . . . . . 10.2.9. Rearrangements to Electron-De®cient Nitrogen . . . . . . . . . . . . 10.3. Reactions Involving Free-Radical Intermediates . . . . . . . . . . . . . . . . . . 10.3.1. Sources of Radical Intermediates . . . . . . . . . . . . . . . . . . . . . . 10.3.2. Introduction of Functionality by Radical Reactions . . . . . . . . . . 10.3.3. Addition Reactions of Radicals to Substituted Alkenes . . . . . . . 10.3.4. Cyclization of Free-Radical Intermediates . . . . . . . . . . . . . . . . 10.3.5. Fragmentation and Rearrangement Reactions . . . . . . . . . . . . . . General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

595 596 602 609 612 614 617 620 625 634 637 639 641 642 646 651 652 654 657 660 674 679 680

Chapter 11. Aromatic Substitution Reactions . . . . . . . . . . . . . . . . . . . . . .

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Chapter 12. Oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Electrophilic Aromatic Substitution. . . . . . . . . . . . . . . . . . . 11.1.1. Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1.2. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1.3. Friedel±Crafts Alkylations and Acylations . . . . . . . . 11.1.4. Electrophilic Metalation . . . . . . . . . . . . . . . . . . . . 11.2. Nucleophilic Aromatic Substitution. . . . . . . . . . . . . . . . . . . 11.2.1. Aryl Diazonium Ions as Synthetic Intermediates. . . . 11.2.2. Substitution by the Addition±Elimination Mechanism 11.2.3. Substitution by the Elimination±Addition Mechanism 11.2.4. Transition-Metal-Catalyzed Substitution Reactions . . 11.3. Aromatic Radical Substitution Reactions . . . . . . . . . . . . . . . 11.4. Substitution by the SRN1 Mechanism . . . . . . . . . . . . . . . . . General References . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Oxidation of Alcohols to Aldehydes, Ketones, or Carboxylic Acids . . . . . 12.1.1. Transition-Metal Oxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1.2. Other Oxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xi CONTENTS OF PART B

xii

12.2.

CONTENTS OF PART B

12.3. 12.4. 12.5.

12.6. 12.7.

Addition of Oxygen at Carbon±Carbon Double Bonds . . . . . . 12.2.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . 12.2.2. Epoxides from Alkenes and Peroxidic Reagents. . . . . 12.2.3. Transformations of Epoxides . . . . . . . . . . . . . . . . . 12.2.4. Reaction of Alkenes with Singlet Oxygen. . . . . . . . . Cleavage of Carbon±Carbon Double Bonds . . . . . . . . . . . . . . 12.3.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . 12.3.2. Ozonolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selective Oxidative Cleavages at Other Functional Groups . . . . 12.4.1. Cleavage of Glycols . . . . . . . . . . . . . . . . . . . . . . . 12.4.2. Oxidative Decarboxylation . . . . . . . . . . . . . . . . . . . Oxidation of Ketones and Aldehydes . . . . . . . . . . . . . . . . . . 12.5.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . 12.5.2. Oxidation of Ketones and Aldehydes by Oxygen and Peroxidic Compounds . . . . . . . . . . . . . . . . . . . . . . 12.5.3. Oxidation with Other Reagents . . . . . . . . . . . . . . . . Allylic Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.6.1. Transition-Metal Oxidants . . . . . . . . . . . . . . . . . . . 12.6.2. Other Oxidants. . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidations at Unfunctionalized Carbon. . . . . . . . . . . . . . . . . General References ............................ Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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757 757 767 772 782 786 786 788 790 790 792 794 794

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798 802 803 803 805 807 809 809

Chapter 13. Planning and Execution of Multistep Syntheses . . . . . . . . . . . . 821 13.1.

13.2. 13.3. 13.4. 13.5.

13.6. 13.7.

Protective Groups . . . . . . . . . . . . . . . . . . . . . . . . 13.1.1. Hydroxyl-Protecting Groups . . . . . . . . . . . 13.1.2. Amino-Protecting Groups. . . . . . . . . . . . . 13.1.3. Carbonyl-Protecting Groups . . . . . . . . . . . 13.1.4. Carboxylic Acid-Protecting Groups . . . . . . Synthetic Equivalent Groups . . . . . . . . . . . . . . . . . Synthetic Analysis and Planning . . . . . . . . . . . . . . Control of Stereochemistry . . . . . . . . . . . . . . . . . . Illustrative Syntheses . . . . . . . . . . . . . . . . . . . . . . 13.5.1. Juvabione . . . . . . . . . . . . . . . . . . . . . . . 13.5.2. Longifolene . . . . . . . . . . . . . . . . . . . . . . 13.5.3. Prelog±Djerassi Lactone. . . . . . . . . . . . . . 13.5.4. Taxol . . . . . . . . . . . . . . . . . . . . . . . . . . 13.5.5. Epothilone A . . . . . . . . . . . . . . . . . . . . . Solid-Phase Synthesis . . . . . . . . . . . . . . . . . . . . . 13.6.1. Solid-Phase Synthesis of Polypeptides . . . . 13.6.2. Solid-Phase Synthesis of Oligonucleotides. . Combinatorial Synthesis . . . . . . . . . . . . . . . . . . . . General References ..................... Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References for Problems Index

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822 822 831 835 837 839 845 846 848 848 859 869 881 890 897 897 900 903 909 910

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 923

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947

1

Alkylation of Nucleophilic Carbon Intermediates Introduction Carbon±carbon bond formation is the basis for the construction of the molecular framework of organic molecules by synthesis. One of the fundamental processes for carbon± carbon bond formation is a reaction between a nucleophilic carbon and an electrophilic one. The focus in this chapter is on enolate ions, imine anions, and enamines, which are the most useful kinds of carbon nucleophiles, and on their reactions with alkylating agents. Mechanistically, these are usually SN2 reactions in which the carbon nucleophile displaces a halide or other leaving group. Successful carbon±carbon bond formation requires that the SN2 alkylation be the dominant reaction. The crucial factors which must be considered include (1) the conditions for generation of the carbon nucleophile; (2) the effect of the reaction conditions on the structure and reactivity of the nucleophile; (3) the regio- and stereoselectivity of the alkylation reaction; and (4) the role of solvents, counterions, and other components of the reaction media that can in¯uence the rate of competing reactions.

1.1. Generation of Carbanions by Deprotonation A very important means of generating carbon nucleophiles involves removal of a proton from a carbon by a Brùnsted base. The anions produced are carbanions. Both the rate of deprotonation and the stability of the resulting carbanion are enhanced by the presence of substituent groups that can stabilize negative charge. A carbonyl group bonded directly to the anionic carbon can delocalize the negative charge by resonance, and carbonyl compounds are especially important in carbanion chemistry. The anions formed by deprotonation of the carbon alpha to a carbonyl group bear most of their negative

1

2 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

charge on oxygen and are referred to as enolates. Several typical examples of protonabstraction equilibria are listed in Scheme 1.1. Electron delocalization in the corresponding carbanions is represented by the resonance structures presented in Scheme 1.2. Scheme 1.1. Generation of Carbon Nucleophiles by Deprotonation O

O

1 RCH2CR′ + NH2–

RCHCR′ + NH3 –

O

O –

2 RCH2COR′ + NR2′′ O

RCHCOR′ + HNR2′′ –

O

O

3 R′OCCH2COR′ + R′O– O

O

O

4 CH3CCH2COR′ + R′O–

O

CH3CCHCOR′ + R′OH – O

O 5 N

O

R′OCCHCOR′ + R′OH –

CCH2COR′ + R′O–

6 RCH2NO2 + HO–

N

CCHCOR′ + R′OH –

RCHNO 2 + H2O –

Scheme 1.2. Resonance in Some Carbanions 1 Enolate of ketone O–

O RCH –

RCH

CR′

CR′

2 Enolate of ester O–

O RCH –

RCH

COR′

COR′

3 Malonic ester anion O–

O R′OC

CH

O

COR′

R′OC

O–

O CH –

COR′

R′OC

O CH

COR′

4 Acetoacetic ester anion O–

O CH3C

CH

O

COR′

O–

O

CH3C

CH –

N

CH –

COR′

CH3C

O CH

COR′

5 Cyanoacetic ester anion O– N

C

CH

COR′

O C

6 Nitronate anion +

O

+

O–

RCH N

RCH N – O–

O–

COR′

O –

N

C

CH

COR′

The ef®cient generation of a signi®cant equilibrium concentration of a carbanion requires choice of a proper Brùnsted base. The equilibrium will favor carbanion formation only when the acidity of the carbon acid is greater than that of the conjugate acid corresponding to the base used for deprotonation. Acidity is quantitatively expressed as pKa , which is equal to log Ka and applies, by de®nition, to dilute aqueous solution. Because most important carbon acids are quite weak acids (pKa > 15), accurate measurement of their acidity in aqueous solutions is impossible, and acidities are determined in organic solvents and referenced to the pKa in an approximate way. The data produced are not true pKa 's, and their approximate nature is indicated by referring to them as simply pK values. Table 1.1 presents a list of pK data for some typical carbon acids. The table also includes examples of the bases which are often used for deprotonation. The strongest acids appear at the top of the table, and the strongest bases at the bottom. A favorable equilibrium between a carbon acid and its carbanion will be established if the base which is used appears below the acid in the table. Also included in the table are pK values determined in dimethyl sulfoxide (pKDMSO). The range of acidities that can be directly measured in dimethyl sulfoxide (DMSO) is much greater than in aqueous media, thereby allowing direct comparisons between compounds to be made more con®dently. The pK values in DMSO are normally greater than in water because water stabilizes anions more effectively, by hydrogen bonding, than does DMSO. Stated another way, many anions are more strongly basic in DMSO than in water. At the present time, the pKDMSO scale includes the widest variety of structural types of synthetic interest.1 From the pK values collected in Table 1.1, an ordering of some important substituents with respect to their ability to stabilize carbanions can be established. The order suggested is NO2 > COR > CN  CO2R > SO2R > SOR > Ph  SR > H > R. By comparing the approximate pK values of the conjugate acids of the bases with those of the carbon acid of interest, it is possible to estimate the position of the acid±base equilibrium for a given reactant±base combination. If we consider the case of a simple alkyl ketone in a protic solvent, for example, it can be seen that hydroxide ion and primary alkoxide ions will convert only a small fraction of such a ketone to its anion. O–

O O–

RCCH3 + RCH2

RC

CH2 + RCH2OH

K<1

The slightly more basic tertiary alkoxides are comparable to the enolates in basicity, and a somewhat more favorable equilibrium will be established with such bases: O–

O CO–

RCCH3 + R3

RC

CH2 + R3COH

K≈1

To obtain complete conversion of ketones to enolates, it is necessary to use aprotic solvents so that solvent deprotonation does not compete with enolate formation. Stronger bases, such as amide anion ( 7 NH2), the conjugate base of DMSO (sometimes referred to as the ``dimsyl'' anion),2 and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide (LDA), which is generated by addition of n-butyllithium to diisopropylamine, is widely used as a strong 1. F. G. Bordwell, Acc. Chem. Res. 21:456 (1988). 2. E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 87:1345 (1965).

3 SECTION 1.1. GENERATION OF CARBANIONS BY DEPROTONATION

4 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

Table 1.1. Approximate pK Values for Some Carbon Acids and Some Common Basesa Carbon acid

pK

O2NCH2NO2 CH3COCH2NO2 PhCH2NO2 CH3CH2NO2 CH3COCH2COCH3 PhCOCH2COCH3 CH3NO2 CH3COCH2CO2CH2CH3 CH3COCH(CH3)COCH3 NCCH2CN CH2(SO2CH2CH3)2 PhCH2NO2 CH2(CO2CH2CH3)2 Cyclopentadiene PhSCH2COCH3 PhCH2COCH3 CH3CH2CH(CO2CH2CH3)2 PhSCH2CN PhCH2CN (PhCH2)2SO2 PhCOCH3 CH3COCH3 CH3CH2COCH2CH3 Fluorene PhSO2CH3 PhCH2SOCH3 CH3CN Ph2CH2 Ph3CH

3.6 5.1 8.6 9 9.6 10.2 10.7 11 11.2 12.2 12.3 12.7 15 15

15.8 20 20.5 25 33

pKDMSO

pK

pKDMSO

CH3CO2

4.2

11.6

PhO

9.9

16.4

12.3 16.7 17.2 14.2 11.0 14.4 16.4 18.7 19.9 20.8 21.9 23.9 24.7 26.5 27.1 22.6 29.0 29.0 31.3 32.2 30.6 43 56

PhCH3 CH4

Common bases

(CH3CH2)3N (CH3CH2)2NH

10.7 11

CH3O HO CH3CH2O (CH3)2CHO (CH3)3CO

15.5 15.7 15.9

NH2 CH3SOCH2 (CH3CH2)2N

35 35 36

19

29.0 31.4 29.8 30.3 32.2

41 35.1

a. F. G. Bordwell, Acc. Chem. Res. 21:456 (1988).

base in synthetic procedures.3 It is a very strong base, yet it is suf®ciently bulky so as to be relatively nonnucleophilic, a feature that is important in minimizing side reactions. The lithium, sodium and potassium salts of hexamethyldisilazane, [(CH3)3Si]2NH, are easily prepared and handled compounds with properties similar to those of lithium diisopropylamide and also ®nd extensive use in synthesis.4 These bases must be used in aprotic solvents such as ether, tetrahydrofuran (THF), or dimethoxyethane (DME). O

OLi

RCCH3 + [(CH3)2CH]2NLi

RC

CH2 + [(CH3)2CH]2NH

K>1

LDA

3. H. O. House, W. V. Phillips, T. S. B. Sayer, and C.-C. Yau, J. Org. Chem. 43:700 (1978). 4. E. H. Amonoco-Neizer, R. A. Shaw, D. O. Skovlin, and B. C. Smith, J. Chem. Soc. 1965:2997; C. R. Kruger and E. G. Rochow, J. Organmet. Chem. 1:476 (1964).

Sodium hydride and potassium hydride can also be used to prepare enolates from ketones. The reactivity of the metal hydrides is somewhat dependent on the means of preparation and puri®cation of the hydride.5 The data in Table 1.1 allow one to estimate the position of the equilibrium for any of the other carbon acids with a given base. It is important to keep in mind the position of such equilibria as other aspects of reactions of carbanions are considered. The base and solvent used will determine the extent of deprotonation. There is another important physical characteristic which needs to be kept in mind, and that is the degree of aggregation of the carbanion. Both the solvent and the cation will in¯uence the state of aggregation, as will be discussed further in Section 1.6.

1.2. Regioselectivity and Stereoselectivity in Enolate Formation tion:

An unsymmetrical dialkyl ketone can form two regioisomeric enolates on deprotona-

O–

O R2CHCCH2R′

B–

R2C

O–

CCH2R′ or R2CHC

CHR′

In order to exploit fully the synthetic potential of enolate ions, control over the regioselectivity of their formation is required. Although it may not be possible to direct deprotonation so as to form one enolate to the exclusion of the other, experimental conditions can often be chosen to provide a substantial preference for the desired regioisomer. To understand why a particular set of experimental conditions leads to the preferential formation of one enolate while other conditions lead to the regioisomer, we need to examine the process of enolate generation in more detail. The composition of an enolate mixture may be governed by kinetic or thermodynamic factors. The enolate ratio is governed by kinetic control when the product composition is determined by the relative rates of the two or more competing proton-abstraction reactions. O– R2C ka

O

CCH2R′ A ka [A] = [B] kb

R2CHCCH2R′ + B– kb

O– R2CHC CHR′ B

Kinetic control of isomeric enolate composition

On the other hand, if enolates A and B can be interconverted readily, equilibrium is established and the product composition re¯ects the relative thermodynamic stability of the 5. C. A. Brown, J. Org. Chem. 39:1324 (1974); R. Pi. T. Friedl, P. v. R. Schleyer, P. Klusener, and L. Brandsma, J. Org. Chem. 52:4299 (1987); T. L. Macdonald, K. J. Natalie, Jr., G. Prasad, and J. S. Sawyer, J. Org. Chem. 51:1124 (1986).

5 SECTION 1.2. REGIOSELECTIVITY AND STEREOSELECTIVITY IN ENOLATE FORMATION

Scheme 1.3. Composition of Enolate Mixtures

6 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

1a

O–

O CH3

CH3

CH3

Kinetic control (Ph3CLi/ dimethoxyethane) Thermodynamic control (Ph3CLi/ equilibration in the presence of excess ketone)

72

94

6

O–

CH3

CH3

CH3

Kinetic control (LDA/ dimethoxyethane) Thermodynamic control (Et3N/DMF)

O

3d Ph

1

99

78

22

O–

O–

Ph

Kinetic control (LDA/tetrahydrofuran, –70°C)d Thermodynamic control (KH, tetrahydrofuran)c

H

4a

Ph

Only enolate Only enolate

H

O

H Kinetic control (Ph3CLi/ dimethoxyethane) Thermodynamic control (equilibration in the presence of excess ketone)

5e

H

H

13

87

53

47

O

CH3CH2CH2C

CH2

Only enolate

O–

CH3 C

CH3

CH2CH3 Z-enolate

CH2CH3 C

C

H Kinetic control (lithium 2,2,6,6-tetramethylpiperidide/ tetrahydrofuran) Thermodynamic control (equilibration in the presence of excess ketone)

O–

O–

Kinetic control (LDA/tetrahydrofuran, –78°C)

CH3CH2CCH2CH3

H

O–

O CH3CH2CH2CCH3

6f

28

O–

O

2b,c

O–

C O–

H E-enolate

13

87

84

16

Scheme 1.3. (continued ) O

7g

O–

CH3

CH3CH2CC(CH3)3

C

O

>98

<2

O– C

g. h.

Ph C

Ph

C O–

H

Z

E

>98

<2

O– CH3(CH2)4C

Kinetic control (LDA, –78°C) Kinetic control (LDA TMSCl) Kinetic control (NDA/tetramethylenediamine) Thermodynamic control (KH, tetrahydrofuran, 20°C)

e. f.

CH3

C

O CH3CH2CH2CCH3

a. b. c. d.

O– E

H

9h

C

H

Z

CH3

Kinetic control (LDA/ tetrahydrofuran)

C(CH3)3 C

C(CH3)3

Kinetic control (LDA/ tetrahydrofuran)

CH3CH2CPh

CH3

C

H

8g

7

O– CH2

CH3(CH2)3CH

CCH3

26 5 9 54

74 95 91 46

H. O. House and B. M. Trost, J. Org. Chem. 30:1341 (1965). H. O. House, M. Gall, and H. D. Olmstead, J. Org. Chem. 36:2361 (1971). H. O. House, L. J. Czuba, M. Gall, and H. D. Olmstead, J. Org. Chem.34:2324 (1969). E. Vedejs, J. Am. Chem. Soc. 96:5944 (1974); H. J. Reich, J. M. Renga, and I. L. Reich, J. Am. Chem. Soc. 97:5434 (1975). G. Stork, G. A. Kraus, and G. A. Garcia, J. Org. Chem. 39:3459 (1974). Z. A. Fataftah, I. E. Kopka, and M. W. Rathke, J. Am. Chem. Soc. 102:3959 (1980); Y. Balamraju, C. D. Sharp, W. Gammill, N. Manue, and L. M. Pratt, Tetrahedron 54:7357 (1998). C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, and J. Lampe, J. Org. Chem. 45:1066 (1980). R. D. Clark and C. H. Heathcock, J. Org. Chem. 41:1396 (1976); C. A. Brown, J. Org. Chem. 39:3913 (1974); E. J. Corey and A. W. Gross, Tetrahedron Lett. 25:495 (1984); P. C. Andrews, N. D. R. Barnett, R. E. Malvey, W. Clegg, P. A. D. Neil, D. Barr, L. Couton, A. J. Dawson, and B. J. Wake®eld, J. Organomet. Chem. 518:85 (1996).

enolates. The enolate ratio is then governed by thermodynamic control. O– R2C ka

O

CCH2R′ A

k–a

R2CHCCH2R′ + B–

[A] = K [B]

K kb

k–b

O– R2CHC B

CHR′

Thermodynamic control of isomeric enolate composition

By adjusting the conditions under which an enolate mixture is formed from a ketone, it is possible to establish either kinetic or thermodynamic control. Ideal conditions for kinetic control of enolate formation are those in which deprotonation is rapid, quantitative,

SECTION 1.2. REGIOSELECTIVITY AND STEREOSELECTIVITY IN ENOLATE FORMATION

8 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

and irreversible.6 This ideal is approached experimentally by using a very strong base such as LDA or hexamethyldisilyamide (HMDS) in an aprotic solvent in the absence of excess ketone. Lithium is a better counterion than sodium or potassium for regioselective generation of the kinetic enolate. Lithium maintains a tighter coordination at oxygen and reduces the rate of proton exchange. Aprotic solvents are essential because protic solvents permit enolate equilibration by reversible protonation±deprotonation, which gives rise to the thermodynamically controlled enolate composition. Excess ketone also catalyzes the equilibration by proton exchange. Scheme 1.3 shows data for the regioselectivity of enolate formation for several ketones under various reaction conditions. A quite consistent relationship is found in these and related data. Conditions of kinetic control usually favor the less substituted enolate. The principal reason for this result is that removal of the less hindered hydrogen is faster, for steric reasons, than removal of more hindered protons. Removal of the less hindered proton leads to the less substituted enolate. Steric factors in ketone deprotonation can be accentuated by using more highly hindered bases. The most widely used base is the hexamethyldisilylamide ion, as a lithium or sodium salt. Even more hindered disilylamides such as hexaethyldisilylamide7 and bis(dimethylphenylsilyl)amide8 may be useful for speci®c cases. On the other hand, at equilibrium the more substituted enolate is usually the dominant species. The stability of carbon±carbon double bonds increases with increasing substitution, and this effect leads to the greater stability of the more substituted enolate. The terms kinetic control and thermodynamic control are applicable to other reactions besides enolate formation; the general concept was covered in Part A, Section 4.4. In discussions of other reactions in this chapter, it may be stated that a given reagent or set of conditions favors the ``thermodynamic product.'' This statement means that the mechanism operating is such that the various possible products are equilibrated after initial formation. When this is true, the dominant product can be predicted by considering the relative stabilities of the various possible products. On the other hand, if a given reaction is under ``kinetic control,'' prediction or interpretation of the relative amounts of products must be made by analyzing the competing rates of product formation. For many ketones, stereoisomeric as well as regioisomeric enolates can be formed, as is illustrated by entries 6, 7, and 8 of Scheme 1.3. The stereoselectivity of enolate formation, under conditions of either kinetic or thermodynamic control, can also be controlled to some extent. We will return to this topic in more detail in Chapter 2. It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in cis-2,6-dimethylcyclohexanone or 4-(t-butyl)cyclohexanone.

O H3C

O CH3

HS HR

HR HS

C(CH3)3

6. For a review, see J. d'Angelo, Tetrahedron 32:2979 (1976). 7. S. Masamune, J. W. Ellingboe, and W. Choy, J. Am. Chem. Soc. 104:5526 (1982). 8. S. R. Angle, J. M. Fevig, S. D. Knight, R. W. Marquis, Jr., and L. E. Overman, J. Am. Chem. Soc. 115:3966 (1993).

The most studied bases are chiral amides such as C±F.9 CH3

9 Li

CH3 N

Ph

N

Ph

Li N

Li C10

Li

N

N

N

C(CH3)3

Ph

Ph

D11

12

F13

E

Enantioselective enolate formation can also be achieved by kinetic resolution by preferential reaction of one of the enantiomers of a racemic chiral ketone such as 2-(tbutyl)cyclohexanone (see Part A, Section 2.2 to review the principles of kinetic resolution). O

O C(CH3)3

OTMS C(CH3)3

R*2NLi (D)

C(CH3)3 +

trimethylsilyl chloride 45%, yield, 90% e.e.

Ref. 14 51%, yield, 94% e.e.

(e.e. = enantiomeric excess)

Such enantioselective deprotonations depend upon kinetic selection between prochiral or enantiomeric protons and the chiral base resulting from differences in diastereomeric transition states.15 For example, transition state G has been proposed for deprotonation of 4-substituted cyclohexanones by base F.16 R O N

Li

Ph H

Cl– N CH2C(CH3)3 Li G

Kinetically controlled deprotonation of a,b-unsaturated ketones usually occurs preferentially at the a0 carbon adjacent to the carbonyl group. The polar effect of the 9. P. O'Brien, J. Chem. Soc., Perkin Trans 1 1998:1439; H. J. Geis, Methods of Organic Chemistry (HoubenWeyl), Vol. E21a, G. Thiemer, Stuttgart, 1996, p. 589. 10. P. J. Cox and N. S. Simpkins, Tetrahedron Asymmetry, 2:1 (1991); N. S. Simpkins, Pure Appl. Chem. 68:691 (1996); B. J. Bunn and N. S. Simpkins, J. Org. Chem. 58:533 (1993). 11. C. M. Cain, R. P. C. Cousins, G. Coumbarides, and N. S. Simpkins, Tetrahedron 46:523 (1990). 12. D. Sato, H. Kawasaki, T. Shimada, Y. Arata, K. Okamura, T. Date, and K. Koga, J. Am. Chem. Soc. 114:761 (1992); T. Yamashita, D. Sato, T. Kiyoto, A. Kumar, and K. Koga, Tetrahedron Lett. 37:8195 (1996); H. Chatani, M. Nakajima, H. Kawasaki, and K. Koga, Heterocycles 46:53 (1997); R. Shirai, D. Sato, K. Aoki, M. Tanaka, H. Kawasaki, and K. Koga, Tetrahedron 53:5963 (1997). 13. M. Asami, Bull. Chem. Soc. Jpn. 63:721 (1996). 14. H. Kim, H. Kawasaki, M. Nakajima, and K. Koga, Tetrahedron Lett. 30:6537 (1989); D. Sato, H. Kawasaki, T. Shimada, Y. Arata, K. Okamura, T. Date, and K. Koga, J. Am. Chem. Soc. 114:761 (1992). 15. A. Corruble, J.-Y. Valnot, J. Maddaluno, Y. Prigent, D. Davoust, and P. Duhamel, J. Am. Chem. Soc. 119:10042 (1997); D. Sato, H. Kawasaki, and K. Koga, Chem. Pharm. Bull. 45:1399 (1997); K. Sugasawa, M. Shindo, H. Noguchi, and K. Koga, Tetrahedron Lett. 37:7377 (1996). 16. M. Toriyama, K. Sugasawa, M. Shindo, N. Tokutake, and K. Koga, Tetrahedron Lett. 38:567 (1997).

SECTION 1.2. REGIOSELECTIVITY AND STEREOSELECTIVITY IN ENOLATE FORMATION

10

carbonyl group is probably responsible for the faster deprotonation at this position.

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

O–Li+

O NCH(CH3)2 Li+

Ref. 17 THF, 0°C

CH3

CH3

CH3

CH3 (only enolate)

Under conditions of thermodynamic control, however, it is the enolate corresponding to deprotonation of the g carbon that is present in the greater amount. γ

CH3

O–

O

CH3 C β

CHCCH3 α

α′

NaNH2

CH2 γ

NH3

C

CH α

CCH3 >

CH3

γ

major enolate (more stable)

H

O–

CH3 α′

C CH3

CH α

C

CH2 α′

Ref. 18

γ

(less stable)

I

These isomeric enolates differ in stability in that H is fully conjugated, whereas the p system in I is cross-conjugated. In isomer I, the delocalization of the negative charge is restricted to the oxygen and the a0 carbon, whereas in the conjugated system of H, the negative charge is delocalized on oxygen and both the a and the g carbon.

1.3. Other Means of Generating Enolates The recognition of conditions under which lithium enolates are stable and do not equilibrate with regioisomers allows the use of other reactions in addition to proton abstraction to generate speci®c enolates. Several methods are shown in Scheme 1.4. Cleavage of trimethylsilyl enol ethers or enol acetates by methyllithium (entries 1 and 3, Scheme 1.4) is a route to speci®c enolate formation that depends on the availability of these starting materials in high purity. The composition of the trimethylsilyl enol ethers prepared from an enolate mixture will re¯ect the enolate composition. If the enolate formation can be done with high regioselection, the corresponding trimethylsilyl enol ether can be obtained in high purity. If not, the silyl enol ether mixture must be separated. Trimethylsilyl enol ethers can be cleaved by tetraalkylammonium ¯uoride salts (entry 2, Scheme 1.4). The driving force for this reaction is the formation of the very strong Si F bond, which has a bond energy of 142 kcal=mol.19 Trimethylsilyl enol ethers can be prepared directly from ketones. One procedure involves reaction with trimethylsilyl chloride and a tertiary amine.20 This procedure gives the regioisomers in a ratio favoring the thermodynamically more stable enol ether. Use of 17. R. A. Lee, C. McAndrews, K. M. Patel, and W. Reusch, Tetrahedron Lett. 1973:965. 18. G. BuÈchi and H. Wuest, J. Am. Chem. Soc. 96:7573 (1974). 19. For reviews of the chemistry of O-silyl enol ethers, see J. K. Rasmussen, Synthesis 1977:91; P. Brownbridge, Synthesis 1:85 (1983); I. Kuwajima and E. Nakamura, Acc. Chem. Res. 18:181 (1985). 20. H. O. House, L. J. Czuba, M. Gall, and H. D. Olmstead, J. Org. Chem. 34:2324 (1969); R. D. Miller and D. R. McKean, Synthesis 1979:730.

t-butyldimethylsilyl chloride with potassium hydride as the base also seems to favor the thermodynamic product.21 Trimethylsilyl tri¯uoromethanesulfonate (TMS tri¯ate), which is more reactive, gives primarily the less substituted trimethylsilyl enol ether.22 Higher ratios of less substituted to more substituted enol ether are obtained by treating a mixture of ketone and trimethylsilyl chloride with LDA at 78 C.23 Under these conditions, the kinetically preferred enolate is immediately trapped by reaction with trimethylsilyl chloride. Even greater preferences for the less substituted silyl enol ether can be obtained by using the more hindered amide from t-octyl-t-butylamine. Trimethylsilyl enol ethers can also be prepared by 1,4-reduction of enones using silanes as reductants. Several effective catalysts have been found.24 The most versatile of these catalysts appears to be a Pt complex of divinyltetramethyldisiloxane.25 This catalyst gives good yields of substituted silyl enol ethers. O

O

R

OSiR′3

R′3SiH Si Pt Si

SiR′3, = Si(Et)3, Si(i-Pr)3, Si(Ph)3, Si(Me)2C(Me)3 R

Lithium±ammonia reduction of a,b-unsaturated ketones (entry 6, Scheme 1.4) provides a very useful method for generating speci®c enolates.26 The desired starting materials are often readily available, and the position of the double bond in the enone determines the structure of the resulting enolate. This and other reductive methods for generating enolates from enones will be discussed more fully in Chapter 5. Another very important method for speci®c enolate generation, the addition of organometallic reagents to enones, will be discussed in Chapter 8.

1.4. Alkylation of Enolates Alkylation of enolate is an important synthetic method.27 The alkylation of relatively acidic compounds such as b-diketones, b-ketoesters, and esters of malonic acid can be carried out in alcohols as solvents using metal alkoxides as bases. The presence of two electron-withdrawing substituents facilitates formation of the enolate resulting from removal of a proton from the carbon situated between them. Alkylation then occurs by an SN2 process. Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.5. These reactions are all mechanistically similar in that a

21. J. Orban. J. V. Turner, and B. Twitchin, Tetrahedron Lett. 25:5099 (1984). 22. H. Emde, A. GoÈtz, K. Hofmann, and G. Simchen, Justus Liebigs Ann. Chem. 1981:1643; see also E. J. Corey, H. Cho, C. RuÈcker, and D. Hua Tetrahedron Lett. 1981:3455. 23. E. J. Corey and A. W. Gross, Tetrahedron Lett. 25:495 (1984). 24. I. Ojima and T. Kogure, Organometallics 1:1390 (1982); T. H. Chan and G. Z. Zheng, Tetrahedron Lett. 34:3095 (1993); D. E. Cane and M. Tandon, Tetrahedron Lett. 35:5351 (1994). 25. C. R. Johnson and R. K. Raheja, J. Org. Chem. 59:2287 (1994). 26. For a review of a,b-enone reduction, see D. Caine, Org. React. 23:1 (1976). 27. D. Caine, in Carbon±Carbon Bond Formation, Vol. 1, R. L. Augustine, ed., Marcel Dekker, New York, 1979, Chapter 2.

11 SECTION 1.4. ALKYLATION OF ENOLATES

Scheme 1.4. Generation of Speci®c Enolates

12 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

A. Cleavage of trimethylsilyl enol esters 1a

O–Li+

OSiMe3 CH(CH3)2

CH(CH3)2

CH3Li

+ (CH3)4Si

dimethoxyethane

CH3

CH3

CH3

2b

CH3 +

O– PhCH2N(CH3)3

OSi(CH3)3 + PhCH2N(CH3)3F

H3C

CH3 + (CH3)3SiF

THF

B. Cleavage of enol acetates 3c

O PhCH

COCCH3

2 equiv CH3Li

PhCH

dimethoxyethane

CH3

CO–Li+ + (CH3)3COLi CH3

C. Regioselective silylation of ketones by in situ enolate trapping O d

4

C6H13CCH3

OSi(CH3)3

(CH3)3SiCl

C6H13C

add LDA at –78°C

CH2 + C5H11CH

95%

O 5e

(CH3)2CHCCH3

OSi(CH3)3 CCH3

5%

OSi(CH3)3 (CH3)3SiO3SCF3 20°C, (C2H5)3N

(CH3)2CHC

OSi(CH3)3

CH2 + (CH3)2C

84%

CCH3 16%

D. Reduction of a,b-unsaturated ketones 6f + Li

NH3

NH3 –

–O

O 7g

O O O

+Li–O

OSi(i-Pr)3 (i-Pr)3SiH Pt[CH2=CHSi(CH3)2]2O

O O

a. G. Stork and P. F. Hudrlik, J. Am. Chem. Soc. 90:4464 (1968); see also H. O. House, L. J. Czuba, M. Gall, and H. D. Olmstead, J. Org. Chem. 34:2324 (1969). b. I. Kuwajima and E. Nakamura, J. Am. Chem. Soc. 97:3258 (1975). c. G. Stork and S. R. Dowd, Org. Synth. 55:46 (1976); see also H. O. House and B. M. Trost, J. Org. Chem. 30:2502 (1965). d. E. J. Corey and A. W. Gross, Tetrahedron Lett. 25:495 (1984). e. H. Emde, A. GoÈtz, K. Hofmann, and G. Simchen, Justus Liebigs Ann. Chem. 1981:1643. f. G. Stork, P. Rosen, N. Goldman, R. V. Coombs, and J. Tsuji, J. Am. Chem. Soc. 87:275 (1965). g. C. R. Johnson and R. K. Raheja, J. Org. Chem. 59:2287 (1994).

carbanion, formed by deprotonation using a suitable base, reacts with an electrophile by an SN2 mechanism. The alkylating agent must be reactive toward nucleophilic displacement. Primary halides and sulfonates, especially allylic and benzylic ones, are the most reactive alkylating agents. Secondary systems react more slowly and often give only moderate yields because of competing elimination. Tertiary halides give only elimination products. Methylene groups can be dialkylated if suf®cient base and alkylating agent are used. Dialkylation can be an undesirable side reaction if the monoalkyl derivative is the desired product. Use of dihaloalkanes as the alkylating reagent leads to ring formation, as illustrated by the diethyl cyclobutanedicarboxylate synthesis (entry 7) shown in Scheme 1.5. This example illustrates the synthesis of cyclic compounds by intramolecular alkylation reactions. The relative rates of cyclization for o-haloalkyl malonate esters are 650,000 : 1 : 6500 : 5 for formation of three-, four-, ®ve-, and six-membered rings, respectively.28 (See Section 3.9 of Part A to review the effect of ring size on SN2 reactions.) Relatively acidic carbon acids such as malonic esters and b-keto esters were the ®rst class of carbanions for which reliable conditions for alkylation were developed. The reason being that these carbanions are formed using easily accessible alkoxide ions. The preparation of 2-substiuted b-keto esters (entries 1, 4, and 8) and 2-substituted derivatives of malonic ester (entries 2 and 7) by the methods illustrated in Scheme 1.5 are useful for the synthesis of ketones and carboxylic acids, since both b-ketoacids and malonic acids undergo facile decarboxylation: O X

C R

H

C

O C

OH

–CO2

O

X

R′

C

O C

R

X

R′

C

CH

R

R′

β = keto acid: X = alkyl or aryl = ketone substituted substituted malonic acid: X = OH = acetic acid

Examples of this approach to the synthesis of ketones and carboxylic acids are presented in Scheme 1.6. In these procedures, an ester group is removed by hydrolysis and decarboxylation after the alkylation step. The malonate and acetoacetate carbanions are the synthetic equivalents of the simpler carbanions lacking the ester substituents. In the preparation of 2-heptanone (entries 1, Schemes 1.5 and 1.6), for example, ethyl acetoacetate functions as the synthetic equivalent of acetone. It is also possible to use the dilithium derivative of acetoacetic acid as the synthetic equivalent of acetone enolate.29 In this case, the hydrolysis step is unnecessary, and decarboxylation can be done directly on the alkylation product. Li+ O–

O CH3CCH2CO2H

2 n-BuLi

CH3C

O CHCO–Li+

O 1) R—X +

2) H (–CO2)

CH3CCH2R

28. A. C. Knipe and C. J. Stirling, J. Chem. Soc., B 1968:67; for a discussion of factors which affect intramolecular alkylation of enolates, see J. Janjatovic and Z. Majerski, J. Org. Chem. 45:4892 (1980). 29. R. A. Kjonaas and D. D. Patel, Tetrahedron Lett. 25:5467 (1984).

13 SECTION 1.4. ALKYLATION OF ENOLATES

Scheme 1.5. Alkylations of Relatively Acidic Carbon Acids

14 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

NaOEt

1a CH3COCH2CO2C2H5 + CH3(CH2)3Br

CH3COCHCO2C2H5 (CH2)3CH3

NaOEt

2b CH2(CO2C2H5)2 +

Cl

3c CH3COCH2COCH3 + CH3I

K2CO3

CHCO2C2H5)2

CH3COCHCOCH3

69–72%

61%

75–77%

CH3 4d CH3COCH2CO2C2H5 + ClCH2CO2C2H5

NaOEt

CH3COCHCO2C2H5 CH2CO2C2H5

5e Ph2CHCN + KNH2

Ph2CCN –

Ph2CCN + PhCH2Cl –

Ph2CCN

98–99%

CH2Ph 6f

PhCH2CO2C2H5 + NaNH2

PhCHCO2C2H5 –

PhCHCO 2C2H5 + PhCH2CH2Br –

PhCHCO2C2H5 CH2CH2Ph

7g CH2(CO2C2H5)2 + BrCH2CH2CH2Cl 8h

77–81%

CO2C2H5

NaOEt

CO2C2H5

O

53–55%

O CO2CH3

+ BrCH2(CH2)5CO2C2H5

NaH DMF

CO2CH3 CH2(CH2)5CO2C2H5 85% on 1-mol scale

a. b. c. d. e. f. g. h.

C. S. Marvel and F. D. Hager, Org. Synth. I:248 (1941). R. B. Moffett, Org. Synth. IV:291 (1963). A. W. Johnson, E. Markham, and R. Price, Org. Synth. 42:75 (1962). H. Adkins, N. Isbell, and B. Wojcik, Org. Synth. II:262 (1943). C. R. Hauser and W. R. Dunnavant, Org. Synth. IV:962 (1963). E. M. Kaiser, W. G. Kenyon, and C. R. Hauser, Org. Synth. 47:72 (1967). R. P. Mariella and R. Raube, Org. Synth. IV:288 (1963). K. F. Bernardy. J. F. Poletto, J. Nocera, P. Miranda, R. E. Schaub, and M. J. Weiss, J. Org. Chem. 45:4702 (1980).

Similarly, the dilithium salt of monoethyl malonic dianion is easily alkylated and the product decarboxylates on acidi®cation.30 The use of b-ketoesters and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with ¯uoride ion.31 Tetraalkylammonium ¯uoride salts in anhydrous solvents are normally the 30. J. E. McMurry and J. H. Musser, J. Org. Chem. 40:2556 (1975). 31. I. Kuwajima, E. Nakamura, and M. Shimizu, J. Am. Chem. Soc. 104:1025 (1982).

15

Scheme 1.6. Synthesis of Ketones and Carboxylic Acid Derivatives via Alkylation Followed by Decarboxylation 1a

H2O, –OH

CH3COCHCO2C2H5

H+



CH3COCHCO2

(CH2)3CH3

D

CH3CO(CH2)4CH3

SECTION 1.4. ALKYLATION OF ENOLATES

52–61%

(CH2)3CH3

(see Scheme 1.5) NaOBu

2b CH2(CO2C2H5)2 + C7H15Br C7H15CH(CO2C2H5)2 D

C7H15CH(CO2H)2 3c

CO2C2H5

H2O, –OH

H+

C7H15CH(CO2C2H5)2

C7H15CH(CO2H)2

C8H17CO2H + CO2

H2O, –OH

66–75%

CO2H

H+

CO2C2H5

D

CO2H + CO2

CO2H

(see Scheme 1.5)

4d NCCH2CO2C2H5 +

NaOEt

CH2Cl

CH2CHCN CO2C2H5

Cl

Cl 1) H2O, –OH 2) H+ 3) D, –CO2

CH2CH2CN Cl 5e

O

O CO2CH3 + PhCH2Cl

CO2CH3

Na

CH2Ph O

O CO2CH3 CH2Ph a. b. c. d. e.

CH2Ph + CH3I + CO2

+ LiI

72–76%

J. R. Johnson and F. D. Hager, Org. Synth. I:351 (1941). E. E. Reid and J. R. Ruhoff, Org. Synth. II:474 (1943). G. B. Heisig and F. H. Stodola, Org. Synth. III:213 (1955). J. A. Skorcz and F. E. Kaminski, Org. Synth. 48:53 (1968). F. Elsinger, Org. Synth. V:76 (1973).

¯uoride ion source. H3C

CH3

H3C

CH3

H3C

1) LDA

R4 CH2

2) TMSCl

O

CH3

CH3

N+F–

TMSO

CH3

Ref. 32

CHCH2Br

CH2

CHCH2 O

CH3

Several examples of alkylation of ketone enolates are given in Scheme 1.7. 32. A. B. Smith III and R. Mewshaw, J. Org. Chem. 49:3685 (1984).

Scheme 1.7. Regioselective Enolate Alkylation

16 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

1a

H

H

Li

CH3(CH2)3I

43%

NH3

Li+–O

O

2b

O

H

O–Li+

O CH3

O CH3

Li, NH3

H (CH2)3CH3 O

CH3

CH3I

CH3

+

CH3

H3C

60%

3c H3C

4d

LDA

O

H3C

H3C

PhCH2Br

CH2Ph 42–45%

O–

O CH3

2%

O–Li+

O

O–

CH3

LDA

CH3

CH3

25°C

O

Br

CH3 Br

Br

THF, –78°C

79%

5e

O–Li+

O

O CH2CH

CH2=CHCH2Br

Li, NH3

CH3

CH3

CH2

CH3 45% trans/cis ~20/1

6f

(CH3)3SiO

O CH(CH3)2

CH3 CH(CH3)2

1) MeLi 2) CH3I

H3C CH3 7g

80%

H3C CH3

OSi(CH3)3 H3C

O CH2CH

H3C

1) MeLi 2) ICH2CH CCH3

90%

CO2C(CH3)3

8h

(CH3)3SiO

O CH3

1) R4N+F–, THF 2) PhCH2Br

CCH3 CO2C(CH3)3

PhCH2

CH3 72% 3:1 trans:cis

17

Scheme 1.7. (continued ) 9i

H

CH3 CH3

H

CH3 CH3

SECTION 1.4. ALKYLATION OF ENOLATES

1) R4N+F– 2) CH2

(CH3)3SiO a. b. c. d. e. f. g. h. i.

CHCH2Br

CH2

CH3

CHCH2 O

CH3 59%

G. Stork, P. Rosen, N. Goldman, R. V. Coombs, and J. Tsujii, J. Am. Chem. Soc. 87:275 (1965). H. A. Smith, B. J. L. Huff, W. J. Powers III, and D. Caine, J. Org. Chem. 32:2851 (1967). M. Gall and H. O. House, Org. Synth. 52:39 (1972). S. C. Welch and S. Chayabunjonglerd, J. Am. Chem. Soc. 101:6768 (1979). D. Caine, S. T. Chao, and H. A. Smith, Org. Synth. 56:52 (1977). G. Stork and P. F. Hudrlik, J. Am. Chem. Soc. 90:4464 (1968). P. L. Stotter and K. A. Hill, J. Am. Chem. Soc. 96:6524 (1974). I. Kuwajima, E. Nakamura, and M. Shimizu, J. Am. Chem. Soc. 104:1025 (1982). A. B. Smith III and R. Mewshaw, J. Org. Chem. 49:3685 (1984).

The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the reaction which is crucial in many cases is the stereoselectivity. The alkylation step has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, since the electrons which are involved in bond formation are the p electrons. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile will approach from the less hindered of the two faces, and the degree of stereoselectivity depends upon the steric differentiation. For simple, conformationally based cyclohexanone enolates such as that from 4-t-butylcyclohexanone, there is little steric differentiation. The alkylation product is a nearly 1 : 1 mixture of the cis and trans isomers. O– (CH3)3C

O C2H5I or Et3O+BF4–

(CH3)3C

H

O + (CH3)3C

C2H5

C2H5 H Ref. 33

The cis product must be formed through a transition state with a twistlike conformation to adhere to the requirements of stereoelectronic control. The fact that this pathway is not disfavored is consistent with other evidence that the transition state in enolate alkylations occurs early and re¯ects primarily the structural features of the reactant, not the product. A late transition state should disfavor the formation of the cis isomer because of the strain energy associated with the nonchair conformation of the product. The introduction of an alkyl substituents at the a carbon in the enolate enhances stereoselectivity somewhat. This is attributed to a steric effect in the enolate. To minimize steric interaction with the solvated oxygen, the alkyl group is distorted somewhat from coplanarity. This biases the enolate toward attack from the axial direction. The alternative approach from the upper face would enhance the steric interaction by forcing the alkyl 33. H. O. House, B. A. Terfertiller, and H. D. Olmstead, J. Org. Chem. 33:935 (1968).

18 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

group to become eclipsed with the enolate oxygen.34 O

O O (CH3)3C

CD3I

(CH3)3C

+ (CH3)3C CD3

CH3

CH3

CD3

CH3

83%

17%

When an additional methyl substituent is placed at C-3, there is a strong preference for alkylation anti to the 3-methyl group. This can be attributed to the conformation of the enolate, which places the methyl in a pseudoaxial conformation because of allylic strain (see Part A, Section 3.3.) The C-3 methyl then shields the lower face of the enolate.35 R′

O–

CH3

R′—X

CH3

CH3 CH3

O–

CH3 CH3

O

favored

disfavored

The enolates of 1- and 2-decalone derivatives provide further insights into the factors governing stereoselectivity in enolate alkylations. The 1(9)-enolate of 1-decalone shows a preference for alkylation to give the cis ring juncture. This is believed to be due primarily to a steric effect. The upper face of the enolate presents three hydrogens in a 1,3-diaxial relationship to the approaching electrophile. The corresponding hydrogens on the lower face are equatorial.36 H

O H

H

O– R—X

R H

The 2(1)-enolate of trans-2-decalone is preferentially alkylated by an axial approach of the electrophile.

H

R

H O–

R′—X

H

H

R

O

R′

The stereoselectivity is enhanced if there is an alkyl substituent at C-1. The factors operating in this case are similar to those described for 4-t-butylcyclohexanone. The transdecalone framework is conformationally rigid. Axial attack from the lower face leads directly to the chair conformation of the product. The 1-alkyl group enhances this 34. H. O. House and M. J. Umen, J. Org. Chem. 38:1000 (1973). 35. R. K. Boeckman, Jr., J. Org. Chem. 38:4450 (1973). 36. H. O. House and B. M. Trost, J. Org. Chem. 30:2502 (1965).

stereoselectivity because a steric interaction with the solvated enolate oxygen distorts the enolate in such a way as to favor the axial attack.37 The placement of an axial methyl group at C-10 in a 2(1)-decalone enolate introduces a 1,3-diaxial interaction with the approaching electrophile. The preferred alkylation product results from approach on the upper face of the enolate. R

H

H O–

R′—X

H R′

R′

O

R O CH3

CH3

CH3

R

The prediction and interpretation of alkylation stereochemistry also depends on consideration of conformational effects in the enolate. The decalone enolate 1 was found to have a strong preference for alkylation to give the cis ring junction, with alkylation occurring syn to the t-butyl substituent.38 O–

O

CH3

CH3I

1

H

C(CH3)3

C(CH3)3

H

According to molecular mechanics calculations, the minimum-energy conformation of the enolate is a twist-boat conformation (because the chair leads to an axial orientation of the tbutyl group). The enolate is convex in shape, with the second ring shielding the lower face of the enolate, and alkylation therefore occurs from the top. –O

H

–O

H

O CH3I

C(CH3)3 C(CH3)3

CH3 H

C(CH3)3 H

H

If the alkylation is intramolecular, additional conformational restrictions on the direction of approach of the electrophile to the enolate become important. Baldwin et al. have summarized the general principles that govern the energetics of intramolecular ring-closure reactions.39 (See Part A, Section 3.9). The intramolecular alkylation reaction of 2 gives exclusively 3.40 The transition state must achieve a geometry that permits interaction of the p orbital of the enolate to achieve an approximately collinear alignment with the sulfonate leaving group. The alkylation probably occurs through a transition state like J. The transition state K for formation of the trans ring junction would be more 37. R. S. Mathews, S. S. Grigenti, and E. A. Folkers, J. Chem. Soc., Chem. Commun. 1970:708; P. Lansbury and G. E. DuBois, Tetrahedron Lett. 1972:3305. 38. H. O. House, W. V. Phillips, and D. Van Derveer, J. Org. Chem. 44:2400 (1979). 39. J. E. Baldwin, R. C. Thomas, L. I. Kruse, and L. Silberman, J. Org. Chem. 42:3846 (1977). 40. J. M. Conia and F. Rouessac, Tetrahedron 16:45 (1961).

19 SECTION 1.4. ALKYLATION OF ENOLATES

20

strained because of the necessity to span the opposite face of the enolate p system.

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

O– CH3

CH3 (CH2)4OSO2Ar H

H

H CH3

H

O

H

H O3SAr

3

2

O–

OSO2Ar

O–

J

CH3 K

These examples illustrate the issues which must be considered in analyzing the stereoselectivity of enolate alkylation. The major factors are the conformation of the enolate, the stereoelectronic requirement for an approximately perpendicular trajectory, and the steric preference for the least hindered path of approach.

1.5. Generation and Alkylation of Dianions In the presence of a suf®ciently strong base, such as an alkyllithium, sodium or potassium hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be converted to their dianions by two sequential deprotonations.41 For example, reaction of benzoylacetone with sodium amide leads ®rst to the enolate generated by deprotonation at the methylene group between the two carbonyl groups. A second equivalent of base deprotonates the benzyl methylene group to give a diendiolate. O

Li+O–

O

PhCH2CCH2CCH3

2 NaNH2

PhCH

C

O–Li+ CH

C

CH3

PhCHCH3 Cl

O

O

PhCHCCH2CCH3

Ref. 42

PhCHCH3

Alkylation reactions of dianions occur at the more basic carbon. This technique allows alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Because, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.8.

1.6. Medium Effects in the Alkylation of Enolates The rate of alkylation of enolate ions is strongly dependent on the solvent in which the reaction is carried out.43 The relative rates of reaction of the sodium enolate of diethyl n-butylmalonate with n-butyl bromide are shown in Table 1.2. 41. For reviews, see T. M. Harris and C. M. Harris, Org. React. 17:155 (1969); E. M. Kaiser, J. D. Petty, and P. L. A. Knutson, Synthesis 1977:509; C. M. Thompson and D. L. C. Green, Tetrahedron 47:4223 (1991); C. M. Thompson, Dianion Chemistry in Organic Synthesis, CRC Press, Boca Raton, Florida, 1994. 42. D. M. von Schriltz, K. G. Hamton, and C. R. Hauser, J. Org. Chem. 34:2509 (1969). 43. For reviews, see (a) A. J. Parker, Chem. Rev. 69:1 (1969); (b) L. M. Jackmamn and B. C. Lange, Tetrahedron 33:2737 (1977).

Scheme 1.8. Generation and Alkylation of Dianions 1a

O–

O CH3CCH2CHO

2b

O

KNH2 2 equiv

CH2

C

O– CH

O–

O

NaNH2 CH3CCH2CCH3 2 equiv

CH2

C

CH

SECTION 1.6. MEDIUM EFFECTS IN THE ALKYLATION OF ENOLATES

O 1) PhCH2Cl 2) H3O+

PhCH2CH2CCH2CHO

O– CH

21

O

CCH3

1) BuBr 2) H3O+

80%

O

CH3(CH2)4CCH2CCH3 81–82%

3c

O–

O CHOH

CH3

KNH2 2 equiv

O CHO–

CH3

CH3

CHO–

BuBr

CH3(CH2)3

NaOH, H2O

O CH3 CH3(CH2)3 54–74%

4d

O CH3CCH2CO2CH3

1) NaH 2) RLi

CH2

O–

O–

CCH

COCH3

O 1) EtBr 2) H3O+

CH3(CH2)2CCH2CO2CH3 84%

5e CH2

O–

O–

CCH

COCH3 + (CH3)2C

O CHCH2Br

(CH3)2C

CHCH2CH2CCH2CO2CH3 85%

a. T. M. Harris, S. Boatman, and C. R. Hauser, J. Am. Chem. Soc. 85:3273 (1963); S. Boatman, T. M. Harris, and C. R. Hauser, J. Am. Chem. Soc. 87:82 (1965); K. G. Hampton, T. M. Harris, and C. R. Hauser, J. Org. Chem. 28:1946 (1963). b. K. G. Hampton, T. M. Harris, and C. R. Hauser, Org. Synth. 47:92 (1967). c. S. Boatman, T. M. Harris, and C. R. Hauser, Org. Synth. 48:40 (1968). d. S. N. Huckin and L. Weiler, J. Am. Chem. Soc. 96:1082 (1974). e. F. W. Sum and L. Weiler, J. Am. Chem. Soc. 101:4401 (1979).

DMSO and N,N-dimethylformamide (DMF) are particularly effective in enhancing the reactivity of enolate ions, as Table 1.2 shows. Both of these compounds belong to the polar aprotic class of solvents. Other members of this class that are used as solvents in reactions between carbanions and alkyl halides include N-methylpyrrolidone (NMP) and hexamethylphosphoric triamide (HMPA). Polar aprotic solvents, as their name implies, are materials which have high dielectric constants but which lack hydroxyl groups or other Table 1.2 Relative Alkylation Rates of Sodium Diethyl n-Butylmalonate in Various Solventsa Solvent

Dielectric constant, e

Relative rate

Benzene Tetrahydrofuran Dimethoxyethane Dimethylformamide Dimethyl sulfoxide

2.3 7.3 6.8 37 47

1 14 80 970 1420

a. From H. E. Zaugg, J. Am. Chem. Soc. 83:837 (1961).

22 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

hydrogen-bonding groups. Polar aprotic solvents possess excellent metal-cation coordination ability, so they can solvate and dissociate enolates and other carbanions from ion pairs and clusters.

O– H3C

CH3 + dimethyl sulfoxide (DMSO) e = 47

O H

S

C

N N(CH3)2

N,N-dimethylformamide (DMF) e = 37

O

CH3

O

N-methylpyrrolidone (NMP) e = 32

P[N(CH3)2]3

hexamethylphosphoric triamide (HMPA) e = 30

The reactivity of alkali-metal (Li‡ , Na‡ , K‡ ) enolates is very sensitive to the state of aggregation, which is, in turn, in¯uenced by the reaction medium. The highest level of reactivity, which can be approached but not achieved in solution, is that of the ``bare'' unsolvated enolate anion. For an enolate±metal ion pair in solution, the maximum reactivity would be expected in a medium in which the cation was strongly solvated and the enolate was very weakly solvated. Polar aprotic solvents are good cation solvators and poor anion solvators. Each one (DMSO, DMF, HMPA, and NMP) has a negatively polarized oxygen available for coordination to the alkali-metal cation. Coordination to the enolate ion is much less effective because the positively polarized atom of these molecules is not nearly as exposed as the oxygen. Thus, these solvents provide a medium in which enolate±metal ion pairs are dissociated to give a less encumbered, more reactive enolate. O–M+

O– + solvent →

+ [M(solvent)n]+

n aggregated ions

dissociated ions

Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents for enolate alkylation reactions because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding. The solvated enolate is relatively less reactive because the hydrogenbonded enolate must be disrupted during alkylation. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive than the same enolate in a polar aprotic solvent such as DMSO. O– M+ + solvent–OH →

O– … HO-solvent + [M(solvent–OH)n]+ solvated ions

THF and DME are slightly polar solvents which are moderately good cation solvators. Coordination to the metal cation involves the oxygen lone pairs. These solvents, because of their lower dielectric constants, are less effective at separating ion pairs and higher aggregates than are the polar aprotic solvents. The crystal structures of the lithium and potassium enolates of methyl t-butyl ketone have been determined by X-ray crystal-

lography.44 The structures are shown in Figs. 1.1 and 1.2. While these represent the solidstate structural situation, the hexameric clusters are a good indication of the nature of the enolates in relatively weakly coordinating solvents. Despite the somewhat reduced reactivity of aggregated enolates, THF and DME are the most commonly used solvents for synthetic reactions involving enolate alkylation. They are the most suitable solvents for kinetic enolate generation and also have advantages in terms of product workup and puri®cation over the polar aprotic solvents. Enolate reactivity in these solvents can often be enhanced by adding a reagent that can bind alkali-metal cations more strongly. Popular choices are HMPA, tetramethylethylenediamine (TMEDA), and the crown ethers.45 TMEDA can chelate metal ions through the electron pairs on nitrogen. The crown ethers can coordinate metal ions in structures in which the metal ion is encapsulated by the ether oxygens. The 18-crown-6 structure is of such a size as to allow sodium or potassium ions to ®t comfortably in the cavity. The smaller 12-crown-4 binds Li‡ preferentially. The cation complexing agents lower the degree of aggregation of the enolate±metal-cation ion pairs and result in enhanced reactivity. The reactivity of enolates is also affected by the metal counterion. Among the most commonly used ions, the order of reactivity is Mg2‡ < Li‡ < Na‡ < K‡ . The factors that are responsible for this order are closely related to those described for solvents. The smaller, harder Mg2‡ and Li‡ cations are more tightly associated with the enolate than are the Na‡ and K‡ ions. The tighter coordination decreases the reactivity of the enolate and gives rise to more highly associated species.

1.7. Oxygen versus Carbon as the Site of Alkylation Enolate anions are ambident nucleophiles. Alkylation of an enolate can occur at either carbon or oxygen. Because most of the negative charge of an enolate is on the oxygen atom, it might be supposed that O-alkylation would dominate. A number of factors other than charge density affect the C=O-alkylation ratio, and it is normally possible to establish reaction conditions that favor alkylation on carbon.

O– C-alkylation

RC

O CH2 + R′X

O– O-alkylation

RC

RCCH2R′ OR′

CH2 + R′X

RC

CH2

O-Alkylation is most pronounced when the enolate is dissociated. When the potassium salt of ethyl acetoacetate is treated with diethyl sulfate in the polar aprotic solvent HMPA, the major product (83%) is the O-alkylated one. In THF, where ion clustering occurs, all of the product is C-alkylated. In t-butanol, where the acetoacetate 44. P. G. Williard and G. B. Carpenter, J. Am. Chem. Soc. 108:462 (1986). 45. C. L. Liotta and T. C. Caruso, Tetrahedron Lett. 26:1599 (1985).

23 SECTION 1.7. OXYGEN VERSUS CARBON AS THE SITE OF ALKYLATION

24 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

Fig. 1.1. Unsolvated hexameric aggregate of lithium enolate of methyl t-butyl ketone; large circles ˆ oxygen, small circles ˆ lithium. (Reproduced with permission from Ref. 44. Copyright 1986 American Chemical Society.)

Fig. 1.2. Potassium enolate of methyl t-butyl ketone; large cirlces ˆ oxygen, small circles ˆ potassium. (a) Left-hand plot shows only methyl t-butyl ketone residues. (b) Right-hand plot shows only the solvating THF molecules. The crystal is a composite of these two structures. (Reproduced with permission from Ref. 44. Copyright 1986 American Chemical Society.)

anion is hydrogen-bonded by solvent, again only C-alkylation is observed.46 O– K+ CH3C

CHCO2CH2CH3 + (CH3CH2O)2SO2

CH3CH2O CH3C

O CHCO2CH2CH3 + CH3CCHCO2CH2CH3 CH2CH3

in HMPA in t-butanol in THF

83% 0% 0%

15% (2% dialkyl) 94% (6% dialkyl) 94% (6% dialkyl)

46. A. L. Kurts, A. Masias, N. K. Genkina, I. P. Beletskaya, and O. A. Reutov, Dokl. Akad. Nauk. SSR (Engl. Transl.) 187:595 (1969).

Higher C=O-alkylation ratios are observed with alkyl halides than with alkyl sulfonates and sulfates. The highest C=O-alkylation ratios are obtained with alkyl iodides. For ethylation of the potassium salt of ethyl acetoacetate in HMPA, the product compositions shown below were obtained.47 O–K+ CH3C

CHCO2CH2CH3 + CH3CH2X

HMPA

CH3CH2O CH3C

O CHCO2CH2CH3 + CH3CCHCO2CH2CH3 CH2CH3 11% (1% dialkyl) 32% (8% dialkyl) 38% (23% dialkyl) 71% (16% dialkyl)

88% 60% 39% 13%

X = OTs X = Cl X = Br X=I

Leaving-group effects on the ratio of C- to O-alkylation can be correlated by reference to the ``hard±soft-acid±base'' (HSAB) rationale.48 Of the two nucleophilic sites in an enolate ion, oxygen is harder than carbon. Nucleophilic substitution reactions of the SN2 type proceed best when the nucleophile and leaving group are either both hard or both soft.49 Consequently, ethyl iodide, with the very soft leaving group iodide, reacts preferentially with the softer carbon site rather than the harder oxygen. Oxygen leaving groups, such as sulfonate and sulfate, are harder, and alkyl sulfonates and sulfates react preferentially at the hard oxygen site of the enolate. The hard±hard combination is favored by an early transition state, where the charge distribution is the most important factor. The soft±soft combination is favored by a later transition state, where partial bond formation is the dominant factor. The C-alkylation product is more stable than the O-alkylation product (because the bond energy of CˆO ‡ C C is greater than that of CˆC ‡ C O). Therefore, conditions that favor a dissociated, more reactive enolate favor O-alkylation. Similar effects are also seen with enolates of simple ketones. For isopropyl phenyl ketone, the inclusion of one equivalent of 12-crown-4 in a DME solution of the lithium enolate changes the C=O-alkylation ratio from 1.2 : 1 to 1 : 3, with methyl sulfate as the alkylating agent.50 With methyl iodide as the alkylating agent, C-alkylation is strongly favored with or without 12-crown-4. O– Li+

O CH3

CH3

(CH3O)2SO2

OCH3 C(CH3)3

CH3 + CH3 favored by added crown ether

To summarize, the amount of O-alkylation is maximized by use of an alkyl sulfate or alkyl sulfonate in a polar aprotic solvent. The amount of C-alkylation is maximized by use of an alkyl halide in a less polar or protic solvent. The majority of synthetic operations involving ketone enolates are carried out in THF or DME using an alkyl bromide or alkyl iodide, and C-alkylation is favored. 47. 48. 49. 50.

A. L. Kurts, N. K. Genkina, A. Masias, I. P. Beletskaya, and O. A. Reutov, Tetrahedron 27:4777 (1971). T.-L. Ho, Hard and Soft Acids and Bases Principle in Organic Chemistry, Academic Press, New York, 1977. R. G. Pearson and J. Songstad, J. Am. Chem. Soc. 89:1827 (1967). L. M. Jackman and B. C. Lange, J. Am. Chem. Soc. 103:4494 (1981).

25 SECTION 1.7. OXYGEN VERSUS CARBON AS THE SITE OF ALKYLATION

26 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

Intramolecular alkylation of enolates leads to formation of cyclic products. In addition to the other factors that govern C=O-alkylation ratios, the element of stereoelectronic control comes into play in such cases. The following reactions illustrate this point.51

CH3

CH3

Br LDA ether

CH3 O

CH3 via

CH3

CH3

O

H2C

Br

CH3 O–

H2C

(only product)

CH3

CH3 LDA ether

CH3 O

CH3

Br

CH3

CH3

via CH 3

O

–O

CH2

(only product)

Br

In order for C-alkylation to occur, the p orbital at the a carbon must be aligned with the C Br bond in the linear geometry associated with the SN2 transition state. When the ring to be closed is six-membered, this geometry is accessible, and cyclization to the cyclohexanone occurs. With ®ve-membered rings, colinearity cannot be achieved easily. Cyclization at oxygen then occurs faster than does cyclopentanone formation. The transition state for O-alkylation involves an oxygen lone-pair orbital and is less strained than the transition state for C-alkylation.

Br C

H

H C

H H O O

H

H

H H H

H Br

:

C

O

H

H

H

– geometry required for intramolecular C-alklation of enolate

H C H

O

H

geometry required for intramolecular O-alklation of enolate

In enolates formed by proton abstraction from a,b-unsaturated ketones, there are three potential sites for attack by electrophiles: the oxygen, the a carbon, and the g carbon. The kinetically preferred site for both protonation and alkylation is the a carbon.

δ−

O

δ− α

β

δ− γ

51. J. E. Baldwin and L. I. Kruse, J. Chem. Soc., Chem. Commun. 1977:233.

Protonation of the enolate provides a method for converting a,b-unsaturated ketones and esters to the less stable b,g-unsaturated isomers.

H3C

C8H17

H3C AcOH

H3C

C8H17

H3C

O

C8H17

H3C

+

H2O

–O

H3C

O (major)

(minor)

Ref. 52

CH3CH

CHCO2C2H5

LiNR2

H2O

CH2

CHCH2CO2C2H5 + CH3CH

CHCO2C2H5

87%

Ref. 53

13%

Alkylation also takes place selectively at the a carbon.17 The selectivity for electrophilic attack at the a carbon presumably re¯ects a greater negative charge, as compared with the g carbon.

CH3

O

β

C CH3

CHCCH3 + CH2 α

CHC

CHCH2Br

NaNH2 NH3

CH2

CHCH2

CH3

CH3

γ

CHC

88%

CH3

α

O

CHCCH3 C β

γ

CH2

Phenoxide ions are a special case related to enolate anions but with a strong preference for O-alkylation because C-alkylation disrupts aromatic conjugation.

O–

O R

OH

X R

H H

R

Phenoxides undergo O-alkylation in solvents such as DMSO, DMF, ethers, and alcohols. In water and tri¯uoroethanol, however, extensive C-alkylation occurs.54 These latter solvents form particularly strong hydrogen bonds with the oxygen atom of the phenolate 52. J. H. Ringold and S. K. Malhotra, Tetrahedron Lett. 1962:669; S. K. Malhotra and H. J. Ringold, J. Am. Chem. Soc. 85:1538 (1963). 53. M. W. Rathke and D. Sullivan, Tetrahedron Lett. 1972:4249. 54. N. Kornblum, P. J. Berrigan, and W. J. LeNoble, J. Am. Chem. Soc. 85:1141 (1963); N. Kornblum, R. Seltzer, and P. Haber®eld, J. Am. Chem. Soc. 85:1148 (1963).

27 SECTION 1.7. OXYGEN VERSUS CARBON AS THE SITE OF ALKYLATION

28

anion. This strong solvation decreases the reactivity at oxygen and favors C-alkylation.

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

OCH2Ph

97%

DMF

O– + PhCH2Br CH2Ph

CF3CH2OH

OH

OCH2Ph +

85%

7%

1.8. Alkylation of Aldehydes, Esters, Amides, and Nitriles Among the compounds capable of forming enolates, the alkylation of ketones has been most widely studied and used synthetically. Similar reactions of esters, amides, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One limitation is the fact that aldehydes are rapidly converted to aldol condensation products by base (see Chapter 2 for more discussion of this reaction). Only when the enolate can be rapidly and quantitatively formed is aldol condensation avoided. Success has been reported using potassium amide in liquid ammonia55 and potassium hydride in THF. Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions will be discussed in Section 1.9. (CH3)2CHCHO

1) KH, THF 2) BrCH2CH=C(CH3)2

(CH3)2CCH2CH

(CH3)2

Ref. 56

CHO 88%

Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Chapter 2). The successful formation of ester enolates typically involves an amide base, usually LDA or potassium hexamethyldisilylamide (KHMDS) at low temperature.57 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the reaction. Some examples are given in Scheme 1.9. Carboxylic acids can be directly alkylated by conversion to dianions by two equivalents of LDA. The dianions are alkylated at the a carbon as would be expected.58 (CH3)2CHCO2H

2LDA

O–Li+

CH3 C CH3

C O–Li+

CH3 CH3(CH2)3Br H+

CH3(CH2)3C

CO2H

CH3 (80%)

55. S. A. G. De Graaf, P. E. R. Oosterhof, and A. van der Gen, Tetrahedron Lett. 1974:1653. 56. P. Groenewegen, H. Kallenberg, and A. van der Gen, Tetrahedron Lett. 1978:491. 57. (a) M. W. Rathke and A. Lindert, J. Am. Chem. Soc. 93:2318 (1971); (b) R. J. Cregge, J. L. Herrmann, C. S. Lee, J. E. Richman, and R. H. Schlessinger, Tetrahedron Lett. 1973:2425; (c) J. L. Herrmann and R. H. Schlessinger, J. Chem. Soc., Chem. Commun. 1973:711. 58. P. L. Creger, J. Am. Chem. Soc. 89:2500 (1967); P. L. Creger, Org. Synth. 50:58 (1970); P. L. Creger, J. Org. Chem. 37:1907 (1972).

Scheme 1.9. Alkylation of Esters, Amides, Imides and Nitriles 1a CO2CH3

2b

SECTION 1.8. ALKYLATION OF ALDEHYDES, ESTERS, AMIDES, AND NITRILES

CO2CH3

1) LDA, THF, –70°C

~90%

2) CH3(CH2)6I, HMPA, 25°C

(CH2)6CH3

NCH(CH3)2 Li+, –78°C

1)

CH3(CH2)4CO2C2H5

29

CH3(CH2)3CHCO2C2H5

2) CH3CH2CH2CH2Br

75%

CH2CH2CH2CH3 3c

H

CH3

O O CH3

4d

O H

O O

2) CH2=CH(CH2)3Br 3) LDA, DME 4) CH3I

O H

H

CH3

1) LDA, DME

H3C

H

CH2

O

2) CH3I, HMPA

H

5e HO

(CH2)3CH CH3

O

CH3 1) LDA

86%

82%

CH3O 1) 2 LDA, THF, –78°C

O

2) 2 CH3I, HMPA, –45°C

O

CH3

O 6f

65%

O O

PhCH2

O 1) LDA

N

PhCH2

2) (CH3)2C=CH(CH2)4O3SAr

(CH2)4CH

C(CH3)2

N 83%

7g

O O

O

O N

1) LDA

O

O N

2) PhCH2Br

CH3

Ph

8h

CH2Ph Ph

CH3

O

O

78%

O

O 1) NaHMDS

O

N

2) CH3I

O

N CH3 77%

Scheme 1.9. (continued )

30 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

9i

H3C

H3C CN

H3C

1) LDA, THF, HMPA

H3C

(CH2)4OTMS

H3C

2) Br(CH2)4OTMS

H3C

H

CN H 83%

10j

O

H

CH2CH2 NaHMDS

O

O

O

O

CH2Br CN

O

CN

O

O

83%

a. b. c. d. e. f. g. h. i.

T. R. Williams and L. M. Sirvio, J. Org. Chem. 45:5082 (1980). M. W. Rathke and A. Lindert, J. Am. Chem. Soc. 93:2320 (1971). S. C. Welch, A. S. C. Prakasa Rao, C. G. Gibbs, and R. Y. Wong, J. Org. Chem. 45:4077 (1980). W. H. Pirkle and P. E. Adams, J. Org. Chem. 45:4111 (1980). H.-M. Shieh and G. D. Prestwich, J. Org. Chem. 46:4319 (1981). D. Kim, H. S. Kim, and J. Y. Yoo, Tetrahedron Lett. 32:1577 (1991). D. A. Evans, M. D. Ennis, and D. J. Mathre, J. Am. Chem. Soc. 104:73 (1982). A. Fadel, Synlett. 1992:48. L. A. Paquette, M. E. Okazaki, and J.-C. Caille, J. Org. Chem. 53:477 (1988).

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of N-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. Li+ O

O

O–

O

O

O

R′

R O

N

CH2R

LDA

O

N

R′X

O

N

R

CHCH3

H CHCH3

H CHCH3

CH3

CH3

CH3

4 Li+ O

O

O–

O

O

O

R

R O

N

CH2R

LDA

O

N

R′X

O

N

H Ph

CH3

Ph

CH3

R′ H

Ph

CH3

5

In 4 the upper face is shielded by the isopropyl group whereas in 5 the lower face is shielded by the methyl and phenyl groups. As a result, alkylation of the two derivatives gives products of the opposite con®guration. Subsequent hydrolysis or alcoholysis provides acids or esters in enantiomerically enriched form. The initial alkylation product 59. D. A. Evans, M. D. Ennis, and D. J. Mathre, J. Am. Chem. Soc. 104:1737 (1982); D. J. Ager, I. Prakash, and D. R. Schaad, Chem. Rev. 96:835 (1996); D. J. Ager, I. Prakash, and D. R. Schaad, Aldrichimica Acta 30:3 (1997).

ratios are typically 95 : 5 in favor of the major isomer. Because the intermediates are diastereomeric mixtures, they can be separated. The ®nal products can then be obtained in >99% enantiomeric purity. Several other oxazolidinones have been developed for use as chiral auxiliaries. 5,5-Diaryl derivatives are quite promising.60 O

O

C O

C NH

O

NH

Naph

Ph

Naph

Ph

Acetonitrile (pKDMSO ˆ 31.3) can be deprotonated, provided a strong nonnucleophilic base such as LDA is used. CH3C

N

LDA THF

LiCH2C

N

1) O 2) (CH3)3SiCl

(CH3)3SiOCH2CH2CH2C

N

Ref. 61

78%

Phenylacetonitrile (pKDMSO ˆ 21.9) is considerably more acidic than acetonitrile. Deprotonation can be done with sodium amide. Dialkylation has been used in the synthesis of meperidine, an analgesic substance.62 CH2CN + CH3N(CH2CH2Cl)2

NaNH2

NCH3 CN

NCH3 CO2CH2CH3 meperidene

1.9. The Nitrogen Analogs of Enols and EnolatesÐEnamines and Imine Anions The nitrogen analogs of ketones and aldehydes are called imines, azomethines, or Schiff bases. Imine is the preferred name and will be used here. These compounds can be prepared by condensation of primary amines with ketones and aldehydes.63 O R

C

R + RNH2 → R

N

R

C

R + H2O

60. T. Hintermann and D. Seebach, Helv. Chim. Acta 81:2093 (1998); C. L. Gibson, K. Gillon, and S. Cook, Tetrahedron Lett. 39:6733 (1998). 61. S. Murata and I. Matsuda, Synthesis 1978:221. 62. O. Eisleb, Berichte 74:1433 (1941); cited in H. Kagi and K. Miescher, Helv. Chim. Acta 32:2489 (1949). 63. For general reviews of imines and enamines see P. Y. Sollenberger and R. B. Martin, in The Chemistry of the Amino Group, S. Patai, ed., John Wiley & Sons, 1968, Chapter 7; G. Pitacco and E. Valentin, in The Chemistry of Amino, Nitroso and Nitro Groups and Their Derivatives, Part 1, S. Patai, ed., John Wiley & Sons, New York, 1982, Chapter 15; P. W. Hickmott, Tetrahedron 38:3363 (1982); A. G. Cook, ed., Enamines: Synthesis, Structure and Reactions, Marcel Dekker, New York, 1988.

31 SECTION 1.9. THE NITROGEN ANALOGS OF ENOLS AND ENOLATESÐ ENAMINES AND IMINE ANIONS

32 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

When secondary amines are heated with ketones or aldehydes in the presence of an acidic catalyst, a related condensation reaction occurs and can be driven to completion by removal of water by azetropic distillation or use of molecular sieves. The condensation product is a substituted vinylamine or enamine. O

OH

RCCHR2 + R2′ NH

R2′ N

C

CHR2

H+

+

R2′ N

R

C

CHR2

–H+

R2N

C

R

CR2

R

There are other methods for preparing enamines from ketones that utilize strong dehydrating reagents to drive the reaction to completion. For example, mixing carbonyl compounds and secondary amines followed by addition of titanium tetrachloride rapidly gives enamines. This method is especially applicable to hindered amines.64 Triethoxysilane can also be used.65 Another procedure involves converting the secondary amine to its N-trimethylsilyl derivative. Because of the higher af®nity of silicon for oxygen than nitrogen, enamine formation is favored and takes place under mild conditions.66 (CH3)2CHCH2CH

O + (CH3)3SiN(CH3)2

(CH3)2CHCH

CHN(CH3)2

88%

The b-carbon atom of an enamine is a nucleophilic site because of conjugation with the nitrogen atom. Protonation of enamines takes place at the b carbon, giving an iminium ion. R2′ N

+

C

R2′ N

CR2

R

C



CR2

R2′ N

R

C

CR2

H+

+

R2′ N

R

C

CHR2

R

The nucleophilicity of the b-carbon atoms permits enamines to be used in synthetically useful alkylation reactions: .. R2′ N

R C R

CR2 CH2 R′′

X

+

R2′ N

C

C

R

R

CH2R′′

H2O

O

R

RC

C

CH2R′′

R

The enamines derived from cyclohexanones have been of particular interest. The pyrrolidine enamine is most frequently used for synthetic applications. In the enamine mixture formed from pyrrolidine and 2-methylcyclohexanone, structure 6 is predominant.67 The tendency for the less substituted enamine to predominate is quite general. A steric effect is responsible for this preference. Conjugation between the nitrogen atom and the p orbitals of the double bond favors coplanarity of the bonds that are darkened in the structures. A serious nonbonded repulsion (A1,3 strain) destabilizes isomer 7. Furthermore, in isomer 6 the methyl group adopts a quasi-axial conformation to avoid steric interaction 64. W. A. White and H. Weingarten, J. Org. Chem. 32:213 (1967); R. Carlson, R. Phan-Tan-Luu, D. Mathieu, F. S. Ahounde, A. Babadjamian, and J. Metzger, Acta Chem. Scand. B32:335 (1978); R. Carlson, A. Nilsson, and M. Stromqvist, Acta Chem. Scand. B37:7 (1983); R. Carlson and A. Nilsson, Acta Chem. Scand. B38:49 (1984); S. Schubert, P. Renaud, P.-A. Carrupt, and K. Schenk, Helv. Chim. Acta 76:2473 (1993). 65. B. E. Love and J. Ren, J. Org. Chem. 58:5556 (1993). 66. R. Comi, R. W. Franck, M. Reitano, and S. M. Weinreb, Tetrahedron Lett.1973:3107. 67. W. D. Gurowitz and M. A. Joseph, J. Org. Chem. 32:3289 (1967).

with the amine substituents.68 H H H

33 H

H N

H H C

H

N

H H C H H

H H H

6

SECTION 1.9. THE NITROGEN ANALOGS OF ENOLS AND ENOLATESÐ ENAMINES AND IMINE ANIONS

H steric repulsion

7

Because of the predominance of the less substituted enamine, alkylations occur primarily at the less substituted a carbon. Synthetic advantage can be taken of this selectivity to prepare 2,6-disubstituted cyclohexanones. The iminium ions resulting from C-alkylation are hydrolyzed in the workup procedure. +

N

N

H3C

H3C + ICH2CH

CH2CH

CCH3

CCH3 CO2C(CH3)3

CO2C(CH3)3

+

H

O H3C

CH2CH

CCH3

Ref. 69

CO2H 52%

Alkylation of enamines requires relatively reactive alkylating agents for good results. Methyl iodide, allylic and benzylic halides, a-haloesters, a-haloethers, and a-haloketones are the most successful alkylating agents. Some typical examples of enamine alkylation reactions are shown in Scheme 1.10. Enamines also react with electrophilic alkenes. This aspect of their chemistry will be described in Section 1.10. Imines can be deprotonated at the a carbon by strong bases to give the nitrogen analogs of enolates. Originally, Grignard reagents were used for deprotonation, but LDA is now commonly used. These anions are usually referred to as imine anions or metalloenamines.70 Imine anions are isoelectronic and structurally analogous to both enolates and allyl anions and can also be called azaallyl anions. NR′ RC



NR′ CHR′′2

base

RC

′′ CR – 2

NR′

RC

CR′′2

Spectroscopic investigations of the lithium derivatives of cyclohexanone N-phenylimine indicate that it exists as a dimer in toluene and that as a better donor solvent, THF, is added, equilibrium with a monomeric structure is established. The monomer is favored at high THF concentrations.71 A crystal structure determination has been done on the 68. F. Johnson, L. G. Duquette, A. Whitehead, and L. C. Dorman, Tetrahedron 30:3241 (1974); K. Muller, F. Previdoli, and H. Desilvestro, Helv. Chim. Acta 64:2497 (1981); J. E. Anderson, D. Casarini, and L. Lunazzi, Tetrahedron Lett. 25:3141 (1988). 69. P. L. Stotter and K. A. Hill, J. Am. Chem. Soc. 96:6524 (1974). 70. For a general review of imine anions, see J. K. Whitesell and M. A. Whitesell, Synthesis 1983:517.

Scheme 1.10. Enamine Alkylation

34 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

1a

O

O 1) pyrrolidine 2) CH2=CHCH2Br 3) H2O

2b

CH2CH

CH2

66%

O

CH3

O

C2H5

1) pyrrolidine 2) MeCHICO2Et

CHCO2C2H5

C2H5

3) H2O

3c

O

O 1) pyrrolidine 2) MeCOCHBrMe

CH3O2CCH2

CH3 O CHCCH3

CH3O2CCH2

31%

3) H2O

4d

O

O CH3

1) pyrrolidine 2) MeI

60%

3) H2O

OCH3 5e CH3

OCH3 CH3

CH3

O

O

1) pyrrolidine 2) CH2

CH3

O

O

CCH2Cl, NaI, diisopropylamine Cl

91%

3) H2O

CH2 O a. b. c. d. e.

CH2C

CCH2 Cl

O

CH2

Cl

G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, and R. Terrell, J. Am. Chem. Soc. 85:207 (1963). D. M. Locke and S. W. Pelletier, J. Am. Chem. Soc. 80:2588 (1958). K. Sisido. S. Kurozumi, and K. Utimoto, J. Am. Chem. Soc. 34:2661 (1969). G. Stork and S. D. Darling, J. Am. Chem. Soc. 86:1761 (1964). J. A. Marshall and D. A. Flynn, J. Org. Chem. 44:1391 (1979).

lithiated N-phenylimine of methyl t-butyl ketone. It is a dimeric structure with the lithium cation positioned above the nitrogen and closer to the phenyl ring than to the b carbon of the imine anion.72 The structure is shown in Fig. 1.3. Just as enamines are more nucleophilic than enols, imine anions are more nucleophilic than enolates and react ef®ciently with alkyl halides. One application of imine

71. N. Kallman and D. B. Collum, J. Am. Chem. Soc. 109:7466 (1987). 72. H. Dietrich, W. Mahdi, and R. Knorr, J. Am. Chem. Soc. 108:2462 (1986).

35 SECTION 1.9. THE NITROGEN ANALOGS OF ENOLS AND ENOLATESÐ ENAMINES AND IMINE ANIONS

Fig. 1.3. Crystal structure of dimer of lithium derivative of N-phenyl imine of methyl t-butyl ketone. (Reproduced with permission from Ref. 72. Copyright 1986 American Chemical Society.)

anions is for the alkylation of aldehydes.

MgBr (CH3)2CHCH

NC(CH3)3

EtMgBr

(CH3)2C

CH

N C(CH3)3

Ref. 73

PhCH2Cl H2O +

(CH3)2CCH

O

H3O

(CH3)2C

CH2Ph

CH

NC(CH3)3

CH2Ph

80% overall yield

CH3CH

CH

CH

N

1) LDA H3C

O

CH3

O

CH3

2) ICH2CH2 3) H2O

CH3CH

C

CH

O

CH2CH2 CH3

O

CH3

O

CH3

Ref. 74

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in 73. G. Stork and S. R. Dowd, J. Am. Chem. Soc. 85:2178 (1963). 74. T. Kametani, Y. Suzuki, H. Furuyama, and T. Honda, J. Org. Chem. 48:31 (1983).

36

which the nitrogen substituent R0 is syn to the double bond are the more stable.75

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

R′

CH3

R′ N

N

C

CH2R

R′

R′

Li+ –N HC H

C

N– Li+

or

C

CH3

CH2R

CH3

CH R

C

CH2R

R′

R′

N– Li+

HC H

C

Li+ –N or

CH2R

CH3

C

CH R

For methyl ketimines, good regiochemical control in favor of methyl deprotonation, regardless of imine stereochemistry, is observed using LDA at 78 C. With larger substituents, deprotonation at 25 C occurs anti to the nitrogen substituent.76 R′

RCH2CCH3

R′

R′ N–Li+

N LDA –78°C

RCH2C

CH2

R′ Li+–N

N RCH2CCH2R′′

LDA 0°C

RCH

CCH2R′′

However, the syn and anti isomers of imines are easily thermally equilibrated. They cannot be prepared as single stereoisomers directly from ketones and amines so this method cannot be used to control regiochemistry of deprotonation. By allowing lithiated ketimines to come to room temperature, the thermodynamic composition is established. The most stable structures are those shown below, which in each case represent the less substituted isomer. Li+ –N H3C

C

R

R

R N– Li+

C

H

CH3

H2C

H3C

C CH2CH3

C

N– Li+ C

CH3

CH2CH3

Li+ –N (CH3)2CHC

R′

C

H

CH3

The complete interpretation of regiochemistry and stereochemistry of imine deprotonation also requires consideration of the state of aggregation and solvation of the base.77 One of the most useful aspects of the imine anions is that they can be readily prepared from enantiomerically pure amines. When imines derived from these amines are alkylated, the new carbon±carbon bond is formed with a bias for one of the two possible stereochemical con®gurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.3 lists some reported examples.78 75. K. N. Houk, R. W. Stozier, N. G. Rondan, R. R. Frazier, and N. Chauqui-Ottermans, J. Am. Chem. Soc. 102:1426 (1980). 76. J. K. Smith, M. Newcomb, D. E. Bergbreiter, D. R. Williams, and A. I. Meyer, Tetrahedron Lett. 24:3559 (1983); J. K. Smith, D. E. Bergbreiter, and M. Newcomb, J. Am. Chem. Soc. 105:4396 (1983); A. Hosomi, Y. Araki, and H. Sakurai, J. Am. Chem. Soc. 104:2081 (1982). 77. M. P. Bernstein and D. B. Collum, J. Am. Chem. Soc. 115:8008 (1993). 78. For a review, see D. E. Bergbreiter and M. Newcomb, in Asymmetric Synthesis, Vol. 2, J. D. Morrison, ed., Academic Press, New York, 1983, Chapter 9.

The interpretation and prediction of the relationship between the con®guration of the newly formed chiral center and the con®guration of the amine are usually based on steric differentiation of the two faces of the imine anion. Most imine anions that show high stereoselectivity incorporate a substituent which can hold the metal cation in a compact transition state by chelation. In the case of entry 2 in Table 1.3, for example, the observed enantioselectivity is rationalized on the basis of transition state L.

N CH3O

L

CH3OCH2

N

Li X C H H R

Li+X–

RCH2

The fundamental features of this transition state are (1) the chelation of the methoxy group with the lithium ion, which establishes a rigid transition state; (2) the interaction of the

Table 1.3. Enantioselective Alkylation of Ketimines Amine (CH3)3C

Ketone

Alkyl group

Yield

% E.E.

Reference

H

(CH3)3CO2C

Cyclohexanone

CH2

CHCH2Br

75

84

a

Cyclohexanone

CH2

CHCH2Br

80

>99

b

2-Carbomethoxycyclohexanone

CH3I

57

>99

c

3-pentanone

CH3CH2CH2I

57

97

d

80

94

e

NH2

PhCH2 H

CH2OCH3

H2N (CH3)3CH

H

(CH3)3CO2C

N

NH2

NH2

CH2OCH3 PhCH2 H

CH2OCH3

5-Nonanone

CH2

CHCH2Br

H2N a. b. c. d. e.

S. Hashimoto and K. Koga, Tetrahedron Lett. 1978:573. A. I. Meyers, D. R. Williams, G. W. Erickson, S. White, and M. Druelinger, J. Am. Chem. Soc. 103:3081 (1981). K. Tomioka, K. Ando, Y. Takemasa, and K. Koga, J. Am. Chem. Soc. 106:2718 (1984). D. Enders, H. Kipphardt, and P. Fey, Org. Synth. 65:183 (1987). A. I. Meyers, D. R. Williams, S. White, and G. W. Erickson, J. Am. Chem. Soc. 103:3088 (1981).

37 SECTION 1.9. THE NITROGEN ANALOGS OF ENOLS AND ENOLATESÐ ENAMINES AND IMINE ANIONS

38 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

lithium ion with the bromide leaving group; and (3) the steric effect of the benzyl group, which makes the underside the preferred direction of approach for the alkylating agent. Hydrazones can also be deprotonated to give lithium salts which are reactive toward alkylation at the b carbon. Hydrazones are more stable than alkylimines and therefore have some advantages in synthesis.79 The N,N-dimethylhydrazones of methyl ketones are kinetically deprotonated at the methyl group. This regioselectivity is independent of the stereochemistry of the hydrazone.80 Two successive alkylations of the N,N-dimethylhydrazone of acetone can provide unsymmetrical ketones. N(CH3)2

N(CH3)2 N CH3CCH3

N 1) n-BuLi, 0°C 2) C5H11I

O 1) n-BuLi, –5°C

CH3(CH2)5CCH3

2) BrCH2CH=CH2 3) H+, H2O

CH3(CH2)5CCH2CH2CH

CH2

Ref. 81

The anion of cyclohexanone N,N-dimethylhydrazone shows a strong preference for axial alkylation.82 2-Methylcyclohexanone N,N-dimethylhydrazone is alkylated by methyl iodide to give cis-2,6-dimethylcyclohexanone. The methyl group in the hydrazone occupies a pseudoaxial orientation. Alkylation apparently is preferred anti to the lithium cation, which is on the face opposite the 2-methyl substituent. N N(CH3)2

N

LDA

Li CH3

CH3

N(CH3)2 CH3I

N N(CH3)2 H3C CH 3

CH3

H2O

H3C

O

Chiral hydrazones have also been developed for enantioselective alkylation of ketones. The hydrazones can be converted to the lithium salt, alkylated, and then hydrolyzed to give alkylated ketone in good chemical yield and with high enantioselectivity83 (see entry 4 in Table 1.3). Hydrazones are substantially more stable toward hydrolysis than imines or enamines. Several procedures have been developed for conversion of the hydrazones back to ketones.81±83 Mild conditions are particularly important when stereochemical con®guration must be maintained at the enolizable position adjacent to the carbonyl group. A procedure for enantioselective synthesis of carboxylic acids is based on sequential alkylation of the oxazoline 8 via its lithium salt. Chelation by the methoxy group leads preferentially to the transition state in which the lithium is located as shown. The lithium acts as a Lewis acid in directing the approach of the alkyl halide. This is reinforced by a steric effect from the phenyl substituent. As a result, alkylation occurs predominantly from the lower face of the anion. The sequence in which the groups R and R0 are introduced 79. E. J. Corey and D. Enders, Tetrahedron Lett. 1976:3. 80. D. E. Bergbreiter and M. Newcomb, Tetrahedron Lett. 1979:4145; M. E. Jung and T. J. Shaw, Tetrahedron Lett. 1979:4149. 81. M. Yamashita, K. Matsumiya, M. Tanabe, and R. Suetmitsu, Bull. Chem. Soc. Jpn. 58:407 (1985). 82. D. B. Collum, D. Kahne, S. A. Gut, R. T. DePue, F. Mohamadi, R. A. Wanat, J. Clardy, and G. VanDuyne, J. Am. Chem. Soc. 106:4865 (1984). 83. D. Enders, H. Eichenauer, U. Bas, H. Schubert, and K. A. M. Kremer, Tetrahedron 40:1345 (1984); D. Enders, H. Kipphardt, and P. Fey, Org. Synth. 65:183 (1987); D. Enders and M. Klatt, Synthesis 1996:1403.

determines the chirality of the product. The enantiomeric purity of disubstituted acetic acids obtained after hydrolysis is in the range of 70±90%.84 O

Ph 1) LiNR2

H3C

2) R—X

N 8

R

Ph

O

LiNR2

RCH2

H N

CH2OCH3

Ph

O N

CH2OCH3

CH2

Li

O CH3 R′-X

H

R

R′

O Ph N CH2OCH3

1.10. Alkylation of Carbon Nucleophiles by Conjugate Addition The previous sections have dealt primarily with reactions in which the new carbon± carbon bond is formed by an SN2 reaction between the nucleophilic carbanions and the alkylating reagent. Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,b-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon± carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sul®de anions also react similarly, but we will focus on the carbon±carbon bondforming reactions. In contrast to the reaction of an enolate anion with an alkyl halide, which requires one equivalent of base, conjugate addition of enolates can be carried out with a catalytic amount of base. All the steps are reversible. O–

O RCCHR2 +

B–

RC

O– RC

O R

X CR2 +

C

CR2 + BH

RC

C

C

X C C–

R O R RC

C R

C

X

O R

X C–

+ BH

RC

C

C

C

H + B–

R

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as b-ketoesters or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 84. A. I. Meyers, G. Knaus, K. Kamata, and M. E. Ford, J. Am. Chem. Soc. 98:567 (1976).

39 SECTION 1.10. ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION

Scheme 1.11. Alkylation of Carbon by Conjugate Addition

40 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

1a

O

O CH3

+ H2C

CHCO2CH3

CH3

KOC(CH3)3

53%

CH2CH2CO2CH3

CN 2b PhCH2CHCN + H2C

CHCN

NH3 (l)

PhCH2CCH2CH2CN

CONH2

CONH2

3c CH2(CO2C2H5)2 + H2C

CCO2C2H5

NaOEt

(H5C2O2C)2CHCH2CHCO2C2H5

Ph

(CH3)2CHNO2 + CH2

Ph

55–60%

CH3

+

4d

100%

CHCO2CH3

PhCH2N(CH3)3–OH

O2NCCH2CH2CO2CH3 CH3

O 5e

NO2

CHCCH2CH3

(CH3)2CHNO2 + CH2

Amberlyst A27

O

(CH3)2CCH2CH2CCH2CH3 70%

CH2CO2C2H5

6f BrZnCH2CO2C2H5 + Cl

CH

CHNO2

Cl

CHCH2NO2 81%

7g

CO2CH3 CH3NO2 + CH2

KF

C

O N

NO2CH2CH2CHCO2CH3 O N O

O

80%

CN

CN

8h PhCHCO2C2H5 + CH2

CHCN

KOH (CH3)3COH

PhCCH2CH2CN

69–83%

CO2C2H5 O 9i

O + CH3CCH2CO2C2H5 CO2CH3

CCH3 R4N+ –OH

CHCO2C2H5 86%

CO2CH3

Scheme 1.11. (continued ) 10j

CH3

41 SECTION 1.10. ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION

CH3 O

N + CH2

CHCCH3

O

1) dioxane, 16 h

O

2) NaOAc, HOAc, H2O reflux

CH2CH2CCH3

CH(CH3)2

CH(CH3)2 66%

a. b. c. d. e. f. g. h. i.

H. O. House, W. L. Roelofs, and B. M. Trost, J. Org. Chem. 31:646 (1966). S. Wakamatsu, J. Org. Chem. 27:1285 (1962). E. M. Kaiser, C. L. Mao, C. F. Hauser, and C. R. Hauser, J. Org. Chem. 35:410 (1970). R. B. Moffett, Org. Synth. IV:652 (1963). R. Ballini, P. Marziali, and A. Mozziacafreddo, J. Org. Chem. 61:3209 (1996). R. Menicagli and S. Samaritani, Tetrahedron 52:1425 (1996). M. J. Crossley, Y. M. Fung, J. J. Potter, and A. W. Stamford, J. Chem. Soc., Perkin Trans 1 1998:1113. E. C. Horning and A. F. Finelli, Org. Synth. IV:776 (1963). K. Alder, H. Wirtz, and H. Koppelberg, Justus Liebigs Ann. Chem. 601:138 (1956).

The ¯uoride ion is an effective catalyst for Michael additions involving relatively acidic carbon compounds.85 The reactions can be done in the presence of excess ¯uoride, where the formation of the [F H F ] ion occurs, or by use of a tetraalkylammonium ¯uoride in an aprotic solvent. O CH3CCH2CO2C2H5 + (CH3O)2CHCH

4 equiv KF

CHCO2CH3

(CH3O)2CHCHCH2CO2CH3

CH3OH 72 h, 65°C

CH3CCHCO2C2H5 O

CHCOCH3

(CH3)2CHNO2 + CH2

CH3

0.5 equiv R4N+F–

98%

O

O2NCCH2CH2CCH3

2 h, 25°C

Ref. 86

CH3

Ref. 87

95%

Fluoride ion can also induce reaction of silyl enol ethers with electrophilic alkenes. OCH3 + CH3CH

O

F–

C

CHCO2CH3 O

CH3

Ref. 88

OSi(CH3)3

The hindered aluminum tris(2,6-diphenylphenoxide) is an effective promoter of Michael additions of enolates to enones.89 O

O O–Li+ + CH3(CH2)4C

CH2

Al(OAr)3

Ar = 2,6-diphenylphenyl

85. 86. 87. 88. 89.

O 84%

CH2C(CH2)4CH3

J. H. Clark, Chem. Rev. 80:429 (1980). S. Tori, H. Tanaka, and Y. Kobayashi, J. Org. Chem. 42:3473 (1977). J. H. Clark, J. M. Miller, and K.-H. So, J. Chem. Soc., Perkin Trans. 1 1978:941. T. V. Rajan Babu, J. Org. Chem. 49:2083 (1984). S. Saito, I. Shimada, Y. Takamori, M. Tanaka, K. Maruoka, and H. Yamamoto, Bull. Chem. Soc. Jpn. 70:1671 (1997).

42 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

Conjugate addition can also be carried out by completely forming the nucleophilic enolate under kinetic conditions. Ketone enolates formed by reaction with LDA in THF react with enones to give 1,5-diketones (entries 1 and 2, Scheme 1.12). Esters of 1,5dicarboxylic acids are obtained by addition of ester enolates to a,b-unsaturated esters (entry 5, Scheme 1.12). Among Michael acceptors that have been demonstrated to react with ketone and ester enolates under kinetic conditions are methyl a-trimethylsilylvinyl ketone90 methyl amethylthioacrylate,91 methyl methylthiovinyl sulfoxide,92 and ethyl a-cyanoacrylate.93 The latter class of acceptors has been shown to be capable of generating contiguous quanternary carbon centers. NC O– Li+

H3C C

CHCO2C2H5

CN

C

+

C

H3C

CO2C2H5

Ref. 93

OCH3

H3C

CO2CH3 CH3

Several other examples of conjugate addition of carbanions carried out under kinetically controlled conditions are given in Scheme 1.12. There have been several studies of the stereochemistry of conjugate addition reactions. If there are substituents on both the nucleophilic enolate and the acceptor, either syn or anti adducts can be formed. O– +

R1

R4

R3

R3

O

O

O R4

R1

R2

R3

O

R4

R1

+

R2

O

R2 syn

anti

The reaction shows a dependence on the E- or Z-stereochemistry of the enolate. Z-Enolates favor anti adducts and E-enolates favor syn adducts. These tendencies can be understood in terms of a chelated transition state.94 R4

R4 O Li

O

R2

R1

R3 H

H

O

R2

O R1

R3 H

R3

O

R4

R1

H

R2

Z-enolate

anti

R4

R4 O O

H R3

Li R1

R2

O

H E-enolate

O

O

R3

O

H R3

R1 R2

H

O R4

R1 R2 syn

90. G. Stork and B. Ganem, J. Am. Chem. Soc. 95:6152 (1973). 91. R. J. Cregge, J. L. Herrmann, and R. H. Schlessinger, Tetrahedron Lett. 1973:2603. 92. J. L. Hermann, G. R. Kieczykowski, R. F. Romanet, P. J. Wepple, and R. H. Schlessinger, Tetrahedron Lett. 1973:4711. 93. R. A. Holton, A. D. Williams, and R. M. Kennedy, J. Org. Chem. 51:5480 (1986). 94. D. Oare and C. H. Heathcock, J. Org. Chem. 55:157 (1990); D. A. Oare and C. H. Heathcock, Top. Stereochem. 19:227 (1989).

Scheme 1.12. Michael Additions under Kinetic Conditions O– Li+ 1a

(CH3)3CC

O

O

CH2 + PhCH CHCPh

THF 20 h

O– Li+ 2b

(CH3)2CHC

Ph

O

CHCCH3

SECTION 1.10. ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION

O

(CH3)3CCCH2CHCH2CPh

O

CHCH3 + CH3CH

90%

CH3

O

(CH3)2CHCCHCHCH2CCH3

O

43

88%

CH3

O

O– Li+ 3c

(CH3)2C

+

COCH3

83%

(CH3)2C CO2CH3 4d

O

O– Li+ H

C

C

OC(CH3)3

+

O

CC(CH3)3

H C

(CH3)3COC

C H

CH3CH2

H

CH3 5e

O– Li+ H3C

C

C

OC2H5

+

H3C C

CH3 H

THF–HMPA

C

–78°C

CO2C2H5

6

H3C

O– Li+

O

82%

O CH2CHCCH3

CCCH3

SPh

SPh H3C

CH2CO2C2H5 C

H CH3 H3C

O + CH2

86%

C

H5C2O2C

H f

O CH2CC(CH3)3

C

C

CH3

H

H

CH2CH3 H

71%

H3C

CH3

CH3

O O– Li+ 7g

CH3CH2CH

COCH3 + CH2

CO2CH3 O

SCH3 C

CH3CH2CHCH2CHSCH3 SCH3

SCH3

95%

CN O– Li+ 8h (CH3)2CHC

C(CH3)2 +

CO2C2H5

CHCO2C2H5

CN

C

C

O H3C

C

CH3 CH(CH3)2 95%

O 9i (CH3)2NCCH(CH3)2 + CH3CH

O CHCCH2CH(CH3)2

1) LDA, –78°C 2) NH4Cl, H2O

O

CH3

O

(CH3)2NCC(CH3)2CHCH2CCH2CH(CH3)2 78%

a. b. c. d. e. f. g. h. i.

J. Bertrand, L. Gorrichon, and P. Maroni, Tetrahedron 40:4127 (1984). D. A. Oare and C. H. Heathcock, Tetrahedron Lett. 27:6169 (1986). A. G. Schultz and Y. K. Yee, J. Org. Chem. 41:4044 (1976). C. H. Heathcock and D. A. Oare, J. Org. Chem. 50:3022 (1985). M. Yamaguchi, M. Tsukamoto, S. Tanaka, and I. Hirao, Tetrahedron Lett. 25:5661 (1984). K. Takaki, M. Ohsugi, M. Okada, M. Yasumura, and K. Negoro, J. Chem. Soc., Perkin Trans. 1 1984:741. J. L. Herrmann, G. R. Kieczykowski, R. F. Romanet, P. J. Wepplo, R. H. Schlessinger, Tetrahedron Lett. 1973:4711. R. A. Holton, A. D. Williams, and R. M. Kennedy, J. Org. Chem. 51:5480 (1986). D. A. Oare, M. A. Henderson, M. A. Sanner, and C. H. Heathcock, J. Org. Chem. 55:132 (1990).

44 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

The stereoselectivity can be enhanced by addition of Ti(O-i-Pr)4. The active nucleophile under these conditions is expected to be an ``ate'' complex in which the much larger Ti(O-i-Pr)3 group replaces Li‡ .95 Here too, the syn : anti ratio depends on the stereochemistry of the enolate. O–Li+ CH3

R

OTi(O-i-Pr)3

Ti(O-i-Pr)4

O

O

CH3

R

R4

O

R4

O

R4CH CHCR1

R1

R

R1

R

CH3

CH3

anti

R Et Ph Ph i-Pr i-Pr

O

+

syn

enolate

R1

R4

anti : syn

yield (%)

Z Z Z Z E

t-Bu Me t-Bu t-Bu t-Bu

Ph Ph Ph Ph Ph

95 : 5 > 97 : 3 > 92 : 8 > 97 : 3 17 : 83

69 70 85 65 91

When the conjugate addition is carried out under kinetic conditions with stoichiometric formation of the enolate, the adduct is also an enolate until the reaction mixture is quenched with a proton source. It should therefore be possible to effect a second reaction of the enolate if an electrophile is added prior to protonation of the enolate. This can be done by adding an alkyl halide to the solution of the adduct enolate, which results in an alkylation. Two or more successive reactions conducted in this way are referred to as tandem reactions.

H3C

O– Li+

CH3

O– Li+ C

+ CH3CH

CHCO2C2H5

–78°C

(CH3)3CO2CCH2CHCH

CH3I, HMPA

COC2H5

OC(CH3)3 CH3 (CH3)3CO2CCH2CHCHCO2C2H5

60%

Ref. 96

CH3

O O–Li+ H3C

C

CH

COC2H5 +

CH3 O–

O CH2CH CH3 CH

C

CO2C2H5

CH2

H2C=CHCH2Br

CH2

CH3 CH

C

Ref. 97

CH2

CO2C2H5

95. A. Bernardi, P. Dotti, G. Poli, and C. Scolastico, Tetrahedron 48:5597 (1992); A. Bernardi, Gazz. Chim. Ital. 125:539 (1995). 96. M. Yamaguchi, M. Tsukamoto, and I. Hirao, Tetrahedron Lett. 26:1723 (1985). 97. W. Oppolzer, R. P. Heloud, G. Bernardinelli, and K. Baettig, Tetrahedron Lett. 24:4975 (1983).

N

2)

C(CH2)4OCH2Ph

N

CH3O2C

45

CH2CH2CH2OCH2Ph H

1) LDA

O

78%

3)

O CH3O2C

I

CH2CH2CH

Ref. 98

C(CH3)2

Tandem conjugate addition±alkylation has proven to be an ef®cient means of introducing both a and b substituents at enones.99 Conditions for effecting conjugate addition in the presence of Lewis acids have also been developed. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at 78 C.100 O

OSi(CH3)3 PhCCH

C(CH3)2 + CH2

TiCl4

C

CH3 O

PhCCH2CCH2CPh

Ph

O

Ref. 101

72–78%

CH3

Similarly, titanium tetrachloride or stannic tetrachloride induces addition of silyl enol ethers to nitroalkenes. The initial adduct is trapped in cyclic form by trimethylsilylation.102 Hydrolysis of this intermediate regenerates the carbonyl group.103 O CH3 + CH2

C

CH3

NO2

OSi(CH3)3

CH2CCH3

H2O

TiCl4

O OTMS

N+

O–

O

Other Lewis acids can also effect conjugate addition of silyl enol ethers to electrophilic alkenes. For example, Mg(ClO4)2 catalyzes addition of ketene silyl acetals: TMSO

CH3

CH3O

CH3

O + H2C

CH3

CHCCH3

Mg(ClO4)2

O Ref. 104

CH3O2CCCH2CH2CCH3 CH3

Lanthanide salts have been found to catalyze addition of a-nitroesters, even in aqueous solution.105 CH3 O2NCHCO2CH3 + H2C

O CHCCH3

Yb(O3SCF3)3 10 mol %

CH3

O

CH3O2CCCH2CH2CCH3

99%

Ref. 106

NO2

98. 99. 100. 101. 102. 103. 104. 105. 106.

C. H. Heathcock, M. M. Hansen, R. B. Ruggeri, and J. C. Kath, J. Org. Chem. 57:2545 (1992). For additional examples, see M. C. Chapdelaine and M. Hulce, Org. React. 38:225 (1990). K. Narasaka, K. Soai, Y. Aikawa, and T. Mukaiyama, Bull. Chem. Soc. Jpn. 49:779 (1976). K. Narasaka, Org. Synth. 65:12 (1987). A. F. Mateos and J. A. de la Fuento Blanco, J. Org. Chem. 55:1349 (1990). M. Miyashita, T. Yanami, T. Kumazawa, and A. Yoshikoshi, J. Am. Chem. Soc. 106:2149 (1984). S. Fukuzumi, T. Okamoto, K. Yasui, T. Suenobu, S. Itoh, and J. Otera, Chem. Lett. 1997:667. J. B. N. F. Engberts, B. L. Feringa, E. Keller, and S. Otto, Rec. Trav. Chim. Pays-Bas 115:457 (1996). E. Keller and B. L. Feringa Synlett. 1997:842.

SECTION 1.10. ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION

46 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. An alcoholic solution of potassium or sodium cyanide is suitable for simple enones. CH3

CH3

CH3

KCN, NH4Cl

+

EtOH—H2O

O

O CH3

H3C

Ref. 107 O

CN

H3C

12%

CN 42%

Triethylaluminum±hydrogen cyanide and diethylaluminum cyanide are also useful reagents for conjugate addition of cyanide. The latter is the more reactive of the two reagents. These reactions presumably involve the coordination of the aluminum reagent as a Lewis acid at the carbonyl oxygen. H3C

C8H17

H3C

H3C

Et3Al—HCN

Ref. 108

O

CH3CO2

C8H17

H3C

CH3CO2

O

CN 92–93%

O

O O

O

O

O (C2H5)2AlCN

Ref. 109 O

CN

O O

O

Diethylaluminum cyanide mediates conjugate addition of cyanide to a,b-unsaturated oxazolines. With a chiral oxazoline, 30±50% diastereomeric excess (d.e.) can be achieved. Hydrolysis gives partially resolved a-substituted succinic acids. NC O

R

O

Et2AlCN –CN

Ph

N R = CH3, Ph

Ph

R

HCl H2O

CO2H

HO2C R

N

Ref. 110

R = CH3, d.e. = 50–56%; e.e. = 45–50% R = Ph, d.e. = 45–52%; e.e. = 57%

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.111 This is anticipated on stereoelectronic grounds because the p 107. 108. 109. 110.

O. R. Rodig and N. J. Johnston, J. Org. Chem. 34:1942 (1969). W. Nagata and M. Yoshioka, Org. Synth. 52:100 (1972). W. Nagata, M. Yoshioka, and S. Hirai, J. Am. Chem. Soc. 94:4635 (1972). M. Dahuron and N. Langlois, Synlett. 1996:51.

47

orbital of the enamine is the site of nucleophilicity.

SECTION PROBLEMS

O H2C

H

CHCPh

H

H

O

Ph

CH2CH2CPh

H2O

O NR2

H

H

NR2

H

O

Another very important method for adding a carbon chain at the b-carbon of a,bunsaturated carbonyl system involves organometallic reagents, particularly organocopper intermediates. This reaction will be discussed in Chapter 8.

General References D. E. Bergbreiter and M. Newcomb, in Asymmetric Synthesis, J. D. Morrison, ed., Academic Press, New York, 1983, Chapter 9. D. Caine, in Carbon±Carbon Bond Formation, Vol. 1, R. L. Augustine, ed., Marcel Dekker, New York, 1979, Chapter 2. A. G. Cook, ed., Enamines: Synthesis, Structure and Reactions, 2nd ed., Marcel Dekker, New York, 1988. H. O. House, Modern Synthetic Reactions, 2nd ed., W. A. Benjamin, Menlo Park, California, 1972, Chapter 9. P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis, Pergamon Press, New York, 1992. V. Snieckus, ed., Advances in Carbanion Chemistry, Vol. 1, JAI Press, Greenwich, Connecticut, 1992. J. C. Stowell, Carbanions in Organic Synthesis, Wiley-Interscience, New York, 1979.

Problems (References for these problems will be found on page 923.) 1. Arrange each series of compounds in order of decreasing acidity: O

(a) CH3CH2NO2, (CH3)2CHCPh, CH3CH2CN, CH2(CN)2 (b) [(CH3)2CH]2NH, (CH3)2CHOH, (CH3)2CH2, (CH3)2CHPh O

O

O

O

O

(c) CH3CCH2CO2CH3, CH3CCH2CCH3, CH3OCCH2Ph, CH3COCH2Ph O

O

O

O

(d) PhCCH2Ph, (CH3)3CCCH3, (CH3)3CCCH(CH3)2, PhCCH2CH2CH3 111. E. Valentin, G. Pitacco, F. P. Colonna, and A. Risalti, Tetrahedron 30:2741 (1974); M. Forchiassin, A. Risalti, C. Russo, M. Calligaris, and G. Pitacco, J. Chem. Soc. 1974:660.

48 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

2. Write the structures of all possible enolates for each ketone. Indicate which you would expect to be favored in a kinetically controlled deprotonation. Which would you expect to be the most stable enolate in each case? (a)

(b)

CH3

(c) O

O

O

(CH3)2CHCCH2CH3 CH3 C(CH3)3

(d) CH3

(e)

(f)

O CH3

O

CH3

CH3 H3C

O

CH3 EtO

(g)

CH3

H3C

OEt

CH3

(h)

O

CH3

CH3 CH2 O CH3

3. Suggest reagents and reaction conditions suitable for effecting each of the following conversions: (a) 2-methylcyclohexanone to 2-benzyl-6-methylcyclohexanone. (b)

O

O

CH3

CH3 to

CH3 CH3

CH3

(c)

O

O to Ph

Ph

(d)

CH2Ph

CH3 CH2CN

CH2CN to

N CH2Ph

N CH2Ph

(e)

O CH3CCH

(f)

49

OSi(CH3)3 CH2

to

CH2

C

O

CH

CH2

PROBLEMS

O

CCH3 to CH2CH2CH2Br

(g)

O

O

CCH3

C

CH3

to CH2CH2CH2Br

4. Intramolecular alkylation of enolates has been used to advantage in synthesis of biand tricyclic compounds. Indicate how such a procedure could be used to synthesize each of the following molecules by drawing the structure of a suitable precursor. (a)

(c)

CO2CH3

(e)

CH3 OCH2Ph

O O

O H3C

(b)

CO2CH3

CH3

(d)

(f)

H3C

CH3

O H3CO2C

O

5. Predict the major product of each of the following reactions: (a) PhCHCO2Et CH2CO2Et

(b) PhCHCO2Et CH2CO2H

(c) PhCHCO2H CH2CO2Et

(1) 1 equiv LiNH2/NH3 (2) CH3I (1) 2 equiv LiNH2/NH3 (2) CH3I (1) 2 equiv LiNH2/NH3 (2) CH3I

6. Treatment of 2,3,3-triphenylpropionitrile with 1 equiv of potassium amide in liquid ammonia followed by addition of benzyl chloride affords 2-benzyl-2,3,3-triphenylpropionitrile in 97% yield. Use of 2 equiv of potassium amide gives an 80% yield of 2,3,3,4-tetraphenylbutyronitrile under the same reaction conditions. Explain. 7. Suggest readily available starting materials and reaction conditions suitable for obtaining each of the following compounds by a procedure involving alkylation of

50

nucleophilic carbon.

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

(a) PhCH2CH2CHPh

O

(b) (CH3)2C CHCH2CH2CCH2CO2CH3

CN

(c)

(d) CH2

O

CHCH

CHCH2CH2CO2H

CH3 CH2CO2H CH3 O

(e)

(f)

2,3-diphenylpropanoic acid

(g)

2,6-diallylcyclohexanone

(h)

CN H2C

CH3O CH3CH2

(i)

O O

CH3CO

O CH2CH

CHCH2CPh CNH2

CH2

O

(j) CH2

O

CHCHCH2C

CH

CO2CH2CH3

CH3CCH2CH2 O

8. Suggest starting materials and reaction conditions suitable for obtaining each of the following compounds by a procedure involving a Michael reaction. (a) 4,4-dimethyl-5-nitropentan-2-one (b) diethyl 2,3-diphenylglutarate (c) ethyl 2-benzoyl-4-(2-pyridyl)butyrate (d) 2-phenyl-3-oxocyclohexaneacetic acid (e)

(f)

O

O

CH2CH2CN

NCCH2

O CH2CCH3 O

(g) CH3CH2CHCH2CH2CCH3

(h) (CH3)2CHCHCH2CH2CO2CH2CH3

NO2

(i)

O

Ph

CH

(k)

O

O

CHCH2NO2 Ph

O

O

OCH3 CHNO2

NO2

CH3

(j)

Ph

(l)

O

CH

HO

PhCHCHCH2CCH3

O

CH2CH2CCH3

H3C

CN

51

O

O O O

9. In planning a synthesis, the most effective approach is to reason backwards from the target molecule to some readily available starting material. This is called retrosynthetic analysis and is indicated by an open arrow of the type shown below. In each of the following problems, the target molecule is shown on the left and the starting material on the right. Determine how you could prepare the target molecule from the indicated starting material using any necessary organic or inorganic reagents. In some cases, more than one step is necessary. (a)

O

O CH3

CO2C2H5

O

(b) O

(c)

O H3C

O

CCH3

H3C

CH3

H3C O

O

CH3CO

(d)

H3C

CH3CO O

O

O

(CH3O)2PCH2C(CH2)4CH3

(e) PhCH2CH2CHCO2C2H5

O

(CH3O)2PCH2CCH3 PhCH2CO2C2H5

Ph

(f)

O O

CH3

CH3CH

CHCO2CH3

O

(g)

CH3 O

CN O

NCCH2CO2C2H5

CCH3

PROBLEMS

52 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

(h)

OCH2CH

CH2

OH

O

HO

O

HO

O

(i)

CH3

CH3

CCH2CH2C O

CH2

CCH2CO2CH2CH3

CH3

O

10. In a synthesis of diterpenes via compound C, a key intermediate B was obtained from carboxylic acid A. Suggest a series of reactions for obtaining B from A. HO

OH

A

CO2H O

O

HO2C

B

H3C

CH3 C

11. In a synthesis of the terpene longifolene, the tricyclic intermediate D was obtained from a bicyclic intermediate by an intermolecular Michael addition. Deduce the possible structure(s) of the bicyclic precursor. H3C O O

CH3 D

12. Substituted acetophenones react with ethyl phenylpropiolate under the conditions of the Michael reaction to give pyrones. Formulate a mechanism. Ph O CCH2R + PhC

R CCO2C2H5 Ph

O

O

13. The reaction of simple ketones such as 2-butanone or phenylacetone with a,bunsaturated ketones gives cyclohexenones when the reaction is effected by heating in methanol with potassium methoxide. Explain how the cyclohexenones are formed. What structures are possible for the cyclohexenones? Can you suggest means for distinguishing between possible isomeric cyclohexenones?

14. Analyze the factors that would be expected to control the stereochemistry of the following reactions, and predict the stereochemistry of the product(s). (a)

O H3C EtAlCN

CH3O

OSiR3 CH3

(b)

CH3 CH2CH

2) CH3I

1) NaH

CH(CH3)2

O

2) CH3I

CN C

PhCH2OCH2

CH3

CH2CH(CH3)2

R

CH3CH2OCH

RO

(d) CH3O2C

N

1) LDA

Ph

2) BrCH2CH CH2

O

H3C

H3C

Cl

O

O

(e)

1) K+ –N(SiMe3)2 25°C

O

CH3

(c)

CCH3

CO2CH3 CO2CH3

1) NaH 2) BrCH2C CH2

(f)

N

CH3

OH

H

CH3

C

CH3I LiNH2

O

H O O

(g) O

NCCH2CH3

Ph

(h)

1) NaN[Si(CH3)3]2 2) CH2

CHCH2I

CH3

Ph3COCH2

O O

Ph

1) LDA/CH3I 2) LDA/CH2

CH3

(i)

1) LDA/HMPA

O O

2) C2H5I

CHCH2Br

53 PROBLEMS

54 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

15. Indicate reaction sequences and approximate conditions that could be used to effect the following transformations. More than one step may be required. CH3CH IH2C

CH3

O

(a)

CCH

H2C

O

H3C

O CH3

O

CH3

O

H3C

O

CH3

O

(b) CH3CCH2CO2H

CH3CCH2CH2CH

CH2

O

(c)

O

(CH3)2CHCH2CH2CCH2CO2CH3

(CH3)2CHCH2CHCCH2CO2CH3 CH3CH2 CH2 H3C

H3C

(d)

H C

C

CH3O2C CO2CH3

H

O H3C

(e)

C C

H

CH3

O H3C

CH3

CH2CO2C(CH3)3

O H3C

O

O

H

O

CH3 O

CH3

(f) O

(CH2)3Cl

CH3

CCH2

CH2

H3C

16. Offer an explanation for the stereoselectivity observed in the following reactions. (a) 1) NaH, DME

(CH3)3CO2C

O

2)

CH2Br

CO2CH2Ph CO2CH2Ph

(CH3)3CO2C

N CH3

O

O

CO2CH2Ph CO2CH2Ph O syn:anti = 1:4

N CH3

55

Li+ N–

Ph

(b)

Ph

1)

CH3O

O

CH3O

CH3

CH3

OSi(C2H5)3 H

2) (C2H5)3SiCl

O

O 1) LiCl, THF Li+

H

(c)

N–

Ph

O

H

Ph

O

2)

O O

CH3

high e.e.

OSi(C2H5)3

CH3

O

3) (C2H5)3SiCl

H

H

(d) O

O

O

1) LiHMDS 2) n-C4H9I

O

O

(CH2)3CH3

O

+ (CH2)3CH3

56%

5%

17. One of the compounds shown below undergoes intramolecular cyclization to give a tricyclic ketone on being treated with [(CH3)3Si]2NNa. The other does not. Suggest a structure for the product. Explain the difference in reactivity.

O

O CH2CH2CH2OTs

CH2CH2CH2OTs

18. The alkylation of 3-methyl-2-cyclohexenone with several dibromides led to the products shown below. Discuss the course of each reaction and suggest an explanation for the dependence of the product structure on the structure of the dihalide. CH3

1) NaNH2 2) Br(CH2)nBr

CH3

O

CH2 +

(n = 2)

+ starting material

O

O

31%

25%

CH2 n=3

55%

O CH2 n=4

42%

O

42%

PROBLEMS

56 CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON INTERMEDIATES

19. Treatment of ethyl 2-azidobutanoate with catalytic quantities of lithium ethoxide in tetrahydrofuran leads to the evolution of nitrogen. On quenching the resulting solution with 3 N hydrochloride acid, ethyl 2-oxobutanonate is isolated in 86% yield. Suggest a mechanism for this process. O CH3CH2CHCO2CH2CH3

1) LiOEt, THF 2) H3O+

CH3CH2CCO2CH2CH3 86%

N3

20. Suggest a mechanism for the reaction CH3O2C H N CH

CO2CH3

+

CH3CN

CH3 N

CH3O2C

C(CH3)2

CO2CH3

H

CH3 42%

21. Suggest a route for the enantioselective synthesis of the following substance. OCH3

OCH3 from

O O

N H

R enantiomer of the antidepressant drug rolipran

HO2CCH

CH

O

2

Reaction of Carbon Nucleophiles with Carbonyl Groups Introduction The reactions described in this chapter include some of the most useful synthetic methods for carbon±carbon bond formation: the aldol and Claisen condensations, the Robinson annulation, and the Wittig reaction and related ole®nation methods. All of these reactions begin by the addition of a carbon nucleophile to a carbonyl group. The product which is isolated depends on the nature of the substituent (X) on the carbon nucleophile, the substituents (A and B) on the carbonyl group, and the ways in which A, B, and X interact to control the reaction pathways available to the addition intermediate. O

X C– + A

C

B

X

O–

C

C

B

product

A

The fundamental mechanistic concepts underlying these reactions were introduced in Chapter 8 of Part A. Here we will explore the scope and synthetic utility of these reactions.

2.1. Aldol Addition and Condensation Reactions 2.1.1. The General Mechanism The prototypical aldol addition reaction is the acid- or base-catalyzed dimerization of a ketone or aldehyde.1 Under certain conditions, the reaction product may undergo 1. A. T. Nielsen and W. J. Houlihan, Org. Rect. 16: 1 (1968); R. L. Reeves in Chemistry of the Carbonyl Group, S. Patai, ed., Interscience, New York, 166, pp. 580±593; H. O. House, Modern Synthetic Reactions 2nd ed., W. A. Benjamin, Menlo Park, California, 1972, pp. 629±682.

57

58

dehydration leading to an a,b-unsaturated aldehyde or ketone.

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O 2 RCH2CR′

OH RCH2C

O

O –H2O

CHCR′

RCH2C

R′ R

CCR′

R′ R

R′ = H or alkyl or aryl

The mechanism of the base-catalyzed reaction involves equilibrium formation of the enolate ion, followed by addition of the enolate to a carbonyl group of the aldehyde or ketone.

Base catalyzed mechanism 1. Addition phase a. Enolate formation: RCH2CR′ + B–

RCH

CHR′ + BH O–

O b. Nucleophilic addition: O– RCH2CR′ + RCH

CR′

R′ RCH2C

O

–O

O CHCR′ R

c. Proton transfer: R′ RCH2C –O

O CHCR′ + BH R

R′ RCH2C HO

O CHCR′ + B– R

2. Dehydration phase O R′ RCH2C HO

O CHCR′ + B– R

CR′

R′ C RCH2

+ BH + HO–

C R

Entries 1 and 2 in Scheme 2.1 illustrate the preparation of aldol reaction products by the base-catalyzed mechanism. In entry 1, the product is a b-hydroxyaldehyde, whereas in entry 2 dehydration has occurred and the product is an a,b-unsaturated aldehyde. Under conditions of acid catalysis, it is the enol form of the aldehyde or ketone which functions as the nucleophile. The carbonyl group is activated toward nucleophilic attack by

Scheme 2.1. Aldol Condensation of Simple Aldehydes and Ketones

59 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

HO 1a

KOH

CH3CH2CH2CH O

CH3CH2CH2CHCHCH O

75%

C2H5 2b

C7H15CH

O

NaOEt

C7H15CH

CCH

O

79%

C6H13 O 3c CH3CCH3

OH O Ba(OH)2

(CH3)2CCH2CCH3

71%

O 4d

Dowex-50 resin

(CH3)2CO

(CH3)2C

H+ form

CHCCH3

79%

O Cl

5e O

a. b. c. d. e.

71%

HCl

V. Grignard and A. Vesterman, Bull. Chim. Soc. Fr. 37:425 (1925). F. J. Villani and F. F. Nord, J. Am. Chem. Soc. 69:2605 (1947). J. B. Conant and N. Tuttle, Org. Synth. 1:199 (1941). N. B. Lorette, J. Org. Chem. 22:346 (1957). O. Wallach, Berichte 40:70 (1907); E. Wenkert, S. K. Bhattacharya, and E. M. Wilson, J. Chem. Soc. 1964:5617.

oxygen protonation. Acid catalyzed mechanism 1. Addition phase a. Enolization: RCH2CR′ + A–

RCH2CR′ + HA O

+ OH

RCH2CR′

RCH

+ OH

CR′ + H+ OH

b. Nucleophilic addition:

RCH2CR′ + RCH

+

OH

R′

OH

CR′

RCH2C

CHCR′

+OH

HO

R

c. Proton transfer: +

R′

OH

R′

RCH2C

CHCR′

RCH2C

HO

R

HO

O CHCR′ + H+ R

2. Dehydration phase O R′ RCH2C HO

O CHCR′ + H+ R

R′

CR′ C

RCH2

C

+ H2O R

60 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

Entries 4 and 5 in Scheme 2.1 depict acid-catalyzed aldol reactions. In entry 4, condensation is accompanied by dehydration. In entry 5, a b-chloroketone is formed by addition of hydrogen chloride to the enone. In general, the reactions in the addition phase of both the base- and acid-catalyzed mechanisms are reversible. The equilibrium constant for addition is usually unfavorable for acyclic ketones. The equilibrium constant for the dehydration phase is usually favorable, because of the conjugated a,b-unsaturated carbonyl system that is formed. When the reaction conditions are suf®ciently vigorous to cause dehydration, the overall reaction will go to completion, even if the equilibrium constant for the addition step is unfavorable. Entry 3 in Scheme 2.1 illustrates a clever way of overcoming the unfavorable equilibrium of the addition step. The basic catalyst is contained in a separate compartment of a Soxhlet extractor. Acetone is repeatedly passed over the basic catalyst by distillation and then returns to the reaction ¯ask. The concentration of the addition product builds up in the reaction ¯ask as the more volatile acetone distills preferentially. Because there is no catalyst in the reaction ¯ask, the adduct remains stable. 2.1.2. Mixed Aldol Condensations with Aromatic Aldehydes Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. O O ArCH

OH

O + RCH2CR′

O

ArCHCHCR′

–H2O

CR′ ArCH

C R

R

There are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen± Schmidt condensation. Scheme 2.2 presents some representative examples. There is a pronounced preference for the formation of a trans double bond in the Claisen±Schmidt condensation of methyl ketones. This stereoselectivity arises in the dehydration step. In the transition state for elimination to a cis double bond, an unfavorable steric interaction between the ketone substituent (R) and the phenyl group occurs. This interaction is absent in the transition state for elimination to the trans double bond. : base

O RC

H

Ph

H

: base

H Ph RC O

H H

Ph

H

H

OH

less favorable

H CR OH O

more favorable

O H

Ph

CR

H

Scheme 2.2. Mixed Condensation of Aromatic Aldehydes with Ketones O 1a

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

O

(CH3)3CCCH3 + PhCHO

NaOH

(CH3)3CCCH

ethanol – H2O

CHPh

90%

O

COCH3 2b

CCH

KOH

CHPh

72%

+ PhCHO H C

O

3c

+

CHO

O

CH3

O

NaOMe

75%

O CH3 CH3

CHO 4d

+ CH3CH2COCH2CH3

NaOEt

O

60%

CHO CH3 O

5e

CH

O HCl

O + CH3CCH2CH3

CH

CCCH3

85%

CH3 a. b. c. d. e.

G. A. Hill and G. Bramann, Org. Synth. I:81 (1941). S. C. Bunce. H. J. Dorsman, and F. D. Popp, J. Chem. Soc. 1963:303. A. M. Islam and M. T. Zemaity, J. Am. Chem. Soc. 79:6023 (1957). D. Meuche, H. Strauss, and E. Heilbronner, Helv. Chim. Acta 41:2220 (1958). M. E. Kronenberg and E. Havinga, Rec. Trav. Chim. 84:17, 979 (1965).

Additional insight into the factors affecting product structure was obtained by study of the condensation of 2-butanone with benzaldehyde.2

O PhCH

CCCH3

O HCl

PhCH

O + CH3CCH2CH3

O NaOH

PhCH

61

CHCCH2CH3

CH3

The results indicate that the product ratio is determined by the competition between the various reaction steps. Under base-catalyzed conditions, 2-butanone reacts with benzaldehyde at the methyl group to give 1-phenylpent-1-en-3-one. Under acid-catalyzed conditions, the product is the result of condensation at the methylene group, namely, 3-methyl-4phenylbut-3-en-2-one. Under the reaction conditions used, it is not possible to isolate the intermediate ketols, because the addition step is rate-limiting. These intermediates can be 2. M. Stiles, D. Wolf, and G. V. Hudson, J. Am. Chem. Soc. 81: 628 (1959); D. S. Noyce and W. L. Reed, J. Am. Chem. Soc. 81: 618, 620, 624 (1959).

62 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

prepared by alternative methods, and they behave as shown in the following equations: OH

O

O

PhCHCH2CCH2CH3 OH

NaOH

PhCH

O

CHCCH2CH3 + PhCH

O

PhCHCHCCH3

O + CH3CH2CCH3

O NaOH

PhCH

O + CH3CH2CCH3

CH3 OH

O

O

PhCHCH2CCH2CH3 OH

HCl

PhCH

O

CHCCH2CH3 + PhCH

O + CH3CCH2CH3

O

O

PhCHCHCCH3

HCl

PhCH

O

CCCH3 + PhCH

O + CH3CCH2CH3

CH3

CH3

These results establish that the base-catalyzed dehydration is slow relative to the reverse of the addition phase for the branched-chain isomer. The reason for selective formation of the straight-chain product under conditions of base catalysis is then apparent. In base, the straight-chain ketol is the only intermediate which is dehydrated. The branched-chain ketol reverts to starting material. Under acid conditions, both intermediates are dehydrated; however, the branched-chain ketol is formed most rapidly, because of the preference for acid-catalyzed enolization to give the more substituted enol (see Section 7.3 of Part A). OH

OH

O CH3CCH2CH3

H+

CH3C

CHCH3 + CH2 major

OH CH3C

OH CHCH3 + PhCH O

slow

CCH2CH3 minor

O

O

PhCHCHCCH3 CH3

fast

PhCH

CCCH3 CH3

In general, the product ratio of a mixed aldol condensation will depend upon the individual reaction rates. Most ketones show a pattern similar to butanone in reactions with aromatic aldehydes. Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference.

2.1.3. Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehydes and Ketones 2.1.3.1. Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired

structure. The term directed aldol reaction is given to these reactions.3 Directed aldol reactions must be carried out under conditions designed to ensure that the desired product is obtained. In general, this requires that the product structure be controlled by kinetic factors, both in the formation of the enolate and in the addition step, and that equilibration by reversibility of either step be avoided. Scheme 2.3 illustrates some of the procedures which have been developed to achieve this goal. Scheme 2.3. Directed Aldol Additions A. Condensations of lithium enolates under kinetic control O 1

a

O HO 1) CH3CH2CH2CH O

LDA –78°C

CH3CH2CH2CCH3

15 min, –78°C 2) CH3CO2H

O– +Li 2b

CH3CH

CH3CH2CH2CCH2CHCH2CH2CH3

CH3

HO

+ PhCH2OCH2CHCH O

C

CH3CHCHCHCH2OCH2Ph C

LDA –78°C

1) (CH3)2CHCH O

(CH3)2CH

2) NH4Cl

C

O

C

C(CH3)2

CH3

CH3

4d CH3C

O C

OTMS OH LDA –78°C

COTMS

1) CH3CH2CH O 1.5 h 2) NH4Cl

CH3

79%

O CH3

OH

O 3c CH3CH2CC(CH3)2

65%

O

61%

OTMS

CH3

CH3CH2CHCH2C

COTMS

68%

CH3

B. Condensations of boron enolates O

O HO

5e PhCH2CH2CCH3

O 6f

R2BO3SCF3

1) PhCH O

2,6-lutidine 78°C, 3h

–78°C, 5 h 2) H2O2, pH 7

HB

PhCH2CH2CCH2CHPh

1) O

2

C5H11CCHN2

C5H11C

O

CH

OBR2

CH2

C2H5

2) TMS

N

N

O

CH3CH2CH O

EtN(i-Pr)2

CH3CH2CN(CH3)2

70%

OH CH3

1) (C6H11)2BI, Et3N

Ph

CON(CH3)2

2) PhCH O

OH 96% yield, 95:5 anti:syn in CCl4 at OºC

3. T. Mukaiyama, Org. React. 28: 203 (1982).

OTBDMS

C2H5

O 8h

60%

CH3 (C5H11)2BO3SCF3

OTMS

C5H11CCH2CH

OTBDMS 7g

88%

O

63 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

64

Scheme 2.3. (continued )

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O

9i

H3C

CCH2CH3

H3C

N

1) Bu2BO3SCF3, EtN

O

N 2)

O

Ph

Ph

H3C

CH

O

O

92%

O

O

OH

O

O

O

10j

CCH2CH3

(CH3)2CH

N O

CH

O R2BO3SCF3 EtN(i-Pr)2

H3C

CH2OCH2Ph H

O

NaOCH3 CH3OH

OH CH3O2C

CH2OCH2Ph CH3

CH3

O

O

C. Tin, titanium, and zirconium enolates 11k

O

O

O

O

OH

1) TiCl4(i-Pr)2NEt

O

N

O

2) PhCH O

CH3 CH2Ph

N

Ph

CH3 CH2Ph

CH3

81% yields, 96:4 syn:anti

a. b. c. d. e. f. g. h. i. j.

G. Stork, G. A Kraus, and G. A. Garcia, J. Org. Chem. 39:3459 (1974). S. Masamune, J. W. Ellingboe, and W. Choy, J. Am. Chem. Soc. 104:5526 (1982). R. Bal, C. T. Buse, K. Smith, and C. Heathcock, Org. Synth. 63:89 (1984). P. J. Jerris and A. P. Smith III, J. Org. Chem. 46:577 (1981). T. Inoue, T. Uchimaru, and T. Mukaiyama, Chem. Lett. 1977:153. J. Hooz, J. Oudenes, J. L. Roberts, and A. Benderly, J. Org. Chem. 52:1347 (1987). S. Masamune, W. Choy, F. A. J. Kerdesky, and B. Imperiali, J. Am. Chem. Soc. 103:1566 (1981). K. Ganesan and H. C. Brown, J. Org. Chem. 59:7346 (1994). S. F. Martin and D. E. Guinn, J. Org. Chem. 52:5588 (1987). D. Seebach, H.-F. Chow, R. F. W. Jackson, K. Lawson, M. A. Sutter, S. Thaisrivongs, and J. Zimmermann, J. Am. Chem. Soc. 107:5292 (1985).

Entries 1±4 in Scheme 2.3 represent cases in which the nucleophilic component is converted to the enolate under kinetically controlled conditions by the methods discussed in Section 1.2. Such enolates are usually highly reactive toward aldehydes so that addition occurs rapidly when the aldehyde is added, even at low temperature. When the addition step is complete, the reaction is stopped by neutralization and the product is isolated. The guiding mechanistic concept for reactions carried out under these conditions is that they occur through a cyclic transition state in which lithium or another metal cation is coordinated to both the enolate oxygen and the carbonyl oxygen.4 R1 H R2 R

O Li O –

R1 H

+

R2 R

R2 + O Li O–

H+

R1

R O

HO

4. H. E. Zimmerman and M. D. Traxler, J. Am. Chem. Soc. 79:1920 (1957); C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, and J. Lampe, J. Org. Chem. 45:1066 (1980).

This transition-state model has been the basis both for development of other reaction conditions and for the interpretation of the stereochemistry of the reaction. Most enolates can exist as two stereoisomers. Also, most aldol condensation products formed from a ketone enolate and an aldehyde can have two diastereomeric structures. These are designated as syn and anti. The cyclic-transition-state model provides a basis for understanding the relationship between enolate geometry and the stereochemistry of the aldol product. R2

O–

H

O–

H

R1

R2

R1

O

OH

R1 Z-enolate

O R

E-enolate

OH

R1

R

R2

R2

syn-ketol

anti-ketol

The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlled conditions is the Z-isomer. When it reacts with benzaldehyde, only the syn aldol is formed.4 This stereochemical relationship is accounted for by a cyclic transition state with a chair-like conformation. The product stereochemistry is correctly predicted if the aldehyde is in a conformation such that the phenyl substituent occupies an equatorial position in the cyclic transition state. H

PhCHO –72°C

(CH3)3C O

δ−

Ph

Ph

O–

CH3

CH3 O Li+ Oδ−

CH3

C(CH3)3

H

OH

H

t-Bu

78% yield, 100% syn

A similar preference for formation of the syn aldol is found for other Z-enolates derived from ketones in which one of the carbonyl substituents is bulky.5 Ketone enolates in which the other carbonyl substituent is less bulky show a decreasing stereoselectivity in the order t-butyl > i-propyl > ethyl.4 This trend re¯ects a decreasing preference for formation of the Z-enolate.

CH3CH2CR O R = C2H5 CH(CH3)2 C(CH3)3

LDA

R

CH3 C

C O– Li

H

C

+

PhCH O

C

H

R

OH

O

O– Li+

CH3

O

OH

Ph + R

R

Ph

CH3

CH3

E

Z

anti

syn

70 40 2

30 60 98

36 18 2

64 82 98

The E : Z ratio can be modi®ed by the precise conditions for formation of the enolate. For example, the E : Z ratio can be increased for 3-pentanone and 2-methyl-3-pentanone by use of a 1 : 1 lithium tetramethylpiperidide (LiTMP)±LiBr mixture for kinetic enolization.6 The precise mechanism of this effect is not clear, but it probably is due to an aggregate 5. P. Fellman and J. E. Dubois, Tetrahedron 34:1349 (1978). 6. P. L. Hall, J. H. Gilchrist, and D. B. Collum, J. Am. Chem. Soc. 113:9571 (1991).

65 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

66

species containing bromide acting as the base.7

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

E:Z Stereoselectivity LDA

LiTMP

LiTMP + LiBr

O CH3CH2CCH2CH3 O

3.3 : 1

5:1

50 : 1

(CH3)2CHCCH2CH3 O

1.7 : 1

2:1

21 : 1

(CH3)3CCCCH2CH3

1 : >50

1 : >20

1 : >20

The enolates derived from cyclic ketones are necessarily E-isomers. The enolate of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric products under kinetically controlled conditions. The stereochemistry can be raised to about 6 : 1 in favor of the anti isomer under optimum conditions.8 O– Li+

O

O

OH

H

Ph

+ PhCH O

H

OH Ph

+

16%

84%

From these and related examples, the following generalizations have been drawn about kinetic stereoselection in aldol additions.9 (1) The chair transition-state model provides a basis for explaining the stereoselectivity observed in aldol reactions of ketones having one bulky substituent. The preference is Z-enolate ! syn aldol; E-enolate ! anti aldol. (2) When the enolate has no bulky substituents, stereoselectivity is low. (3) ZEnolates are more stereoselective than E-enolates. Table 2.1 gives some illustrative data. Because the aldol reaction is reversible, it is possible to adjust reaction conditions so that the two stereoisomeric aldol products equilibrate. This can be done in the case of lithium enolates by keeping the reaction mixture at room temperature until the product composition reaches equilibrium. This has been done, for example, for the product from the reaction of the enolate of ethyl t-butyl ketone and benzaldehyde. Li+ Li

+ –O

O

CH3 PhCH O fast

(CH3)3C

(CH3)3C

H

Li+

O–

O 25°C slow

Ph

(CH3)3C

CH3 CH3 O Li

O

H syn

Ph CH3

syn

Ph

O–

anti

O

Ph

Li

O

CH3 C(CH3)3

anti

C(CH3)3

7. F. S. Mair, W. Clegg, and P. A. O'Neil, J. Am. Chem. Soc. 115:3388 (1993). 8. M. Majewski and D. M. Gleave, Tetrahedron Lett. 30:5681 (1989). 9. D. A. Evans, J. V. Nelson, and T. R. Taber, Top. Stereochem. 13:1 (1982); C. H. Heathcock, in Comprehensive Carbanion Chemistry, Part B, E. Buncel and T. Durst, eds., Elsevier, Amsterdam, 1984, pp. 177±237; C. H. Heathcock, in Asymmetric Synthesis, Vol. 3, J. D. Morrison, ed., Academic Press, New York, 1984, pp. 111± 212.

Table 2.1. Stereoselectivity of Lithium Enolates toward Benzaldehydea OLi

OH

OLi

R1 Z

R1

1

Ph

R

+

O

Ph

R anti

Enolate geometry, Z=E

Aldol stereostructure, syn : anti

100 : 0 0 : 100 30 : 70 66 : 34 > 98 : 2 32 : 68 0 : 100 > 98 : 2 > 98 : 2 > 98 : 2 8 : 92 87 : 13

50 : 50 65 : 35 64 : 36 77 : 23 90 : 10 58 : 42 45 : 55 > 98 : 2 > 98 : 2 88 : 12 8 : 92 88 : 12

H H Et Et i-Pr i-Pr iPr t-Bu 1-Adamantyl Ph Mesityl Mesityl

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

1

syn

E

R1

OH

O

PhCHO

+

67

a. From C. H. Heathcock, in Asymmetric Synthesis, Vol. 3, J. D. Morrison, ed., Academic Press, New York, 1984, Chapter 2.

For synthetic ef®ciency, it is useful to add MgBr2.

1) LDA 2) (CH3)2CHCH O

O

Ref. 10

+

3) MgBr2

O

OH syn

O

OH anti

kinetic 31:69 syn : anti thermodynamic (MgBr2) 9:91 syn : anti

The greater stability of the anti isomer is attributed to the pseudoequatorial position of the methyl group in the chair-like chelate. With larger substituent groups, the thermodynamic preference for the anti isomer is still greater.11 Thermodynamic equilibration can be used to control product composition if one of the desired stereoisomers is signi®cantly more stable than the other. The requirement that an enolate have at least one bulky substituent restricts the types of compounds that can be expected to give highly stereoselective aldol additions. Furthermore, only the enolate formed by kinetic deprotonation is directly available. Ketones with one tertiary alkyl substituent give mainly the Z-enolate. However, less highly substituted ketones usually give mixtures of E- and Z-enolates.12 Therefore, efforts aimed at expanding the scope of stereoselective aldol condensations have been directed at 10. K. A. Swiss, W.-B. Choi, D. C. Liotta, A. F. Abdel-Magid, and C. A. Maryanoff, J. Org. Chem. 56:5978 (1991). 11. C. H. Heathcock and J. Lampe, J. Org. Chem. 48:4330 (1983). 12. R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. Soc. 98:2868 (1976); W. A. Kleschick, C. T. Buse, and C. H. Heathcock, J. Am. Chem. Soc. 99:247 (1977); Z. A. Fataftah, I. E. Kopka, and M. W. Rathke, J. Am. Chem. Soc. 102:3959 (1980).

68 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

two facets of the problem: (1) control of enolate stereochemistry and (2) enhancement of the stereoselectivity in the addition step. We will return to this topic in Section 2.1.3.5. The enolates of other carbonyl compounds can be used in mixed aldol condensations. Extensive use has been made of the enolates of esters, thioesters, amides, nitriles, and nitroalkanes. Scheme 2.4 gives a selection of such reactions. Because of their usefulness in aldol additions and other synthetic methods (see especially Section 6.5.2), there has been a good deal of interest in the factors that control the stereoselectivity of enolate formation from esters. For simple esters such as ethyl propanoate, the E-enolate is preferred under kinetic conditions using a strong base such as LDA in THF solution. Inclusion of a strong cation solvating co-solvent, such as HMPA or tetrahydro-1,3-dimethyl-2(1H)pyrimidone (DMPU) favors the Z-enolate.13 OSi(CH3)3 TMSCl

LDA THF

CH3CH2CO2CH2CH3

OCH2CH3

CH3

E-ketene silyl acetal

OCH2CH3 CH3CH2CO2CH2CH3

LDA THF, HMPA

TMSCl

OSi(CH3)3

CH3

Z-ketene silyl acetal

These observations are explained in terms of a cyclic transition state for the LDA=THF conditions and an open transition state in the presence of an aprotic dipolar solvent. H O R2N–

Li+ –O

OR R

OR

O

Li+ –O

R

H

Li H

OR

H

R

R

H

E-enolate

–NR 2

OR H

Z-enolate

Simple alkyl esters show rather low stereoselectivity. However, highly hindered esters derived from 2,6-dimethylphenol or 2,6-di-t-butyl-4-methylphenol provide the anti stereoisomers. O R2

R2 OR1

RCH

H

OR1

O

OH

O– +Li

LDA

O

OH

O

OR1 + R

R R2

OR1 R2

Some illustrative data are given in Table 2.2. The lithium enolates of a-alkoxy esters have been extensively explored, and several cases in which high stereoselectivity is observed have been documented.14 This stereoselectivity can be explained in terms of a chelated ester enolate which is approached by the 13. R. E. Ireland, P. Wipf, and J. D. Armstrong III, J. Org. Chem. 56:650 (1991). 14. A. I. Meyers and P. J. Reider, J. Am. Chem. Soc. 101:2501 (1979); C. H. Heathcock, M. C. Pirrung, S. D. Young, J. P. Hagen, E. T. Jarvi, U. Badertscher, H.-P. MaÈrki, and S. H. Montgomery, J. Am. Chem. Soc. 106:8161 (1984).

Scheme 2.4. Addition Reactions of Carbanions Derived from Esters, Carboxylic Acids, Amides, and Nitriles

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

OH 1a CH3CO2C2H5 + Ph2CO 2b

1) LiNH2

Ph2CCH2CO2C2H5

2) NH4Cl

75–84%

CH3CO2C2H5 + LiN[Si(CH3)3]2

LiCH2CO2C2H5

O

HO

CH2CO2C2H5

LiCH2CO2C2H5 +

3c

CH3

O

CH3

O

79–90%

O

1) LDA, THF, –70°C 2) CH3CH2CH

O

CH3 CH3

CH3

O

O

CHCH2CH3 O OH H3C

85%

CO2H 2 mol

4d (CH3)2CHCO2H

R2NLi

(CH3)2CCO2Li

(CH3CH2)2C

O

(CH3CH2)2C

Li

C(CH3)2

77%

OH

O 5e

CH3

THPOCH2CH2CCH3 + LiCH2CO2C2H5

THPOCH2CH2CCH2CO2C2H5

80%

OH O 6f

CH3CN(CH3)2

OH

1) LDA, pentane

88%

2) cyclohexanone, THF

CH2CN(CH3)2 O OH 7g CH3CN

1) n-BuLi, THF, –80°C 2) (CH3CH2)2C O 1) n-BuLi, THF, –78°C CH

8h

(CH3CH2)2CCH2CN

O

68%

OTMS

2)

CH3CN

69

CH2CN

96%

3) TMS-Cl

a. W. R. Dunnavant and C. R. Hauser, Org. Synth. V:564 (1973). b. M. W. Rathke, Org. Synth. 53:66 (1973). c. C. H. Heathcock, S. D. Young, J. P. Hagen, M. C. Pirrung, C. T. White, and D. VanDerveer, J. Org. Chem. 45:3846 (1980). d. G. W. Moersch and A. R. Burkett, J. Org. Chem. 36:1149 (1971). e. J. D. White, M. A. Avery, and J. P. Carter, J. Am. Chem. Soc. 104:5486 (1982). f. R. P. Woodbury and M. W. Rathke, J. Org. Chem. 42:1688 (1977). g. E. M. Kaiser and C. R. Hauser, J. Org. Chem. 33:3402 (1968). h. J. J. P. Zhou, B. Zhong, and R. B. Silverman, J. Org. Chem. 60:2261 (1995).

Table 2.2. Stereoselectivity of Ester Enolates toward Aldehydesa

70 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O

OH

OLi OR1

O

OH

R3CHO

LDA

R2

OR1

R3

OR1

THF

R2 E

R1

R2

Me Me Me MeOCH2 MeOCH2 DMPb DMP DMP DMP DMP DMP DMP DMP BHTb BHT BHT BHT BHT

Me Me Me Me Me Me H2CˆCHCH2 Me H2CˆCHCH2 Me Et H2CˆCHCH2 Me Me H2CˆCHCH2 H2CˆCHCH2 Me H2CˆCHCH2

+

O OR1

R3

R2

R2

anti

syn

R3

anti=syn

Reference

Ph i-Pr Me i-Pr Me Ph Ph n-C5H11 Et i-Pr i-Pr i-Pr t-Bu Ph Ph Et i-Pr i-Pr

55 : 45 55 : 45 57 : 43 90 : 10 67 : 33 88 : 12 91 : 9 86 : 14 84 : 16 > 98 : 2 > 98 : 2 > 98 : 2 > 98 : 2 > 98 : 2 > 94 : 6 > 98 : 2 > 98 : 2 > 98 : 2

c c c c c d d d d d d d d d d d d d

a. From a more extensive compilation by C. H. Heathcock, in Asymmetric Synthesis, Vol. 3, J. D. Morrison, ed., Academic Press, New York, 1984, Chapter 2. b. DMP ˆ 2,6-dimethylphenyl; BHT ˆ 2,6-di-t-butyl-4-methylphenyl. c. A. I. Meyers and P. Reider, J. Am. Chem. Soc. 101:2501 (1979). d. C. H. Heathcock, M. C. Pirrung, S. H. Montgomery, and J. Lampe, Tetrahedron 37:4087 (1981).

aldehyde in such a manner that the aldehyde R group avoids being between the a-alkoxy and the methyl group in the ester enolate. When the ester alkyl group R becomes very bulky, the stereoselectivity is reversed. CH3

R

CH3

OR

H

H

OR

R O

R2O

O–

R2O

O

Li+

Li+

favored

disfavored

O–

Regioselective aldol addition of a,b-unsaturated aldehydes has been achieved using a method in which the enal and the carbonyl acceptor are treated ®rst with a bulky Lewis acid, aluminum tris-(2,6-diphenoxide), and then LDA is added. Ph Al O

CH

O +

CH

O

Ph

Ref. 15

3

CH

LDA 53%

OH

15. S. Saito, M. Shiozawa, M. Ito, and H. Yamamoto, J. Am. Chem. Soc. 120:813 (1998).

O

This selectivity presumably re¯ects several circumstances. Both carbonyl oxygens are presumably complexed by aluminum. The allylic stabilization of the g-deprotonation product can then lead to kinetic selectivity in the deprotonation. Selectivity for g-attack by the dienolate is accentuated by the steric bulk near the a position. 2.1.3.2. Boron Enolates. Another important version of the aldol reaction involves the use of boron enolates. A cyclic transition state is believed to be involved, and, in general, the stereoselectivity is higher than for lithium enolates. The O B bond distances are shorter than the O Li bond in the lithium enolates, and this leads to a more compact transition state, which magni®es the steric interactions that control stereoselectivity. R1 H R2 R

R1 H O BL2 O

O BL 2 O

R2 R

H

R1 H O BL2 O

H R R2

H E-enolate

R1 H R R2

Z-enolate

anti

O BL 2 O

H

syn

Boron enolates can be prepared by reaction of the ketone with a dialkylboron tri¯uoromethanesulfonate (tri¯ate) and a tertiary amine.16 The Z-stereoisomer is formed preferentially for ethyl ketones with various R1 substituents. The resulting aldol products are predominantly the syn stereoisomers. O

O R1CCH2CH3

L2BOSO2CF3 (i-Pr)2NEt

L2BO

CH3 C

C

R1

RCH

H

O

OH

R1

R CH3

The E-boron enolate from cyclohexanone shows a preference for the anti ketol product. OBL2

O

H

OH

O R

+ RCH O major

H

OH R

+ minor

The exact ratio of stereoisomeric ketols is a function of the substituents on boron and the solvent. The E-boron enolates of some ketones can be preferentially obtained with the use of dialkylboron chlorides.17 The data in Table 2.3 pertaining to 3-pentanone and 2-methyl-3pentanone illustrate this method. Use of boron tri¯ates with a more hindered amine favors the Z-enolate. The contrasting stereoselectivity of the boron tri¯ates and chlorides has been discussed in terms of reactant conformation and the stereoelectronic requirement for perpendicular alignment of the hydrogen being removed with the carbonyl group.18 The 16. D. A. Evans, E. Vogel, and J. V. Nelson, J. Am. Chem. Soc. 101:6120 (1979); D. A. Evans, J. V. Nelson, E. Vogel, and T. R. Taber, J. Am. Chem. Soc. 103:3099 (1981). 17. H. C. Brown, R. K. Dhar, R. K. Bakshi, P. K. Pandiarajan, and B. Singaram, J. Am. Chem. Soc. 111:3441 (1989); H. C. Brown, R. K. Dhar, K. Ganesan, and B. Singaram, J. Org. Chem. 57:499 (1992); H. C. Brown, R. K. Dhar, K.Ganesan, and B. Singaram, J. Org. Chem. 57:2716 (1992); H. C. Brown, K. Ganesan, and R. K. Dhar, J. Org. Chem. 58:147 (1993); K. Ganesan and H. C. Brown, J. Org. Chem. 58:7162 (1993). 18. J. M. Goodman and I. Paterson, Tetrahedron Lett. 33:7223 (1992).

71 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

72 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

two preferred transitions states are shown below. CF3SO3 R H

BR2

R R

O CH3

H

OBR2

H

CH3

H

O

CH3

Cl

R

BR2 CH3

H

OBR2 H

B:

B:

Other methods are also available for generation of boron enolates. Dialkylboranes react with acyclic enones to give Z-enolates by a 1,4-reduction.19 The preferred Zstereochemistry is attributed to a cyclic mechanism for hydride transfer: R2B H

O

O

H

OBR2

R2BH

R

R′

R

R′

R

H

H

R′ H

Z-Boron enolates can also be obtained from silyl enol ethers. This method is necessary for ketones such as ethyl t-butyl ketone, which gives E-boron enolates by other methods. The Z-stereoisomer is formed from either the Z- or E-silyl enol ether.20 OTMS

OBBN

OTMS

9-BBN-Br

9-BBN-Br

The E-boron enolates show a modest preference for formation of the anti aldol product. R1

O

R2 + RCH O

R2BO

H

HO

O

HO

R + R1

R1 2

R 2

R

R

major

minor

The general trend then is that boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. They also have the advantage of providing access to both stereoisomeric enol derivatives. Table 2.3 gives a compilation of some of the data on stereoselectivity of aldol reactions with boron enolates. Boron enolates can also be obtained from esters21 and amides,22 and these too undergo aldol addition reactions. Various combinations of boronating reagents and amines have been used, and the E : Z ratios are dependent on the reagents and conditions. In most 19. D. A. Evans and G. C. Fu, J. Org. Chem. 55:5678 (1990); G. P. Boldrini, M. Bortolotti, F. Mancini, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J. Org. Chem. 56:5820 (1991). 20. J. L. Duffy, T. P. Yoon, and D. A. Evans, Tetrahedron Lett. 36:9245 (1993). 21. K. Ganesan and H. C. Brown, J. Org. Chem. 59:2336 (1994). 22. K. Ganesan and H. C. Brown, J. Org. Chem. 59:7346 (1994).

Table 2.3. Stereoselectivity of Boron Enolates toward Aldehydesa O

OBL2 L2BOTf

R1

R1

Lb

Et Et Et Et Et Et Et i-Bu i-Bu i-Pr i-Pr t-Bu c-C6H11 c-C6H11 Ph Et i-Pr c-C6H11 t-Bu Et i-Pr c-C6H11 t-Bu Et i-Pr c-C6H11 t-Bu Et n-C5H11 n-C9H19 PhCH2 3-C5H11 c-C6H11 c-C6H11

n-C4H9 c-C5H9 n-C4H9 n-C4H9 n-C4H9 n-C4H9 n-C4H9 n-C4H9 c-C5H9 n-C4H9 c-C5H9 n-C4H9 c-C5H9 9-BBN n-C4H9 9-BBN 9-BBN 9-BBN 9-BBN c-C6H11 c-C6H11 c-C6H11 c-C6H11 2-BCOB 2-BCOB 2-BCOB 2-BCOB n-C4H9 n-C4H9 n-C4H9 n-C4H9 n-C4H9 n-C4H9 n-C4H9

O

OH

R2CHO

R1

1

R2

R

+

syn

E

Z

R1

OH

OBL2 +

73 O 1

R2

R anti

R2

Z=E

syn : anti

Reference

Ph Ph Ph n-Pr t-Bu H2CˆC(CH3) (E)-C4H7 Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph PhCH2CH2

> 97 : 3 82 : 18 69 : 31 > 97 : 3 > 97 : 3 > 97 : 3 > 97 : 3 > 99 : 1 ± 45 : 55 19 : 81 > 99 : 1 12 : 88 > 99 : 1 99 : 1

> 97 : 3 84 : 16 72 : 28 > 97 : 3 > 97 : 3 92 : 8 93 : 7 > 97 : 3 84 : 16 44 : 56 18 : 82 > 97 : 3 14 : 86 > 97 : 3 > 97 : 3 > 97 : 3 46 : 54 96 : 4 < 3 : 97 21 : 79 < 3 : 97 < 1 : 99 < 3 : 97 3 : 97 < 3 : 97 < 3 : 97 < 3 : 97 95 : 5 94 : 6 91 : 9 95 : 5 > 99 : 1 > 99 : 1 > 98 : 2

c c c c c c c c c c c c d d c c c e e c e e e f f f f g g g g g g g

96 : 4 95 : 5 91 : 9 95 : 5 99 : 1 98 : 2 98 : 2

a. From a more complete compilation by C. H. Heathcock, in Asymmetric Synthesis, Vol. 3, J. D. Morrison, ed., Academic Press, New York, 1984, Chapter 3. b. 9-BBN ˆ 9-borabicyclo[3.3.1]nonane; 2-BCOB ˆ bis-(bicyclo[2.2.2]octyl)borane. c. D. A. Evans, J. V. Nelson, E. Vogel, and T. R. Taber, J. Am. Chem. Soc. 103:3099 (1981). d. D. E. Van Horn and S. Masumune, Tetrahedron Lett. 1979:2229. e. Using dialkylboron chloride and (i-Pr)2 NEt; H. C. Brown, R. K. Dhar, R. K. Bakshi, P. K. Pandjarajan, and P. Singaram, J. Am. Chem. Soc. 111:3441 (1989); H. C. Brown, K. Ganesan, and R. K. Dhar, J. Org. Chem. 58:147 (1993). f. Using bis(bicyclo[2.2.2]octyl)boron chloride and Et3N; H. G. Brown, K. Ganesan, and R. K. Dhar, J. Org. Chem. 57:3767 (1992). g. I. Kuwajima, M. Kato, and A. Mori, Tetrahedron Lett. 21:4291 (1980).

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

74

cases, esters give Z-enolates which lead to syn adducts, but there are exceptions.

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

OH CH3CH2CO2C2H5

1) Bu2BO3SCF3, i-Pr2NEt 2) (CH3)2CHCH O

CO2C2H5

(CH3)2CH

81% yield, 95:5 syn:anti

CH3 OH RCH2CO2C2H5

1) (C6H11)2BI, Et3N

OH

Ph

2) PhCH O

Ref. 23

CO2C2H5 or Ph R

CO2C2H5 R

syn favored for R = CH3, CH2CH3

anti favored for R = i-Pr, t-Bu, Ph

2.1.3.3. Titanium, Tin, and Zirconium Enolates. Metals such as Ti, Sn, and Zr give enolates which are intermediate in structural character between the largely ionic Li‡ enolates and covalent boron enolates. The Ti, Sn, or Zr enolates provide oxygen±metal bonds that are largely covalent in character but can also accommodate additional ligands at the metal. Depending on the degree of substitution, both cyclic and acyclic transition states can be involved. Titanium enolates can be prepared from lithium enolates by reaction with trialkoxytitanium(IV) chlorides, such as (isopropoxy)titanium chloride.24 Titanium enolates can also be prepared directly from ketones by reaction with TiCl4 and a tertiary amine.25

O

OTiCl3 1) TiCl4

O (CH3)2CHCH

OH

O

2) (i-Pr)2NEt

Under these conditions, the Z-enolate is formed and the aldol adducts have syn stereochemistry. The addition can proceed through a cyclic transition state assembled around titanium.

R Ti

O O

H

R R′ RE RZ

Ti

O O

H R′ RE RZ

RE = H syn RZ = H anti

Titanium enolates can also be prepared from N-acyloxazolidinones. These enolates 23. A. Abiko, J.-F. Liu, and S. Masamune, J. Org. Chem. 61:2590 (1996). 24. C. Siegel and E. Thornton, J. Am. Chem. Soc. 111:5722 (1989). 25. D. A. Evans, D. L. Rieger, M. T. Bilodeau, and F. Urpi, J. Am. Chem. Soc. 113:1047 (1991).

are considered to be chelated with the oxazolidinone carbonyl oxygen.26

Cl O O

Cl

O TiCl4, (i-Pr)2NEt

N CH2Ph

O

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

Cl

Ti

O

75

O

O CH3

N

O

(CH3)2CHCH O

OH

O N

CH3 CH2Ph

CH2Ph

87% yield, 94:6 syn:anti

Trialkoxytitanium chlorides, which are somewhat less reactive, can also be used. Reactions of these enolates with aldehydes give mainly syn products, with the absolute stereochemistry being determined by the con®guration of the oxazolidinone.27 O O

O

O N

1) LDA 2) (i-PrO)3TiCl

O

O

OH

N

3) PhCH O

Ph CH3

These results are explained on the basis of a transition state which is hexacoordinate at titanium. The oxazolidinone substituent dictates the approach of the aldehyde.

O

Ph

CH3

Ph

O

Ti O

CH3 H

Ti O N

O

O

O

OH

N

N

O

O

O

Ph CH3

O

Procedures which are catalytic in titanium have been developed.28 These reactions appear to exhibit the same stereoselectivity trends as other titanium-mediated additions.

O

O + PhCH O

5% TiF4

OH Ph

86%

CH3CH2CN

26. D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark, and M. T. Bilodeau, J. Am. Chem. Soc. 112:8215 (1990). 27. M. Nerz-Stormes and E. R. Thornton, J. Org. Chem. 56:2489 (1991). 28. R. Mahrwald, Chem.Ber. 128:919 (1995).

76 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

Tin enolates can be generated from ketones and Sn(O3SCF3)2 in the presence of tertiary amines.29,30 The subsequent aldol addition is syn-selective.31 O

Sn(O3SCF3)2

(CH3)2CHCH

O

O

N

OH

O

CH3

syn

CH3

anti

68%

CH2CH3

O

5%

O Sn(O3SCF3)2

OH

OH

PhCH O >95% syn

N CH2CH3

Tin(II) enolates prepared in this way also show good reactivity toward ketones as the carbonyl component. Sn(O3SCF3)2

O

CF3SO3SnO

Ph

O

OH C

O

CHCH3

Ref. 32

Ph

Ph

N CH2CH3

76%

CH3

N-Acylthiazolinethiones are also useful enolate precursors under these conditions. Sn S

O R

N

R

S

S+

O

Sn(O3SCF3)2

N

OH

R′CH O

S

S

O

R′

N

N

Ref. 33

S

R

CH2CH3

> 97:3 syn:anti

Uncatalyzed additions of trialkylstannyl enolates to benzaldehyde show anti stereoselectivity, suggesting a cyclic transition state.34 CH3 Ph

OSn(Et)3 CH3

+ PhCH

O

–78°C

Ph

CH3 Ph

OH

+

Ph

O

Ph OH

O

9:1 anti:syn

Isolated tributylstannyl enolates react with benzaldehyde under the in¯uence of metal salts 29. T. Mukaiyama and S. Kobayashi, Org. React. 46:1 (1994). 30. T. Mukaiyama, N. Iwasawa, R. W. Stevens, and T. Haga, Tetrahedron 40:1381 (1984); I. Shibata and A. Babu, Org. Prep. Proc. Int. 26:85 (1994). 31. T. Mukaiyama, R. W. Stevens, and N. Iwasawa, Chem. Lett. 1982:353. 32. R. W. Stevens, N. Iwasawa, and T. Mukaiyama, Chem. Lett. 1982:1459. 33. T. Mukaiyama and N. Iwasawa, Chem. Lett. 1982:1903; N. Iwasawa, H. Huang, and T. Mukaiyama, Chem. Lett. 1985:1045. 34. S. S. Labadie and J. K. Stille, Tetrahedron 40:2329 (1984).

including Pd(O3SCF3)2, Zn(O3SCF3)2, and Cu(O3SCF3)2.35 The anti : syn ratio depends on the catalyst. OSn(n-C4H9)3

O

+ PhCH

OH Ph

Zn(O3SCF3)2

O

toluene 57:43 syn:anti

Zirconium enolates are prepared by reaction of lithium enolates with (Cp)2ZrCl2 (Cp ˆ Z5-C5H5).36 They act as nucleophiles in aldol addition reactions.

C H

O

OZr(Cp)2Cl

CH3 C

O

OH

+ PhCH O

OH

Ph +

CH2CH3

OZr(Cp)2Cl

O

CH3

Ph

CH3

CH3

syn 67%

anti 33%

O

CH3 OH

CH3 OH

Ph +

+ PhCH O

Ref. 38

Ph

anti 83%

Ref. 37

syn 17%

Aldol additions of silyl enol ethers and ketene silyl acetals can be catalyzed by (Cp)2Zr2‡ species, including [(Cp)2ZrO-t-Bu]‡ and (Cp)2Zr(O3SCF3)2.39 O

TMSO C

CH2 + CH3CCH2CH3

O

(Cp)2Zr(O3SCF3)2 5 mol %

CH2CH3

Ph

Ph

CH3 OTMS

A comprehensive comparison of the anti : syn diastereoselectivity of the lithium, dibutylboron, and (Cp)2Zr enolates of 3-methyl-2-hexanone with benzaldehyde has been reported.38 The order of stereoselectivity is Bu2B > (Cp)2Zr > Li. These results are consistent with reactions proceeding through a cyclic transition state. O

OM CH3C

OH

CCH2CH3 + PhCH O

O

OH

Ph +

CH3

CH3

E-enolate

syn:anti

Z-enolate

syn:anti

Li Bu2B (Cp)2ZrCl

17:83 3:97 9:91

Li Bu2B (Cp)2ZrCl

45:55 94:6 86:14

CH2CH3 syn

Ph CH3

CH2CH3 anti

35. A. Yanagisawa, K. Kimura, Y. Nakatsuka, and M. Yamamoto, Synlett 1998:958. 36. (a) D. A. Evans and L. R. McGee, Tetrahedron Lett. 21:3975 (1980); (b) M. Braun and H. Sacha, Angew. Chem. Int. Ed. Engl. 30:1318 (1991); (c) S. Yamago, D. Machii, and E. Nakamura, J. Org. Chem. 56:2098 (1991). 37. Y. Yamamoto and K. Maruyama, Tetrahedron Lett. 21:4607 (1980). 38. (a) T. K. Hollis, N. P. Robinson, and B. Bosnich, Tetrahedron Lett. 33:6423 (1992); (b) Y. Hong, D. J. Norris, and S. Collins, J. Org. Chem. 58:3591 (1993). 39. S. Yamago, D. Machii, and E. Nakamura, J. Org. Chem. 56:2098 (1991).

77 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

78 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

2.1.3.4. The Mukaiyama Reaction. The Mukaiyama reaction refers to Lewis acidcatalyzed aldol addition reactions of enol derivatives. The initial examples involved silyl enol ethers.40 Silyl enol ethers do not react with aldehydes because the silyl enol ether is not a strong enough nucleophile. However, Lewis acids do cause reaction to occur by activating the ketone. The simplest mechanistic formulation of the Lewis acid catalysis is that complexation occurs at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. TMSO

O+

H R2

O

C

+ R1

A

R

OH

R1

H

R′ R2

If there is no other interaction, such a reaction should proceed through an acyclic transition state, and steric factors should determine the amount of syn versus anti addition.41 This seems to be the case with BF3, where stereoselectivity increases with the steric bulk of the silyl enol ether substituent R1.42 –BF

O+



3

CH3

H

BF3

O+

CH3

H syn

Ph R1

syn Ph

H

H R1

TMSO

OTMS Z-enol silane

E-enol silane

syn:anti 60:40 56:44 <5:95 47:53

syn:anti 57:43 35:65 – – 30:70

R1 Et i-Pr t-Bu Ph

a-Substituted aldehydes show a preference for a syn relationship between the asubstituent and hydroxy group. This is consistent with a Felkin±Ahn transition state (see Section 3.10 to review the effect of a-substituents on carbonyl addition reactions.).43

CH3 +

O

H

R

H H

OTMS

R′

R

H R′

CH3 CH

OH

CH3

F3B–

Ph

O

CH3

OSiTBDMS O

+ CH2

C C(CH3)3

C(CH3)3

Ph OH

O

24:1 syn:anti

The results suggest that competition between antiperiplanar and synclinal transitions 40. T. Mukaiyama, K. Banno, and K. Narasaka, J. Am. Chem. Soc. 96:7503 (1974). 41. S. Murata, M. Suzuki, and R. Noyori, J. Am. Chem. Soc. 102:3248 (1980); Y. Yamamoto, H. Yatagai, Y. Naruta, and K. Maruyama, J. Am. Chem. Soc. 102:7107 (1980). 42. C. H. Heathcock, K. T. Hug, and L. A. Flippin, Tetrahedron Lett. 25:5973 (1984). 43. C. H. Heathcock and L. A. Flippin, J. Am. Chem. Soc. 105:1667 (1983).

79

states is controlled by both steric and electrostatic effects. H H H

CH3 +

O F3B–

C

R

R OTMS

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

H

TMSO

H CH3 +

H

O F3B–

R antiperiplanar

H C

H

R synclinal

The analysis of the transition-state effect on stereoselectivity has been extended to incorporate a,b-disubstituted systems.44 Quite a number of Lewis acids besides TiCl4 and BF3 can catalyze the Mukaiyama reaction, including Bu2Sn(O3SCF3)2,45 Bu3SnClO4,46 Sn(O3SCF3)2,47 Zn(O3SCF3)2 48 and LiClO4.49 Triaryl perchlorate salts are also very active catalysts.50 Examples of these reactions are included in Scheme 2.5. Trialkylsilyl cations may play a key role in Lewis acid-catalyzed reactions. Trimethylsilyl tri¯ate itself is not a good catalyst, but in combination with other Lewis acids it generates excellent catalytic activity. CH3 Ph

OTBDMS

CH

O

+ CH2

C Ph

CH3 TBDMSO3SCF3 B(O3SCF3)3

Ph

Ref. 51

TBDMSO

O

82% yield, 25:1 syn:anti

Hindered bis-(phenoxy)aluminum derivatives are also powerful co-catalysts (see entry 15, Scheme 2.5). They are believed to act by sequestering the tri¯ate anion.52 Silyl enol ethers react with formaldehyde and benzaldehyde in water±THF mixtures with the use of lanthanide tri¯ates such as Yb(O3SCF3)3 as catalysts. The catalysis re¯ects the strong af®nity of lanthanides for carbonyl oxygen, even in aqueous solution. OTMS PhCH O +

OH Yb(O3SCF3)3 10 mol %

O

Ph

Ref. 53

91% yield, 73:27 syn:anti

Cerium, samarium, and other lanthanide halides promote addition of ketene silyl enol ethers to aldehydes.54 Imines react with ketene silyl acetals in the presence of Yb(O3SCF3)3. Preferential addition to the imine occurs even in the presence of aldehyde 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.

D. A. Evans, M. J. Dart, J. L. Duffy, and M. G. Yang, J. Am. Chem. Soc. 118:4322 (1996). T. Sato, J. Otera, and H. Nozaki, J. Am. Chem. Soc. 112:901 (1990). J. Otera and J. Chen, Synlett 1996:321. T. Oriyama, K. Iwanami, Y. Miyauchi, and G. Koga, Bull. Chem. Soc. Jpn. 63:3716 (1990). M. Chini, P. Crotti, C. Gardelli, F. Minutolo, and M. Pineschi, Gazz. Chim. Ital. 123:673 (1993). M. T. Reetz and D. N. A. Fox, Tetrahedron Lett. 34:1119 (1993). T. Mukaiyama, S. Kobayashi, and M. Murakami, Chem. Lett. 1985:447; T. Mukaiyama, S. Kobayashi, and M. Murakami, Chem. Lett. 1984:1759; S. E. Denmark and C.-T. Chen, Tetrahedron Lett. 35:4327 (1994). A. P. Davis and S. J. Plunkett, J. Chem. Soc., Chem. Commun. 1995:2173; A. P. Davis, J. E. Muir, and S. J. Plunkett, Tetrahedron Lett. 37:9401 (1996). M. Oishi, S. Aratake, and H. Yamamoto, J. Am. Chem. Soc. 120:8271 (1998). S. Kobayashi and I. Hachiya, J. Org. Chem. 59:3590 (1994). P. Van de Weghe and J. Collin, Tetrahedron Lett. 34:3881 (1993); A. E. Vougioukas and H. B. Kagan, Tetrahedron Lett. 28:5513 (1987).

Scheme 2.5. Mukaiyama Reactions

80 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

A. Reactions of silyl end ethers with aldehydes and ketones OTMS 1a

O

CH3

1) R4N+ –F

+ PhCH O

CH3 2b

Ph

CH3 BF3

C

CH3

Ph CH3

OH

TMSO + CH3CH O

96%

CH3

O PhC

O

TiCl4

OH

4

75%

O

3c

d

68%

2) H2O

OTBDMS

PhCHCH O + CH2

OH

CH3

CH2 + (CH3)2C

TiCl4

O

H

HO

PhCCH2C(CH3)2

70–74%

OTMS B. Reactions with acetals 5e

CH3

CH3

OTMS

PhCHCH(OCH3)2 + CH2

CC(CH3)3

TiCl4

CH3 C(CH3)3 +

Ph

–78°C

OCH3

C(CH3)3

Ph

O

OCH3

84% yield, 2.5:1 syn:anti

6f

OTMS

O + (CH3)2C(OCH3)2

OCH3

(CH3)3SiO3SCF3 5 mol %

C(CH3)2

CH3 7g

CH3

TMSO

CH3

Ph3C+ –ClO4

O

C(CH3)2 OTMS

OCH3

Bu2Sn(O3SCF3)2 5 mol % CC(CH3)3 –78°C

+ CH2

CH3 O CH3(CH2)3CCH2CC(CH3)3

OCH3 CH3

OCH3

CO2CH3

9i

CH3

CH3 TiCl4

+

CH3 H

O O

CO2CH3

CH3 CH3

CH3

80%

OCH3

C(CH3)2

CH3(CH2)3CCH3

O CH3

O +

8h

87%

OTMS O

CH3

96%

100%

O

Scheme 2.5. (continued )

81 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

C. Catalytic Mukaiyama reactions 10j

CH3 O

CH3

OTMS

O

+ (CH3)2C

C

CH3

CH3 LiClO4

O

O

CH

>98% syn

H3C CH3

OCH3 O

CO2CH3 TMSO OTMS

11k

(CH3)2CHCH O + H2C

C

O (Cp)2Ti(O3SCF3)2

(CH3)2CHCHCH2CPh

Ph OTMS 12l

CH3CH2CH O + CH3CH

C

TMSO CH3 (Cp)2Ti(O3SCF3)2

CO2CH3

OCH3

OH 91% yield, 1:1.4 syn:anti

OTBDMS

OCH2Ph

13m CH3

CH

+ H2C

C

OCH2Ph

LiClO4 3 mol % –30°C

CO2CH3

OCH3

O

OH 92:8 syn:anti

14n CH3

CH

+ H2C

C

C(CH3)3

C(CH3)3

O

>97% syn

OH OH

Ph

OTMS + H2C

O

TiCl4

O 15o

PhCH2O

OTMS

OCH2Ph

90%

TMSOTf

C Ph

MABR 5%

O

MABR = bis(4-bromo-2,6-di-tert butylphenoxy) methyl aluminum

a. R. Noyori, K. Yokoyama, J. Sakata, I. Kuwajima, E. Nakamura, and M. Shimizu, J. Am. Chem. Soc. 99:1265 (1977). b. C. H. Heathcock and L. A. Flippin, J. Am. Chem. Soc. 105:1667 (1983). c. T. Yanami, M. Miyashita, and A. Yoshikoshi, J. Org. Chem. 45:607 (1980). d. T. Mukaiyama and K. Narasaka, Org. Synth. 65:6 (1987). e. I. Mori, K. Ishihara, L. A. Flippin, K. Nozaki, H. Yamamoto, P. A. Bartlett, and C. H. Heathcock,J. Org. Chem. 55:6107 (1990). f. S. Murata, M. Suzuki, and R. Noyori, Tetrahedron 44:4259 (1988). g. T. M. Meulmans, G. A. Stork, B. J. M. Jansen, and A. de Groot, Tetrahedron Lett.39:6565 (1998). h. T. Satay, J. Otera, and H. N. Zaki, J. Am. Chem. Soc. 112:901 (1990). i. A. S. Kende, S. Johnson, P. San®lippo, J. C. Hodges, and L. N. Jungheim, J. Am. Chem. Soc. 108:3513 (1986). j. J. Ipaktschi and A. Heydari, Chem. Ber. 126:1905 (1993). k. T. K. Hollis, N. Robinson, and B. Bosnich, Tetrahedron Lett. 33:6423 (1992). l. Y. Hong, D. J. Norris, and S. Collins, J. Org. Chem. 58:3591 (1993). m. M. T. Reetz and D. N. A. Fox, Tetrahedron Lett. 34:1119 (1993). n. M. T. Reetz, B. Raguse, C. F. Marth, H. M. Hugel, T. Bach, and D. N. A. Fox, Tetrahedron 48:5731 (1992). o. M. Oishi, S. Aratake, and H. Yamamoto, J. Am. Chem. Soc. 120:8271 (1998).

82 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

and is attributed to coordination of the lanthanide at the imine nitrogen.55 CH3(CH2)6CH NCH2Ph + TMSOC

C(CH3)2

Yb(O3SCF3)3 20 mol %

PhCH2 NHCH3 CH3(CH2)6CHCCO2CH3

OCH3

86%

CH3

In addition to aldehydes, acetals and ketals can serve as electrophiles in Mukaiyama reactions.56 RCH O+R′ + [R′OMXn]O

RCH(OR′)2 + MXn RCH O+R′ + R2CH

CR3

RCHCHCR3

OTMS

R′O R2

Effective catalysts include TiCl4,57 SnCl4,58 (CH3)3SiO3SCF3,59 and Bu2SnO3SCF3.60 Indium trichloride catalyzes Mukaiyama additions in aqueous solution. The reaction is best conducted by preforming the aldehyde±InCl3 complex and then adding the silyl enol ether and water. OTMS ArCH

OH

O

InCl3, H2O

O +

Ref. 61

Ar 60–80%

It has been proposed that there may be a single-electron-transfer mechanism for the Mukaiyama reaction.62 For example, photolysis of benzaldehyde dimethylacetal and 1trimethylsilyloxycyclohexene in the presence of a typical photoelectron acceptor, triphenylpyrylium cation, gives an excellent yield of the addition product. OTMS

OH

O



PhCH(OMe)2 +

Ph

Ph

Ph

O+

Ph

Ref. 63

94% yield, 66:34 syn:anti

These reactions may operate by providing a source of trimethylsilyl cations, which act as the active catalyst. 55. S. Kobayashi and S. Nagayama, J. Am. Chem. Soc. 119:10049 (1997); S. Kobayashi and S. Nagayama, J. Org. Chem. 62:232 (1997). 56. T. Mukaiyama and M. Murakami, Synthesis 1987:1043. 57. T. Mukaiyama and M. Hayashi, Chem. Lett. 1974:15. 58. R. C. Cambie, D. S. Larsen, C. E. F. Rickard, P. S. Rutledge, and P. D. Woodgate, Austr. J. Chem. 39:487 (1986). 59. S. Murata, M. Suzuki, and R. Noyori, Tetrahedron 44:4259 (1988). 60. T. Sato, J. Otera, and H. Nozaki, J. Am. Chem. Soc. 112:901 (1990). 61. T.-P. Loh, J. Pei, K. S.-V. Koh, G.-Q. Cao, and X.-R. Li, Tetrahedron Lett. 38:3465, 3993 (1997). 62. T. Miura and Y. Masaki, J. Chem. Soc., Perkin Trans. 1 1994:1659; T. Miura and Y.Masaki, J. Chem. Soc., Perkin Trans. 1 1995:2155; J. Otera, Y. Fujita, N. Sakuta, M.Fujita, and S. Fukuzumi, J. Org. Chem. 61:2951 (1996). 63. M. Kamata, S. Nagai, M. Kato, and E. Hasegawa, Tetrahedron Lett. 37:7779 (1996).

2.1.3.5. Control of Enantioselectivity. In the previous sections, the most important factors in determining the syn or anti stereoselectivity of aldol and Mukaiyana reactions were identi®ed as the nature of the transition state (cyclic versus acyclic) and the con®guration (E or Z) of the enolate. Additional factors affect the enantioselectivity of aldol additions and related reactions. Nearby chiral centers in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Although the general principles of control of the stereochemistry of aldol addition reactions have been developed for simple molecules, the application of the principles to more complex molecules and the selection of the optimum enolate system requires analysis of the individual cases.64 Not infrequently, one of the enolate systems proves to be superior,65 or a remote structural feature strongly in¯uences the stereoselectivity.66 The issues that need to be addressed in speci®c cases include the structure of the enolate, including its stereochemistry and potential sites for chelation, the organization of the transition state (cyclic versus acyclic), and the factors effecting the facial selectivity. Up to this point, we have considered primarily the effect of enolate geometry on the stereochemistry of the aldol condensation and have considered achiral or racemic aldehydes and enolates. If the aldehyde is chiral, particularly when the chiral center is adjacent to the carbonyl group, the selection between the two diastereotopic faces of the carbonyl group will in¯uence the stereochemical outcome of the reaction. Similarly, there will be a degree of selectivity between the two faces of the enolate when the enolate contains a chiral center. If both the aldehyde and enolate are chiral, mutual combinations of stereoselectivity will come into play. One combination should provide complementary, reinforcing stereoselection, whereas the alternative combination would result in opposing preferences and lead to diminished overall stereoselectivity. The combined interactions of chiral centers in both the aldehyde and the enolate determine the stereoselectivity. The result is called double stereodifferentiation.67

R-enolate

favored

R-enolate

R-aldehyde

favored

S-aldehyde

or S-enolate

favored

S-aldehyde

S-enolate

favored

R-aldehyde

The analysis and prediction of the direction of preferred reaction depend on the same principles as for simple diastereoselectivity and are done by analysis of the attractive and repulsive interactions in the presumed transition state. Analysis of results for a-substituted aldehydes with E- and Z-enolates indicates that the cyclic transition states shown below are favored with lithium and boron enolates.64a 64. (a) W. R. Roush, J. Org. Chem. 56:4151 (1991); (b) C. Gennari, S. Vieth, A. Comotti, A. Vulpetti, J. M. Goodman, and I. Paterson, Tetrahedron 48:4439 (1992); (c) D. A. Evans, M. J. Dart, J. L. Duffy, and M. G. Yang, J. Am. Chem. Soc. 118:4322 (1996); (d) A. S. Franklin and I. Paterson, Contemp. Org. Synth. 1:317 (1994). 65. E. J. Corey, G. A. Reichard, and R. Kania, Tetrahedron Lett. 34:6977 (1993). 66. A. Balog, C. Harris, K. Savin, X.-G. Zhang, T. C. Chou, and S. J. Danishefsky, Angew. Chem. Int. Ed. Engl. 37:2675 (1998). 67. S. Masamune, W. Choy, J. S. Petersen, and L. R. Sita, Angew. Chem. Int. Ed. Engl. 24:1 (1985).

83 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

84

The larger a-substituent is aligned anti to the approaching enolate.

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

CH3

X H

H

O H C O

M H

R

CH3

X H

CH3

CH3

OH O H C O M

R

R

X

H CH3

C

2,3-anti-3,4-syn

H

X

H

O

M

O

H

CH3

CH3

E-enolate R > CH3

R

O

CH3

R

C

OH

X O

H

O

R

O

H

CH3

M

X CH3

CH3

CH3

2,3-syn-3,4-anti

Z-enolate R > CH3

The stereoselectivity resulting from interactions of chiral aldehydes and enolates has been useful in the construction of systems with several contiguous chiral centers. H Ph

CH3

CH3 CH3 + HC

TMSO

O–Li+

Ph

CH3

TMSO O

O

S

CH3 CH3

S

+

OH

major

Ph

CH3 CH3

CH3

complementary selectivity ratio = 9:1

TMSO O

OH

minor

Ref. 68 H CH3 TMSO R

CH3

Ph CH3 + HC O–Li+

CH3

Ph

CH3

CH3

TMSO O

O S

+

OH

major

CH3

Ph

CH3

CH3

opposed selectivity ratio = 1.3:1

TMSO O

OH

minor

Other structural features may in¯uence the stereoselectivity of aldol condensations. One such factor is chelation by a donor substituent.69 Several b-alkoxyaldehydes show a preference for syn-aldol products on reaction with Z-enolates. A chelated transition state can account for the observed stereochemistry.70 The chelated aldehyde is most easily 68. S. Masamune, S. A. Ali, D. L. Snitman, and D. S. Garvey, Angew. Chem. Int. Ed. Engl. 19:557 (1980). 69. M. T. Reetz, Angew. Chem. Int. Ed. Engl. 23:556 (1984). 70. S. Masamune, J. W. Ellingboe, and W. Choy, J. Am. Chem. Soc. 104:5526 (1982).

85

approached from the face opposite the methyl and R0 substituents. O– +Li

CH3

CH3

CH3

R′

CH

O +

CH3 R′ R O C O Li+ CH3 H H

CH3

R′ H

RO

RO

OH

O

syn

O–

R = CH2OCH2Ph, R′ = H, Et, PhCH2

A similar stereoselectivity has been noted for the TiCl4-mediated condensation of b-alkoxyaldehydes with silyl enol ethers. CH3 CH3

OTMS

CH3 CH

PhCH2O

H

Ph

Ph

CH3

TiCl4

O +

–78°C

Ref. 71

PhCH2O

OH

O

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.72 A very useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1±3, which are readily available in enantiomerically pure form. H

H N

(CH3)2CH

PhCH2

N

O

CH3

H N

Ph

O

O

O

O

O 2

1

3

These compounds can be acylated and converted to the lithium or boron enolates by the same methods applicable to ketones. The enolates are the Z-stereoisomers.73 R O

H CH2R

N R′

O O

O L2BO3SCF3

BL2

N R′

O O

The oxazolinone substituents R0 then direct the approach of the aldehyde. Because of the differing steric encumbrance provided by 1 and 3, the products have the opposite con®guration at the new stereogenic sites. The acyl oxazolidinones are easily solvolyzed 71. M. T. Reetz and A. Jung, J. Am. Chem. Soc. 105:4833 (1983). 72. M. Braun and H. Sacha, J. Prakt. Chem.335:653 (1993). 73. D. A. Evans, J. Bartoli, and T. L. Shih, J. Am. Chem. Soc. 103:2127 (1981).

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

86

in water or alcohols to give the enantiomeric b-hydroxy acid or ester.

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

R R2

OH R2

H O

(CH3)2CH

N

RCH

O

O

(CH3)2CH

BL2

R2

O

R

HO2C

N O

O

OH

O R

R2

OH R2

H CH3

O N

RCH

BL2

O

R2 O

CH3

O

O Ph

O

R

HO2C

N

OH

O

Ph

1,3-Thiazoline-2-thiones are another useful type of chiral auxiliary. These can be used in conjunction with Sn(O3SCF3)2,74 Bu2BO3SCF3,75 or TiCl476 for generation of enolates. S S R

N CCH2R O

R = C3H5, (CH3)3C, CO2CH3

The chiral auxiliaries can be used under conditions where either cyclic or noncyclic transition states are involved. This frequently allows control of the syn or anti stereoselectivity. Scheme 2.6 gives some examples where good stereoselectivity has been achieved. The selectivity is believe to be determined by the cyclic or acyclic nature of the transition state.77 Enantioselectivity can also be induced by use of chiral boronates in the preparation of boron enolates. Both the (‡ ) and ( ) enantiomers of diisopinocamphylboron tri¯ate have been used to generate syn adducts through a cyclic transition state.78 The enantioselectivity was greater than 80% for most cases that were examined. 1) (Ipc)2BO3SCF3 (i-Pr)2NEt

R

2) R′CH

O R = Et, Ph, i-Pr

CH3 R

R′

O

O

OH

R′ = Me, n-Pr, i-Pr

74. Y. Nagao, Y. Hagiwara, T. Kumagai, M. Ochiai, T. Inoue, K. Hashimoto, and E. Fujita, J. Org. Chem. 51:2391 (1986). 75. C.-N. Hsiao, L. Liu, and M. J. Miller, J. Org. Chem. 52:2201 (1987). 76. D. A. Evans, S. J. Miller, M. D. Ennis, and P. L. Ornstein, J. Org. Chem. 57:2067 (1992). 77. T. H. Yan, C. W. Tan, H.-C. Lee, H-C. Lo, and T. Y. Huang, J. Am. Chem. Soc. 115:1613 (1993). 78. I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann, C. K. McClure, and R. D. Norcross, Tetrahedron 46:4663 (1990).

Scheme 2.6. Control of syn : anti Selectivity by Use of Alternate Reaction Conditions with Chiral Auxiliaries O 1a

O

O

O

1) Bu2BO3SCF3 (i-Pr2)NEt

N

2) RCH=O TiCl4 or Ti(O-i-Pr)3Cl

O

O

87 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

OH

N

R

CH3 CH(CH3)2

CH(CH3)2

R = i-Pr, Bu, Ph

O 2b

O

O

O

OH

1) Bu2BO3SCF3

O

N

2) RCH=O/Et2AlCl

O

N

R

CH3 CH(CH3)2

CH(CH3)2

R = Et, i-Pr, t-Bu, i-Bu, Ph

3c

O

2) RCH=O

N

OH

O

1) Et2BO3SCF3 (i-Pr2)NEt

R

N

SO2

CH3

SO2

R = Me, Et, i-Pr, Ph

4d

O

O

1) Et2BO3SCF3 (i-Pr2)NEt 2) RCH=O/TiCl4

N

R

N CH3

SO2

SO2

OH

R = Me, Et, i-Pr, i-Bu, Ph

a. M. Nerz-Stormes and E. R. Thornton, J. Org. Chem. 56:2489 (1991); D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark, and M. T. Bilondeau, J. Am. Chem. Soc. 112:8215 (1990). b. M. A. Walker and C. H. Heathcock, J. Org. Chem.56:5747 (1991). c. W. Oppolzer, J. Blagg, I. Rodriquez, and E. Walther, J. Am. Chem. Soc. 112:2767 (1990). d. W. Oppolzer and P. Lienhard, Tetrahedron Lett. 34:4321 (1993).

Another promising boron enolate is derived from ( )-menthone. It gives E-boron enolates that give good enantioselectivity and result in formation of anti products.79

CH3

2BCl

Et3N

O

H

CH3 R

R′CH O

OB(CH2menth)2 R = Et, i-Pr, R′ = Et, cyclohexyl, i-Pr

R′

R O

OH

e.e. = 6.6–12.1:1

79. G. Gennari, C. T. Hewkin, F. Molinari, A. Bernardi, A. Comotti, J. M. Goodman, and I. Paterson, J. Org. Chem. 57:5173 (1992).

88 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

The stereoselectivity in these cases has its origin in steric effects of the boron substituents. Several hetereocyclic boron enolates with chirality installed at boron have been found to be useful for enantioselective additions. The diazaboridine below is an example.80 Ph

Ph ArSO2N

NSO2Ar B Br

Ar = 3,5-di(trifluoromethyl)phenyl

Derivatives with various substituted sulfonamides have also been developed and used to form enolates from esters and thioesters.81 An additional feature of these chiral auxiliaries is the ability to select for syn or anti products, depending upon choice of reagents and reaction conditions. The diastereoselectivity is determined by whether the E- or Z-enolate is formed.82 Ph

Ph

NTs

TsN

O

O

B

OH

(CH3)2CHCH O

Br (i-Pr)2NEt

CH3 85% yield, 98:2 syn:anti, 95% e.e.

Ph

Ph Ar′SO2N

CH3CH2CO2C(CH3)3

OH

NSO2Ar′ B

CH

O

CO2C(CH3)3

Br Et3N

Ar = 3,5-di(trifluoromethyl)phenyl

CH3 96:4 syn:anti, 75% e.e.

Considerable effort has been devoted to ®nding Lewis acid or other catalysts that could induce high enantioselectivity in the Mukaiyama reaction. As with aldol addition reactions involving enolates, high diastereoselectivity and enantioselectivity requires involvement of a transition state with substantial facial selectivity with respect to the electrophilic reactant and a preferred orientation of the nucleophile. Scheme 2.4 shows some examples of enantioselective catalysts. One example involves the addition of stannyl enol ethers to benzaldehyde in the presence of silver tri¯ate and the chiral 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl

80. E. J. Corey, R. Imwinkelried, S. Pikul, and Y. B. Xiang, J. Am. Chem. Soc. 111:5493 (1989). 81. E. J. Corey and S. S. Kim, J. Am. Chem. Soc. 112:4976 (1990). 82. E. J. Corey and D. H. Lee, Tetrahedron Lett. 34:1737 (1993).

(BINAP) ligand. The observed enantioselectivity can be accounted for by a cyclic transition state.

* OH

OSnBu3 R-(BINAP)-AgO3SCF3

PhCH O +

O

P R1 Ag+ SnBu3 O O E

H

Ph R2 93% anti 94% e.e.

P

R3

Ref. 83

H

Scheme 2.7 gives some examples of chiral Lewis acids that have been used to catalyze aldol and Mukaiyama reactions. Scheme 2.8 shows some enantioselective aldol additions effected with these reagents.

2.1.4. Intramolecular Aldol Reactions and the Robinson Annulation The aldol reaction can be applied to dicarbonyl compounds in which the two carbonyl groups are favorably disposed for intramolecular reaction. For formation of ®ve- and sixmembered rings, the use of a catalytic amount of a base is frequently satisfactory. With more complex structures, the special techniques required for directed aldol condensations are used. Scheme 2.9 illustrates intramolecular aldol condensations. A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. O CH3CCH

CH2 –O

conjugate addition

H2C O

CH2

C H3C

O

aldol addition and dehydration

O

A precursor of methyl vinyl ketone, 4-(trimethylamino)-2-butanone, was used as the reagent in the early examples of the reaction. This compound generates methyl vinyl ketone in situ, by b elimination. Other a,b-unsaturated enones can be used, but the reaction 83. A. Yanagisawa, Y. Matsumoto, H. Nakashima, K. Asakawa, and H. Yamamoto, J. Am. Chem. Soc. 119:9319 (1997). 84. E. D. Bergmann, D. Ginsburg, and R. Pappo, Org. React. 10:179 (1950); J. W. Cornforth and R. Robinson, J. Chem. Soc. 1949:1855; R. Gawley, Synthesis 1976:777; M. E. Jung, Tetrahedron 32:3 (1976); B. P. Mundy, J. Chem. Educ. 50:110 (1973).

89 SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

Scheme 2.7. Chiral Catalysts for the Mukaiyama Reaction

90 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

H3C

CH3 N N

Sn

ArSO2

CH3

N

O

ArSO2N

ArSO2

B

O

N B

H Bb

Aa

O

Ph

Ph

CH(CH3)2 O

O

CH3

Cc

CH3

B

N

Br

N

Dd

ArSO2

CH3 O

O

O

NSO2Ar

Cc

H

N

N

B

Cu

C4H9

C(CH3)3

(CH3)3C

H Ee

Ff t-Bu

O

N

TiX2

Ti O O O t-Bu O

O

Gg

X = Cl or OCH(CH3)2

Hh

t-Bu

t-Bu

a. b. c. d. e.

S. Kobayashi and M. Horibe, Chem. Eur. J. 3:1472 (1997). S. Kiyooka, Y. Kaneko, M. Komura, H. Matsuo, and M. Nakano, J. Org. Chem. 56:2276 (1991). E. R. Parmee, O. Tempkin, S. Masamune, and A. Akibo, J. Am. Chem. Soc. 113:9365 (1991). E. J. Corey, R. Imwinkelried, S. Pakul, and Y. B. Xiang, J. Am. Chem. Soc. 111:5493 (1989). E. J. Corey, C. L. Cywin, and T. D. Roper, Tetrahedron Lett. 33:6907 (1992); E. J. Corey, D. Barnes-Seeman, and T. W. Lee, Tetrahedron Lett. 38:1699 (1997). f. D. A. Evans, J. A. Murry, and M. C. Kozlowski, J. Am. Chem. Soc. 118:5814 (1996); D. A. Evans, M. C. Kozlowski, C. S. Burgey, and D. W. C. MacMillan, J. Am. Chem. Soc. 119:7893 (1997); D. A. Evans, D. W. C. MacMillan, and K. R. Campos, J. Am. Chem. Soc. 119:10859 (1997). g. K. Mitami and S. Matsukawa, J. Am. Chem. Soc. 115:7039 (1993); K. Mitami and S. Matsukawa, J. Am. Chem. Soc. 116:4077 (1994); G. E. Keck and D. Krishnamurthy, J. Am. Chem. Soc. 117:2363 (1995); G. E. Keck, D. Krishnamurthy, and M. C. Grier, J. Org. Chem. 58:6543 (1993); G. E. Keck, X.-Y. Li, and D. Krishnamurthy, J. Org. Chem. 60:5998 (1995). h. E. M. Carreira, R. A. Singer, and W. Lee, J. Am. Chem. Soc. 116:8837 (1994).

is somewhat sensitive to substitution at the b carbon, and adjustment of the reaction conditions is necessary.85 The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of the more substituted enolate and gives a product with a substituent at a ring juncture when monosubstituted cyclohexanones are used as reactants. The alternative regiochemistry can be achieved by using an enamine of the ketone. As discussed in Section 1.9, the less substituted enamine is favored, so addition occurs at the less substituted position. Entry 4 of Scheme 2.10 illustrates this variation of the reaction. 85. C. J. V. Scanio and R. M. Starrett, J. Am. Chem. Soc. 93:1539 (1971).

Scheme 2.8. Enantioselective Aldol and Mukaiyama Additions

1) cat D

OC(CH3)3

2) Et3N 3) PhCH O

CO2C(CH3)3

Ph

(CH3)2C

CH3

H3C cat C

+

C

93% yield, 94% e.e.

CH3

OTMS 2b

CH

81% yield, >98% e.e.

C2H5O2C

O

OC2H5

OTMS

(CH3)2C

cat B

+ TBSO

C

CH3

H3C

OTMS 3c

CH

OTBS

C2H5O2C

O

OC2H5 OH cat B

+ PhCH O

C

88%

OTMS

OTMS 4d (CH3)2C

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

OH

O 1a

91

CO2C2H5

Ph

OC2H5

CH3

92% yield, 90% e.e.

CH3

OTMS 5e CH2

C

cat E

+ Ph

CH

O

Ph

O

OH OTMS 6f

a. b. c. d. e. f.

CH2

+

C Ph

CH

Ph

O

100% yield, 92% e.e.

O

cat H

O

Ph

CO2CH3

97% e.e.

OH

E. J. Corey and S. S. Kim, J. Am. Chem. Soc. 112:4976 (1990). E. R. Parmee, O. Tempkin, S. Masamune, and A. Akibo, J. Am. Chem. Soc. 113:9365 (1991). J. Mulzer, A. J. Mantoulidis, and E. Ohler, Tetrahedron Lett. 39:8633 (1998). S. Kiyooka, Y. Kaneko, and K. Kume, Tetrahedron Lett. 33:4927 (1992). E. J. Corey, C. L. Cywin, and T. D. Roper, Tetrahedron Lett. 33:6907 (1992). E. M. Carreira, R. A. Singer, and W. Lee, J. Am. Chem. Soc. 116:8837 (1994).

Robinson annulation can also be carried out using aluminum tris(2,6-diphenylphenoxide) to effect the conjugate addition and cyclization.

O

O–

+ CH 3

H CH3

CH3

H

CH3

1) Al(OAr)3

Ref. 86

2) KOH, EtOH

O

O

50% yield, 88:12

86. S. Saito, I. Shimada, Y. Takamori, M. Tanaka, K. Maruoka, and H. Yamamoto, Bull. Chem. Soc. Jpn. 70:1671 (1997).

Scheme 2.9. Intramolecular Aldol and Mukaiyama Additions

92 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

CHO 1a

O

H2O

CH(CH2)3CHCH O

115°C

C3H7 C3H7 O 2b CH3CH2CH 3c

HO–

CHCH2CH2CCH2CH2CH O

CH3CH2CH

O

NaOH

N

73%

O

O

HO

H3C

CHCH2

80%

O

H3C

N

O

CH3C O 4d

H

H3C

O

H

H3C

O

OH

NaOCH3

R3SiO H3C 5e

O CH2CH

63%

O O

R3SiO H3C

TMSO

O OCH3

CH2

59%

ZnCl2

CH(OCH3)2 H

H

H3C 6f

H

CH3

H3C

CH3 CH3

NaOCH3

CH3

CH3 O

7g

CH3

CH3 O

CHCH2 H3C

HO

CH3 O

O DBU

CH3 CH3O2C

66%

HO

O

a. b. c. d. e. f. g.

CH3

CH3

O CH3

H

H3C

65–70%

CH3 H

OTMS CH3O2C

H

OTMS

J. English and G. W. Barber, J. Am. Chem. Soc. 71:3310 (1949). A. I. Meyers and N. Nazarenko, J. Org. Chem. 38:175 (1973). K. Wiesner, V. Musil, and K. J. Wiesner, Tetrahedron Lett. 1968:5643. G. A. Kraus, B. Roth, K. Frazier, and M. Shimagaki, J. Am. Chem. Soc. 104:1114 (1982). M. D. Taylor, G. Minaskanian, K. N. Winzenberg, P. Santone, and A. B. Smith III, J. Org. Chem. 47:3960 (1982). K. Yamada, H. Iwadare, and T. Mukaiyama, Chem. Pharm. Bull. 45:1898 (1997). J. R. Tagat, M. S. Puar, and S. W. McCombie, Tetraheron Lett. 37:8463 (1996).

93

Scheme 2.10. The Robinson Annulation Reaction 1a

O

O CH3 + CH2

CH2CH2COCH3

KOH

CHCOCH3

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

CH3

O

O

O

CH3

pyrrolidine

63–65%

O 2b

CO2CH2CH3

CO2CH2CH3 + CH2

CHCOCH2CH3

NaOEt

59%

EtOH

O

O CH3

3c

O

CH3

H3C

O +

+ CH3COCH2CH2N(CH3)3

–OEt

CH3O 4d

CH3O

CH3

CH3

CH3 1) CH2

O

5e

CHCOCH3 benzene, reflux 2) HOAc, NaOAc, H2O, reflux

N

O

O O

CH3 + CH2

CHCCH2CH3

O

45%

O CH3

1) DABCO 2) Et3N, PhCO2H 140°C 24 h

75%

O CH3

6f O

OCH3

O OCH3

OCH3

1) LDA

OCH3

O

62%

2) CH3CH CCCH3

O 3) MeO–

Si(CH3)3

O O

7g + CH2 O– +Li

CCCH3

SPh

–70°C

SPh OH

O

80%

71%

94

Scheme 2.10. (continued )

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

CH3

O

O

8h + CH2CH

CHCCH3

CH3

TiCl4

OTMS

72%

O KOH

CH3

O a. b. c. d. e. f. g. h.

S. Ramachandran and M. S. Newman, Org. Synth. 41:38 (1961). D. L. Snitman, R. J. Himmelsbach, and D. S. Watt, J. Org. Chem. 43:4578 (1978). J. W. Cornforth and R. Robinson, J. Chem. Soc. 1949:1855. G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz, and R. Terrell, J. Am. Chem. Soc. 85:207 (1963). F. E. Ziegler, K.-J. Hwang, J. F. Kadow, S. I. Klein, U. K. Pati, and T.-F. Wang, J. Org. Chem. 51:4573 (1986). G. Stork, J. D. Winkler, and C. S. Shiner, J. Am. Chem. Soc. 104:3767 (1982). K. Takaki, M. Okada, M. Yamada, and K. Negoro, J. Org. Chem. 47:1200 (1982). J. W. Huffman, S. M. Potnis, and A. V. Satish, J. Org. Chem. 50:4266 (1985).

Another version of the Robinson annulation procedure involves the use of methyl 1trimethylsilylvinyl ketone. The reaction follows the normal sequence of conjugate addition, aldol cyclization, and dehydration.

O

O + CH3CC –O

CH3CCHCH2

CH2

Si(CH3)3

Si(CH3)3

O Ref. 87

–OH

(CH3)3Si

(CH3)3SiOH + O

O

The role of the trimethylsilyl group is to stabilize the enolate formed in the conjugate addition. The silyl group is then removed during the dehydration step. The advantage of methyl 1-trimethylsilylvinyl ketone is that it can be used under aprotic conditions which are compatible with regiospeci®c methods for enolate generation. The direction of annulation of unsymmetrical ketones can therefore be controlled by the method of 87. G. Stork and B. Ganem, J. Am. Chem. Soc. 95:6152 (1973); G. Stork and J. Singh, J. Am. Chem. Soc. 96:6181 (1974).

95

enolate formation. CH3

CH3

Si(CH3)3 CH2

O

CH3Li

(CH3)3SiO

LiO

H

CH3

CCCH3

Ref. 88

H

H O

69%

Methyl 1-phenylthiovinyl ketones can also be used as enones in kinetically controlled Robinson annulation reactions, as illustrated by entry 7 in Scheme 2.10. The product in entry 1 of Scheme 2.10 is commonly known as the Wieland±Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The S-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantioselective synthesis of steroids.91 O H3C

H

H3C

O

H+

H

CH3CCH2CH2

O

O

O

H3C

CO2–

+

N

O

O

OH

The detailed mechanism of this enantioselective transformation remains under investigation.92 It is known that the acidic carboxylic group is crucial. The cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. There is evidence that a second molecule of the catalyst is involved, and it has been suggested that this molecule participates in the proton-transfer step which completes the cyclization reaction.93 H3C

O

H3C

O

+

N

N O

+

H CO2– N

CO2– H

OH H N

CO2–

CO2–

88. R. K. Boeckman, Jr., J. Am. Chem. Soc. 96:6179 (1974). 89. J. Gutzwiller, P. Buchshacher, and A. FuÈrst, Synthesis 1977:167; P. Buchshacher and A. FuÈrst, Org. Synth. 63:37 (1984). 90. Z. G. Hajos and D. R. Parrish, J. Org. Chem. 39:1615 (1974); U. Eder, G. Sauer, and R. Wiechert, Angew. Chem. Int. Ed. Engl. 10:496 (1971). Z. G. Hajos and D. R. Parrish, Org. Synth. 63:26 (1985). 91. N. Cohen, Acc. Chem. Res. 9:412 (1976). 92. P. Buchschacher, J.-M. Cassal, A. FuÈrst, and W. Meier, Helv. Chim. Acta 60:2747 (1977); K. L. Brown, L. Damm, J. D. Dunitz, A. Eschenmoser, R. Hobi, and C. Kratky, Helv. Chim. Acta 61:3108 (1978); C. Agami, F. Meynier, C. Puchot, J. Guilhem, and C. Pascard, Tetrahedron 40:1031 (1984). 93. C. Agami, J. Levisalles, and C. Puchot, J. Chem. Soc., Chem. Commun. 1985:441; C. Agami, Bull. Soc. Chim. Fr. 1988:499.

SECTION 2.1. ALDOL ADDITION AND CONDENSATION REACTIONS

96 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

2.2. Addition Reactions of Imines and Iminium Ions Imines and iminium ions are nitrogen analogs of carbonyl compounds, and they undergo nucleophilic additions like those involved in aldol condensations. The reactivity order is CˆNR < CˆO < [CˆNR2] ‡ < [CˆOH] ‡ . Because iminium ions are more reactive than imines, condensations involving imines are frequently run under acidic conditions where the imine is protonated. 2.2.1. The Mannich Reaction The Mannich reaction is the condensation of an enolizable carbonyl compound with an iminium ion.94 The reaction effects a-alkylation and introduces a dialkylaminomethyl substituent. O RCH2CR′ + CH2

O O + HN(CH3)2 → (CH3)2NCH2CHCR′ R

The electrophilic species is often generated in situ from the amine and formaldehyde. CH2

O + HN(CH3)2

HOCH2N(CH3)2

H+

H2O + CH2

+

N(CH3)2

The reaction is usually limited to secondary amines, because dialkylation can occur with primary amines. The dialkylation reaction can be used advantageously in ring closures. O CH3CH2 O CH3O2CCH

C

CH2CH3 CHCO2CH3 + CH2O + CH3NH2

C2H5

C2H5

CH3O2C

CO2CH3

Ref. 95

N CH3

Entries 1 and 2 in Scheme 2.11 show the preparation of ``Mannich bases'' from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as bis(dimethylamino)methane in entry 3. On treatment with tri¯uoroacetic acid, this aminal generates the iminium tri¯uoroacetate as a reactive electrophile. N,N-Dimethylmethyleneammonium iodide is commercially available and is known as ``Eschenmoser's salt''.96 This compound is suf®ciently electrophilic to react directly with silyl enol ethers in neutral solution.97 The reagent can be added to a solution of an enolate

94. F. F. Blicke, Org. React. 1:303 (1942); J. H. Brewster and E. L. Eliel, Org. React. 7:99 (1953); M. Tramontini and L. Angiolini, Tetrahedron 46:1791 (1990); M. Tramontini and L. Angiolini, Mannich BasesÐChemistry and Uses, CRC Press, Boca Raton, Florida, 1994; M. Ahrend, B. Westerman, and N. Risch, Angew. Chem. Int. Ed. Engl. 37:1045 (1998). 95. C. Mannich and P. Schumann, Berichte 69: 2299 (1936). 96. J. Schreiber, H. Maag, N. Hashimoto, and A. Eschenmoser, Angew. Chem. Int. Ed. Engl. 10:330 (1971). 97. S. Danishefsky, T. Kitahara, R. McKee, and P. F. Schuda, J. Am. Chem. Soc. 98:6715 (1976).

Scheme 2.11. Synthesis and Utilization of Mannich Bases H PhCOCH2CH2N(CH3)2Cl–

+

1a

PhCOCH3 + CH2O + (CH3)2NH2Cl–

H CH3COCH2CH2N(C2H5)2Cl–

+

4d

OSiMe3

O

O 87%

H+, –OH

2) H2O,

OK

O CH2N(CH3)2

+

KH

(CH3)2N CH2

THF, 0°C

I–

+

6f

CH2N(CH3)2

+

1) (CH3)2N CH2

THF

66–75%

(CH3)2CHCOCH2CH2N(CH3)2

OLi CH3Li

5e

+

CF3CO2H

(CH3)2CHCOCH3 + [(CH3)2N]2CH2

SECTION 2.2. ADDITION REACTIONS OF IMINES AND IMINIUM IONS

70%

+

2b CH3COCH3 + CH2O + (CH3CH2)2NH2Cl– 3c

97

CH3CH2CH2CH O + CH2O + (CH3)2NH2Cl–

1) 60°C, 6 h 2) distill

CH2

88%

CCH

O

73%

CH2CH3 7g

O

O CH3

+ (CH2O)n 8h

+

O

a. b. c. d. e. f. g. h. i.

90%

O + PhCOCH2CH2N(CH3)2

9i

CH2

PhNH2 CF3CO2–, THF

PhCOCH2CH2N(CH3)2 + KCN

NaOH

PhCOCH2CH2CN

CH2CH2COPh

52%

67%

C. E. Maxwell, Org. Synth. III:305 (1955). A. L. Wilds, R. M. Nowak, and K. E. McCaleb, Org. Synth. IV:281 (1963). M. Gaudry, Y. Jasor, and T. B. Khac, Org. Synth. 59:153 (1979). S. Danishefsky, T. Kitahara, R. McKee, and P. F. Schuda, J. Am. Chem. Soc. 98:6715 (1976). J. L. Roberts, P. S. Borromeo, and C. D. Poulter, Tetrahedron Lett. 1977:1621. C. S. Marvel, R. L. Myers, and J. H. Saunders, J. Am. Chem. Soc. 70:1694 (1948). J. L. Gras, Tetrahedron Lett. 1978:2111, 2955. A. C. Cope and E. C. Hermann, J. Am. Chem. Soc. 72:3405 (1950). E. B. Knott, J. Chem. Soc. 1947:1190.

or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 of Scheme 2.11 illustrate the preparation of Mannich bases with Eschenmoser's salt. The dialkylaminomethyl ketones formed in the Mannich reaction are useful synthetic intermediates.98 Thermal elimination of the amines or the derived quaternary salts provides

98. G. A. Gevorgyan, A. G. Agababyan, and O. L. Mndzhoyan, Russ. Chem. Rev. (Engl. Transl.) 54:495 (1985).

98

a-methylene carbonyl compounds.

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

(CH3)2CHCHCH

O



(CH3)2CHCCH

CH2N(CH3)2

O

Ref. 99

CH2

These a,b-unsaturated ketones and aldehydes are used as reactants in Michael additions (Section 1.10) and Robinson annulations (Section 2.1.4), as well as in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.11 illustrate Michael reactions carried out by in situ generation of a,b-unsaturated carbonyl compounds from Mannich bases. a-Methylene lactones are present in a number of natural products.100 The reaction of ester enolates with N,N-dimethylmethyleneammonium tri¯uoroacetate,101 or Eschenmoser's salt,102 has been used for introduction of the a-methylene group in the synthesis of vernolepin, a compound with antileukemic activity.103,104 CH2

CH

O

CH2

OH

O

H H

CH

OH

O

1) LDA, THF, HMPA

H

+

2) CH2 N(CH3)2I– 3) H3O+

O

H

4) CH3I

O

CH2

5) NaHCO3

O

CH2 O

vernolepin

O

Mannich reactions, or a close mechanistic analog, are important in the biosynthesis of many nitrogen-containing natural products. As a result, the Mannich reaction has played an important role in the synthesis of such compounds, especially in syntheses patterned after the mode of biosynthesis, i.e., biogenetic-type synthesis. The earliest example of the use of the Mannich reaction in this way was the successful synthesis of tropinone, a derivative of the alkaloid tropine, by Sir Robert Robinson in 1917. CO2– CH2CH

O

CH2CH

O

+ H2NCH3 + C

O

CH3N

O

CH3N

O

Ref. 105

CH2 CO2–

99. 100. 101. 102. 103. 104.

CO2–

CH2

CO2–

C. S. Marvel, R. L. Myers, and J. H. Saunders, J. Am. Chem. Soc. 70:1694 (1948). S. M. Kupchan, M. A. Eakin, and A. M. Thomas, J. Med. Chem. 14:1147 (1971). N. L. Holy and Y. F. Wang, J. Am. Chem. Soc. 99:499 (1977). J. L. Roberts, P. S. Borromes, and C. D. Poulter, Tetrahedron Lett. 1977:1621. S. Danishefsky, P. F. Schuda, T. Kitahara, and S. J. Etheredge, J. Am. Chem. Soc. 99:6066 (1977). For reviews of methods for the synthesis of a-methylene lactones, see R. B. Gammill, C. A. Wilson, and T. A. Bryson, Synth. Commun. 5:245 (1975); J. C. Sarma and R. P. Sharma, Heterocycles 24:441 (1986); N. Petragnani, H. M. C. Ferraz, and G. V. J. Silva, Synthesis 1986:157. 105. R. Robinson, J. Chem. Soc. 1917:762.

Even more reactive CˆN bonds are present in N-acyliminium ions.106

SECTION 2.2. ADDITION REACTIONS OF IMINES AND IMINIUM IONS

O CR R2C N+ R

These compounds are suf®ciently electrophilic that they are usually prepared in situ in the presence of a potential nucleophile. There are several ways of generating acyliminium ions. Cyclic examples can be generated by partial reduction of imides.107

(CH2)n O

N

(CH2)n OR

NaBH4

O

O

R

N

(CH2)n N+

O

H

R

R

Various oxidations of amines can also generate acyliminium ions. The methods most used in synthetic procedures involve electrochemical oxidation to form a-alkoxy amides and lactams, which then generate acyliminium ions.108 Acyliminium ions are suf®ciently electrophilic to react with enolate equivalents such as silyl enol ethers109 and enol esters.110

O2CCH3 + CH2

N O

OTMS

TMS

C Ph

99

CH2CPh (CH3)3SiO3SCF3

O

89%

N O

H

Acyliminium ions can be used in enantioselective additions with enolates having chiral auxiliaries, such as boron enolates or N-acylthiazolidinethiones.

106. H. Hiemstra and W. N. Speckamp, in Comprehensive Organic Synthesis, Vol. 2, B. Trost and I.Fleming, eds., 1991, pp. 1047±1082. 107. J. C. Hubert, J. B. P. A. Wijnberg, and W. Speckamp, Tetrahedron 31:1437 (1975); H. Hiemstar, W. J. Klaver, and W. N. Speckamp, J. Org. Chem. 49:1149 (1984); R. A. Pilli, L. C. Dias, and A. O. Maldaner, J. Org. Chem. 60:717 (1995). 108. T. Shono, H. Hamaguchi, and Y. Matsumura, J. Am. Chem. Soc. 97:4264 (1975); T. Shono, Y. Matsamura, K. Tsubata, Y. Sugihara, S Yamane, T. Kanazawa, and T. Aoki, J. Am. Chem. Soc. 104:6697 (1982); T. Shono, Tetrahedron 40:811 (1984). 109. R. P. Attrill, A. G. M. Barrett, P. Quayle, J. van der Westhuizen, and M. J. Betts, J. Org. Chem. 49:1679 (1984); K. T. Wanner, A. Kartner, and E. Wadenstorfer, Heterocycles 27:2549 (1988); M. A. Ciufolini, C. W. Hermann, K. H. Whitmire, and N. E. Byrne, J. Am. Chem. Soc. 111:3473 (1989). 110. T. Shono, Y. Matsumura, and K. Tsubata, J. Am. Chem. Soc. 103:1172 (1981).

100 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O O N

O CH3CO2

O2CCH3

O + PhCH2OCH2CH2CH

N

B

C

O N

CH2Ph

Ref. 111

CH3CO2 H N

O

O

OCH2Ph CH2Ph

O CH3

Sn O

O2CCH3 CH3 N O

O

S

S N

N

H O

S

N

Ref. 112 S

TMS

2.2.2. Amine-Catalyzed Condensation Reactions Iminium ions are intermediates in a group of reactions which form a,b-unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations.113 The general mechanism is believed to involve iminium ions as the active electrophiles, rather than the amine simply acting as a base for the aldol condensation. Knoevenagel condensation conditions frequently involve both an amine and a weak acid. The reactive electrophile is probably the protonated form of the imine, because this is a more reactive electrophile than the corresponding carbonyl compound.114 ArCH

O + C4H9NH2

ArCH

H+ ArCH

H+

NC4H9

ArCHNHC4H9

CH2NO2

CH2NO2



NC4H9

ArCH H

NHC4H9

ArCH

CHNO2

CHNO2

The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather acidic compounds containing two electron-attracting substituents. Malonic esters, cyanoacetic esters, and cyanoacetamide are examples of compounds which undergo condensation reactions under Knoevenagel conditions.115 Nitroalkanes are also effective nucleophilic reactants. The single nitro group suf®ciently activates the a hydrogens to permit deprotonation under the weakly basic conditions. Usually, the product that is isolated is 111. R. A. Pilli and D. Russowsky, J. Org. Chem. 61:3187 (1996). 112. Y. Nagao, T. Kumagai, S. Tamai, T. Abe, Y. Kuramoto, T. Taga, S. Aoyagi, Y. Nagase, M. Ochiai, Y. Inoue, and E. Fujita, J. Am. Chem. Soc. 108:4673 (1986). 113. G. Jones, Org. React. 15:204 (1967); R. L. Reeves, in The Chemistry of the Carbonyl Group, S. Patai, ed., Interscience, New York, 1966, pp. 593±599. 114. T. I. Crowell and D. W. Peck, J. Am. Chem. Soc. 75:1075 (1953). 115. A. C. Cope, C. M. Hofmann, C. Wyckoff, and E. Hardenbergh, J. Am. Chem. Soc. 63:3452 (1941).

the ``dehydrated,'' i.e., a,b-unsaturated, derivative of the original adduct.

SECTION 2.3. ACYLATION OF CARBANIONS

B H R2C

CO2R

CO2R

C

R2C

C

CN

X

CN

X = OH or NR2

A relatively acidic proton in the nucleophile is important for two reasons. First, it permits weak bases, such as amines, to provide a suf®cient concentration of the enolate for reaction. A highly acidic proton also facilitates the elimination step which drives the reaction to completion. Malonic acid and cyanoacetic acid can also be used as the potential nucleophiles. The mechanism of the addition step is likely to involve iminium ions when secondary amines are used as catalysts. With malonic acid or cyanoacetic acid as reactant, the products usually undergo decarboxylation. This may occur as a concerted decomposition of the adduct.116 O

X

RCR + CH2(CO2H)2

R2C

CHCO2H C

X = OH or NR2

R2C

CHCO2H

O

–O

Decarboxylative condensations of this type are sometimes carried out in pyridine. Pyridine can not form an imine intermediate, but it has been shown to catalyze the decarboxylation of arylidene malonic acids.117 The decarboxylation occurs by concerted decomposition of the adduct of pyridine to the a,b-unsaturated diacid. H+ N ArCH

C(CO2H)2 +

101

ArCH N

+

CHCO2H C

O

O

H

ArCH

CHCO2H

Scheme 2.12 gives some examples of Knoevenagel condensation reactions.

2.3. Acylation of Carbanions The reactions to be discussed in this section involve carbanion addition to carbonyl centers with a potential leaving group. The tetrahedral intermediate formed in the addition step then reacts by expulsion of the leaving group. The overall transformation results in the 116. E. J. Corey, J. Am. Chem. Soc. 74:5897 (1952). 117. E. J. Corey and G. Fraenkel, J. Am. Chem. Soc. 75:1168 (1953).

Scheme 2.12. Amine-Catalyzed Condensations of the Knoevenagel Type

102 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O O 1a

CCH3

piperidine

CH3CH2CH2CH O + CH3CCH2CO2C2H5

CH3CH2CH2CH C

81%

CO2C2H5 CO2C2H5

RNH3–OAc

2b

O + NCCH2CO2C2H5

C

(R = ion exchange resin)

100%

CN

3c

CN

β-alanine

C2H5COCH3 + N CCH2CO2C2H5

C2H5C

CH3 4d

CH3(CH2)3CHCH O + CH2(CO2C2H5)2

piperidine

81–87%

C CO2C2H5

CH3(CH2)3CHCH C(CO2C2H5)2

RCO2H

CH2CH3 5e

87%

CH2CH3

O + NCCH2CO2H

CN

NH4OAc

65–76%

C CO2H

6f

CO2H

pyridine

PhCH O + CH3CH2CH(CO2H)2

PhCH

C

60%

C2H5 7g CH2

8h

CHCH

O + CH2(CO2H)2

pyridine

CHO + CH2(CO2H)2

CH2

60°C

pyridine

CHCO2H

CH

O2N a. b. c. d. e. f. g. h.

CHCH

42–46%

CHCO2H

75–80%

O2N

A. C. Cope and C. M. Hofmann, J. Am. Chem. Soc. 63:3456 (1941). R. W. Hein, M. J. Astle, and J. R. Shelton, J. Org. Chem. 26:4874 (1961). F. S. Prout, R. J. Hartman, E. P.-Y. Huang, C. J. Korpics, and G. R. Tichelaar, Org. Synth. IV:93 (1963). E. F. Pratt and E. Werbie, J. Am. Chem. Soc. 72:4638 (1950). A. C. Cope, A. A. D'Addieco, D. E. Whyte, and S. A. Glickman, Org. Synth. IV:234 (1963). W. J. Gensler and E. Berman, J. Am. Chem. Soc. 80:4949 (1958). P. J. Jessup, C. B. Petty, J. Roos, and L. E. Overman, Org. Synth. 59:1 (1979). R. H. Wiley and N. R. Smith, Org. Synth. IV:731 (1963).

acylation of the carbon nucleophile. O–

O RC



X + R′2CY

RC X

O CR2′ Y

RCCR2′ Y

An important group of these reactions involves esters, in which case the leaving group is alkoxy or aryloxy. The self-condensation of esters is known as the Claisen condensation.118 Ethyl acetoacetate, for example, is prepared by Claisen condensation of ethyl

118. C. R. Hauser and B. E. Hudson, Jr., Org. React. 1:266 (1942).

103

acetate. All of the steps in the mechanism are reversible. CH3CO2CH2CH3 + CH3CH2O–

–CH

2CO2CH2CH3

SECTION 2.3. ACYLATION OF CARBANIONS

+ CH3CH2OH

O–

O CH3COCH2CH3 + –CH2CO2CH2CH3

CH3COCH2CH3 CH2CO2CH2CH3

O– CH3C

O CH3CCH2CO2CH2CH3 + CH3CH2O–

OCH2CH3

CH2CO2CH2CH3 O

O

CH3CCH2CO2CH2CH3 + CH3CH2O–

CH3CCHCO 2CH2CH3 + CH3CH2OH –

The ®nal step drives the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present, and it is converted to its conjugate base in the ®nal step. A full equivalent of base is needed to bring the reaction to completion. The b-ketoester product is obtained after neutralization and workup. As a practical matter, the alkoxide used as the base must be the same as the alcohol portion of the ester to prevent product mixtures resulting from ester interchange. Because the ®nal proton transfer cannot occur when asubstituted esters are used, such compounds do not condense under the normal reaction conditions. This limitation can be overcome by use of a very strong base that converts the reactant ester completely to its enolate. Entry 2 of Scheme 2.13 illustrates the use of triphenylmethylsodium for this purpose. Sodium hydride with a small amount of alcohol is frequently used as the base for ester condensation. It is likely that the reactive base is the sodium alkoxide formed by reaction of sodium hydride with the alcohol released in the condensation. R′OH + NaH

R′ONa + H2

The sodium alkoxide is also no doubt the active catalyst in procedures in which sodium metal is used, such as in entry 3 of Scheme 2.13. The alkoxide is formed by reaction of the alcohol that is formed as the reaction proceeds with sodium. The intramolecular version of ester condensation is called the Dieckmann condensation.119 It is an important method for the formation of ®ve- and six-membered rings and has occassionally been used for formation of larger rings. Entries 3±6 in Scheme 2.13 are illustrative. Because ester condensation is reversible, product structure is governed by thermodynamic control, and in situations in which more than one enolate may be formed, the product is derived from the most stable enolate. An example of this effect is the cyclization of the diester 4.120 Only 6 is formed, because 5 cannot be converted to a stable enolate. If 5, synthesized by another method, is subjected to the conditions of the cyclization, it is isomerized to 6 by the reversible condensation mechanism: O–

O CO2C2H5 CH3 5

CH3 C2H5O2CCH2(CH2)3CHCO2C2H5

NaOEt xylene

4

CO2C2H5

CH3

6 NaOEt xylene

119. J. P. Schaefer and J. J. Bloom®eld, Org. React. 15:1 (1967). 120. N. S. Vul'fson and V. I. Zaretskii, J. Gen. Chem. USSR 29:2704 (1959).

Scheme 2.13. Acylation of Nucleophilic Carbon by Esters

104 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

A. Intermolecular ester condensations 1a CH3(CH2)3CO2C2H5

NaOEt

CH3(CH2)3COCHCO2C2H5

77%

CH2CH2CH3 O 2b

Ph3C– Na+

CH3CH2CHCO2C2H5

CH2CH3

CH3CH2CHC

CCO2C2H5

CH3

CH3

63%

CH3

B. Cyclization of diesters 3c C2H5O2C(CH2)4CO2C2H5

O

Na, toluene

CO2C2H5

74–81%

CO2C2H5 CH2CH2CO2C2H5 4d

CH3

N

NaOEt

HCl

+

CH3N

benzene

CH2CH2CO2C2H5

O

71%

H CO2C2H5

CO2C2H5

CH3

NaH

5e C2H5O2CCH2CH2CHCHCH3

92%

CO2C2H5 O

C2H5O2C 6f

PhCH2O

O

CH3 CO2CH3

O

CO2CH3

PhCH2O

PhCH2O

O

CH3 CO2CH3

O

[(CH3)3Si]2NNa dilute solution

PhCH2O

O

C. Mixed ester condensations COCO2C2H5 g

7

(CH2CO2C2H5)2 + (CO2C2H5)2

NaOEt

CHCO2C2H5

86–91%

CH2CO2C2H5 8h

CO2C2H5 + CH3(CH2)2CO2C2H5 N

9i

C17H35CO2C2H5 + (CO2C2H5)2

COCHCO2C2H5

NaH

CH2CH3 N

NaOEt

C16H33CHCO2C2H5 COCO2C2H5

68–71%

68%

77%

Scheme 2.13. (continued )

10j

CO2C2H5 + CH3CH2CO2C2H5

(i-Pr)2NMgBr

105 COCHCO2C2H5

SECTION 2.3. ACYLATION OF CARBANIONS

51%

CH3 a. b. c. d. e. f. g. h. i. j.

R. R. Briese and S. M. McElvain, J. Am. Chem. Soc. 55:1697 (1933). B. E. Hudson, Jr., and C. R. Hauser, J. Am. Chem. Soc. 63:3156 (1941). P. S. Pinkney, Org. Synth. II:116 (1943). E. A. Prill and S. M. McElvain, J. Am. Chem. Soc. 55:1233 (1933). M. S. Newman and J. L. McPherson, J. Org. Chem. 19:1717 (1954). R. N. Hurd and D. H. Shah, J. Org. Chem. 38:390 (1973). E. M. Bottorff and L. L. Moore, Org. Synth. 44:67 (1964). F. W. Swamer and C. R. Hauser, J. Am. Chem. Soc. 72:1352 (1950). D. E. Floyd and S. E. Miller, Org. Synth. IV:141 (1963). E. E. Royals and D. G. Turpin, J. Am. Chem. Soc. 76:5452 (1954).

Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol condensations (Section 2.1.2) One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combinations which work most effectively involve one ester that cannot form an enolate but that is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples are shown in Section C of Scheme 2.13. Acylation of ester enolates can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must be done in inert solvents to avoid solvolysis of the acylating agent. The preparation of diethyl benzoylmalonate (entry 1 in Scheme 2.14) is an example employing an acid anhydride. Entries 2±5 illustrate the use of acyl chlorides. Acylations with these more reactive compounds can be complicated by competing O-acylation. N-Methoxy-N-methylamides are also useful for acylation of ester enolates.

O

O– Li+

OCH3

CH3(CH2)4CN

+ CH2 CH3

C OC2H5

O

1) –78°C 2) 25°C

CH3(CH2)4CCH2CO2C2H5

3) HCl

Ref. 121

82%

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion.

–O

R′O2CCH2CO2H + 2 RMgX R′O 121. J. A. Turner and W. S. Jacks, J. Org. Chem. 54:4229 (1989).

Mg2+ O– O

106 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

Scheme 2.14. Acylation of Ester Enolates with Acyl Halides, Anhydrides, and Imidazolides A. Acylation with acyl halides and mixed anhydrides O O 1a PhCOCOC2H5 + C2H5OMgCH(CO2C2H5)2

PhCOCH(CO2C2H5)2

68–75%

O O– 2b CH3C

3c

O CHCO2C2H5 + PhCOCl

CCH3

PhC

O

CCO 2C2H5 –

PhCCH2CO2C2H5

COCl + C2H5OMgCH(CO2C2H5)2

COCH(CO2C2H5)2

NO2

68–71%

82–88%

NO2 O

O– 4d CH3C

O

O

CHCO2C2H5 + ClC(CH2)3CO2C2H5

C2H5O2C(CH2)3C

O

5e

CH3CO2C2H5

R2NLi

LiCH2CO2C2H5

(CH3)3CCCl –78°C

CCH3 CHCO2C2H5

61–66%

O (CH3)3CCCH2CO2C2H5

70%

O 6f CH3CO2CH3

1) LDA 2) ClCO(CH2)12CH3 3) H+

CH3O2CCH2C(CH2)12CH3

83%

B. Acylation with imidazolides 7g O

CH2CN

N + Mg(O2CCH2CO2C2H5)2

1) 25°C 2) H+

O

O CH2CCH2CO2C2H5

O

66%

CH3 8h + LiCH2CO2C(CH3)3

O O

C

–78°C

H+

1h

N N

CH3 83%

O O

CCH2CO2C(CH3)3

Scheme 2.14. (continued )

107 SECTION 2.3. ACYLATION OF CARBANIONS

O –

9i

O2NCH2 + CH3CN

H+

65°C

N

16 h

CH3CCH2NO2

80%

O 1) N

H 10j

NCN

N

H

O

t-BuO2CNCHCO2H

t-BuO2CNCHCCH2CO2C2H5

O

CH(CH3)2

O 83%

CH(CH3)2

O 2) Mg O OEt

a. b. c. d. e. f. g. h. i. j.

J. A. Price and D. S. Tarbell, Org. Synth.IV:285 (1963). J. M. Straley and A. C. Adams, Org. Synth. IV:415 (1963). G. A. Reynolds and C. R. Hauser, Org. Synth. IV:708 (1963). M. Guha and D. Nasipuri, Org. Synth. V:384 (1973). M. W. Rathke and J. Deitch, Tetrahedron Lett. 1971:2953. D. F. Taber, P. B. Deker, H. M. Fales, T. H. Jones, and H. A. Lloyd, J. Org. Chem. 53:2968 (1988). A. Barco, S. Bennetti, G. P. Pollini, P. G. Baraldi, and C. Gandol®, J. Org. Chem. 45:4776 (1980). E. J. Corey, G. Wess, Y. B. Xiang, and A. K. Singh, J. Am. Chem. Soc. 109:4717 (1987). M. E. Jung, D. D. Grove, and S. I. Khan, J. Org. Chem. 52:4570 (1987). J. Maibaum and D. H. Rich, J. Org. Chem. 53:869 (1988).

These carbon nucleophiles react with acyl chlorides122 or acyl imidazolides.123 The initial products decarboxylate readily so the isolated products are b-ketoesters.

–O

Mg2+ O– +

R′O

O

RCOCl or RCOIm

O R′O2CCHCR CH3

CH3

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. b-Keto esters are formed by reaction of magnesium salts of monoalkyl esters of malonic acid with imidazolides.

O

O RC

N

N + Mg(O2CCH2CO2R′)2

H+ –CO2

RCCH2CO2R′

Acyl imidazolides have also been used for acylation of ester enolates and nitromethane anion, as illustrated by entries 9 and 10 in Scheme 2.14. 122. R. E. Ireland and J. A. Marshall, J. Am. Chem. Soc. 81:2907 (1959). 123. J. Maibaum and D. H. Rich, J. Org. Chem. 53:869 (1988); W. H. Moos, R. D. Gless, and H. Rapoport, J. Org. Chem. 46:5064 (1981); D. W. Brooks, L. D.-L. Lu, and S. Masamune, Angew. Chem. Int. Ed. Engl. 18:72 (1979).

108 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

Both diethyl malonate and ethyl acetoacetate can be acylated by acyl chlorides using magnesium chloride and triethylamine or pyridine.124 O

O

(C2H5O2C)2CH2

MgCl2

RCCl

(C2H5O2C)2CHCR

Et3N

O

O

O

C2H5O2CH2CCH3

MgCl2

RCCl

CR

C2H5O2CCHCCH3

pyridine

O

Rather similar conditions can be used to convert ketones to b-ketoacids by carboxylation.125 O

O

CH3CH2CCH2CH3

H+

MgCl2, NaI CH3CN, CO2 Et3N

CH3CH2CCHCH3 CO2H

Such reactions presumably involve formation of a magnesium chelate of the ketoacid. The b-keto acid is liberated when the reaction mixture is acidi®ed during workup.

–O

Mg2+ O–

R

O R

Carboxylation of ketones and esters can be achieved by using the magnesium salt of monomethyl carbonate: O

O

CCH3 + Mg(O2COCH3)2

DMF 110°C

H+

O

CCH2CO2H

O HO2C

O

O

1) Mg(O2COMe)2

75%

2) H+

C8H17

O

Ref. 126

O

C8H17

O

Ref. 127

O

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are all b-dicarbonyl compounds. They are all rather acidic and can be alkylated by the procedures described in Section 1.4. Reaction of ketone enolates 124. 125. 126. 127.

M. W. Rathke and P. J. Cowan, J. Org. Chem. 50:2622 (1985). R. E. Tirpak, R. S. Olsen, and M. W. Rathke, J. Org. Chem. 50:4877 (1985). M. Stiles, J. Am. Chem. Soc. 81:2598 (1959). W. L. Parker and F. Johnson, J. Org. Chem. 38:2489 (1973).

with formate esters gives a b-keto aldehydes. Because these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. O

O NaOEt

RCH2CR′ + HCO2C2H5

H+

RCCR′ H

C

ONa

RC H

CR′

C

O OH

Ketones are converted to b-ketoesters by acylation with diethyl carbonate or diethyl oxalate, as illustrated by entries 5 and 6 in Scheme 2.15. Alkyl cyanoformate can be used as the acylating reagent under conditions where a ketone enolate has been formed under kinetic control.128 O

O

CH3

CO2C2H5

CH3 LDA

EtO2CCN

86%

H2O

TMF HMPA

When this type of reaction is quenched with trimethylsilyl chloride, rather than by neutralization, a trimethylsilyl ether of the adduct is isolated. This result shows that the tetrahedral adduct is stable until the reaction mixture is hydrolyzed. O

OSi(CH3)3

O

COC2H5 1) LDA

(Me)3SiCl

Ref. 129

CN

2) EtO2CCN

b-Keto sulfoxides can be prepared by acylation of dimethyl sulfoxide ion with esters.130 O

O

RCOR′ +

O

–CH SCH 2 3

O –

RCCHSCH3 + R′OH

Mechanistically, this reaction is similar to ketone acylation. The b-keto sulfoxides have several synthetic applications. The sulfoxide substituent can be removed reductively, leading to methyl ketones: O CH3O

CCH2SOCH3

O Zn Hg

CH3O

CCH3

Ref. 131

128. L. N. Mander and S. P. Sethi, Tetrahedron Lett. 24:5425 (1983). 129. F. E. Ziegler and T.-F. Wang, Tetrahedron Lett. 26:2291 (1985). 130. E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 87:1345 (1965); H. D. Becker, G. J. Mikol, and G. A. Russell, J. Am. Chem. Soc. 85:3410 (1963). 131. G. A. Russell and G. J. Mikol, J. Am. Chem. Soc. 88:5498 (1966).

109 SECTION 2.3. ACYLATION OF CARBANIONS

Scheme 2.15. Acylation of Ketones with Esters

110 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

1a

O

O CHOH + HCO2C2H5

2b

H

70–74%

NaH

O

H + HCO2C2H5

O CHOH

NaH ether

H

H 69%, mixture of cis and trans at ring junction

O 3

c

O

CH3CCH3 + CH3(CH2)4CO2C2H5

NaH

CH3CCH2C(CH2)4CH3

O

O

4d CH3CCH3 + 2 (CO2C2H5)2 5e

NaOEt

H+

CH3

O

54–65%

O

H5C2O2CCCH2CCH2CCO2C2H5

O C(OC2H5)2

NaH

CO2C2H5

CH2OSiR3

CH3

CH2OSiR3

91–94%

CH3

CH2OSiR3

1) LDA

CO2Me

+

2) MeO2CCN

H

85%

O + O

6f

O

O

H major

O CO2Me

H

O

minor

a. C. Ainsworth, Org. Synth. IV:536 (1963). b. P. H. Lewis, S. Middleton, M. J. Rosser, and L. E. Stock, Aust. J. Chem. 32:1123 (1979). c. N. Green and F. B. La Forge, J. Am. Chem. Soc. 70:2287 (1948); F. W. Swamer and C. R. Hauser, J. Am. Chem. Soc. 72:1352 (1950). d. E. R. Riegel and F. Zwilgmeyer, Org. Synth. II:126 (1943). e. A. P. Krapcho, J. Diamanti, C. Cayen, and R. Bingham, Org. Synth. 47:20 (1967). f. F. E. Ziegler, S. I. Klein, U. K. Pati, and T.-F. Wang, J. Am. Chem. Soc.107:2730 (1985).

The b-keto sulfoxides can be alkylated via their anions. Inclusion of an alkylation step prior to the reduction provides a route to ketones with longer chains. PhCOCH2SOCH3

1) NaH 2) CH3I

PhCOCHSOCH3

Zn Hg

PhCOCH2CH3

CH3

Dimethyl sulfone can be subjected to similar reaction sequences.133 132. P. G. Gassman and G. D. Richmond, J. Org. Chem. 31:2355 (1966). 133. H. O. House and J. K. Larson, J. Org. Chem. 33:61 (1968).

Ref. 132

2.4. The Wittig and Related Reactions of Phosphorus-Stabilized Carbon Nucleophiles The Wittig reaction involves phosphorus ylides as the nucleophilic carbon species.134 An ylide is a molecule that has a contributing Lewis structure with opposite charges on adjacent atoms, each of which has an octet of electrons. Although this de®nition includes other classes of compounds, the discussion here will be limited to ylides with the negative charge on carbon. Phosphorus ylides are stable, but usually quite reactive, compounds. They can be represented by two limiting resonance structures, which are sometimes referred to as the ylide and ylene forms. The ylene form is pentavalent at phosphorus and implies involvement of phosphorus 3d orbitals. Using (CH3)3PCH2 (trimethylphosphonium methylide) as an example, the two forms are +

(CH3)3P

CH2–

(CH3)3P

ylide

CH2

ylene

Nuclear magnetic resonance (NMR) spectroscopic studies (1H, 13C, and 31P), are consistent with the dipolar ylide structure and suggest only a minor contribution from the ylene structure.135 Theoretical calculations support this view, also.136 The synthetic potential of phosphorus ylides was initially developed by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphorus ylide with an aldehyde or ketone introduces a carbon±carbon double bond in place of the carbonyl bond: +

R3P



CR2′ + R2′′C

O

R2′′C

CR2′ + R3P

O

The mechanism proposed is an addition of the nucleophilic ylide carbon to the carbonyl group to yield a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism might involve direct formation of the oxaphosphetane.137 There have been several theoretical studies of these intermediates.138 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.139 Betaine intermediates have been observed only under special conditions that retard the 134. For general reviews of the Wittig reaction, see A. Maercker, Org. React. 14:270 (1965); I. Gosney and A. G. Rowley, in Organophosphorus Reagents in Organic Synthesis, J. I. G. Cadogan, ed., Academic Press, London, 1979, pp. 17±153; B. A. Maryanoff and A. B. Reitz, Chem. Rev. 89:863 (1989); A. W. Johnson, Ylides and Imines of Phosphorus, John Wiley & Sons, New York, 1993; K. C. Nicolaou, M. W. Harter, J. L. Gunzer, and A. Nadin, Liebigs Ann. Chem. 1997:1283. 135. H. Schmidbaur, W. Bucher, and D. Schentzow, Chem. Ber. 106:1251 (1973). 136. A. Streitwieser, Jr., A. Rajca, R. S. McDowell, and R. Glaser, J. Am. Chem. Soc. 109:4184 (1987); S. M. Bachrach, J. Org. Chem. 57:4367 (1992). 137. E. Vedejs and K. A. J. Snoble, J. Am. Chem. Soc. 95:5778 (1973); E. Vedejs and C. F. Marth, J. Am. Chem. Soc. 112:3905 (1990). 138. R. Holler and H. Lischka, J. Am. Chem. Soc. 102:4632 (1980); F. Volatron and O. Eisenstein, J. Am. Chem. Soc. 106:6117 (1984); F. Mari, P. M. Lahti, and W. E. McEwen, J. Am. Chem. Soc. 114:813 (1992); A. A. Restrepocossio, C. A. Gonzalez, and F. Mari, J. Phys. Chem. 102:6993 (1998); H. Yamataka and S. Nagase, J. Am. Chem. Soc. 120:7530 (1998). 139. E. Vedejs, G. P. Meier, and K. A. J. Snoble, J. Am. Chem. Soc. 103:2823 (1981); B. E. Maryanoff, A. B. Reitz, M. S. Mutter, R. R. Inners, H. R. Almond, Jr., R. R. Whittle, and R. A. Olofson, J. Am. Chem. Soc. 108:7684 (1986).

111 SECTION 2.4. THE WITTIG AND RELATED REACTIONS OF PHOSPHORUSSTABILIZED CARBON NUCLEOPHILES

112 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

cyclization and elimination steps.140 +

R3P

CR2′



+

R3P



CR2′ + R2′′C

O CR′′2 (betaine intermediate)

O

R3P

CR2′

O

CR′′2

R3P

O + R′′2C

CR2′

(oxaphosphetane intermediate)

Phosphorus ylides are usually prepared by deprotonation of phosphonium salts. The phosphonium salts most often used are alkyltriphenylphosphonium halides, which can be prepared by the reaction of triphenylphosphine and an alkyl halide: Ph3P + RCH2X

+

Ph3P

CH2RX–

X = I, Br, or Cl + –

Ph3PCH2R

base

Ph3P

CHR

The alkyl halide must be one that is reactive toward SN2 displacement. Alkyltriphenylphosphonium halides are only weakly acidic, and strong bases must be used for deprotonation. These include organolithium reagents, the sodium salt of dimethyl sulfoxide, amide ion, or substituted amide anions such as hexamethyldisilylamide (HMDS). The ylides are not normally isolated so the reaction is carried out either with the carbonyl compound present or it may be added immediately after ylide formation. Ylides with nonpolar substituents, for example, H, alkyl, or aryl, are quite reactive toward both ketones and aldehydes. Scheme 2.16 gives some examples of Wittig reactions. When a hindered ketone is to be converted to a methylene derivative, the best results have been obtained when a potassium t-alkoxide is used as a base in a hydrocarbon solvent. Under these conditions, the reaction can be carried out at elevated temperature.141 Entries 10 and 11 in Scheme 2.16 illustrate this procedure. b-Ketophosphonium salts are condsiderably more acidic than alkylphosphonium salts and can be converted to ylides by relatively weak bases. The resulting ylides, which are stabilized by the carbonyl group, are substantially less reactive than unfunctionalized ylides. More vigorous conditions may be required to bring about reactions with ketones. Entries 6 and 7 in Scheme 2.16 involve stabilized ylides. The stereoselectivity of the Wittig reaction depends strongly on both the structure of the ylide and the reaction conditions. The broadest generalization is that unstabilized ylides give predominantly the Z-alkene whereas stabilized ylides give mainly the Ealkene.142 Use of sodium amide or sodium hexamethyldisilylamide as bases gives higher selectivity for Z-alkenes than is obtained when ylides are prepared with alkyllithium reagents as base (see entries 3 and 5 of Scheme 2.16). The dependence of the stereoselectivity on the nature of the base is attributed to complexes involving the lithium halide salt which is present when alkyllithium reagents are used as bases. Stabilized ylides 140. R. A. Neumann and S. Berger, Eur. J. Org. Chem. 1998:1085. 141. J. M. Conia and J. C. Limasset, Bull. Soc. Chim. Fr. 1967:1936; J. Provin, F. Leyendecker, and J. M. Conia, Tetrahedron Lett. 1975:4053; S. R. Schow and T. C. Morris, J. Org. Chem. 44:3760 (1979). 142. M. Schlosser, Top. Stereochem. 5:1 (1970).

such as (carboethoxymethylidene)triphenylphosphorane (entries 6 and 7) react with aldehydes to give exclusively trans double bonds. Benzylidenetriphenylphosphorane (entry 8) gives a mixture of both cis- and trans-stilbene on reaction with benzaldehyde. The stereoselectivity of the Wittig reaction is believed to be the result of steric effects which develop as the ylide and carbonyl compound approach one another. The three phenyl substituents on phosphorus impose large steric demands which govern the formation of the diastereomeric adducts.143 Reactions of unstabilized phosphoranes are believed to proceed through an early transition state, and steric factors usually make such transition states selective for the Z-alkene.144 The empirical generalization concerning the preference for Z-alkenes from unstabilized ylides under salt-free conditions and E-alkenes from stabilized ylides serves as a guide to predicting stereoselectivity. The reaction of unstabilized ylides with aldehydes can be induced to yield E-alkenes with high stereoselectivity by a procedure known as the Schlosser modi®cation of the Wittig reaction.145 In this procedure, the ylide is generated as a lithium halide complex and allowed to react with an aldehyde at low temperature, presumably forming a mixture of diastereomeric betaine±lithium halide complexes. At the temperature at which the addition is carried out, fragmentation to an alkene and triphenylphosphine oxide does not occur. This complex is then treated with an equivalent of strong base such as phenyllithium to form a b-oxido ylide. Addition of t-butyl alcohol protonates the b-oxido ylide stereoselectively to give the more stable syn-betaine as a lithium halide complex. Warming the solution causes the syn-betaine±lithium halide complex to give the E-alkene by a syn elimination. Li RCH Li+O–

CHR′

PhLi

P+Ph3

RCH Li+O–

O– Li+

H

CR′

t-BuOH

R

P+Ph3

R′ H

P+Ph3

H

R′

R

H

A useful extension of this method is one in which the b-oxido ylide intermediate, instead of being protonated, is allowed to react with formaldehyde. The b-oxido ylide and formaldehyde react to give, on warming, an allylic alcohol. Entry 12 in Scheme 2.16, is an example of this reaction. The reaction is valuable for the stereoselective synthesis of Z-allylic alcohols from aldehydes.146 O–

O– RCHCH R′ betaine

+

PPh3

RLi –25°C

RCHC

PPh3

R′

1) CH2

O

R

CH2OH

H

R′

2) 25°C

β-oxido ylide

143. M. Schlosser and B. Schaub, J. Am. Chem. Soc. 104:5821 (1982); H. J. Bestmann and O. Vostrowsky, Top. Curr. Chem. 109:85 (1983); E. Vedejs, T. Fleck, and S. Hara, J. Org. Chem. 52:4637 (1987). 144. E. Vedejs and C. F. Marth, J. Am. Chem. Soc. 110:3948 (1988). 145. M. Schlosser and K.-F. Christmann, Justus Liebigs Ann. Chem. 708:1 (1967); M. Schlosser, K.-F. Christmann, and A. Piskala, Chem. Ber. 103:2814 (1970). 146. E. J. Corey and H. Yamamoto, J. Am. Chem. Soc. 92:226 (1970); E. J. Corey, H. Yamamoto, D. K. Herron, and K. Achiwa, J. Am. Chem. Soc. 92:6635 (1970); E. J. Corey and H. Yamamoto, J. Am. Chem. Soc. 92:6636 (1970); E. J. Corey and H. Yamamoto, J. Am. Chem. Soc. 92:6637 (1970); E. J. Corey, J. I. Shulman, and H. Yamamoto, Tetrahedron Lett. 1970:447.

113 SECTION 2.4. THE WITTIG AND RELATED REACTIONS OF PHOSPHORUSSTABILIZED CARBON NUCLEOPHILES

Scheme 2.16. The Wittig Reaction

114 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

1a

NaCH2S(O)CH3

+

Ph3PCH3 I–

Ph3P

DMSO

O + Ph3P

CH2

DMSO

CH2

+

CH2

n-BuLi

2b Ph3PCH2CH2CH2CH2CH3 Br–

Ph3P

DMSO

86%

CHCH2CH2CH2CH3

O CH3CCH3 + Ph3P 3c

+

NaNH2

CH3CH2PPh3 Br–

DMSO

CHCH2CH2CH2CH3 CH3CH

NH3

C6H5CHO + CH3CH

PPh3

(CH3)2C

CHCH2CH2CH2CH3

56%

PPh3 C6H5CH

benzene

CHCH3

98% yield, 87% Z

4c

+

n-BuLi

CH3CH2PPh3 I–

CH3CH

C6H5CHO + CH3CH

PPh3

PPh3

LiI benzene

C6H5CH

CHCH3

76% yield, 58% Z +

5d CH3CH2CH2CH2CH2PPh3 Br–

Na+ –N(SiMe3)2

CH3CH2CH2CH2CH

THF

PPh3

O HC(CH2)7CH2OAc + CH3CH2CH2CH2CH

PPh3

CH3(CH2)3CH

CH(CH2)7CH2OAc

79% yield, 98% Z

6e

+

Ph3PCH2CO2CH2CH3 Br–

NaOH

Ph3P CHCO2CH2CH3 stable, isolable ylide

H2O

H CO2CH2CH3

CHO + Ph3P O

+

8g C6H5CH2PPh3 Cl–

benzene

(2 equiv.)

OH

7f C6H5CHO + Ph3P

CHCO2CH2CH3

EtOH

CHCO2CH2CH3 PhLi ether

C6H5CHO + C6H5CH

C6H5CH

PPh3

reflux 2h

O

C6H5CH

CHCO2CH2CH3 77%, yield, only Z-isomer

PPh3

C6H5CH

CHC6H5

82% yield, 70% Z

9f O + C6H5CH

10h

CH3

CH3

PPh3

+

Ph3PCH3 Br–, KOCR3, toluene

CHC6H5

CH3

CH3 56%

90°C, 30 min

O

CH3

60%

CH2

CH3

OH

H

86%

115

Scheme 2.16. (continued ) 11i

CH3

CH3

CH3

SECTION 2.4. THE WITTIG AND RELATED REACTIONS OF PHOSPHORUSSTABILIZED CARBON NUCLEOPHILES

CH3

+

Ph3PCH3 Br– KOCR3

91%

100°C, 2 h

CH3

12b

CH3

O

CH3CH2CH2CH2CHO + CH3CH PPh3

CH2 1) LiBr, THF, –78°C

CH3CH2CH2CH2

CH2OH C

2) BuLi 3) CH2O, 25°C

C

H

CH3

Boc 13j

CH3

P+Ph3 I– +

CH3

OCH3

N

CH

O LiHMDS THF/HMPA

O H

OCH3

O

N Boc H3C

O 14k

CHO + Ph3P+CH2

NC

O

satd. K2CO3, CH2Cl2 phase transfer

CH3 O

NC

CH

CH O

100% yield, 72:28 Z:E

15l ArO

ArO + Ph3P+(CH2)4CO2H O

OH

NaHMDS toluene –78°C

HO

Ar = 4-methoxybenzyl

a. b. c. d. e. f. g. h. i. j. k. l.

69%

R. Greenwald, M. Chaykovsky, and E. J. Corey, J. Org. Chem. 28:1128 (1963). U. T. Bhalerao and H. Rapoport, J. Am. Chem. Soc. 93:4835 (1971). M. Schlosser and K. F. Christmann, Justus Liebigs Ann. Chem. 708:1 (1967). H. J. Bestmann, K. H. Koschatzky, and O. Vostrowsky, Chem. Ber. 112:1923 (1979). Y. Y. Liu, E. Thom, and A. A. Liebman, J. Heterocycl. Chem. 16:799 (1979). G. Wittig and W. Haag, Chem. Ber. 88:1654 (1955). G. Wittig and U. SchoÈllkopf, Chem. Ber. 87:1318 (1954). A. B. Smith III and P. J. Jerris, J. Org. Chem. 47:1845 (1982). L. Fitjer and U. Quabeck, Synth. Commun. 15:855 (1985). J. D. White, T. S. Kim, and M. Nambu, J. Am. Chem. Soc. 119:103 (1997). N. Daubresse, C. Francesch, and G. Rolando, Tetrahedron 54:10761 (1998). D. J. Critcher, S. Connoll, and M. Wills, J. Org. Chem. 62:6638 (1997).

CO2H

60%

116 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

The Wittig reaction can be extended to functionalized ylides.147 Methoxymethylene and phenoxymethylene ylides lead to vinyl ethers, which can be hydrolyzed to aldehydes.148

Ph3P

O

CHOMe

OCH2OCH2CH2OCH3

CHOCH3

Ref. 149

OCH2OCH2CH2OCH3

2-(1,3-Dioxolanyl)methyl ylides can be used for the introduction of a,b-unsaturated aldehydes (see entry 14 in Scheme 2.16). Methyl ketones have been prepared by an analogous reaction. O CH3(CH2)5CHO + CH3OC

PPh3

DME –40°C

CH3(CH2)5CH

COCH3

CH3

H2O, HCl CH3OH, ∆

CH3(CH2)5CH2CCH3

CH3

57%

Ref. 150

An important complement to the Wittig reaction is the reaction of phosphonate carbanions with carbonyl compounds.151 The alkylphosphonate esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are more nucleophilic than an analogous ylide, and even when R is a carbanion-stabilizing substituent, they react readily with aldehydes and ketones to give alkenes. Phosphonate carbanions are generated by treating alkylphosphonate esters with bases such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.152 Reactions with phosphonoacetate esters are used frequently to prepare a,b-unsaturated esters. This is known as the Wadsworth±Emmons reaction. These reactions usually lead to the E-isomer. Scheme 2.17 gives a number of examples. O RCH2X + P(OC2H5)3

RCH2P(OC2H5)2 + C2H5X

O

O

RCH2P(OC2H5)2 O –

RCHP(OC2H5)2 + R2′ C

base



RCHP(OC2H5)2 O

O O

–O

R2′ C

P(OC2H5)2

R2′ C

CHR + (C2H5O)2P

O–

CHR

147. S. Warren, Chem. Ind. (London) 1980:824. 148. S. G. Levine, J. Am. Chem. Soc. 80:6150 (1958); G. Wittig, W. Boll, and K. H. Kruck, Chem. Ber. 95:2514 (1962). 149. M. Yamazaki, M. Shibasaki, and S. Ikegami, J. Org. Chem. 48:4402 (1983). 150. D. R. Coulsen, Tetrahedron Lett. 1964:3323. 151. For reviews of reactions of phosphonate carbanions with carbonyl compounds, see: J. Boutagy and R. Thomas, Chem. Rev. 74:87 (1974); W. S. Wadsworth, Jr., Org. React. 25:73 (1977); H. Gross and I. Keitels, Z. Chem. 22:117 (1982). 152. F. Texier-Boullet, D. Villemin, M. Ricard, H. Moison, and A. Foucaud, Tetrahedron 41:1259 (1985); M. Mikolajczyk and R. Zurawinski, J. Org. Chem. 63:8894 (1998).

Three modi®ed phosphonoacetate esters have been found to show selectivity for the Z-enoate product. Tri¯uoroethyl,153 phenyl,154 and 2,6-di¯uorophenyl155 esters give good Z-stereoselectivity. O RCH

H

H

R

CO2CH3

O + CH3O2CCH2P(OR′)2 R′ = CH2CF3, phenyl, 2,6-difluorophenyl

An alternative procedure for effecting the condensation of phophonates is to carry out the reaction in the presence of lithium chloride and an amine such as N,N-diisopropyl-Nethylamine or diazabicycloundecene (DBU). The lithium chelate of the substituted phosphonate is suf®ciently acidic to be deprotonated by the amine.156 Li+

Li+

O

O

(R′O)2P

C

CH2

O

R3N

(R′O)2P

OR

O–

R′′CH

O

C C H

R′′CH

CHCO2R

OR

Entries 10 and 11 of Scheme 2.17 also illustrate this procedure. Intramolecular reactions have been used to prepare cycloalkenes.157 CH3 NaH

CH3C(CH2)3CCH2P(OC2H5)2 O

O

Ref. 158

O O

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution has been utilized in macrocycle synthesis (entries 8 and 9 in Scheme 2.17) Carbanions derived from phosphine oxides also add to carbonyl compounds. The adducts are stable but undergo elimination to form alkenes on heating with a base such as sodium hydride. This reaction is known as the Horner±Wittig reaction.159 O Ph2PCH2R

O RLi

Ph2PCHR Li

O R′CH

O

O–

Ph2PCHCR′

RCH

CHR′

R H

The unique feature of the Horner±Wittig reaction is that the addition intermediate can be isolated and puri®ed. This provides a means for control of the stereochemistry of the reaction. It is possible to separate the two diastereomeric adducts in order to prepare the pure alkenes. The elimination process is syn so that the stereochemistry of the alkene depends on the stereochemistry of the adduct. Usually, the anti adduct is the major product, so it is the Z-alkene which is favored. The syn adduct is most easily obtained by reduction of b-keto phosphine oxides.160 153. 154. 155. 156. 157. 158. 159. 160.

W. C. Still and C. Gennari, Tetrahedron Lett. 24:4405 (1983). K. Ando, Tetrahedron Lett. 36:4105 (1995); K. Ando, J. Org. Chem. 63:8411 (1998). K. Kokin, J. Motoyoshiya, S. Hayashi, and H. Aoyama, Synth. Commun. 27:2387 (1997). M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune, W. R. Roush, and T. Sakai, Tetrahedron Lett. 25:2183 (1984). K. B. Becker, Tetrahedron 36:1717 (1980). P. A. Grieco and C. S. Pogonowski, Synthesis 1973:425. For a review, see J. Clayden and S. Warren, Angew. Chem. Int. Ed. Engl. 35:241 (1996). A. D. Buss and S. Warren, J. Chem. Soc., Perkin Trans. 1 1985:2307.

117 SECTION 2.4. THE WITTIG AND RELATED REACTIONS OF PHOSPHORUSSTABILIZED CARBON NUCLEOPHILES

Scheme 2.17. Carbonyl Ole®nation Using Phosphonate Carbanions

118 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O

1a

O + (C2H5O)2PCH2CO2C2H5

CHCO2C2H5

O

C2H5 2b CH2

NaH benzene

C2H5

NaOEt

+ (C2H5O)2PCH2CO2C2H5

C

67–77%

CH2

EtOH

H

C

CHO

C

66%

C CO2C2H5

H O NaH DME

3c C6H5CHO + (C2H5O)2PCH2C6H5

trans-C6H5CH CHC6H5

63%

O 4d (CH3CH2CH2)2C

5e

O + (C2H5O)2PCH2CN O

OCH3

NaH DME

(CH3CH2CH2)2C

O

74%

OCH3

NaH DMSO

+ (C2H5O)2PCH2C(CH2)4CH3

CHCN

(CH2)4CH3

55%

CHO O 6f

CHO

+ Ph3P

CO2CH3

CCO2C2H5 CH3

CH3

CH3

CH3 85% yield, 1.3:1 E:Z

O

O O

7g

P(OCH3)2 + O

Al2O3, KOH

CH(CH2)5CO2CH3

CH(CH2)5CO2CH3

(CH2)5CH3

(CH2)5CH3 76% yield, 1.3:1 E:Z

8h LiOCH(CH3)2

CHO O

CH2P(OC2H5)2

O

O

O

O O

9i

66%

benzene-THF-HMPA

O

O

(CH3O)2P CHO

NaH 70%

DME

O CH3

O

O CH3

O

Scheme 2.17. (continued ) 10j

119 SECTION 2.4. THE WITTIG AND RELATED REACTIONS OF PHOSPHORUSSTABILIZED CARBON NUCLEOPHILES

PhCH2O R3SiO

+O

CH

P(OCH3)2 O

CO2CH3

LiCl, DBU 25ºC, 2h CH3CN

O

PhCH2O R3SiO CO2CH3 70%

O O

11k

O

CSC2H5

CSC2H5 OH

OH CH3CHCH2CH

O

O

LiCl, (IPr)2) NEt

P(OC2H5)2 TBSO

TBSO O

H3C

O

O

O

H3C

72%

a. b. c. d. e. f. g. h. i. j.

W. S. Wadsworth, Jr. and W. D. Emmons, Org. Synth. 45:44 (1965). R. J. Sundberg, P. A. Buckowick, and F. O. Holcombe, J. Org. Chem. 32:2938 (1967). W. S. Wadsworth, Jr. and W. D. Emmons, J. Am. Chem. Soc. 83:1733 (1961). J. A. Marshall, C. P. Hagan, and G. A. Flynn, J. Org. Chem. 40:1162 (1975). N. Finch, J. J. Fitt, and I. H. S. Hsu, J. Org. Chem. 40:206 (1975). A. G. M. Barrett, M. Pena, and J. A. Willardsen, J. Org. Chem. 61:1082 (1996). M. Mikolajczyk and R. Zurawinski, J. Org. Chem. 63:8894 (1998). G. Stork and E. Nakamura, J. Org. Chem. 44:4010 (1979). K. C. Nicolaou, S. P. Seitz, M. R. Pavia, and N. A. Petasis, J. Org. Chem. 44:4010 (1979). M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune, W. R. Roush, and T. Sakai, Tetrahedron Lett. 25:2183 (1984). k. G. E. Keck and J. A. Murry, J. Org. Chem. 56:6606 (1991).

O

O

Ph2PCHCH2CH2Ph

PhCH2CH2

CH3

NaBH4 1) BuLi

2) CH3CH O

H

OH

PhCH2CH2

HO

CH3 +

PhCH2CH2

CH3

Ph2P O

Ph2P O

CH3 CH3

Ph2P O

separate

NaH

CH3

H

CH3 CH3

NaH

CH2CH2Ph

CH3

CH2CH2Ph

CH3

CH3

H

Ref. 161 H

161. A. D. Buss and S. Warren, Tetrahedron Lett. 24:111, 3931 (1983); A. D. Buss and S. Warren, J. Chem. Soc., Perkin Trans. 1 1985:2307.

120 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

2.5. Reactions of Carbonyl Compounds with a-Trimethylsilylcarbanions b-Hydroxyalkyltrimethylsilanes are converted to alkenes in either acidic or basic solution.162 These eliminations provide a synthesis of alkenes that begins with the nucleophilic addition of an a-trimethylsilyl-substituted carbanion to an aldehyde or ketone. The reaction is sometimes called the Peterson reaction.163 For example, the organometallic reagents derived from chloromethyltrimethylsilane adds to an aldehyde or ketone, and the intermediate can be converted to a teminal alkene by base.164

(CH3)3SiCH2X

n-BuLi

(CH3)3SiCHX

R2C

O

R2C

CHX

Li

Similarly, organolithium reagents of the type (CH3)3SiCH(Li)X, where X is a carbanionstabilizing substituent, can be prepared by deprotonation of (CH3)3SiCH2X with nbutyllithium. These reagents usually react with aldehydes and ketones to give substituted alkenes directly. No separate elimination step is necessary because fragmentation of the intermediate occurs spontaneously under the reaction conditions. In general, the elimination reactions are anti under acidic conditions and syn under basic conditions. This stereoselectivity is the result of a cyclic elimination mechanism under basic conditions, whereas under acidic conditions an acyclic b-elimination occurs. OH O

SiR3

H

base

R R

H

H

R

R

H

R

H

R

H SiR3

acid

R3Si

OH acid

R

H

H

R SiR3

R H

O+H2 H R

H

H

R

R

base

The anti elimination can also be achieved by converting the b-silyl alcohols to tri¯uoroacetate esters.165 Because the overall stereoselectivity of the Peterson ole®nation depends on the generation of pure syn or anti b-silyl alcohols, several strategies have been developed for their stereoselective preparation.166 Several examples of synthesis of substituted alkenes in this way are given in Scheme 2.18.

162. P. F. Hudrlik and D. Peterson, J. Am. Chem. Soc. 97:1464 (1975). 163. For reviews, see D. J. Ager, Org. React. 38:1 (1990); D. J. Ager, Synthesis 1984:384; A. G. M. Barrett, J. M. Hill, E. M. Wallace, and J. A. Flygare, Synlett 1991:764. 164. D. J. Peterson, J. Org. Chem. 33:780 (1968). 165. M. F. Connil, B. Jousseaume, N. Noiret, and A. Saux, J. Org. Chem. 59:1925 (1994). 166. A. G. M. Barrett and J. A. Flygare, J. Org. Chem. 56:638 (1991); L. Duhamel, J. Gralak, and A. Bouyanzer, J. Chem. Soc., Chem. Commun. 1993:1763.

Scheme 2.18. Carbonyl Ole®nation Using Trimethylsilyl-Substituted Organolithium Reagents 1a Me3SiCHCO2C2H5 Li

SECTION 2.5. REACTIONS OF CARBONYL COMPOUNDS WITH

CHCO2C2H5

O +

94%

2b Me3SiCHCO2Li +

Li

CHCO2H

O

3c Me3SiCHCN + C6H5CH

CHCHO

C6H5CH

84%

CHCH

CHCN

95%

Li O 4d

CH3

Me3SiCHSC6H5 + (CH3)3CCCCH3

C6H5SCH

C

55%

C(CH3)3

Li O

O

5e Me3SiCHSC6H5 + C6H5CH

CHCHO

C6H5CH

CHCN

CHSC6H5

70%

Li S

6f

+ CH3CH2CHO

S

S

Li

SiMe3

CH3CH2CH

75%

S

O

O

7d Me3SiCHP(OC2H5)2 + (CH3)2CHCHO

(CH3)2CHCH CHP(OC2H5)2

92%

Li 8g Me3SiC(SeC6H5)2 + C6H5CHO

C6H5CH

C(SeC6H5)2

75%

Li 9h

KH

O + Me3SiCHOCH3

51%

OCH3

Li 10i

CH3O

H

CH3

CH3

CHO + (C2H5)3SiCCH

1) –30°C

N

2) CF3CO2H, 0°C

Li

H3C

CH3O

OTBDMS

H

CH3

CH3 CHO 91%

H3C OTBDMS a. b. c. d. e. f. g. h. i.

K. Shimoji, H. Taguchi, H. Yamamoto, K. Oshima and H. Hozaki, J. Am. Chem. Soc. 96:1620 (1974). P. A. Grieco, C. L. J. Wang, and S. D. Burke, J. Chem. Soc., Chem. Commun. 1975:537. I. Matsuda, S. Murata, and Y. Ishii, J. Chem. Soc., Perkin Trans. 1 1979:26. F. A. Carey and A. S. Court, J. Org. Chem. 37:939 (1972). F. A. Carey and O. Hernandez, J. Org. Chem. 38:2670 (1973). D. Seebach, M. Kolb, and B.-T. Grobel, Chem. Ber. 106:2277 (1973). B. T. Grobel and D. Seebach, Chem. Ber. 110:852 (1977). P. Magnus and G. Roy, Organometallics 1:553 (1982). S. F. Martin, J. A. Dodge, L. E. Burgess, and M. Hartmann, J. Org. Chem. 57:1070 (1992).

121

122 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

2.6. Sulfur Ylides and Related Nucleophiles Sulfur ylides are next to phosphorus ylides in importance as synthetic reagents.167 Dimethylsulfonium methylide and dimethylsulfoxonium methylide are especially useful.168 These sulfur ylides are prepared by deprotonation of the corresponding sulfonium salts, both of which are commercially available.

O +

(CH3)2SCH3 I–

+

NaCH2SCH3

(CH3)2S

DMSO

CH2–

dimethylsulfonium methylide

O

O

(CH3)2SCH3 I– +

NaH DMSO

CH2– + dimethylsulfoxonium methylide

(CH3)2S

There is an important difference between the reactions of these sulfur ylides and those of phosphorus ylides. Whereas phosphorus ylides normally react with carbonyl compounds to give alkenes, dimethylsulfonium methylide and dimethylsulfoxonium methylide yield epoxides. Instead of a four-center elimination, the adducts formed from the sulfur ylides undergo intramolecular displacement of the sulfur substituent by oxygen. O– R2C

+

O + (CH3)2S



CH2

O + (CH3)2S +

CH2

O–

O R2C

R2C



CH2

R2C

O

+

S(CH3)2

R2C

O CH2

S(CH3)2 +

CH2 + (CH3)2S O

R2C

CH2 + (CH3)2S

O

Examples of the use of dimethylsulfonium methylide and dimethylsulfoxonium methylide in the preparation of epoxides are listed in Scheme 2.19. Entries 1±4 illustrate epoxide formation with simple aldehydes and ketones. Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a,b-unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition to give cyclopropanes (entries 5 and 6 in Scheme 2.19). It appears that the reason for the difference in their behavior lies in the relative rates of the two reactions available to the betaine intermediate: (a) reversal to starting materials or (b) intramolecular nucleophilic displacement.169 Presumably, both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide, the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation 167. B. M. Trost and L. S. Melvin, Jr., Sulfur Ylides, Academic Press, New York, 1975; E. Block, Reactions of Organosulfur Compounds, Academic Press, New York, 1978. 168. E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 87:1353 (1965). 169. C. R. Johnson, C. W. Schroeck, and J. R. Shanklin, J. Am. Chem. Soc. 95:7424 (1973).

Scheme 2.19. Reactions of Sulfur Ylides 1a

O

SECTION 2.6. SULFUR YLIDES AND RELATED NUCLEOPHILES

O –

+

DMSO–THF 0°C

+

DMSO–THF 0°C

+ CH2S(CH3)2

2a

123



C6H5CHO + CH2S(CH3)2

97%

C6H5 75%

O 3b

O

O

O



+ CH2S(CH3)2

DMSO

67–76%

+

4c

CH3

CH3

CH3

67%

– O + CH 2S(CH3)2

DMSO

O

50°C

CH3 5a

CH3

CH3

CH3 O



O

+

CH3

6a

H2C

CH3

CH3

CH3 O

O



O

+

+ CH2S(CH3)2

H2C

89%

DMSO–THF 0°C

+ CH2S(CH3)2

H2C

CH3

CH3

CH3

O

DMSO

81%

50°C

CH3

H2C

CH3

7d + O –

H2C

+

O

CH2

O

DMSO–THF

ylide: CH2S(CH3)2

0°C

6%

94%

65%

27%

O –

ylide:

DMSO

CH2S(CH3)2

O 8e

+

CH3

60°C

CH3

CH3C(CH2)3CH(CH2)3CH(CH2)3CH(CH3)2

NaNH2 (CH3)3S+Cl–

O CH3

CH3

CH3

(CH2)3CH(CH2)3CH(CH2)3CH(CH3)2

92%

Scheme 2.19. (continued )

124 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

CH3

9f

CH3

CH3

CH3

(CH3)3S+Cl– NaOH

O

O

CH3 10g

87%

CH3 O

O –+

+ (CH3)2CSPh2

11h CH3

CH3 82%

DME 50°C

CH3

–+ CO2CH3 + (CH3)2CSPh 2

DME –20°C

CH3 CH3

CH3 O

12i

O CH3 –

+

H2C

+

SPh2

DMSO 25°C

CH3

CH3C(CH2)5CH3

+

O Ph

CH3 75%

CH3

O

14j

CH3

H2C

CH3 13j

CO2CH3 CH3



+

SPh2

DMSO 25°C

(CH2)5CH3 92%

O

H3C

O

CNOCH3 CH3

+ [(CH3)2CH]2S NSO2Ar

n-BuLi

CH3 O 97%

Ph

CNOCH3 CH3

a. b. c. d. e. f. g. h. i. j. k.

E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 87:1353 (1965). E. J. Corey and M. Chaykovsky, Org. Synth. 49:78 (1969). M. G. Fracheboud, O. Shimomura, R. K. Hill, and F. H. Johnson, Tetrahedron Lett. 1969:3951. R. S. Bly, C. M. DuBose, Jr., and G. B. Konizer, J. Org. Chem. 33:2188 (1968). G. L. Olson, H.-C. Cheung, K. Morgan, and G. Saucy, J. Org. Chem. 45:803 (1980). M. Rosenberger, W. Jackson, and G. Saucy, Helv. Chim. Acta 63:1665 (1980). E. J. Corey, M. Jautelat, and W. Oppolzer, Tetrahedron Lett.1967:2325. E. J. Corey and M. Jautelat, J. Am. Chem.Soc. 89:3112 (1967). B. M. Trost and M. J. Bogdanowicz, J. Am. Chem. Soc. 95:5307 (1973). B. M. Trost and M. J. Bogdanowicz, J. Am. Chem. Soc. 95:5311 (1973). K. E. Rodrigues, Tetrahedron Lett. 32:1275 (1991).

72%

125

takes place. CH3

O– –

O

+

+ CH2S(CH3)2

H2C

CH3

CH3 O

CH2

slow

CH3

H2C

fast

+

CH2

S(CH3)2

CH3

H2C

CH3

With the more stable dimethylsulfoxonium methylide, the reversal is relatively more rapid, and product formation takes place only after conjugate addition. CH3

CH3 O– CH2

H2C

CH3

S(CH3)2 +

CH2

slow

CH3

H2C

CH3

fa st

O

O

O

O



+ CH2S(CH3)2 +

O H2C

CH3

(CH3)2S +

CH3 CH2

H2C

O–

H2C

CH3

H2C

CH3

O

fast

CH3

Another difference between dimethylsulfonium methylide and dimethylsulfoxonium methylide concerns the stereoselectivity in formation of epoxides from cyclohexanones. Dimethylsulfonium methylide usually adds from the axial direction whereas dimethylsulfoxonium methylide favors the equatorial direction. This result may also be due to reversibility of addition in the case of the sulfoxonium methylide.169 The product from the sulfonium ylide would be the result of the kinetic preference for axial addition by small nucleophiles (see Part A, Section 3.10). In the case of reversible addition of the sulfoxonium ylide, product structure would be determined by the rate of displacement, and this may be faster for the more stable epoxide. H2C

O (CH3)3C

O + (CH3)3C

(CH3)3C –

+

ylide: CH2S(CH3)2 O –

ylide: CH2S(CH3)2

O CH2

THF 0°C

83%

17%

THF 65°C

not formed

only product

Dimethylsulfonium methylide reacts with reactive alkylating reagents such as allylic and benzylic bromides to give terminal alkenes. A similar reaction occurs with primary alkyl bromides in the presence of LiI. The reaction probably involves alkylation of the

SECTION 2.6. SULFUR YLIDES AND RELATED NUCLEOPHILES

126 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

ylide, followed by elimination.170 X + CH2

RCH2

S+(CH3)2

RCH2CH2S+(CH3)2

RCH

CH2

Sulfur ylides are also available which allow transfer of substituted methylene units, such as isopropylidene (entries 10 and 11 in Scheme 2.19) or cyclopropylidene (entries 12 and 13). The oxaspiropentanes formed by reaction of aldehydes and ketones with diphenylsulfonium cyclopropylide are useful intermediates in a number of transformations such as acid-catalyzed rearrangement to cyclobutanones.171 CH3

(CH2)5CH3

CH3

(CH2)5CH3

92%

H+

C

O

O

Aside from the methylide and cyclopropylide reagents, the sulfonium ylides are not very stable. A related group of reagents derived from sulfoximines offer greater versatility in alkylidene transfer reactions.172 The preparation and use of this class of ylides is illustrated by the following sequence: O ArSCH2CH3

O NaN3 H2SO4 CHCl3

ArSCH2CH3

O (CH3)3O+BF4–

NH

+



ArSCH2CH3 BF4 N(CH3)2 NaH DMF

O +

ArS



CHCH3

C6H5CHO

C6H5CH

CHCH3

67%

O

N(CH3)2 Ar = p-CH3C6H4–

A similar pattern of reactivity has been demonstrated for the anions formed by deprotonation of S-alkyl-N-p-toluenesulfoximines173 (see entry 14 in Scheme 2.19). O CH3

S

+



NMe2

O

X

C

CH3 Y

dimethylaminooxosulfonium ylide

S NTs



X

C Y

N-tosylsulfoximine anion

The sulfur atom in both these types of reagents is chiral. They have been utilized in the preparation of enantiomerically enriched epoxides and cyclopropanes.174 170. L. Alcaraz, J. J. Harnett, C. Mioskowski, J. P. Martel, T. LeGall, D.-S. Shin, and J. R. Falck, Tetrahedron Lett. 35:5453 (1994). 171. B. M. Trost and M. H. Bogdanowicz, J. Am. Chem. Soc. 95:5321 (1973). 172. C. R. Johnson, Acc. Chem. Res. 6:341 (1973). 173. C. R. Johnson, R. A. Kirchoff, R. J. Reischer, and G. F. Katekar, J. Am. Chem. Soc. 95:4287 (1973). 174. C. R. Johnson and E. R. Janiga, J. Am. Chem. Soc. 95:7673 (1973).

127

2.7. Nucleophilic Addition±Cyclization The pattern of nucleophilic addition at a carbonyl group followed by intramolecular nucleophilic displacement of a leaving group present in the nucleophile can also be recognized in a much older synthetic technique, the Darzens reaction.175 The ®rst step in the reaction is addition of the enolate of the a-halo ester to the carbonyl compound. The alkoxide oxygen formed in the addition then effects nucleophilic attack, displacing the halide and forming an a,b-epoxy ester (also called a glycidic ester). O R2C

O–



CHCO2C2H5

R2C

O CHCO2C2H5

Cl

R2C

CHCO2C2H5

Cl

Scheme 2.20 gives some examples of the Darzens reaction. Trimethylsilylepoxides can be prepared by an addition±cyclization process. Reaction of chloromethyltrimethylsilane with sec-butyllithium at very low temperature gives an achloro lithium reagent which gives an epoxide on reaction with an aldehyde or ketone.176 Me3SiCH2Cl

s-BuLi

Me3SiCHCl

THF, –78°C

Li Cl Me3SiCHCl + CH3CH2CH2CHO

CH3CH2CH2CH

Li

CHSiMe3

CH3CH2CH2CH

CHSiMe3 O

O–

Scheme 2.20. Darzens Condensation Reactions O

1a O + ClCH2CO2C2H5

KOC(Me)3

CO2C2H5

83–95%

H 2b

PhCH O + PhCHCO2C2H5

KOC(Me)3

H

O

Ph

Cl 3

KOC(Me)3

PhCCH3 + ClCHCO2C2H5

75%

Ph

O c

CO2C2H5

O

H3C Ph

CO2C2H5 H

+

Ph

O

H3C

CO2C2H5 H

62% (1:1 mixture of isomers)

4d CH3CH2CHCO2C2H5 Br a. b. c. d.

1) LiN[Si(CH3)3]2 2) CH3CCH3 O

CH3 CH3

O

CO2C2H5 CH2CH3

R. H. Hunt, L. J. Chinn, and W. S. Johnson, Org. Synth. IV:459 (1963). H. E. Zimmerman and L. Ahramjian, J. Am. Chem. Soc. 82:5459 (1960). F. W. Bachelor and R. K. Bansal, J. Org. Chem. 34:3600 (1969). R. F. Borch, Tetrahedron Lett.1972:3761.

175. M. S. Newman and B. J. Magerlein, Org. React. 5:413 (1951). 176. C. Burford, F. Cooke, E. Ehlinger, and P. D. Magnus, J. Am. Chem. Soc. 99:4536 (1977).

SECTION 2.7. NUCLEOPHILIC ADDITION± CYCLIZATION

128 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

General References Aldol Additions and Condensations M. Braun in Advances in Carbanion Chemistry, Vol. 1. V. Snieckus, ed., JAI Press, Greenwich, Connecticut, 1992. D. A. Evans, J. V. Nelson, and T. R. Taber, Top. Stereochem. 13:1 (1982). A. S. Franklin and I. Paterson, Contemp. Org. Synth. 1:317 (1994). C. H. Heathcock, in Comprehensive Carbanion Chemistry, E. Buncel and T. Durst, eds., Elsevier, Amsterdam, 1984. C. H. Heathcock, in Asymmetric Synthesis, Vol 3, J. D. Morrison, ed., Academic Press, New York, 1984. S. Masamune, W. Choy, J. S. Petersen, and L. R. Sita, Angew. Chem. Int. Ed. Engl. 24:1 (1985). T. Mukaiyama, Org. React. 28:203 (1982). A. T. Nielsen and W. T. Houlihan, Org. React. 16:1 (1968).

Annulation Reactions R. E. Gawley, Synthesis 1976:777. M. E. Jung, Tetrahedron 32:3 (1976).

Mannich Reactions F. F. Blicke, Org. React. 1:303 (1942). H. Bohme and M. Heake, in Iminium Salts in Organic Chemistry, H. Bohmne and H. G. Viehe, eds., WileyInterscience, New York, 1976, pp. 107±223. M. Tramontini and L. Angiolini, Mannich BasesÐChemistry and Uses, CRC Press, Boca Raton, Florida, 1994.

Phosphorus-Stabilized Ylides and Carbanions J. Boutagy and R. Thomas, Chem. Rev. 74:87 (1974). I. Gosney and A. G. Rowley in Organophosphorus Reagents in Organic Synthesis, J. I. G. Cadogan, ed., Academic Press, London, 1979, pp. 17±153. A. W. Johnson, Ylides and Imines of Phosphorus, John Wiley & Sons, New York, 1993. A. Maercker, Org.React. 14:270 (1965). W. S. Wadsworth, Jr., Org. React. 25:73 (1977).

Problems (References for these problems will be found on page 924.) 1. Predict the product formed in each of the following reactions: (a) γ-butyrolactone + ethyl oxalate

1) NaOCH2CH3 2) H+

(b) 4-bromobenzaldehyde + ethyl cyanoacetate O

(c) CH3CH2CH2CCH3

1) LiN(i-Pr)2, –78°C 2) CH3CH2CHO, 15 min 3) H2O

ethanol piperidine

(d)

NaOH, H2O

CHO + PhCH2CCH3

O

OAc

(e)

129

O

C6H5CH CH3

PROBLEMS

1) CH3Li, 2 equiv. 2) ZnCl2 3) n-C3H7CHO

O +

(f)

CH2N(CH2CH3)2

I–

+ CH3CCH2CO2CH2CH3

NaOCH2CH3 ethanol, ∆

C10H14O

CH3 O

(g)

O CH3

Na

+ HCO2CH2CH3

ether

O

(h)

CCH3 + (CH3CH2O)2C O

O

NaNH2 toluene

O

(i) C6H5CCH3 + (CH3CH2O)2PCH2CN

NaH THF

O

(j)

NaOCH3 xylene

CH3CH2CCH2CH2CO2CH2CH3

(k)

(l)

O

O

C

CH3 + (CH3)2S

CO2C2H5 + CH2

CH2 O–

O–

CCH

COC2H5

H+

C10H7NO3

N CH3

(m)

O CH(OMe)2

Li 1) (CH3)3SiCHOCH3 2) KH

CH3 CH2

2. Indicate reaction conditions or a series of reactions that could effect each of the following synthetic conversions. OH

(a)

CH3CO2C(CH3)3

(CH3)2CCH2CO2C(CH3)3

(b) O

O(CH2)3CH

O

O

O(CH2)3 H

CH2OH CH3

130 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

O

O

(c)

CHOH

Ph

(d)

Ph2C

CN

O Ph

CO2C2H5

O

(e)

O

CO2C2H5 O

(f)

O

O

O

CH2OH

(g)

O

O

O

O

HO(CH2)3CCH2SCH3 H

(h)

H2C

H O

C

H2C

O

C

CH2CH2CCH3

CH2CH2CCH2CO2C2H5

H H2C

CH3

C CH2

H H2C

O

C

O

CH2CH2CCHCH2CH2CCH3

O

CO2C2H5 O

(i)

H5C2O2CCH2CH2CO2C2H5

O O

(j)

O

O

CCH2CCH3

CH3O

CCH3

O

CCH2CCH2C

O

(k)

OCH3

O CH3O

CCH

CH2

O

(l) CH3O

CH

CH3O

CH3O

(m)

O

CHCH

CH3O H3C

CH3 O CH3

CH

CHSCH2CH2CH2CH3 O

CH3

CH2

(n)

O

131

CH3

HC

PROBLEMS

CSCH2CH3

N H

CSCH2CH3

N H

O

O

(o) CH3

CH3

CH3

CH3

O

(p)

O

CH3

CH3

(CH3)2CH

(CH3)2CH O

(q)

CH2

(CH3)3CCC(CH3)3

(r)

CHOCH3

O

H

CH

Ph

Ph

O

(CH3)3CCC(CH3)3 H

H

H

H Ph

Ph

Ph H H

(s)

CO2CH3

H

(CH3)2CHCH O

H (CH3)2CH

(t)

O

O

(u)

H

Ph

(CH3)3SiO

O

CH3

3. Step-by-step retrosynthetic analysis of each of the target molecules reveals that they can be ef®ciently prepared in a few steps from the starting material shown on the right. Show a retrosynthetic analysis and suggest reagents and conditions for carrying out the desired synthesis. (a)

CH3

CH3 O

CH(CH3)2

O

CH(CH3)2

132

(b)

O

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

CH(CH3)2

OH

CCH3 O

O

O

(c) CCH

CH2

(d)

(CH3)2CHCH2CH

CHCHCH2CH2CO2CH2CH3

CH3

CH(CH3)2 O

C6H5 C6H5CH

CHCH

O

(e)

CH3

CH3

CCH2CH2C O

CH2

CCH3

CH3

O

(f) O CH CH3 3

O

O

(g)

O O

O N

(h)

Ph2C

(i)

CH3CH2CCH CHCO2C2H5

CHCH

O

Ph2C

O CH3CH2CH2CH O, ClCH2CO2C2H5

CH2

(j)

O

CH3NH2, CH2

CHCO2C2H5

N CH3

(k)

OH CO2C2H5 O

(l)

CH(CH2)3CH

O

O

H3C O H3C

(CH3)2CHCH O, CH2

CHCCH3

(m)

133

CH3

O

C

CCH3

CH2NH2

PROBLEMS

OH Br

Br

(n)

CH2CO2CH3

O

O

ClCCH2CH2CCl, CH3O2CCH2CO2H

CO2CH3 O

(o)

O

CH2

CH3O2C

CH3O2C

CO2CH3

PhCH2N CH3O2C

(p)

CH3O

HO2C

CH2O

CO2H CH3O

CH2O O CO2C2H5

O

(q)

CO2C2H5 CH2

CHCH2

N

NHCO2CH2Ph

CO2CH2Ph

4. Offer a mechanism for each of the following transformations. O

O

CO2CH3

(a)

C2H5CC2H5

CH3

NaH, benzene

CO2CH3 O

(b)

O

O

OH

CH

H

CH2P(OCH3)2

(CH3)3CO

KO-t-Bu t-BuOH

O

CH3

(CH3)3CO

CH3

O

(c)

CH3 CH3CH2C O

(d)

CH3

NaOH, MeOH

OCCH3 O

CH3

CH3 OH CH3CH2C Ph

CCH3 Ph

O KOH, H2O dioxane, 150°C

CH3CH2CHCH3 + PhCCH3 Ph

OH

134

O

(e)

CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

+ CH3CH

PPh3

CHCH

CH3 CH3O

(f)

CH3O

CH3O

CH3O

O + H2C

CHCCH3

+

+

N H3C H

(g)

O CH2CH2CH O CO2C2H5

N

O

H3C H

NaOEt

O CH2CH2CH O

H5C2O2C O

O

O

(h) CO2CH2CO2C2H5

1) LDA, 0°C

CCHCO2C2H5

2) H+

OH

(i)

O

O CO2CH3

t-BuO2CCH2C

O

H C

+

H3C

C

CH2CH2

H

O 1) CsCO3

2)

CO2Me

H+,

80°C

CH3 O

O

H

OH O

5. Tetraacetic acid (or a biological equivalent) has been suggested as an intermediate in the biosynthesis of phenolic natural products. Its synthesis has been described, as has its ready conversion to orsellinic acid. Suggest a mechanism for formation of orsellinic acid under the conditions speci®ed. OH O

O

O

CH3CCH2CCH2CCH2CO2H

pH 5.0

H3C

OH CO2H orsellinic acid

6. (a) A stereospeci®c method for deoxygenating epoxides to alkenes involves reaction of the epoxide with the diphenylphosphide ion, followed by methyl iodide. The method results in overall inversion of the alkene stereochemistry. Thus, ciscyclooctene epoxide gives trans-cyclooctene. Propose a mechanism for this process and discuss the relationship of the reaction to the Wittig reaction. (b) Reaction of the epoxide of E-4-octene (trans-2,3-di-n-propyloxirane) with trimethylsilylpotassium affords Z-4-octene as the only alkene in 93% yield. Suggest a reasonable mechanism for this reaction.

7. (a) A fairly general method for ring closure that involves vinyltriphenylphosphonium halides has been developed. Two examples are shown. Comment on the mechanism of the reaction and suggest two additional types of rings that could be synthesized using vinyltriphenylphosphonium salts.

O CH3CCH2CH(CO2C2H5)2 + CH2 CH

O + CH2

+

CHPPh3

+

CHPPh3

CO2C2H5

NaH

H3C

CO2C2H5

acetonitrile

O– Na+

O

(b) The two phosphonium salts shown have both been used in syntheses of cyclohexadienes. Suggest appropriate co-reactants and catalysts that would be expected to lead to cyclohexadienes.

H2C

+

CHCH2PPh3

H2C

CHCH

+

CHPPh3

(c) The product shown below is formed by the reaction of vinyltriphenylphosphonium bromide, the lithium enolate of cyclohexanone, and 1,3-diphenyl-2-propen-1-one. Formulate a mechanism.

CPh Ph

O

8. Compounds A and B are key intermediates in one total synthesis of cholesterol. Rationalize their formation by the routes shown.

135 PROBLEMS

136 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

H3C

H3C O

CH3

H3C CH3

O

1) 1 equiv CH3MgBr –18°C 2) NaOH

O

O

O H3C

CH2CH CH2CH

O

H3C piperidine, acetic acid in benzene

O

CH3

O

CH3

A

O

H3C

O H3C

CH

O

H3C

O B

9. The ®rst few steps of a synthesis of a alkaloid conessine produce D from C. Suggest a sequence of reactions for effecting this conversion.

CO2CH3 H3C

O

CH3O

H3C

CH3 O

CH3O C

D

10. A substance known as elastase is involved in arthritis, various in¯ammations, pulmonary emphysema, and pancreatitis. Elastase activity can be inhibited by a compound known as elasnin, obtained from the culture broth of a particular microorganism. The structure of elasnin is shown. A synthesis of elasnin has been reported which utilized compound E as a key intermediate. Suggest a synthesis of compound E from methyl hexanoate and hexanal.

O O

HO

O CO2CH3

O OH

Elasnin

E

11. Treatment of compound F with lithium diisopropylamide followed by cyclohexanone gives either G or H. G is formed if the aldehyde is added at 78 C whereas H is formed if the aldehyde is added at 0 C. Furthermore, treatment of G with lithium diisopropylamide at 0 C gives H. Explain these results.

HO CH2

CHCHCN

137

CN CCH

OCH2CH2OC2H5

PROBLEMS

CH2

OCH2CH2OC2H5

F

G OH CH2CH

COCH2CH2OC2H5 CN

H

12. Dissect the following molecules into potential precursors by locating all bond connections which could be made by aldol-type reactions. Suggest the structure for potential precursors and conditions for performing the desired condensation.

(a)

(b)

O

CH3

O CH3

CH3

13. Mannich condensations permit one-step reactions to form the following substances from substantially less complex starting materials. By retrosynthetic analysis, identify a potential starting material which could give rise to the product shown in a single step under Mannich reaction conditions. (a)

(b)

N

N CO2CH3

PhCH2OCH2CH2CH2

CH3 O

O CO2CH3

14. (a) The reagent I has found use in constructing rather complex molecules from simple precursors; for example, the enolate of 3-pentanone, treated ®rst with I, then with benzaldehyde, gives J as a 2 : 1 mixture of stereoisomers. Explain the mechanism by which this synthesis occurs. CO2C2H5 CH2

C PO(OC2H5)2 I

O CH3CH2CCH2CH3

O 1) LDA, –78°C 2) I

PhCH O 68°C 45 min

CH3CH2CCHCH2C CH3 J

CHPh

CO2C2H5

74%

138 CHAPTER 2 REACTION OF CARBON NUCLEOPHILES WITH CARBONYL GROUPS

(b) The reagent K converts enolates of aldehydes into the cyclohexadienyl phosphonates L. What is the mechanism of this reaction? What alternative product might have been expected? R

O CHCH

CH2

CHP(OC2H5)2 + R2C K

CH O

R



O

P(OC2H5)2 L

15. Indicate whether the aldol reactions shown below would be expected to exhibit high stereoselectivity. If high stereoselectivity is to be expected, show the relative con®guration which is expected for the predominant product. (a)

O

1) BuLi, –50°C (enolate formation)

Ph3CCCH2CH3

(b)

O

2) PhCH O

CH3 1) (i-Pr)2NC2H5

CH3CH2CCHOSiC(CH3)3

CH3CH2CH O

2) Bu2BOSO2CF3, –78°C

CH3

O

(c)

1) LDA, THF, –70°C

CH3CH2CCH2CH3

(d)

2) C6H5CH O

OSi(CH3)3 CH3

CH3

KF C6H5CH O

(e)

O 1) Bu2BOSO2CF3

PhCCH2CH3

(f)

CH3 CH3CH2C

COSi(CH3)3

O

1) LDA, –70°C 2) (CH3)2CHCH O

CH3

(g) CH3CH2CH O

(h)

2) PhCH O

(i-Pr)2NC2H5 –78°C

1) Et3N (2 equiv) TiCl4 (2 equiv) 2) PhCH O, –78°C

CH3

Ph

1) n-Bu2BO3SCF3

C2H5

N

O O

O

CH

O

2) (C2H5)3N

O

16. The stereoselectivity of several a-oxy derivatives of ketone M are given below. Suggest a transition state which accounts for the observed stereoselectivity.

OR′

CH3 R

C2H5C O

CH3 R

C

1) LDA, TMEDA 2) RCH O

OR′

OH

O

OH R′

PROBLEMS

C

+

M

139

OR′

O

Ratio 8:92 9:91 83:17

CH2OCH3 Si(CH3)3 Si(CH3)2C(CH3)3

17. Suggest a transition state which would account for the observed stereoselectivity of the following reaction sequence. O

O

R3Si O

O

OH

R3Si

1) (c-C6H11)2BCl C2H5N(CH3)2 2) PhCH O

Ph O

CH3 CH3

O

CH3 CH3

R3Si = (C2H5)2C(CH3)Si(CH3)2

18. Provide a mechanistic explanation for the in¯uence of the Lewis acid in determining the stereoselectivity of addition of the silyl enol ether to the aldehyde O

CH

CO2CH3 CH3

(CH3)3C

1) Lewis acid 2)

O

O

OSi(CH3)3 CH2

O

C C(CH3)3

TiCl4 BF3 SnCl4

CH3

cis:trans 29:71 57:43 66:34

19. The reaction of 3-benzyloxybutanal with the trimethylsilyl enol ether of acetophenone is stereoselective for the anti diasteromer. CH3CHCH2CH PhCH2O

O + CH2

CPh OSi(CH3)3

Ph

TiCl4

PhCH2O

OH major

O

PhCH2O

OH

O

minor

Propose a transition state which would account for the observed stereoselectivity.

3

Functional Group Interconversion by Nucleophilic Substitution Introduction The ®rst two chapters dealt with formation of new carbon±carbon bonds by processes in which one carbon acts as the nucleophile and the other as the electrophile. In this chapter, we turn our attention to noncarbon nucleophiles. Nucleophilic substitution at both sp3 and sp2 centers is used in a variety of synthetic operations, particularly in the inverconversion of functional groups. The mechanistic aspects of nucleophilic substitutions were considered in Part A, Chapters 5 and 8.

3.1. Conversion of Alcohols to Alkylating Agents 3.1.1. Sulfonate Esters Alcohols are a very important class of compounds for synthesis. However, because hydroxide is a very poor leaving group, they are not reactive as alkylating agents. The preparation of sulfonate esters from alcohols is an effective way of installing a reactive leaving group on an alkyl chain. The reaction is very general, and complications arise only if the resulting sulfonate ester is suf®ciently reactive to require special precautions. pToluenesulfonate (tosylate) and methanesulfonate (mesylate) esters are the most frequently used groups for preparative work, but the very reactive tri¯uoromethanesulfonates (tri¯ates) are useful when an especially good leaving group is required. The usual method for introducing tosyl or mesyl groups is to allow the alcohol to react with the

141

142 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

sulfonyl chloride in pyridine at 0±25 C.1 An alternative for preparing mesylates and tosylates is to convert the alcohol to a lithium salt, which is then allowed to react with the sulfonyl chloride.2

ROLi + ClSO2

CH3

ROSO2

CH3

Tri¯uoromethanesulfonates of alkyl and allylic alcohols can be prepared by reaction with tri¯uoromethanesulfonic anhydride in halogenated solvents in the presence of pyridine.3 Because the preparation of sulfonate esters does not disturb the C O bond, problems of rearrangement or racemization do not arise in the ester formation step. However, sensitive sulfonate esters, such as allylic systems, may be subject to reversible ionization reactions, so that appropriate precautions must be taken to ensure structural and stereochemical integrity. Tertiary alkyl tosylates are not as easily prepared nor as stable as those from primary and secondary alcohols. Under the standard conditions, tertiary alcohols are likely to be converted to the corresponding alkene.

3.1.2. Halides The prominent role of alkyl halides in formation of carbon±carbon bonds by nucleophilic substitution was evident in Chapter 1. The most common precursors for alkyl halides are the corresponding alcohols, and a variety of procedures have been developed for this transformation. The choice of an appropriate reagent is usually dictated by the sensitivity of the alcohol and any other functional groups present in the molecule. Unsubstituted primary alcohols can be converted to bromides with hot concentrated hydrobromic acid.4 Alkyl chlorides can be prepared by reaction of primary alcohols with hydrochloric acid±zinc chloride.5 These reactions proceed by an SN 2 mechanism, and elimination and rearrangements are not a problem for primary alcohols. Reactions with tertiary alcohols proceed by an SN 1 mechanism so these reactions are preparatively useful only when the carbocation intermediate is unlikely to give rise to rearranged product.6 Because of the harsh conditions, these procedures are only applicable to very acid-stable molecules. Another general method for converting alcohols to halides involves reactions with halides of certain non-metallic elements. Thionyl chloride, phosphorus trichloride, and phosphorus tribromide are the most common examples of this group of reagents. These reagents are suitable for alcohols that are neither acid-sensitive nor prone to structural rearrangements. The reaction of alcohols with thionyl chloride initially results in the formation of a chlorosul®te ester. There are two mechanisms by which the chlorosul®te 1. R. S. Tipson, J. Org. Chem. 9:235 (1944); G. W. Kabalka, M. Varma, R. S. Varma, P. C. Srivastava and F. F. Knapp, Jr. J. Org. Chem. 51:2386 (1986). 2. H. C. Brown, R. Bernheimer, C. J. Kim, and S. E. Scheppele, J. Am. Chem. Soc., 89:370 (1967). 3. C. D. Beard, K. Baum, and V. Grakauskas, J. Org. Chem. 38:3673 (1973). 4. E. E. Reid, J. R. Ruhoff, and R. E. Burnett, Org. Synth. II:246 (1943). 5. J. E. Copenhaver and A. M. Wharley, Org. Synth. I:142 (1941). 6. J. F. Norris and A. W. Olmsted, Org. Synth. I:144 (1941); H. C. Brown and M. H. Rei, J. Org. Chem. 31:1090 (1966).

can be converted to a chloride. In nucleophilic solvents, such as dioxane, the solvent participates and can lead to overall retention of con®guration.7

O ROH + SOCl2

ROSCl + HCl

O O

O + ROSCl

+

O

O

R + SO2 + Cl–

R

Cl + O

O

In the absence of solvent participation, chloride attack on the chlorosul®te ester leads to product with inversion of con®guration.

O ROH + SOCl2

ROSCl + HCl

O Cl– R

OS

Cl

R

Cl + SO2 + Cl–

Another method that provides chlorides from alcohols with retention of con®guration involves conversion to a xanthate ester, followed by reaction with sulfuryl chloride. This method is thought to involve collapse of a chlorinated adduct of the xanthate ester. The reaction is useful for secondary alcohols, including sterically hindered structures.8

RCHR′

1) NaH, CS2, CH3I 2) SO2Cl2

OH R′ RCH

S O

C

RCHR′ Cl

retention

R′ SCH3

RCH

O

S

Cl

C

SCH3

R′ RCH

Cl

O

S

SCH3

C

Cl

R′ RCH

Cl

Cl

The mechanism for the reactions with phosphorus halides can be illustrated using phosphorus tribromide. Initial reaction between the alcohol and phosphorus tribromide leads to a trialkyl phosphite ester by successive displacements of bromide. The reaction stops at this stage if it is run in the presence of an amine which neutralizes the hydrogen bromide that is formed.9 If the hydrogen bromide is not neutralized, the phosphite ester is protonated, and each alkyl group is successively converted to the halide by nucleophilic substitution by bromide ion. The driving force for cleavage of the C O bond is the 7. E. S. Lewis and C. E. Boozer, J. Am. Chem. Soc. 74:308 (1952). 8. A. P. Kozikowski and J. Lee, Tetrahedron Lett. 29:3053 (1988). 9. A. H. Ford-Moore and B. J. Perry, Org. Synth. IV:955 (1963).

143 SECTION 3.1. CONVERSION OF ALCOHOLS TO ALKYLATING AGENTS

144

formation of a strong phosphoryl double bond.

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

ROH + PBr3

(RO)3P + 3 HBr

(RO)3P + HBr

RBr + O

P(OR)2 H OH

O

P(OR)2 + HBr

R

Br + O

POR

H

H

OH O

P

OR + HBr

RBr + O

H P(OH)2

H

Because C Br bond formation occurs by back-side attack, inversion of con®guration at carbon is anticipated. However, both racemization and rearrangement can be observed as competing processes.10 For example, conversion of enantiomerically pure 2-butanol to 2butyl bromide with PBr3 is accompanied by 10±13% racemization, and a small amount of t-butyl bromide is also formed.11 The extent of rearrangement increases with increasing chain length and branching. CH3CH2CHCH2CH3

PBr3 ether

CH3CH2CHCH2CH3 + CH3CH2CH2CHCH3

OH

(CH3)3CCH2OH

PBr3 quinoline

Br

Br

85–90%

10–15%

Ref. 12

(CH3)3CCH2Br + (CH3)2CCH2CH3 + CH3CHCH(CH3)2 63%

Br

Br

26%

11%

Ref. 13

Because of the very acidic solutions involved, these methods are limited to acid-stable molecules. Milder reagents are necessary for most functionally substituted alcohols. A very general and important method for activating alcohols toward nucleophilic substitution is by converting them to alkoxyphosphonium ions.14 The alkoxyphosphonium ions are very reactive toward nucleophilic attack, with the driving force for substitution being formation of the strong phosphoryl bond. E R3′ P + E

Y

+

R3′ P

R3′ P

E + Y–

Y +

R3′ P

E + ROH

+

R3′ P

OR + HE

+

R3′ P

OR + Nu–

R3′ P

O + R

Nu

10. H. R. Hudson, Synthesis 1969:112. 11. D. G. Goodwin and H. R. Hudson, J. Chem. Soc. B, 1968:1333; E. J. Coulson, W. Gerrard, and H. R. Hudson, J. Chem. Soc. 1965:2364. 12. J. Cason and J. S. Correia, J. Org. Chem. 26:3645 (1961). 13. H. R. Hudson, J. Chem. Soc. 1968:664. 14. B. P. Castro, Org. React. 29:1 (1983).

A wide variety of species can function as the electrophile E‡ in the general mechanism. The most useful synthetic procedures for preparation of halides are based on the halogens, positive halogen sources, and diethyl azodicarboxylate. A 1 : 1 adduct formed by triphenylphosphine and bromine converts alcohols to bromides.15 The alcohol displaces bromide ion from the pentavalent adduct, giving an alkoxyphosphonium intermediate. The phosphonium ion intermediate then undergoes nucleophilic attack by bromide ion, displacing triphenylphosphine oxide. PPh3 + Br2

Br2PPh3 +

ROPPh3 Br– + HBr

Br2PPh3 + ROH +

Br– + ROPPh3

RBr + Ph3P

O

Because the alkoxyphosphonium intermediate is formed by a reaction that does not break the C O bond and the second step proceeds by back-side displacement on carbon, the stereochemistry of the overall process is inversion. H3C

C8H17

H3C

H3C

C8H17

H3C

Br2, Ph3P

HO

Ref. 16

Br

2,4,4,6-Tetrabromocyclohexa-2,5-dienone has been found to be a useful bromine source.

O

Ph3P

C12H25

O

Br

O

C12H25 O

Br

OH

Ref. 17

Br

O Br Br

Triphenylphosphine dichloride exhibits similar reactivity and has been used to prepare chlorides.18 The most convenient methods for converting alcohols to chlorides are based on in situ generation of chlorophosphonium ions19 by reaction of triphenylphosphine with various chlorine compounds such as carbon tetrachloride20 and hexachloroacetone.21 Ph3P + CCl4

+

Ph3P

O Ph3P + Cl3CCCCl3 15. 16. 17. 18. 19. 20. 21.

Cl + –CCl3 O

+

Ph3P

Cl + –CCl2CCCl3

G. A. Wiley, R. L. Hershkowitz, B. M. Rein, and B. C. Chung, J. Am. Chem. Soc. 86:964 (1964). D. Levy and R. Stevenson, J. Org. Chem. 30:2635 (1965). A. Tanaka and T. Oritani, Tetrahedron Lett. 38:1955 (1997). L. Horner, H. Oediger, and H. Hoffmann, Justus Liebigs Ann. Chem. 626:26 (1959). R. Appel, Angew. Chem. Int. Ed. Engl. 14:801 (1975). J. B. Lee and T. J. Nolan, Can. J. Chem. 44:1331 (1966). R. M. Magid, O. S. Fruchey, W. L. Johnson, and T. G. Allen, ,J. Org. Chem. 44:359 (1979).

145 SECTION 3.1. CONVERSION OF ALCOHOLS TO ALKYLATING AGENTS

146 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

The chlorophosphonium ion then reacts with the alcohol to give an alkoxyphosphonium ion, which is converted to the chloride: +

Ph3P +

Ph3P

+

Cl + ROH

Ph3P

OR + HCl

Cl–

Ph3P

O + R

OR +

Cl

Various modi®cations of halophosphonium ion-based procedures have been developed. The use of triphenylphosphine and imidazole in combination with iodine or bromine gives good conversion of alcohols to iodides or bromides.22 An even more reactive system consists of chlorodiphenylphosphine, imidazole, and the halogen.23 The latter system has the further advantage that the resulting phosphorus by-product, diphenylphosphinic acid, can be extracted with base during product workup. O N + I + ROH 2

Ph2PCl + H N

RI + Ph2PH

A very mild procedure for converting alcohols to iodides uses triphenylphosphine, diethyl azodicarboxylate (DEAD) and methyl iodide.24 This reaction occurs with clean inversion of stereochemistry.25 The key intermediate is again an alkoxyphosphonium ion. Ph3P + ROH + C2H5O2CN

NCO2C2H5



C2H5O2CNNHCO2C2H5 + CH3I

+



Ph3POR + C2H5O2CNNHCO2C2H5 C2H5O2CNNHCO2C2H5 + I– CH3

+

Ph3POR + I–

RI + Ph3P

O

The role of the diethyl azodicarboxylate is to activate the triphenylphosphine toward nucleophilic attack by the alcohol. In the course of the reaction, the NˆN double bond is reduced. As will be discussed subsequently, this method is applicable for activation of alcohols to attack by other nucleophiles in addition to halide ions. The activation of alcohols to nucleophilic attack by the triphenylphosphine±diethyl azodicarboxylate combination is called the Mitsunobu reaction. There are a number of other useful methods for converting alcohols to halides. A very mild method which is useful for compounds that are prone to allylic rearrangement involves prior conversion of the alcohol to the mesylate, followed by nucleophilic displacement with halide ion: CH3CH2CH2

CH3CH2CH2 C

CH3CH2CH2 22. 23. 24. 25. 26.

CHCH2OH

1) CH3SO2Cl 2) LiCl, DMF

C

CHCH2Cl

83%

Ref. 26

CH3CH2CH2

P. J. Garegg, R. Johansson, C. Ortega, and B. Samuelsson, J. Chem. Soc., Perkin Trans. 1 1982:681. B. Classon, Z. Liu, and B. Samuelsson, J. Org. Chem. 53: 6126 (1988). O. Mitsunobu, Synthesis 1981:1. H. Loibner and E. Zbiral, Helv. Chim. Acta 59:2100 (1976). E. W. Collington and A. I. Meyers, J. Org. Chem. 36:3044 (1971).

Another very mild procedure involves reaction of the alcohol with the heterocyclic 2chloro-3-ethylbenzoxazolium cation.27 The alcohol adds to the electrophilic heterocyclic ring, displacing chloride. The alkoxy group is thereby activated toward nucleophilic substitution, which forms a stable product, 3-ethylbenzoxazolinone. C2H5

C2H5

C2H5

+

+

N

N OR + Cl–

Cl + ROH O

N

O

O + RCl O

The reaction can be used for making either chlorides or bromides by using the appropriate tetraalkylammonium salt as a halide source. Scheme 3.1 gives some examples of the various alcohol-to-halide conversions that have been discussed.

3.2. Introduction of Functional Groups by Nucleophilic Substitution at Saturated Carbon The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 5 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as importantl synthetic processes. The SN 2 mechanism, because of its predictable stereochemistry and avoidance of carbocation intermediates, is the most desirable substitution process from a synthetic point of view. This section will discuss the role of SN 2 reactions in the preparation of several classes of compounds. First, however, the important role that solvent plays in SN 2 reactions will be reviewed. The knowledgeable manipulation of solvent and related medium effects has led to signi®cant improvement of many synthetic procedures that proceed by the SN 2 mechanism. 3.2.1. General Solvent Effects The objective in selecting the reaction conditions for a preparative nucleophilic substitution is to enhance the mutual reactivity of the leaving group and nucleophile so that the desired substitution occurs at a convenient rate and with minimal competition from other possible reactions. The generalized order of leaving-group reactivity RSO3 > I > Br > Cl pertains for most SN 2 processes. (See Part A, Section 5.6, for more complete data). Mesylates, tosylates, iodides, and bromides are all widely used in synthesis. Chlorides usually react rather slowly, except in especially reactive systems, such as allylic and benzylic compounds. The overall synthetic objective normally governs the choice of the nucleophile. Optimization of reactivity, therefore, must be achieved by choice of the reaction conditions, particularly the solvent. Several generalizations about solvents can be made. Hydrocarbons, halogenated hydrocarbons, and ethers are usually unsuitable solvents for reactions involving metal-ion salts. Acetone and acetonitrile are somewhat more polar, but the solubility of most ionic compounds in these solvents is low. Solubility can be considerably improved by use of salts of cations having substantial nonpolar 27. T. Mukaiyama, S. Shoda, and Y. Watanabe, Chem. Lett. 1977:383; T. Mukaiyama, Angew. Chem. Int. Ed. Engl. 18:707 (1979).

147 SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

Scheme 3.1. Preparation of Alkyl Halides

148 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

1a

PBr3

(CH3)2CHCH2OH

2b

3c

PBr3 pyridine

CH2OH

O

(CH3)3CCH2Cl

PPh3

4d CH3

53–61%

92%

CCl4

CHCH2OH

55–60%

CH2Br

O Cl2

(CH3)3CCH2OH

(CH3)2CHCH2Br

CH3

PPh3

CHCH2Cl

CH3 5e

CH3 C

6f 7g

Ph2C

CH3

Cl3CCCCl3

C

H

CH3 O

H

H C

PPh3

C

H

CH2OH

1) tosyl chloride

CHCH2CH2OH

70%

2) LiBr

CH2OH

99%

CH2Cl Ph2C

CHCH2CH2Br

89%

CH2Br 1) tosyl chloride

94%

2) LiBr, acetone

8h

C2H5 +

CH3(CH2)5CHCH3

N

+

Cl

OH

R4N+Cl–

CH3(CH2)5CHCH3

76%

Cl

O H

9i (CH3)2NCH2CH2OH

SOCl2

(CH3)2+NCH2CH2Cl Cl–

90%

CH3

CH3

10j

1) Ph3P, C2H5O2CN NCO2C2H5

HO

90%

2) CH3I

I 11k

PhCH

CHCH2OH

Ph3PBr2

PhCH

CHCH2Br

60–70%

PPh3, I2

12l

N 75%

CH3O

CH2OH

N

CH3O

CH2I

H

a. b. c. d. e. f. g. h. i. j. k. l.

C. R. Noller and R. Dinsmore, Org. Synth. II:358 (1943). L. H. Smith, Org. Synth. III:793 (1955). G. A. Wiley, R. L. Hershkowitz, B. M. Rein, and B. C. Chung, J. Am. Chem. Soc. 86:964 (1964). B. D. MacKenzie, M. M. Angelo, and J. Wolinsky, J. Org. Chem. 44:4042 (1979). R. M. Magid, O. S. Fruchy, W. L. Johnson, and T. G. Allen, J. Org. Chem. 44:359 (1979). M. E. H. Howden, A. Maereker, J. Burdon, and J. D. Roberts, J. Am. Chem. Soc. 88:1732 (1966). K. B. Wiberg and B. R. Lowry, J. Am. Chem. Soc. 85:3188 (1963). T. Mukaiyama, S. Shoda, and Y. Watanabe, Chem. Lett. 1977:383. L. A. R. Hall, V. C. Stephens, and J. H. Burckhalter, Org. Synth. IV:333 (1963). H. Loibner and E. Zbiral, Helv. Chim. Acta 59:2100 (1976). J. P. Schaefer, J. G. Higgins, and P. K. Shenoy, Org. Synth. V:249 (1973). R. G. Linde II, M. Egbertson, R. S. Coleman, A. B. Jones, and S. J. Danishefsky, J. Org. Chem. 55:2771 (1990).

character, such as those containing tetraalkylammonium ions. Alcohols are reasonably good solvents for salts, but the nucleophilicity of hard anions is relatively low in alcohols because of extensive solvation. The polar aprotic solvents, particularly DMF and DMSO, are good solvents for salts, and, by virtue of selective cation solvation, anions usually show enhanced nucleophilicity in these solvents. The miscibility with water of these solvents and their high boiling points can sometimes cause problems in product separation and puri®cation. HMPA, N ,N -diethylacetamide, and N -methylpyrrolidinone are other examples of useful polar aprotic solvents.28 In addition to enhancing reactivity, polar aprotic solvents also affect the order of reactivity of nucleophilic anions. In DMF the halides are all of comparable nucleophilicity,29 whereas in hydroxylic solvents the order is I > Br > Cl and the differences in reactivity are much greater.30 In addition to exploiting solvent effects on reactivity, there are two other valuable approaches to enhancing reactivity in nucleophilic substitutions. These are use of crown ethers as catalysts and the use of phase-transfer conditions. The crown ethers are a family of cyclic polyethers, three examples of which are shown below: O O

O

O

O O 15-crown-5

O

O

O

O

O

O

O

O

O

O

O

18-crown-6

dicyclohexano-18-crown-6

The ®rst number designates the ring size, and the second number, the number of oxygen atoms in the ring. These materials have cation-complexing properties and catalyze nucleophilic substitution under many conditions. By complexing the cation in the cavity of the crown ether, these compounds solubilize many salts in nonpolar solvents. Once in solution, the anions are highly reactive as nucleophiles because they are weakly solvated. Tight ion-pairing is also precluded by the complexation of the cation by the nonpolar crown ether. As a result, nucleophilicity approaches or exceeds that observed in aprotic polar solvents.31 The second method for enhancing nucleophilic substitution processes is to use phasetransfer catalysts.32 The phase-transfer catalysts are ionic substances, usually quaternary ammonium or phosphonium salts, in which the size of the hydrocarbon groups in the cation is large enough to convey good solubility of the salt in organic solvents. In other words, the cation must be highly lipophilic. Phase-transfer catalysis usually is done in a two-phase system. The organic reactant is dissolved in a water-immiscible solvent such as a hydrocarbon or halogenated hydrocarbon. The salt containing the nucleophile is dissolved in water. Even with vigorous mixing, such systems show little tendency to react, because the nucleophile and reactant remain separated in the water and organic 28. 29. 30. 31. 32.

A. F. Sowinski and G. M. Whitesides, J. Org. Chem. 44:2369 (1979). W. M. Weaver and J. D. Hutchinson, J. Am. Chem. Soc. 86:261 (1964). R. G. Pearson and J. Songstad, J. Org. Chem. 32:2899 (1967). M. Hiraoka, Crown Compounds. Their Characteristics and Application, Elsevier, Amsterdam, 1982. E. V. Dehmlow and S. S. Dehmlow, Phase Transfer Catalysis, 3rd ed., Verlag Chemie, Weinheim 1992; W. P. Weber and G. W. Gokel, Phase Transfer Catalysis in Organic Synthesis, Springer Verlag, New York, 1977; C. M. Stark, C. Liotta, and M. Halpern, Phase Transfer Catalysis: Fundamentals, Applications and Industrial Perspective, Chapman and Hall, New York, 1994.

149 SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

150 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

phases, respectively. When a phase-transfer catalyst is added, the lipophilic cations are transferred to the nonpolar phase and, to maintain electrical neutrality in this phase, anions are transferred from the water to the organic phase. The anions are only weakly solvated in the organic phase and therefore exhibit enhanced nucleophilicity. As a result, the substitution reactions proceed under relatively mild conditions. The salts of the nucleophile are often used in high concentration in the aqueous solution, and in some procedures the solid salt is used. 3.2.2. Nitriles The replacement of a halide or tosylate ion, extending the carbon chain by one atom and providing an entry to carboxylic acid derivatives, has been a reaction of synthetic importance since the early days of organic chemistry. The classical conditions for preparing nitriles involves heating a halide with a cyanide salt in aqueous alcohol solution: CH2Cl + NaCN

ClCH2CH2CH2Br + KCN

H2O, C2H5OH

CH2CN

reflux 4 h

H2O, C2H5OH reflux 1.5 h

ClCH2CH2CH2CN

80–90%

40–50%

Ref. 33

Ref. 34

These reactions proceed more rapidly in aprotic polar solvents. In DMSO, for example, primary alkyl chlorides are converted to nitriles in one hour or less at temperatures of 120± 140 C.35 Phase-transfer catalysis by hexadecyltributylphosphonium bromide permits conversion of 1-chlorooctane to octyl cyanide in 95% yield in 2 h at 105 C.36 CH3CH2CH2CH2Cl

CH3(CH2)6CH2Cl

NaCN DMSO 90–160°C

CH3CH2CH2CH2CN

NaCN H2O, decane CH3(CH2)15P+(CH2CH2CH2CH3)3 105°C, 2 h

93%

CH3(CH2)6CH2CN

95%

Catalysis by 18-crown-6 of the reaction of solid potassium cyanide with a variety of chlorides and bromides has been demonstrated.37 With primary bromides, yields are high and reaction times are 15±30 h at re¯ux in acetonitrile (83 C). Interestingly, the chlorides are more reactive and require reaction times of only 2 h. Secondary halides react more slowly, and yields drop because of competing elimination. Tertiary halides do not react satisfactorily because elimination processes dominate. 3.2.3. Azides Azides are useful intermediates for synthesis of various nitrogen-containing compounds. They undergo cycloaddition reactions, as will be discussed in Section 6.2, 33. R. Adams and A. F. Thal, Org. Synth. 1:101 (1932). 34. C. F. H. Allen, Org. Synth. I:150 (1932). 35. L. Friedman and H. Schecter, J. Org. Chem. 25:877 (1960); R. A. Smiley and C. Arnold, J. Org. Chem. 25:257 (1960). 36. C. M. Starks, J. Am. Chem. Soc. 93:195 (1971); C. M. Starks and R. M. Owens, J. Am. Chem. Soc. 95:3613 (1973). 37. F. L. Cook, C. W. Bowers, and C. L. Liotta, J. Org. Chem. 39:3416 (1974).

and can also be easily reduced to primary amines. Azido groups are usually introduced into aliphatic compounds by nucleophilic substitution.38 The most reliable procedures involve heating the appropriate halide with sodium azide in DMSO39 or DMF.40 Alkyl azides can also be prepared by reaction in high-boiling alcohols41: CH3CH2OCH2CH2OCH2CH2OH H2O

CH3(CH2)3CH2I + NaN3

CH3(CH2)3CH2N3

84%

Phase-transfer conditions have also been used for the preparation of azides42: CH3 CH2

Br

CH

CH3 CO2CH3

NaN3 R4P+ –Br

CH2

N3

CH

CO2CH3

4 h, 25°C

Tetramethylguanidinium azide, an azide salt which is readily soluble in halogenated solvents, is a useful source of azide ions in the preparation of azides from reactive halides such as a-haloketones, a-haloamides, and glycosyl halides.43 There are also useful procedures for preparation of azides directly from alcohols. Reaction of alcohols with 2-¯uoro-1-methylpyridinium iodide followed by reaction with lithium azide gives good yields of alkyl azides44: N3–

ROH + +

N

+

F

N

CH3

OR

+ RN3 N

CH3

O

CH3

Diphenylphosphoryl azide reacts with alcohols in the presence of triphenylphosphine and diethyl azodicarboxylate.45 Hydrazoic acid, HN3 , can also serve as the azide ion source under these conditions.46 These reactions are examples of the Mitsunobu reaction discussed earlier. ROH + Ph3P + C2H5O2CN

NCO2C2H5 +

ROPPh3 + N3–

+



ROPPh3 + C2H5O2CNNHCO2C2H5 RN3 + Ph3P

O

38. M. E. C. Bif®n, J. Miller and D. B. Paul, in The Chemistry of the Azido Group, S. Patai, ed., John Wiley & Sons, New York, 1971, Chapter 2. 39. R. Goutarel, A. Cave, L. Tan, and M. Leboeuf, Bull. Soc. Chim. Fr. 1962:646. 40. E. J. Reist, R. R. Spencer, B. R. Baker, and L. Goodman, Chem. Ind. (London) 1962:1794. 41. E. Lieber, T. S. Chao, and C. N. R. Rao, J. Org. Chem. 22:238 (1957); H. Lehmkuhl, F. Rabet, and K. Hauschild, Synthesis 1977:184. 42. W. P. Reeves and M. L. Bahr, Synthesis 1976:823; B. B. Snider and J. V. Duncia, J. Org. Chem. 46:3223 (1981). 43. Y. Pan, R. L. Merriman, L. R. Tanzer, and P. L. Fuchs, Biomed. Chem. Lett. 2:967 (1992); C. Li, A. Arasappan, and P. L. Fuchs, Tetrahedron Lett. 34:3535 (1993); D. A. Evans, T. C. Britton, J. A. Ellman, and R. L. Dorow, J. Am. Chem. Soc. 112:4011 (1990). 44. K. Hojo, S. Kobayashi, K. Soai, S. Ikeda, and T. Mukaiyama, Chem. Lett. 1977:635. 45. B. Lal, B. N. Pramanik, M. S. Manhas, and A. K. Bose, Tetrahedron Lett. 1977:1977. 46. J. Schweng and E. Zbiral, Justus Liebigs Ann. Chem. 1978:1089; M. S. Hadley, F. D. King, B. McRitchie, D. H. Turner, and E. A. Watts, J. Med. Chem. 28:1843 (1985).

151 SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

152 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

Diphenylphosphoryl azide also gives good conversion of primary alkyl and secondary benzylic alcohols to azides in the presence of the strong organic base diazabicycloundecene (DBU). These reactions proceed by O-phosphorylation followed by SN 2 displacement.47 OH

N3

O (PhO)2PN3

Ar

Ar

DBU

This reaction can be extended to secondary alcohols with the more reactive bis(4nitrophenyl)phosphorazidate.48 3.2.4. Oxygen Nucleophiles The oxygen nucleophiles that are of primary interest in synthesis are the hydroxide ion (or water), alkoxide ions, and carboxylate anions, which lead, respectively, to alcohols, ethers, and esters. Because each of these nucleophiles can also act as a base, reaction conditions must be selected to favor substitution over elimination. Usually, a given alcohol is more easily obtained than the corresponding halide so the halide-to-alcohol transformations is not extensively used for synthesis. The hydrolysis of benzyl halides to the corresponding alcohols proceeds in good yield. This can be a useful synthetic transformation, because benzyl halides are available either by side-chain halogenation or by the chloromethylation reaction (Section 11.1.3).

NC

CH2Cl

K2CO3 H2O, 100°C 2.5 h

NC

CH2OH

85%

Ref. 49

Ether formation for alkoxides and alkylating reagents is a reaction of wide synthetic importance. The conversion of phenols to methoxyaromatics, for example, is a very common reaction. Methyl iodide, methyl tosylate, or dimethyl sulfate can be used as the alkylating agent. The reaction proceeds in the presence of a weak base, such as Na2 CO3 or K2 CO3 , which deprotonates the phenol. The conjugate bases of alcohols are considerably more basic than phenoxides, and therefore b elimination can become a problem. Phasetransfer conditions can be used in troublesome cases.50 Fortunately, the most useful and commonly encountered ethers are methyl and benzyl ethers, where elimination is not a problem and the corresponding halides are especially reactive. Entries 13±16 in Scheme 3.2 provide some typical examples of ether preparations. Two methods for converting carboxylic acids to esters fall into the mechanistic group under discussion. One of these methods is the reaction of carboxylic acids with diazo compounds, especially diazomethane. The second is alkylation of carboxylate anions by halides or sulfonates. The esteri®cation of carboxylic acids with diazomethane is a very quick and clean reaction.51 The alkylating agent is the extremely reactive methyldiazonium 47. A. S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J. Mathre, and E. J. J. Grabowski, J. Org. Chem. 58: 5886 (1993). 48. M. Mizuno and T. Shiori, J. Chem. Soc., Chem. Commun. 1997:2165. 49. J. N. Ashley, H. J. Barber, A. J. Ewins, G. Newbery, and A. D. Self, J. Chem. Soc. 1942:103. 50. F. Lopez-Calahorra, B. Ballart, F. Hombrados, and J. Marti, Synth. Commun. 28:795 (1998). 51. T. H. Black, Aldrichimica 16:3 (1983).

ion, which is generated by proton transfer from the carboxylic acid to diazomethane. The collapse of the resulting ion pair with loss of nitrogen is extremely rapid:

+

[RCO2– + CH3N2]

RCO2H + CH2N2

RCO2CH3 + N2

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. One possible alternative is the use of alkyltriazenes as reactive alkylating agents.52 Alkyltriazenes are readily prepared from primary amines and aryldiazonium salts.53 The triazenes, on being protonated by the carboxylic acid, generate a reactive alkylating agent that is equivalent, if not identical, to the alkyldiazonium ions generated from diazoalkanes.

H RCO2H + Ar

N

NNHR′

Ar

+

N

N

N

R′

–O

2CR

RCO2R′ + ArNH2 + N2

H

Especially for large-scale work, esters, may be more safely and ef®ciently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents54 or with crown ether catalysts.55 The reactivity for the salts is Na‡ < K‡ < Rb‡ < Cs‡ . Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due both to high solubility and to the absence of ion pairing with the anion.56 Acetone has been found to be a good solvent for reaction of carboxylate anions with alkyl iodides.57 Cesium ¯uoride in DMF is another useful combination.58 Carboxylate alkylation procedures have been particularly advantageous for preparation of hindered esters that can be relatively dif®cult to prepare by the acidcatalyzed esteri®cation method (Fischer esteri®cation) which will be discussed in Section 3.4.2. Sections F and G of Scheme 3.2 give some speci®c examples of ester synthesis by the reaction of carboxylic acids with diazomethane and by carboxylate alkylation. In the course of synthesis, it is sometimes necessary to invert the con®guration at an oxygen-substituted center. One of the best ways of doing this is to activate a hydroxyl group to substitution by a carboxylate anion. The activation is frequently done using the Mitsunobu reagents.59 Hydrolysis of the resulting ester gives the alcohol of inverted 52. E. H. White, H. Maskill, D. J. Woodcock, and M. A. Schroeder, Tetrahedron Lett. 1969:1713. 53. E. H. White and H. Scherrer, Tetrahedron Lett. 1961:758. 54. P. E. Pfeffer, T. A. Foglia, P. A. Barr, I. Schmeltz, and L. S. Silbert, Tetrahedron Lett. 1972:4063; J. E. Shaw, D. C. Kunerth, and J. J. Sherry, Tetrahedron Lett. 1973:689; J. Grundy, B. G. James, and G. Pattenden, Tetrahedron Lett. 1972:757. 55. C. L. Liotta, H. P. Harris, M. McDermott, T. Gonzalez, and K. Smith, Tetrahedron Lett. 1974:2417. 56. G. Dijkstra, W. H. Kruizinga, and R. M. Kellog, J. Org. Chem. 52:4230 (1987). 57. G. G. Moore, T. A. Foglia, and T. J. McGahan, J. Org. Chem. 44:2425 (1979). 58. T. Sato, J. Otera, and H. Nozaki, J. Org. Chem. 57:2166 (1992). 59. D. L. Hughes, Org. React. 42:335 (1992); D. L. Hughes, Org. Prep. Proced. Int. 28:127 (1996).

153 SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

154 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

con®guration:

HO H3C

H

O

H

PhCO2

Ph3P EtO2CN NCO2Et

CH3

PhCO2H

CH3

H3C

H

CO2CH3 O

HO

O

Ph3P EtO2CN NCO2Et PhCO2H

O

H

89%

Ref. 60

CO2CH3

O O

PhCO2

74%

Ref. 61

Carboxylate anions derived from somewhat stronger acids, such as p-nitrobenzoic acid and chloroacetic acid, seem to be particularly useful in this Mitsunobu inversion reaction.62 Sulfonate esters can also be prepared under Mitsunobu conditions. Use of zinc tosylate in place of the carboxylic acid gives a tosylate of inverted con®guration:

CH3

CH3 Ph3P EtO2CN NCO2Et

96%

Zn(O3SAr)2

HO CH2

Ref. 63

ArSO3 CCH3

CH2

CCH3

Entry 21 in Scheme 3.2 provides another example. The Mitsunobu conditions can also be used to effect a variety of other important and useful nucleophilic substitution reactions, such as conversions of alcohols to mixed phosphite esters.64 The active phosphitylating agent is believed to be a mixed phosphoramidite.

O (CH3O)2PH + i-PrO2CN NCO2-i-Pr + Ph3P

(CH3O)2PNNHCO2-i-Pr + Ph3P O CO2-i-Pr

(CH3O)2PNNHCO2-i-Pr + ROH

ROP(OCH3)2

CO2-i-Pr

60. M. J. Arco, M. H. Trammel, and J. D. White, J. Org. Chem. 41:2075 (1976). 61. C.-T. Hsu, N.-Y. Wang, L. H. Latimer, and C. J. Sih, J. Am. Chem. Soc. 105:593 (1983). 62. J. A. Dodge, J. I. Tujillo, and M. Presnell, J. Org. Chem. 59:234 (1994); M. Saiah, M. Bessodes, and K. Antonakis, Tetrahedron Lett. 33:4317 (1992); S. F. Martin and J. A. Dodge, Tetrahedron Lett. 32:3017 (1991). 63. I. Galynker and W. C. Still, Tetrahedron Lett. 1982:4461. 64. I. D. Grice, P. J. Harvey, I. D. Jenkins, M. J. Gallagher, and M. G. Ranasinghe, Tetrahedron Lett., 37:1087 (1996).

Mixed phosphonate esters can be prepared from alkylphosphonate monoesters, although here the activation is believed to occur at the alcohol.65 ROP+(Ph)3

ROH + i-PrO2CN NCO2-i-Pr + Ph3P O ROP+(Ph)3



+ R′PO2

OCH3

R′POR + Ph3P

O

OCH3

3.2.5. Nitrogen Nucleophiles The alkylation of neutral amines by halides is complicated from a synthetic point of view because of the possibility of multiple alkylation which can proceed to the quaternary ammonium salt in the presence of excess alkyl halide: RNH2 + R′

X

+H RNR′ + RNH2 H

RNR′ + R′ H

X

+

RNR2′ + RNH2 H RNR2′ + R′

X

+H RNR′ + X– H +

RNR′ + RNH3 H +

RNR2′ + X– H +

RNR2′ + RNH3 +

RNR3′ + X–

Even with a limited amount of the alkylating agent, the equilibria between protonated product and the neutral starting amine are suf®ciently fast that a mixture of products may be obtained. For this reason, when monoalkylation of amine is desired, the reaction is usually best carried out by reductive amination, a reaction which will be discussed in Chapter 5. If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and a base to neutralize the liberated acid normally results in complete reaction. Amides are only weakly nucleophilic and react very slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.66 O N–K+ + BrCH2CH2Br O

O NCH2CH2Br

70–80%

Ref. 67

O

The enhanced acidity of the NH group in phthalimide permits formation of an anion which is readily aklylated by alkyl halides or tosylates. The amine can then be liberated by 65. D. A. Campbell, J. Org. Chem. 57:6331 (1992); D. A. Campbell and J. C. Bermak, J. Org. Chem. 59:658 (1994). 66. M. S. Gibson and R. W. Bradshaw, Angew. Chem. Int. Ed. Engl. 7:919 (1968). 67. P. L. Salzberg and J. V. Supniewski, Org. Synth. I:119 (1932).

155 SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

156 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

reaction of the substituted phthalimide with hydrazine:

Br

phthal

CH3O2CCHCH2CHCO2CH3

NH2

CH3O2CCHCH2CHCO2CH3

Br

NH2NH2

HCl

HO2CCHCH2CHCO2H

CH3OH

phthal

NH2

phthal = phthalimido

Ref. 68

Secondary amides can be alkylated on nitrogen by using sodium hydride for proton abstraction, followed by reaction with an alkyl halide69:

O

O NH

NaH, benzene CH3I

NCH3

Neutral tertiary and secondary amides react with very reactive alkylating agents, such as triethyloxonium tetra¯uoroborate, to give O-alkylation.70 The same reaction occurs, but more slowly, with tosylates and dimethyl sulfate. Neutralization of the resulting salt provides iminoethers:

O RCNHR′

1) (CH3O)2SO2 2) –OH

OCH3 RC NR′

Sulfonamides are relatively acidic, and their anions can serve as nucleophiles.71 Sulfonamido groups can be introduced at benzylic positions with a high level of inversion under Mitsunobu conditions.72

OH

TsNHCH2CH(OCH3)2 OCH2Ph

OCH2Ph Ph3P, C2H5O2CN NCO2C2H5 TsNHCH2CH(OCH3)2

OCH2Ph

CH3 OCH3

OCH2Ph

CH3 OCH3

68. J. C. Sheehan and W. A. Bolhofer, J. Am. Chem. Soc. 72:2786 (1950). 69. W. S. Fones, J. Org. Chem. 14:1099 (1949); R. M. Moriarty, J. Org. Chem. 29:2748 (1964). 70. L. Weintraub, S. R. Oles, and N. Kalish, J. Org. Chem. 33:1679 (1968); H. Meerwein, E. Battenberg, H. Gold, E. Pfeil, and G. Willfang, J. Prakt. Chem. 154:83 (1939). 71. T. Doornbos and J. Strating, Org. Prep. Proced. 2:101 (1970). 72. T. S. Kaufman, Tetrahedron Lett. 37:5329 (1996); D. Papaioannou, C. Athanassopoulos, V. Magafa, N. Karamanos, G. Stavropoulos, A. Napoli, G. Sindona, D. W. Aksnes, and G. W. Francis, Acta Chem. Scand. 48:324 (1994).

The Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course of synthesis of analogs of the antitumor agent camptothecin. H3C

N O

N O

CH2OH

+

H

N

O

Ph3P DEAD

O N

O

C2H5 OH

I H3C

N N

O CH2

O

N

O

N

O

I

Ref. 73 O

C2H5 OH

Proline analogs can be obtained by cylization of d-hydroxyalkylamino acid carbamates. NHCO2C2H5

HO

Ph3P, C2H5O2CN

Ph

NCO2C2H5

CO2C2H5

Ref. 74

CO2C2H5

N Ph

CO2C2H5

Mitsunobu conditions are found effective for glycosylation of weak nitrogen nucleophiles, such as indoles. CH3 O

N

O O

PhCH2OCH2

PhCH2O

OH

Ph3P (CH3)2CHO2CN NCO2CH(CH3)2

+ N

N

H

CO2C(CH3)3

PhCH2O

OCH2Ph CH3 O

N

O

PhCH2O

PhCH2OCH2 PhCH2O

O

N

N CO2C(CH3)3

OCH2Ph Ref. 75

73. F. G. Fang, D. D. Bankston, E. M. Huie, M. R. Johnson, M.-C. Kang, C. S. LeHoullier, G. C. Lewis, T. C. Lovelace, M. W. Lowery, D. L. McDougald, C. A. Meerholz, J. J. Partridge, M. J. Sharp, and S. Xie, Tetrahedron 53:10953 (1997). 74. J. van Betsbrugge, D. Tourwe, B. Kaptein, H. Kierkels, and R. Broxterman, Tetrahedron 53:9233 (1997). 75. M. Ohkubo, T. Nishimura, H. Jona, T. Honma, S. Ito, and H. Morishima, Tetrahedron 53:5937 (1997).

157 SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON

158

3.2.6. Sulfur Nucleophiles

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

Anions derived from thiols are very nucleophilic and can easily be alkylated by halides. CH3S–Na+ + ClCH2CH2OH

C2H5OH

CH3SCH2CH2OH

75–80%

Ref. 76

Neutral sulfur compounds are also good nucleophiles. Sul®des and thioamides readily form salts with methyl iodide, for example: (CH3)2S + CH3I

N

S + CH3I

25°C 12–16 h

25°C 12 h

+

(CH3)3S I–

SCH3

+

N

Ref. 77

Ref. 78

CH3

CH3

Even sulfoxides, where nucleophilicity is decreased by the additional oxygen, can be alkylated by methyl iodide. These sulfoxinum salts have useful synthetic applications, as discussed in Section 2.6. (CH3)2S

O + CH3I

25°C 72 h

+

(CH3)3S

O I–

Ref. 79

3.2.7 Phosphorus Nucleophiles Both neutral and anionic phosphorus compounds are good nucleophiles toward alkyl halides. Examples of these reactions were already encountered in Chapter 2 in connection with the preparation of the valuable phosphorane and phosphonate intermediates used for Wittig reactions: Ph3P + CH3Br

room temp 2 days

+

Ph3PCH3 Br–

Ref. 80

O [(CH3)2CHO]3P + CH3I

[(CH3)2CHO]2PCH3 + (CH3)2CHI

Ref. 81

The reaction with phosphite esters is known as the Michaelis±Arbuzov reaction and proceeds through an unstable trialkoxyphosphonium intermediate. The second stage in the reaction is another example of the great tendency of alkoxyphosphonium ions to react with nucleophiles to break the O C bond, resulting in formation of phosphoryl PˆO bond. 76. 77. 78. 79. 80. 81.

W. Windus and P. R. Shildneck, Org. Synth. II:345 (1943). E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 87:1353 (1965). R. Gompper and W. Elser, Org. Synth. V:780 (1973). R. Kuhn and H. Trischmann, Justus Liebigs Ann. Chem. 611:117 (1958). G. Wittig and U. Schoellkopf, Org. Synth. V:75`1 (1973). A. H. Ford-Moore and B. J. Perry, Org. Synth. IV:325 (1963).

3.2.8. Summary of Nucleophilic Substitution at Saturated Carbon In the preceding sections, some of the nucleophilic substitution reactions at sp3 carbon which are most valuable for synthesis have been outlined. These reactions all ®t into the general mechanistic patterns that were discussed in Chapter 5 of Part A. The order of reactivity of alkylating groups is benzyl  allyl > methyl > primary > secondary. Tertiary halides and sulfonates are generally not satisfactory because of the preference for ionization processes over SN 2 substitution. Because of their high reactivity toward nucleophilic substitution, a-haloesters, a-haloketones, and a-halonitriles are usually favorable reactants for substitution reactions. The reactivity of leaving groups is sulfonate > iodide > bromide > chloride. Steric hindrance greatly decreases the rate of nucleophilic substitution. Thus, projected synthetic steps involving nucleophilic substitution must be evaluated for potential steric problems. Scheme 3.2 gives some representative examples of nucleophlic substitution process drawn from Organic Synthesis and from recent synthetic efforts.

3.3. Nucleophilic Cleavage of Carbon±Oxygen Bonds in Ethers and Esters The cleavage of carbon±oxygen bonds in ethers or esters by nucleophilic substitution is frequently a useful synthetic transformation R

O

CH3 + Nu–

RO– + CH3

O

CH3 + Nu–

RCO2– + CH3

Nu

O RC

Nu

The classical ether cleavage conditions involving concentrated hydrogen halides are much too strenuous for most polyfunctional molecules, so several milder reagents have been developed.82 These reagents include boron tribromide,83 dimethylboron bromide,84 trimethyl iodide,85 and boron tri¯uoride in the presence of thiols.86 The mechanism for ether cleavage with boron tribromide involves attack of bromide ion on an adduct formed from the ether and the electrophilic boron reagent. The cleavage step can occur by either an SN 2 or SN 1 process, depending on the nature of the alkyl group. R

O

R + BBr3

R

+

O –

R

+

O

R

–Br

R

BBr3

R

O

R

+

O

R + Br–

BBr2 BBr2 + RBr

BBr2 R 82. 83. 84. 85. 86.

O

BBr2 + 3 H2O

ROH + B(OH)3 + 2 HBr

M. V. Bhatt and S. U. Kulkarni, Synthesis 1983:249. J. F. W. McOmie, M. L. Watts, and D. E. West, Tetrahedron 24:2289 (1968). Y. Guindon, M. Therien, Y, Girard, and C. Yoakim, J. Org. Chem. 52:1680 (1987). M. E. Jung and M. A. Lyster, J. Org. Chem. 42:3761 (1977). M. Node, H. Hori, and E. Fujita, J. Chem. Soc., Perkin Trans. 12237 (1976); K. Fuji, K. Ichikawa, M. Node, and E. Fujita, J. Org. Chem. 44:1661 (1979).

159 SECTION 3.3. NUCLEOPHILIC CLEAVAGE OF CARBON±OXYGEN BONDS IN ETHERS AND ESTERS

Scheme 3.2. Transformation of Functional Groups by Nucleophilic Substitution

160 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

A. Nitriles 1a

CH3CHCH2OH

CH3CHCH2CN 1) CH3SO2Cl, pyridine

85%

2) NaCN, DMF, 40–60°C, 3 h

2b

CH3

CH3

CHCH2OH

CHCH2CN

1) ArSO2Cl

80%

2) NaCN, DMSO, 90°C, 5 h

CH3 3c

CH3 CH2CN

CH2OH 1) ArSO2Cl 2) NaCN, DMSO

CH2OH

CH2CN

B. Azides 4d

R4N+Cl–

CH3CH2CH2CH2Br + NaN3

CH3CH2CH2CH2N3

H2O, 100°C, 6 h

97%

OH

N3 1) CH3SO2Cl, (C2H5)3N

5e

2) NaN3, HMPA

CH3

CH3

CH3

6f

CH3 Ph3P, C2H5O2CN NCO2C2H5

N

N

60%

(PhO)2PN3

OH

N3

O

H

7g

H

OH

N3 O (PhO)2PN3

90%

DBU

O

O C. Amines and amides 8h

NCHCO2C2H5

NH + CH3CHCO2C2H5 Br

9i HN

+

NH2

80–90%

CH3

PhCH2Cl



OH

PhCH2N

NH

65–75%

10j O NH

(CH3O)2SO2

K2CO3

OCH3

benzene

N

60–70%

57%

Scheme 3.2. (continued )

161

D. Hydrolysis by alkyl halides O

11k

NaOH, H2O 4 h, 25°C

CCH

CH3

CCH

CH3

Cl

92%

OH

12l CH3O

SECTION 3.3. NUCLEOPHILIC CLEAVAGE OF CARBON±OXYGEN BONDS IN ETHERS AND ESTERS

O

CH

CHCO2CH3

Br

Br

H2O, 100°C

CH3O

10 min

CH3O

CH

CHCO2CH3

OH

Br

92%

CH3O

E. Ethers by base-catalyzed alkylation 13m

H3C

O

H3C

O

O O O

HO 14n

CH3

NaH, TMF, DMSO, PhCH2Cl heat, 3 h

H3C

O

H3C

O

CH3

O O

PhCH2O

OH

CH3

95%

CH3

OCH2CH2CH2CH3 NO2 + CH3CH2CH2CH2Br

NO2

K2CO3

75–80%

15o CH3O

CH2Cl + HOCH2CH2

NO2

CH3O 16p

O

COCH3

Bu4N+HSO4– 50% aq. NaOH CH2Cl2

NO2

CH2OCH2CH2

88%

COCH3

OH

OH CH3I

55–65%

K2CO3

HO

CH3O

F. Esterification by diazoalkanes 17q

CH2CO2H + CH2N2

CH2CO2CH3

79%

G. Esterification by nucleophilic substitution with carboxylate salts 18r

O

O

(CH3)3CCO2– + BrCH2C 19s

Br

18-crown-6

(CH3)3CCO2CH2C

Br

95%

CH3

CH3

CH3 H3C



CO2 + CH3CH(CH2)5CH3

acetone 56°C

H3C

CO2CH(CH2)5CH3

I CH3

CH3

100%

Scheme 3.2. (continued )

162 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

20t

CH3

CO2H

O

CH3 O

O

CH3I, KF, DMF, 25°C 18 h

CH3

O

O O

CH3

O

CO2CH3

O

CH3 O

84%

CH3

O

CH3

CH3

H. Sulfonate esters 21u

HO

ArSO3 CO2CH3 N

PPh3, i-Pr-O2CN NCO2-i-Pr p-toluenesulfonic acid, (C2H5)3N

CO2CH3 N

CPh

CPh O

O

Ar = p-CH3C6H5

I. Phosphorus nucleophiles 22v

Ph3P + BrCH2CH2OPh

+

Ph3PCH2CH2OPh Br– O

23w [(CH3)2CHO]3P + CH3I

[(CH3)2CHO]2PCH3 + (CH3)2CHI

85–90%

J. Sulfur nucleophiles 24x

CH3(CH2)10CH2Br + S

C(NH2)2

NaOH H2O

25y Na+ –SCH2CH2S– Na+ + BrCH2CH2Br

26z

S

1) CH3I

N CH3

S

2) (CH3)3CO– K+

CH3(CH2)10CH2SH

S

80%

55–60%

62%

N

SCH3

CH3

a. M. S. Newman and S. Otsuka, J. Org. Chem. 23:797 (1958). b. B. A. Pawson, H.-C. Cheung, S. Gurbaxani, and G. Saucy, J. Am. Chem. Soc. 92:336 (1970). c. J. J. Bloom®eld and P. V. Fennessey, Tetrahedron Lett. 1964:2273. d. W. P. Reeves and M. L. Bahr, Synthesis 1976:823. e. D. F. Taber, M. Rahimizadeh, and K. K. You, J. Org. Chem. 60:529 (1995). f. M. S. Hadley, F. D. King, B. McRitchie, D. H. Turner, and E. A. Watts, J. Med. Chem. 28:1843 (1985). g. A. S. Thompson, G. G. Humphrey, A. M. De Marco, D. J. Mathre, and E. J. J. Grabowski, J. Org. Chem. 58:5886 (1993). h. R. B. Moffett, Org. Synth. IV:466 (1963). i. J. C. Craig and R. J. Young, Org. Synth. V:88 (1973). j. R. E. Benson and T. L. Cairns, Org. Synth. IV:588 (1963). k. R. N. McDonald and P. A. Schwab, J. Am. Chem. Soc. 85:4004 (1963). l. E. Adler and K. J. Bjorkquist, Acta Chem. Scand. 5:241 (1951). m. C. H. Heathcock, C. T. White, J. J. Morrison, and D. VanDerveer, J. Org. Chem. 46:1296 (1981). n. E. S. West and R. F. Holden, Org. Synth. III:800 (1955). o. F. Lopez-Calahorra, B. Ballart, F. Hombrados, and J. Marti, Synth. Commun. 28:795 (1998). p. G. N. Vyas and M. N. Shah, Org. Synth. IV:836 (1963). q. L. I. Smity and S. McKenzie, Jr., Org. Chem. 15:74 (1950); A. I. Vogel, Practical Organic Chemistry, third edition, Wiley (1956), p. 973. r. H. D. Durst, Tetrahedron Lett., 2421 (1974). s. G. G. Moore, T. A. Foglia, and T. J. McGahan, J. Org. Chem. 44:2425 (1979). t. C. H. Heathcock, C. T. White, J. Morrison, and D. VanDerveer, J. Org. Chem. 46:1296 (1981). u. N. G. Anderson, D. A. Lust, K. A. Colapret, J. H. Simpson, M. F. Malley, and J. Z. Glougoutas, J. Org. Chem. 61:7955 (1996). v. E. E. Schweizer and R. D. Bach, Org. Synth. V:1145 (1973). w. A. H. Ford-Moore and B. J. Perry, Org. Synth. IV:325 (1963). x. G. G. Urquhart, J. W. Gates, Jr., and R. Conor, Org. Synth. III:363 (1965). y. R. G. Gillis and A. B. Lacey, Org. Synth. IV:396 (1963). z. R. Gompper and W. Elser, Org. Synth. V:780 (1973).

Good yields are generally observed, especially for methyl ethers. The combination of boron tribromide with dimethyl sul®de has been found to be particularly effective for cleaving aryl methyl ethers.87 Trimethylsilyl iodide cleaves methyl ethers in a period of a few hours at room temperature.85 Benzyl and t-butyl systems are cleaved very rapidly, whereas secondary systems require longer times. The reaction presumably proceeds via an initially formed silyl oxonium ion:

R

O

R + (CH3)3SiI

+

R

O

R + I–

R

O

Si(CH3)3 + RI

Si(CH3)3

The direction of cleavage in unsymmetrical ethers is determined by the relative ease of O R bond breaking by either SN 2 (methyl, benzyl) or SN 1 (t-butyl) processes. Because trimethylsilyl iodide is rather expensive, alternative procedures that generate the reagent in situ have been devised:

(CH3)3SiCl + NaI

CH3CN

PhSi(CH3)3 + I2

(CH3)3SiI + NaCl (CH3)3SiI + PhI

Ref. 88 Ref. 89

Diiodosilane, SiH2 I2 ; is an especially effective reagent for cleaving secondary alkyl ethers.90 Trimethylsilyl iodide also effects rapid cleavage of esters. The ®rst products formed are trimethylsilyl esters, but these are hydrolyzed rapidly on exposure to water.91 +OSi(CH ) 3 3

O RCO

R′ + (CH3)3SiI

RCO

R′ + I–

O RCOSi(CH3)3 + R′I

O RCOSi(CH3)3 + H2O

RCO2H + (CH3)3SiOH

Benzyl, methyl, and t-butyl esters are rapidly cleaved, but secondary esters react more slowly. In the case of t-butyl esters, the initial silylation is followed by a rapid ionization to the t-butyl cation. The boron tri¯uoride±alkylthiol combination (Entries 6±8, Scheme 3.3) also operates on the basis of nucleophilic attack on an oxonium ion generated by reaction of the ether 87. P. G. Williard and C. R. Fryhle, Tetrahedron Lett. 21:3731 (1980). 88. T. Morita, Y. Okamoto, and H. Sakurai, J. Chem. Soc., Chem. Commun. 1978:874; G. A. Olah, S. C. Narang, B. G. B. Gupta, and R. Malhotra, Synthesis 1979:61. 89. T. L. Ho and G. A. Olah, Synthesis 1977:417; A. Benkeser, E. C. Mozdzen, and C. L. Muth, J. Org. Chem. 44:2185 (1979). 90. E. Keinan and D. Perez, J. Org. Chem. 52:4846 (1987). 91. T. L. Ho and G. A. Olah, Angew. Chem. Int. Ed. Engl. 15:774 (1976); M. E. Jung and M. A. Lyster, J. Am. Chem. Soc. 99:968 (1977).

163 SECTION 3.3. NUCLEOPHILIC CLEAVAGE OF CARBON±OXYGEN BONDS IN ETHERS AND ESTERS

164

with boron tri¯uoride92:

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

R

O

R + BF3

R

+

O

R

–BF

3

R

+

O



ROBF3 + RSR′ + H+

R + R′SH

–BF 3

Ether cleavage can also be effected by reaction with acetic anhydride and Lewis acids such as BF3 , FeCl3 , and MgBr2 .93 Mechanistic investigations have pointed to acylium ions generated from the anhydride and Lewis acid as the reactive electrophile: (RCO)2O + MXn +

RC

+

O + [MXnO2CR]–

RC

O + R′

O

R′

O

+

R′ + X–

R

C

O

R′

R′

+

R′

O

R′

R

C

O

X + RCO2R′

Scheme 3.3 gives some speci®c examples of ether and ester cleavage reactions.

3.4. Interconversion of Carboxylic Acid Derivatives The classes of compounds which are conveniently considered together as derivatives of carboxylic acids include the carboxylic acid anhydrides, acyl chlorides, esters, and amides. In the case of simple aliphatic and aromatic acids, synthetic transformations among these derivatives are usually a straightforward matter involving such fundamental reactions as ester saponi®cation, formation of acyl chlorides, and the reactions of amines with acid anhydrides or acyl chlorides: RCO2CH3

–OH

H 2O

RCO2H + SOCl2 RCOCl + R2′ NH

RCO2– + CH3OH RCOCl + HCl + SO2 RCONR2′ + HCl

When a multistep synthesis is being undertaken with other sensitive functional groups present in the molecule, milder reagents and reaction conditions may be necessary. As a result, many alternative methods for effecting intereconversion of the carboxylic acid derivatives have been developed, and some of the most useful reactions will be considered in the succeeding sections. 92. K. Fuji, K. Ichikawa, M. Node, and E. Fujita, J. Org. Chem. 44:1661 (1979). 93. C. R. Narayanan and K. N. Iyer, J. Org. Chem. 30:1734 (1965); B. Ganem and V. R. Small, Jr., J. Org. Chem. 39:3728 (1974); D. J. Goldsmith, E. Kennedy, and R. G. Campbell, J. Org. Chem. 40:3571 (1975).

Scheme 3.3. Cleavage of Ethers and Esters 1a

CH3O

HO

OCH3 BBr3

2b

CH

CH2

CH3O2CCH2

CH2OCH3

CO2CH3

5e

CH

CH2 88%

H

(CH3)3SiI

4d

OH

(CH3)3SiCl

83–89%

CO2Si(CH3)3 + CH3I

NaI, CH3CN

OCH3

OH (CH3)3SiI

H2O

CH3

CH3

6f O

CH3

BF3 C2H5SH

CH2

OH

CH3

Br 7g

OCH3

OH H3C BF3 C2H5SH

H H CH3

H CH3

OH

OH CH3

CH3

CH3 CH3

CH3

BF3. OEt2, EtSH NaOAc

H2C

HO

O (CH3)2BBr

75%

H H3C

8h

9i

90%

Br

H3C

PhCH2O

86%

OCH3 OCH3

H3C

SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

75–85%

O O

OCH3

OH

H2O

BBr3, CH2Cl2 –78°C

H

3c

165

Br

OH

85%

CH3 H2C

61%

Scheme 3.3. (continued )

166 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

10j

FeCl3

(CH3)2CHOCH(CH3)2

(CH3CO)2O

(CH3)2CHCO2CH3

83%

a. b. c. d. e. f. g. h.

J. F. W. McOmie and D. E. West, Org. Synth. V:412 (1973). P. A. Grieco, K. Hiroi, J. J. Reap, and J. A. Noguez, J. Org. Chem. 40:1450 (1975). M. E. Jung and M. A. Lyster, Org. Synth. 59:35 (1980). T. Morita, Y. Okamoto, and H. Sakurai, J. Chem. Soc., Chem. Commun. 1978:874. E. H. Vickery, L. F. Pahler, and E. J. Eisenbraun, J. Org. Chem. 44:4444 (1979). K. Fuji, K. Ichikawa, M. Node, and E. Fujita, J. Org. Chem. 44:1661 (1979). M. Nobe, H. Hori, and E. Fujita, J. Chem. Soc., Perkin Trans 1 1976:2237. A. B. Smith III, N. J. Liverton, N. J. Hrib, H. Sivaramakrishnan, and K. Winzenberg, J. Am. Chem. Soc. 108:3040 (1986). i. Y. Guindon, M. Therien, Y. Girard, and C. Yoakim, J. Org. Chem. 52:1680 (1987). j. B. Ganem and V. R. Small, Jr., J. Org. Chem. 39:3728 (1974).

3.4.1. Preparation of Reactive Reagents for Acylation The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. O H3C H3C

O H3C

H ClCOCOCl 25°C

H

H3C

H Ref. 94

H

CO2Na

COCl

Acyl chlorides are highly reactive acylating agents and react very rapidly with amines. For alcohols, preparative procedures often call for use of pyridine as a catalyst. Pyridine catalysis involves initial formation of an acylpyridinium ion, which then reacts with the alcohol. Pyridine is a better nucleophile than the neutral alcohol, but the acylpyridinium ion reacts more rapidly with the alcohol than the acyl chloride.95 O RCCl + N

O RC

N

+

R′OH

O RCOR′ + HN +

Cl–

An even stronger catalytic effect is obtained when 4-dimethylaminopyridine (DMAP) is used as a nucleophilic catalyst.96 The dimethylamino group acts as an electron-donor 94. M. Miyano and C. R. Dorn, J. Org. Chem. 37:268 (1972). 95. A. R. Fersht and W. P. Jencks, J. Am. Chem. Soc. 92:5432, 5442 (1970). 96. G. Ho¯e, W. Steglich, and H. Vorbruggen, Angew. Chem. Int. Ed. Engl. 17:569 (1978); E. F. V. Scriven, Chem. Soc. Rev. 12:129 (1983).

substituent, increasing both the nucleophilicity and the basicity of the pyridine nitrogen. H3C .. CH3 N

H3C

+

N

SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

CH3

.. N .. –

N ..

The inclusion of DMAP to the extent of 5±20 mol% in acylations by acid anhydrides and acyl chlorides increases acylation rates by up to four orders of magnitude and permits successful acylation of tertiary and other hindered alcohols. (CH3)2N

(CH3)2N

O

(CH3)2N O

CR +

N H3C

C

CH3COR′ +

–O

+

N

H O

O

H3C

R′

C

N OR′

O–

The reagent combination of an acid anhydride with MgBr2 and a hindered tertiary amine, for example, …i-Pr†2 N…C2 H5 † or 1,2,2,6,6,-pentamethylpiperidine, gives an even more reactive acylation system which is useful for hindered and sensitive alcohols.97 Another ef®cient catalyst for acylation is Sc…O3 SCF3 †3 . It can be used in combination with anhydrides98 and other reactive acylating agents99 and is a mild reagent for acylation of tertiary alcohols. Other lanthanide tri¯ates have similar catalytic effects. Yb…O3 SCF3 †3 and Lu…O3 SCF3 †3 , for example, were used in selective acylation of 10-deacetylbaccatin III, an important intermediate for preparation of the antitumor agent paclitaxel (taxol).100 HO

O

CH3CO2

OH Lu(O3SCF3)3

HO

(CH3CO)2O

HO

H PhCO2

O

OH

HO

O O2CCH3

167

HO

H PhCO2

O O2CCH3

Trimethylsilyl tri¯ate is also a powerful catalyst for acylations by anhydrides. Reactions of alcohols with a modest excess (1.5 equiv) of anhydride proceed in inert solvents at 0 C. Even tertiary alcohols react rapidly.101 The active acylation reagent is 97. E. Vedejs and O. Daugulis, J. Org. Chem. 61:5702 (1996). 98. K. Ishihara, M, Kubota, H., Kurihara, and H. Yamamoto, J. Org. Chem. 61:4560 (1996); A. G. M. Barrett and D. C. Braddock, J. Chem. Soc., Chem. Commun. 1997:351. 99. H. Zhao, A. Pendri, and R. B. Greenwald, J. Org. Chem. 63:7559 (1998). 100. E. W. P. Damen, L. Braamer, and H. W. Scheeren, Tetrahedron Lett. 39:6081 (1998). 101. P. A. Procopiou, S. P. D. Baugh, S. S. Flack, and G. G. A. Inglis, J. Org. Chem. 63:2342 (1998).

168 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

presumably generated by O-silylation of the anhydride. CH3

CH3

OH

O2CCH3

(CH3CO)2O 5 equiv (CH3)3SiO3SCF3 5 mol %

Tri-n-butylphosphine is also an effective catalyst for acylations by anhydrides. It is thought to act as a nucleophilic catalyst by generating an acylphosphonium ion.102 O

O O Bu3P + RCOCR

CR + RCO2–

P+

Bu3

There are other activation procedures which generate acyl halides in situ in the presence of the nucleophile. Re¯uxing a carboxylic acid, triphenylphosphine, bromotrichloromethane, and an amine gives rise to the corresponding amide103. O RCO2H + R′NH2

PPh3, CBrCl3

RCNR′ H

This reaction presumably proceeds via the acyl chloride, because it is known that triphenylphosphine and carbon tetrachloride convert acids to the corresponding acyl chloride.104 Similarly, carboxylic acids react with the triphenylphosphine±bromine adduct to give acyl bromides.105. Triphenylphosphine=N -bromosuccinimide also generates acyl bromides in situ.106 Alcohols can be esteri®ed by heating in excess ethyl formate or ethyl acetate and triphenylphosphine in carbon tetrabromide.107 All these reactions are mechanistically analogous to the alcohol-to-halide conversions that were discussed in Section 3.1.2. O +

RCO2H + Ph3PBr O Br– + RC

RC

O

+

PPh3 + HBr

O O

+

PPh3

RCBr + Ph3P

O

In addition to acyl chlorides and acyl bromides, there are a number of milder and more selective acylating agents which can readily prepared from carboxylic acids. Imidazolides, the N -acyl derivatives of imidazole, are examples.108 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with 102. E. Vedejs, N. S. Bennett, L. M. Conn, S. T. Diver, M. Gingras, S. Lin, P. A. Oliver, and M. J. Peterson, J. Org. Chem. 58:7286 (1993); E Vedejs and S. T. Diver, J. Am. Chem. Soc. 115:3358 (1993). 103. L. E. Barstow and V. J. Hruby, J. Org. Chem. 36:1305 (1971). 104. J. B. Lee, J. Am. Chem. Soc. 88:3440 (1966). 105. H. J. Bestmann and L. Mott, Justus Liebigs Ann. Chem. 693:132 (1966). 106. K. Sucheta, G. S. R. Reddy, D. Ravi, and N. Rama Rao, Tetrahedron Lett. 35:4415 (1994). 107. H. Hagiwara, K. Morohashi, H. Sakai, T. Suzuki, and M. Ando, Tetrahedron 54:5845 (1998). 108. H. A. Staab and W. Rohr, Newer Methods Prep. Org. Chem. 5:61 (1968).

169

carbonyldiimidazole. O RCO2H + N

N

O

C

N

N

RC

N

N + HN

N + CO2

Two factors are responsible for the high reactivity of the imidazolides as acylating reagents. One is the relative weakness of the ``amide'' bond. Because of the aromatic character of imidazole, there is little of the N ! CˆO delocalization that stabilizes normal amides. The reactivity of the imidazolides is also enhanced by protonation of the other imidazole nitrogen, which makes the imidazole ring a better leaving group. O Nu + RC

O N

N

H+

Nu

CR + N

NH

Imidazolides can also be activated by N-alkylation with methyl tri¯ate.109 Imidazolides react with alcohols on heating to give esters and react at room temperature with amines to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive materials. Dicyclohexylcarbodiimide (DCC) is another example of a reagent which converts carboxylic acids to reactive acylating agents. This compound has been particularly widely applied in the acylation step in the synthesis of polypeptides from amino acids.110 (See also Section 13.6). The reactive species is an O-acyl isourea. The acyl group is highly reactive in this environment because the cleavage of the acyl±oxygen bond converts the carbon±nitrogen double bond of the isourea to a more stable carbonyl group.111 O RCO2H + RN O RC

C

NR

NR O

CNHR

RC O

H+

NR O

CNHR O

RCNu + RNHCNHR

Nu

The combination of carboxyl activation by DCC and catalysis by DMAP provides a useful method for in situ activation of carboxylic acids for reaction with alcohols. The reaction proceeds at room temperature112: Ph2CHCO2H + C2H5OH

DCC DMAP

Ph2CHCO2C2H5

2-Chloropyridinium113 and 3-chloroisoxazolium114 cations also activate carbonxyl groups toward nucleophilic attack. In each instance, the halide is displaced from the 109. G. Ulibarri, N. Choret, and D. C. H. Bigg, Synthesis 1996:1286. 110. F. Kurzer and K. Douraghi-Zadeh, Chem. Rev. 67:107 (1967). 111. D. F. DeTar and R. Silverstein, J. Am. Chem. Soc. 88:1013, 1020 (1966); D. F. DeTar, R. Silverstein, and F. F. Rogers, Jr., J. Am. Chem. Soc. 88:1024 (1966). 112. A. Hassner and V. Alexanian, Tetrahedron Lett. 1978:4475; B. Neises and W. Steglich, Angew. Chem. Int. Ed. Engl. 17:522 (1978). 113. T. Mukaiyama, M. Usui, E. Shimada, and K. Saigo, Chem. Lett. 1975:1045. 114. K. Tomita, S. Sugai, T. Kobayashi, and T. Murakami, Chem. Pharm. Bull. 27:2398 (1979).

SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

170 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

heterocycle by the carboxylate via an addition±elimination mechanism. Nucleophilic attack on the activated carbonyl group results in elimination of the heterocyclic ring with the departing oxygen being converted to an amide-like structure. The positive charge on the heterocylic ring accelerates both the initial addition step and subsequent elimination of the heterocycle. O + RCO2H +

N

Nu

+

Cl

R′

+ RC

N

OCR

N

R′

O

R′

Nu

O

Carboxylic acid esters of thiols are considerably more reactive as acylating reagents than are the esters of alcohols. Particularly reactive are esters of pyridine-2-thiol because there is an additional driving forceÐthe formation of the more stable pyridine-2-thione tuatomer: O Nu

O Nu RC

S

CR +

N

S

N H

Additional acceleration of the rate of acylation can be obtained by inclusion of cupric salts that coordinate at the pyridine nitrogen. This modi®cation is especially useful for preparation of highly hindered esters.115 Pyridine-2-thiol esters can be prepared by reaction of the carboxylic acid with 2,20 -dipyridyl disul®de and triphenylphosphine116 or directly from the acid and 2-pyridyl thiochloroformate.117

PPh3

RCO2H + N

S

S

N

+ R3′N

RCO2H + N

SCCl

O RC

+ Ph3P

+

+ CO2 + R3′ NH Cl

O RC

O

N

S

S

N

O

The 2-pyridyl and related 2-imidazolyl disul®des have found special use in the closure of large lactone rings.118 This type of structure is encountered in a number of antibiotics which, because of the presence of numerous other sensitive functional groups, require mild conditions for cyclization. It has been suggested that the pyridyl and imidazoyl thioesters function by a mechanism in which the heterocyclic nitrogen acts as 115. 116. 117. 118.

S. Kim and J. I. Lee, J. Org. Chem. 49:1712 (1984). T. Mukaiyama, R. Matsueda, and M. Suzuki, Tetrahedron Lett. 1970:1901. E. J. Corey and D. A. Clark, Tetrahedron Lett. 1979:2875. E. J. Corey and K. C. Nicolaou, J. Am. Chem. Soc., 96:5614 (1974); K. C. Nicolaou, Tetrahedron 33:683 (1977).

171

a base, deprotonating the alcohol group:

SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

O N

S

+

C(CH2)xCH2OH

+

N

S

N

S

H

C(CH2)xCH2O–

H

C

O



O

(CH2)x O

CH2

O + N H

S

C

(CH2)x

O

CH2

This provides a cyclic transition state in which hydrogen bonding can enhance the reactivity of the carbonyl group.119 Excellent yields of large-ring lactones are achieved by this method. HO

HO CO2H C

THPO H

O

CH3

CH3

HOC(CH2)3 O H H C C (CH2)3 O

N

S

O

2

75%

O

Ph3P

THPO

O Ref. 118

R N

R N

HO2CCH2CH2CH CH

S R

S N

N

O

R

O

Ph3P

CH OH

CHCH(CH2)4CH3 OH

50%

H2 C

CH O

H2C O

CHCH(CH2)4CH3 OH Ref. 120

Intramolecular lactonization can also be carried out with DCC and DMAP. As with other macrolactonizations, the reactions must be carried out in rather dilute solution to promote the intramolecular transformation in competition with intermolecular reaction, which leads to dimers or higher oligomers. A study with 15-hydroxypentadecanoic acid has demonstrated that a proton source is bene®cial under these conditions and found the hydrochloride of DMAP to be convenient.121 O HO(CH2)14CO2H

DMAP DMAPH+ –Cl DCC

O

C

(CH2)14

119. E. J. Corey, K. C. Nicolaou, and L. S. Melvin, Jr., J. Am. Chem. Soc. 97:654 (1975); E. J. Corey, D. J. Brunelle, and P. J. Stork, Tetrahedron Lett. 1976:3405. 120. E. J. Corey, H. L. Pearce, I. Szekely, and M. Ishiguro, Tetrahedron Lett. 1978:1023. 121. E. P. Boden and G. E. Keck, J. Org. Chem. 50:2394 (1985).

172 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

Scheme 3.4 gives some typical examples of preparation and use of active acylating agents from carboxylic acids. 3.4.2. Preparation of Esters As mentioned in the preceding section, one of the most general methods of synthesis of esters is by reaction of alcohols with an acyl chloride or other activated carboxylic acid derivative. Section 3.2.4 included a discussion of two other important methods, namely, reactions with diazoalkanes and reactions of carboxylate salts with alkyl halides or sulfonate esters. There remains to be mentioned the acid-catalyzed reaction of carboxylic acids with alcohols, which is frequently referred to as Fischer esteri®cation: RCO2H + R′OH

H+

RCO2R′ + H2O

This is an equilibrium process, and there are two techniques which are used to drive the reaction to completion. One is to use a large excess of the alcohol. This is feasible for simple and relatively inexpensive alcohols. The second method is to drive the reaction forward by irreversible removal of water. Azeotropic distillation is one method for doing this. Entries 1±4 in Scheme 3.5 are examples of acid-catalyzed esteri®cations. Entry 5 is the preparation of a diester starting with an anhydride. This is a closely related reaction in which the initial opening of the anhydride ring is followed by an acid-catalyzed esteri®cation. 3.4.3. Preparation of Amides By far the most common method for preparation of amides is the reaction of ammonia or a primary or secondary amine with one of the reactive reagents described in Section 3.4.1. When acyl halides are used, some provision for neutralizing the hydrogen halide is necessary, because it will otherwise react with the reagent amine to form the corresponding salt. Acid anhydrides give rapid acylation of most amines and are convenient if available. The Schotten±Bauman conditions, which involve shaking an amine with excess anhydride or acyl chloride and an alkaline aqueous solution, provide a very satisfactory method for preparation of simple amides. O NH + PhCCl

O NaOH

N

CPh

90%

Ref. 122

A great deal of work has been done on the in situ activation of carboxylic acids toward nucleophilic substitution by amines. This type of reaction forms the backbone of the methods for synthesis of peptides and proteins. (See also Section 13.6). DCC is very widely used for coupling carboxylic acids and amines to give amides. Because amines are better nucleophiles than alcohols, the leaving group in the acylation reagent need not be as reactive as is necessary for alcohols. The p-nitrophenyl123 and 2,4,5-trichlorophenyl124 122. C. S. Marvel and W. A. Lazier, Org. Synth. I:99 (1941). 123. M. Bodanszky and V. DuVigneaud, J. Am. Chem. Soc. 81:5688 (1959). 124. J. Pless and R. A. Boissonnas, Helv. Chim. Acta 46:1609 (1963).

Scheme 3.4. Preparation of Active Acylating Agents 1a

CH3

CH3

CH3CO2

CH3

CH3 ClCOCOCl 25°C

CO2H

173 SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

COCl

CH3

CH3

CH3CO2 CH3

2b (CH3)2C

CHCH2CH2C

CHCH2CH2CH2CO2– Na+

ClCOCOCl

CH3 (CH3)2C 3c

O N

N

C

N

CH2

N

CHCHCH2

N

CH

OH

PhCO2H

CHCH2CH2C

CHCH2CH2CH2COCl

CH2 N

PhCO2CHCH2

60%

O

4d CO2H + HO

DCC

NO2

C

O

NO2

5e +

N

Cl

CH3

PhCH2CO2H

CH3

O

PhCHOH

PhCH2COCHPh

88%

CH3 6f O

CH3CH

7g

CHCH

N

CHCO2H

HCO2CH2

O

SCCl

CH3CH

CH3

O O

(CH2

CHCS

N

HCO2CH2

CCO)2O

O O

DMAP

HCO2(CH2)3CH CH3

CHCH

HCO2(CH2)3CH OH

CH2

CH3

CH3

OCC

CH2 CH2

O 8h

R3SiO

OCH3

R3SiO

O H

OCH3

H

H3C H

OH

CO2H DCC, DMAP

CH2CH3

O

CH3CHCH2CH3

H

H

H3C H

O2CCH CH3

97%

Scheme 3.4. (continued )

174 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

(CH2)5CH3

9i HO2C(CH2)6CH2

H O

1) 2,2′-dipyridyl disulfide, Ph3P 2) AgClO4

CH2CH(CH2)5CH3

H

O 84–88%

OH

10j

HO2C Cl

OTBDMS Cl CH3

CH3 NH CH3

CH3O

CH3

S

OMEM

CH3 CH3

CH3 (n-Bu)3N

S

OMEM

S CH3

CH3

TBDPSOCH2

66%

TBDPSOCH2 CH3

CH3

O

CH3OCH2O

OTBDMS

NC

Cl

S CH3

CH3 11k

CH3O

+

N

O

O

CH3OCH2O O

OH

O

BOP-Cl, (C2H5)3N 100°C

O

50%

O

CO2H

(CH3)3Si

CH2OCH3

(CH3)3Si

CH2OCH3

(TBPP = tert-butyldiphenylsilyl)

a. b. c. d. e. f. g. h. i. j. k.

J. Meinwald, J. C. Shelton, G. L. Buchanan, and A. Courtain, J. Org. Chem. 33:99 (1968). U. T. Bhalerao, J. J. Plattner, and H. Rapaport, J. Am. Chem. Soc. 92:3429 (1970). H. A. Staab and Rohr, Chem. Ber. 95:1298 (1962). S. Neelakantan, R. Padmasani, and T. R. Seshadri, Tetrahedron 21:3531 (1965). T. Mukaiyama, M. Usui, E. Shimada, and K. Saigo, Chem. Lett. 1975:1045. E. J. Corey and D. A. Clark, Tetrahedra Lett. 1979:2875. P. A. Grieco, T. Oguri, S. Gilman, and G. DeTitta, J. Am. Chem. Soc. 100:1616 (1978). Y.-L. Yang, S. Manna, and J. R. Falck, J. Am. Chem. Soc. 106:3811 (1984). A. Thalman, K. Oertle, and H. Gerlach, Org. Synth. 63:192 (1984). M. Benechie and F. Khuong-Huu, J. Org. Chem. 61:7133 (1996). W. R. Rousch and R. J. Sciotti, J. Am. Chem. Soc. 120:7411 (1998).

esters of amino acids are suf®ciently reactive toward amines to be useful in peptide synthesis. Acyl derivatives of N -hydroxysuccinimide are also useful for synthesis of peptides and other types of amides.125,126 Like the p-nitrophenyl esters, the acylated 125. G. W. Anderson, J. E. Zimmerman, and F. M. Callahan, J. Am. Chem. Soc. 86:1839 (1964). 126. E. Wunsch and F. Drees, Chem. Ber. 99:110 (1966); E. Wunsch, A. Zwick, and G. Wendlberger, Chem. Ber. 100:173 (1967).

Scheme 3.5. Acid-Catalyzed Esteri®cation ArSO3H

1a CH3CO2H + HOCH2CH2CH2Cl

H2SO4

CCO2H + CH3OH

3c

CHCO2H + CH3CHCH2CH3

CH3CH

25°C, 4 days

OH 4d PhCHCO2H + C2H5OH

CH3CO2CH2CH2CH2Cl

benzene, azeotropic removal of water

2b HO2CC

HCl 78°C, 5 h

CH3O2CC H2SO4 benzene, azeotropic removal of water

PhCHCO2C2H5

OH

CCO2CH3

CH3CH

SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

93–95%

72–88%

CHCO2CHCH2CH3

85–90%

CH3

82–86%

OH

5e

O H2C

H2C O + CH3OH

CO2CH3

ArSO3H

80–90%

67–68°C, 40 h

CO2CH3

O a. b. c. d. e.

175

C. F. H. Allen and F. W. Spangler, Org. Synth. III:203 (1955). E. H. Huntress, T. E. Lesslie, and J. Bornstein, Org. Synth. IV:329 (1963). J. Munch-Petersen, Org. Synth. V:762 (1973). E. L. Eliel, M. T. Fisk, and T. Prosser, Org. Synth. IV:169 (1963). H. B. Stevenson, H. N. Cripps, and J. K. Williams, Org. Synth. V:459 (1973).

N -hydroxysuccinimides can be isolated and puri®ed, but they react rapidly with free amino groups.

O O

O R1 O

R2 O

+ H2NCHCY

XCNHCHCO N O

O

R2 O

R1 O

XCNHCHCNHCHCY + HO N O

The N -hydroxysuccinimide that is liberated is easily removed because of its solubility in dilute base. The relative stability of the anion of N -hydroxysuccinimide is also responsible for the acyl derivative being reactive toward nucleophilic attack by an amino group. Esters of N -hydroxysuccinimide are also used to carry out chemical modi®cation of peptides, proteins, and other biological molecules by acylation of nucleophilic groups in these molecules. For example, detection of estradiol antibodies can be accomplished using

176

an estradiol analog to which a ¯uorescent label has been attached.

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

HO OH C

O

C(CH2)4NH2 +

O O O2C

N

HO

fluorescein

O O HO O Ref. 127 O

OH C

C(CH2)4NHC O

O

HO

Similarly, photolabels such as 4-azidobenzoylglycine can be attached to peptides and used to detect the peptide binding sites in proteins.128 O O decapeptide—NH2 +

N

O2CCH2NHC

N3 O

O

decapeptide

NH

O

CCH2NHC

N3

1-Hydroxybenzotriazole is also useful in conjunction with DCC.129 For example, tbutoxycarbonyl (Boc)-protected leucine and the methyl ester of phenylalanine can be coupled in 88% yield with these reagents. CH2CH(CH3)2 BocNHCHCO2H

CH2Ph + H2NCHCO2CH3

(CH3)2CHCH2 DCC N-hydroxybenzotriazole, N-ethylmorpholine

CH2Ph

BocNHCHCNHCHCO2CH3

Ref. 130

O

Carboxylic acids can also be activated by formation of mixed anhydrides with various phosphoric acid derivatives. Diphenylphosphoryl azide, for example, is an effective 127. M. Adamczyk, Y.-Y. Chen, J. A. Moore, and P. G. Mattingly, Biorg. Med. Chem. Lett. 8:1281 (1998); M. Adamczyk, J. R. Fishpaugh, and K. J. Heuser, Bioconjug. Chem. 8:253 (1997). 128. G. C. Kundu, I. Ji, D. J. McCormick, and T. H. Ji, J. Biol. Chem. 271:11063 (1996). 129. W. Konig and R. Geiger, Chem. Ber. 103:788 (1970). 130. M. Bodanszky and A. Bodanszky, The Prentice of Peptide Synthesis, 2nd ed., Springer-Verlag, Berlin, 1994, pp. 119±120.

reagent for conversion of amines to amides.131 The postulated mechanism involves formation of the acyl azide as a reactive intermediate: O

O

RCO2– + (PhO)2PN3 O RC

RC

O O

O O

P(OPh)2 + N3–

O

P(OPh)2 + N3–

RCN3 + –O2P(OPh)2

O

O

RCN3 + R′NH2

RCNHR′ + HN3

Another useful reagent for amide formation is compound 1, known as BOP-Cl.132 This reaction also proceeds via a mixed carboxylic phosphoric anhydride. O O O RCO2– + O

N

P

N

O O

N

RC

O

Cl 1

O

P

O

N O

O O

The preparation of amides directly from alkyl esters is also feasible but is usually too slow for preparative convenience. Entries 4 and 5 in Scheme 3.6 are successful examples. The reactivity of ethyl cyanoacetate (entry 4) is higher than that of unsubstituted aliphatic esters because of the inductive effect of the cyano group. Another method for converting esters to amides involves aluminum amides, which can be prepared from trimethylaluminum and the amine. These reagents convert esters directly to amides at room temperature.133 O CO2CH3

H (CH3)2AlNCH2Ph

CNHCH2Ph

78%

The driving force for this reaction is the strength of the aluminum±oxygen bond relative to the aluminum±nitrogen bond. This reaction provides a good way of making synthetically useful amides of N -methoxy-N -methylamine.134 Trialkylamidotin and bis(hexamethyldi131. T. Shiori and S. Yamada, Chem. Pharm. Bull. 22:849 (1974); T. Shioiri and S. Yamada, Chem. Pharm. Bull. 22:855 (1974); T. Shioiri and S. Yamada, Chem. Pharm. Bull. 22:859 (1974). 132. J. Diago-Mesequer, A. L. Palomo-Coll, J. R. Fernandez-Lizarbe, and A. Zugaza-Bilbao, Synthesis 1980:547; R. D. Tung, M. K. Dhaon, and D. H. Rich, J. Org. Chem. 51:3350 (1986); W. J. Colucci, R. D. Tung, J. A. Petri, and D. H. Rich, J. Org. Chem. 55:2895 (1990); J. Jiang, W. R. Li, R. M. Przeslawski, and M. M. Joullie, Tetrahedron Lett. 34:6705 (1993). 133. A. Basha, M. Lipton, and S. M. Weinreb, Tetrahedron Lett. 1977:4171; A. Solladie-Cavallo and M. Benchegroun, J. Org. Chem. 57:5831 (1992). 134. J. I. Levin, E. Turos, and S. M. Weinreb, Synth. Commun. 12:989 (1982); T. Shimizu, K. Osako, and T. Nakata, Tetrahedron Lett. 38:2685 (1997).

177 SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

Scheme 3.6. Synthesis of Amides

178 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

A. From acyl chlorides and anhydrides O 1

a

1) SOCl2

(CH3)2CHCO2H

(CH3)2CHCNH2

2) NH3

70%

O

2b

1) SOCl2

CO2H

CN(CH3)2

2) (CH3)2NH

85–90%

O 3c (CH3CO)2O + H2NCH2CO2H

CH3CNCH2CO2H H

90%

B. From esters O 4

d

NCCH2CO2C2H5

5e

NH4OH

OH

NCCH2CNH2

OH

CH3 trichlorobenzene

+ CO2Ph

75%

185–200°C

H2N

C

NH

O

CH3

C. From carboxylic acids 6f

N3

N3 CO2CH3

N H

PhCO2H, DCC EtN

CO2CH3

N CPh

63%

O 7g

CH2CN

CH2CN

CO2H +

Et3N

NH2

N O

Cl

O

O O

8h

CNH P

2

OCH3

OCH3 OCH3

OCH3 + H2N(CH2)2CO2H

DCC

82%

O

CO2H

CONH(CH2)2CO2H NOH O

D. From nitriles O

9i CH2CN

HCl, H2O 40–50°C, 1h

CH2CNH2

80%

Scheme 3.6. (continued ) 10j

CH3 CN

179

CH3

30% H2O2, NaOH

SECTION 3.4. INTERCONVERSION OF CARBOXYLIC ACID DERIVATIVES

90%

40–50°C, 4h

CNH2 O

a. b. c. d. e. f. g. h. i. j.

R. E. Kent and S. M. McElvain, Org. Synth. III:490 (1955). A. C. Cope and E. Ciganek, Org. Synth. IV:339 (1963). R. M. Herbst and D. Shemin, Org. Synth. II:11 (1943). B. B. Corson, R. W. Scott, and C. E. Vose, Org. Synth. I:179 (1941). C. F. H. Allen and J. Van Allan, Org. Synth. III:765 (1955). D. J. Abraham, M. Mokotoff, L. Sheh, and J. E. Simmons, J. Med. Chem. 26:549 (1983). J. Diago-Mesenguer, A. L. Palamo-Coil, J. R. Fernandez-Lizarbe, and A. Zugaza-Bilbao, Synthesis 1980:547. R. J. Bergeron, S. J. Kline, N. J. Stolowich, K. A. McGovern, and P. S. Burton, J. Org. Chem. 46:4524 (1981). W. Wenner, Org. Synth. IV:760 (1963). C. R. Noller, Org. Synth. II:586 (1943).

silylamido)tin amides as well as tetrakis(dimethylamino)titanium show similar reactivity.135 The cyano group is at the carboxylic acid oxidation level so nitriles are potential precursors of primary amides. Partial hydrolysis is sometimes possible.136

O PhCH2C

N

HCl, H2O 40–50°C 1h

PhCH2CNH2

A milder procedure involves the reaction of a nitrile with an alkaline solution of hydrogen peroxide.137 The strongly nucleophilic hydrogen peroxide adds to the nitrile, and the resulting adduct gives the amide. There are several possible mechanisms for the subsequent decomposition of the peroxycarboximidic adduct.138

NH RC

N + –O2H

RCOO–

NH

O

H2O

RCOOH + H2O2

RCNH2 + O2 + H2O

In all the mechanisms, the hydrogen peroxide is converted to oxygen and water, leaving the organic substrate hydrolyzed, but at the same oxidation level. Scheme 3.6 (Entries 9 and 10) includes two speci®c examples of conversion of nitriles to amides. 135. G. Chandra, T. A. George, and M. F. Lappert, J. Chem. Soc., C 1969:2565; W.-B. Wang and E. J. Roskamp, J. Org. Chem. 57:6101 (1992); W.-B. Wang, J. A. Restituyo, and E. J. Roskamp, Tetrahedron Lett. 34:7217 (1993). 136. W. Wenner, Org. Synth. IV:760 (1963). 137. C. R. Noller, Org. Synth. II:586 (1943); J. S. Buck and W. S. Ide, Org. Synth. II:44 (1943). 138. K. B. Wiberg, J. Am. Chem. Soc. 75:3961 (1953); J. Am. Chem. Soc. 77:2519 (1955); J. E. McIsaac, Jr., R. E. Ball, and E. J. Behrman, J. Org. Chem. 36:3048 (1971).

180

Problems

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

(References for these problems will be found on page 926.) 1. Give the products which would be expected to be formed under the speci®ed reaction conditions. Be sure to specify all aspects of stereochemistry. (a) CH3CH2

(b)

O

O

HCl CH3OH ELH2N(i-Pr)2

CH3(CH2)4CH2OH + ClCH2OCH3

(c)

CH2Cl2 +

C2H5 N

(S)-CH3(CH2)3CHCH3 +

Et3N

Cl

Et4N+Cl–

O

OH

1) Ph3P, HN3

(d) C2H5O2CCH2CHCO2C2H5

2) C2H5O2CN NCO2C2H5

OH O

(e)

(f)

CH3

N(CR)2 PPh3

N

N HOCH2

O2CR

C2H5

(h)

CO2CH3

H CH2CO2H

BBr3, –78°C

Ph

0°C, 1 h CH2Cl2

OCH3

(i)

CH3CHCH2OH

O

RCO2

(g)

DMF, 20°C 10 min

N

N

CCl4

+

(PhO)3PCH3 I–

1) p-toluenesulfonyl chloride 2) PhS– Na+

H OH

(j)

(C6H5)2CHBr + P(OCH3)3

CH3SO2OCH2

Na2S HMPA

CH3SO2OCH2

(k)

(l)

O

CH3O

CO2H

H

CH3O NCH2C6H5

48% HBr heat

C C2H5O2C

C H

t-BuOH DCC, DMAP

2. When …R†-… †-5-hexen-2-ol was treated with triphenylphosphine in re¯uxing carbon tetrachloride, (‡)-5-chloro-1-hexene was obtained. Conversion of (R)-( )-5-hexen-2ol to its p-bromobenzenesulfonate ester and subsequent reaction with lithium chloride

gave (‡)-5-chloro-1-hexene. Reaction of …S†-…‡†-5-hexen-2-ol with phosphorus pentachloride in ether gave ( )-5-chloro-1-hexene. (a) Write chemical equations for each of the reactions described above and specify whether each one proceeds with net retention or inversion of con®guration. (b) What is the sign of rotation of (R)-5-chloro-1-hexene? 3. A careful investigation of the extent of isomeric products formed by reaction of several alcohols with thionyl chloride has been reported. The product compositions for several of the alcohols are given below. Show how each of the rearranged products arises and discuss the structural features which promote isomerization.

ROH

R CH3CH2CH2CH2

RCl Structure and amount of rearranged RCl

Percent unrearranged RCl 100 99.7

(CH3)2CHCH2 (CH3)2CHCH2CH2

SOCl2 100°C

(CH3)2CHCH3 Cl

100 78

CH3CH2CHCH2

CH3CHCH2CH2CH3, CH3CH2CHCH2CH3, CH3CH2C(CH3)2

CH3

Cl

(CH3)3CCH2

0.3%

Cl

1%

CH3CH2C(CH3)2

98

CH3CH2CHCH2CH3

Cl CH3CH2CH2CHCH3

Cl CH3CH2CHCH2CH3

10%

98%

2%

CH3CH2CH2CHCH3

90

Cl 5

(CH3)2CHCHCH3

Cl

11%

2

10%

CH3CH2C(CH3)2 Cl

95%

4. Give a reaction mechanism which will explain the following observations and transformations. (a) Kinetic measurements reveal that solvolytic displacement is about 5  105 faster for B than for A. OSO2Ar

OSO2Ar

O O A

B

181 PROBLEMS

182 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

Br

(b) H2N

(c)

HOAc

CH2CH2CO2CH3 H

S

S

H

CH3 H3C

O

H H N

Br

H

S

C6H5

O

1) (CH3)3O+PF6 – 2) NaCN

CH3 CH3SCHCH2C

H3C

CH3 SOCl2

(d) C6H5CH2SCH2CHCH2SCH2C6H5

CHC6H5

CH3

CN

C6H5CH2SCH2CHCH2Cl

OH

(e)

O

SCH2C6H5 HO

HO

O CO2CH2CH3 CN

NH

KOH t-BuOH

O N

N

(f)

CH3(CH2)6CO2H + PhCH2NH2

(g)

o-nitrophenyl isothiocyanate Bu3P, 25°C

O CH3(CH2)6CNCH2Ph H

99%

OH EtO2CN NCO2Et

NO2

PPh3

92%

CH2NO2

(h) Both C and D gave the same product when subjected to Mitsunobu conditions with phenol as the nucleophile. OH

N(CH3)2 N(CH3)2

C

OH OPh

EtO2CN NCO2Et

EtO2CN NCO2Et

PPh3, PhOH

D

PPh3, PhOH

N(CH3)2

5. Substances such as carbohydrates, amino acids, and other small molecules available from natural sources are valuable starting materials for the synthesis of stereochemically de®ned substances. Suggest a sequence of reactions which could effect the following transformations, taking particular care to ensure that the product would be obtained stereochemically pure. (a)

H O (CH3)2NC

CH3 O O C H

C

CN(CH3)2 OCH3

from

H OH CO2CH3 C CH3O2C C OH H

(b)

OCH3

CH3O

from N CH3

(c)

Ph2P from

CH2PPh2

(CH3)3COC OCH3

CH3O N

from

N

O

O O H C

Ph2P H3C

(f)

HO

PPh2 CH3

from

H

H CH3

O

C

H H C C CH3 H3C OH H3C

OCH2Ph C

C H

(g)

O

H OCH3 C CH2NHCH3 C CH3NHCH2 OCH3 H

CH3

H3C

CH2OH

N

O

(CH3)3COC

(e)

PROBLEMS

HO

N

(d)

183

H OCH3 CH2OH C C HOCH2 O H CH3

CH2CH2CH(SC2H5)2

from

O

PhCH2O

N3

OCH3 O2CCH3 CH2CO2CH3

O

HO

from

H

CO2H C CH2CO2H

CO2CH3

(h)

CH3

CH3 OTBDMS

O O

O

OCH3

OTBDMS

O

from

O

OH

OCH3

SO2-p-C6H4NO2

(i)

O-t-Bu

O-t-Bu

from PhCH2OCH2

O

O

PhCH2OCH2

O

O

6. Suggest reagents and reaction conditions which could be expected to effect the following conversions. (a)

CH3O CH3O CH3O

CH3O CH2CH2CH2CH2OH

CH3O CH3O

CH2CH2CH2CH2I

184

(b)

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

CH(CH3)2 (CH3)2CH

CH(CH3)2

CO2H

(CH3)2CH

CO2CH2CH

CH(CH3)2

(c)

O H

(d)

CH(CH3)2 O

CH3 H

O CH3 CH2OH

CH2

CH3

O CH3 CH2CN

CH2SH

CH2OH

(more than one step is required)

CH2OH

(e)

CH2SH

O CH2CH2CH2CH2OH

O CH2CH2CH2CH2OH (CH3)3COCNCHCNHOCH2C6H5 H O

(CH3)3COCNCHCO2H H

(f)

HO

Br CH2CH

CH HO

CH2CH

CH(CH2)3CO2CH3

CHCH(CH2)4CH3

CH Br

OSiR3

(g) (CH3)2CCH2CHCH3 OH

CH(CH2)3CO2CH3

CHCH(CH2)4CH3 OSiR3

(CH3)2CCH2CHCH3

OH

Br

OH

7. Provide a mechanistic interpretation for each of the following observations. (a) A procedure for inverting the con®guration of alcohols has been developed and demonstrated using cholesterol as a substrate: H3C H3C

C8H17

H3C

C8H17

H3C

1) Ph3P, HCO2H 2) C2H5O2CN NCO2C2H5

HO

HCO2

Show the details of the mechanism of the key step which converts cholesterol to the inverted formate ester. (b) It has been found that triphenylphosphine oxide reacts with tri¯uoromethylsulfonic anhydride to give an ionic substance with the composition of a simple 1 : 1 adduct. When this substance is added to a solution containing a carboxylic acid, followed by addition of an amine, amides are formed in good yield. Similarly, esters are formed by treating carboxylic acids ®rst with the reagent

and then with an alcohol. What is the likely structure for this ionic substance and how can it effect the activation of the carboxylic acids? (c) Sulfonate esters having quarternary nitrogen substituents, such as A and B, show exceptionally high reactivity toward nucleophilic displacement reactions. Discuss factors which might contribute to the reactivity of these substances. O +

+

ROS

ROSO2CH2CH2N(CH3)3 A

N(CH3)3

O

B

(d) Alcohols react with hexachloroacetone in the presence of dimethylformamide to give alkyl trichloroacetates in high yield. Primary alcohols react fastest. Tertiary alcohols to not react. Suggest a reasonable mechanism for this reaction. (e) The hydroxy amino acids serine and threonine can be converted to their respective bis(O-t-butyl) derivatives by reaction with isobutylene and sulfuric acid. Subsequent treatment with 1 equiv of trimethylsilyl tri¯ate and then water cleaves the ester group but not the ether group. What is the basis for the selectivity? R (CH3)3COCHCHCO2C(CH3)3

1) (CH3)3SiO3SCF3 (C2H5)3N

R (CH3)3COCHCHCO2H

2) H2O

NHCO2CH2Ph

NHCO2CH2Ph

R = H or CH3

8. Short synthetic sequences have been used to accomplish synthesis of the material at the left from that on the right. Suggest appropriate methods. No more than three separate steps should be required. (a)

O

CH3

PhCHCNHCHCH2C6H5

PhCHCO2H

OCH3

(with retention of configuration)

OCH3

(b)

H3C (CH3)2CHCH2CH

CHCHCH2CO2C2H5 CH3

(c) TsO

O

O HO

CO2CH3

N CH3C

O

(d)

H H (CH3)2CH

CO2H

CH3 C

C

N H

C

H H

C CH2CN

H

C C

(CH3)2CH

CH3

C

C CH2OH

H

185 PROBLEMS

186

(e)

CH3O

CH3O CO2H

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

CHCH(CH2)4CH3

CHCH3

CH3

OH

CH3O

CH3O

9. Amino acids can be converted to epoxides in high enantiomeric purity by the following reaction sequence. Analyze the stereochemistry at each step of the reaction. CO2H H2N

C

NaNO2

H

RCHCO2H

HCl

R

LiAlH4

KOH

RCHCH2OH

Cl

O H

Cl

R

10. A reagent which has been found to be useful for introduction of the benzyloxycarbonyl group onto amino groups of nucleosides is prepared by allowing benzyl chloroformate to react ®rst with imidazole and then with trimethyloxonium tetra¯uoroborate. What is the structure of the resulting reagent (a salt), and why is it an especially reactive acylating reagent? 11. (a) Write the equilibrium expression for phase transfer involving a tetraalkylammonium salt, R4 N‡ X , NaOH, a water phase, and a nonaqueous phase. (b) The concentration of OH in the nonaqueous phase under phase-transfer conditions is a function of the anion X . What structural characteristics of X would be expected to in¯uence the position of the equilibrium? (c) It has been noted in a comparison of 15% aqueous NaOH versus 50% NaOH that the extent of transfer of OH to the nonaqueous phase is less for 50% NaOH than for lower concentrations. What could be the cause of this? 12. The scope of the reaction of triphenylphosphine=hexachloroacetone with allylic alcohols has been studied. Primary and some secondary alcohols such as 1 and 2 give good yields of unrearranged halides. Certain other alcohols, such as 3 and 4, give more complex mixtures. Discuss structural features which are probably important in determining how cleanly a given alcohol is converted to halide CH3

H

H C

CH2OH

H

H C

C

C

H

CHCH3

1 2 H

H C

C

H

C(CH3)2 3

H C

4

OH

CHC(CH3)2 + ClCH2CH Cl

C(CH3)2 + CH2

CHC

43%

Ph3P O

CH2

18%

CHCHCH(CH3)2 + ClCH2CH Cl 27%

CH2

CH3

21%

Cl3CCCCl3

CHCH(CH3)2

H

CH2

O

OH

H C

Ph3P Cl3CCCCl3

OH

CHCH(CH3)2

15%

+ CH2

CHCH 58%

C(CH3)2

13. Two heterocyclic ring systems which have found some use in the formation of amides under mild conditions are N -alkyl-5-arylisoxazolium salts (structure A) and Nacyloxy-2-alkoxydihydroquinolines (structure B).

Ar

O +N

R N

A

O

OR

COR B

A typical set of reactions conditions is indicated below for each reagent. Consider mechanisms by which these heterocyclic molecules might function to activate the carboxylic acid group under these conditions, and outline the mechanisms you consider to be most likely. Ph

O +

1)

N

O

C2H5

Et3N, 1 min

PhCH2O2CNHCH2CO2H

PhCH2O2CNHCH2CNHCH2Ph

2) PhCH2NH2, 15 h

N

PhCH2O2CNHCH2CO2H + PhNH2

C2H5OC

OC2H5 O

O PhCH2O2CNHCH2CNHPh

25°C, 2 h

14. Either because of potential interference with other functional groups present in the molecule or because of special structural features, the following reactions would require especially careful selection of reagents and reaction conditions. Identify the special requirements of each substrate and suggest appropriate conditions for effecting the desired transformation.

(a)

H H

C

CO2H

H

CHC

RO

O RO

H H

H

C

H

R= O

CH2CH2CH2CHCH3 OH

(b)

NH2

N HOCH2

O

N

N

NH2

N ClCH2

O

N

N N

N HO

CH3

O

H C

OR

HO

187 PROBLEMS

188 CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION

O

(c) O

O

CH3 OH

(CH3)3CSCCH2CH

C

CO2H

CH3 OCCH3

(CH3)3CSCCH2CH

CH3

(d) (CH3)2CH

CO2H

CH3

N(CH3)2

(CH3)2CH

N(CH3)2

CO2H (CH3)2CH

C

CO2C2H5

N(CH3)2

(CH3)2CH

N(CH3)2

15. The preparation of nucleosides by reaction of carbohydrates and heterocyclic bases is fundamental to the study of the important biological activity of such substances. Several methods have been developed for accomplishing this reaction.

O

OH

O

N ..

+

N

H

H

Application of 2-chloro-3-ethylbenzoxazolium chloride to this problem has been investigated using 2,3,4,6-tetra-O-acetyl-b-D-glucopyranose as the carbohydrate derivative. Good yields were observed, and, furthermore, the process was stereoselective, giving the b-nucleoside. Suggest a mechanism and explain the stereochemistry. CH + 2 5

AcOCH2 O

AcO AcO

OH AcO

N

H N

CH3

N

CH3

Cl O 60°C, 10 h

+

N

CH3

N

CH3

AcOCH2 O

AcO AcO AcO

H

16. A route to a-glycosides has been described in which 2,3,4,6-tetra-O-benzyl-a-Dglucopyranosyl bromide is treated with an alcohol and tetraethylammonium bromide and diisopropylethylamiine in dichloromethane. ROCH2

R = CH2Ph

R′OH, Et4N+Br–

O

RO RO RO

EtN(i-Pr)2, CH2Cl2

Br

ROCH2 O

RO RO RO

OR′

Suggest an explanation for the stereochemical course of this reaction.

17. Write mechanisms for the formation of 2-pyridylthio esters by the following reactions.

189 PROBLEMS

(a) RCO2H + N

S

S

+ PPh3 N + R3′ N

(b) RCO2H + N

SCCl O

O RC

N +

+ CO2 + R3NH Cl

O RC

+ Ph3P S

S

N

O

4

Electrophilic Additions to Carbon±Carbon Multiple Bonds

Introduction One of the most general and useful reactions of alkenes and alkynes for synthetic purposes is the addition of electrophilic reagents. This chapter is restricted to reactions which proceed through polar intermediates or transition states. Several other classes of addition reactions are also of importance, and these are discussed elsewhere. Nucleophilic additions to electrophilic alkenes were covered in Chapter 1, and cycloadditions involving concerted mechanisms will be encountered in Chapter 6. Free-radical addition reactions are considered in Chapter 10.

4.1. Addition of Hydrogen Halides Hydrogen chloride and hydrogen bromide react with alkenes to give addition products. In early work, it was observed that addition usually takes place to give the product in which the halogen atom is attached to the more substituted carbon of the double bond. This behavior was suf®ciently general that the name Markownikoff's rule was given to the statement describing this mode of addition. A rudimentary picture of the reaction mechanism reveals the basis of Markownikoff's rule. The addition involves either protonation or a transition state involving a partial transfer of a proton to the double bond. The relative stability of the two possible carbocations from an unsymmetrical alkenes favors formation of the more substituted cationic intermediate. Addition is

191

192

completed when the carbocation reacts with a halide anion.

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

R R2C

CH2 + HX

C R

+

CH3 + X–

R2CCH3 X

A more complete discussion of the mechanism of ionic addition of hydrogen halides to alkenes is given in Chapter 6 of Part A. In particular, the question of whether or not discrete carbocations are always involved is considered there. The term regioselective is used to describe addition reactions that proceed selectively in one direction with unsymmetrical alkenes.1 Markownikoff's rule describes a speci®c case of regioselectivity that is based on the stabilizing effect that alkyl and aryl substituents have on carbocations. +CH CH R 2 2

+

CH3CHR

+

+

CH3CHAr

CH3CR2

+

CH3C(Ar)2

increasing stability

Terminal and disubstituted intermal alkenes react very slowly with HCl. The rate is greatly accelerated in the presence of silica or alumina in noncoordinating solvents such as dichloromethane or chloroform. Preparatively convenient conditions have been developed in which HCl is generated in situ from SOCl2 or ClCOCOCl.2 These heterogeneous reaction systems give Markownikoff addition. The mechanism is thought to involve interaction of the silica or alumina surface with HCl. O

O H

O H

H + Cl H O

+



O

O H

Cl

H

H

Cl

H

H

Another convenient procedure for hydrochlorination involves adding trimethylsilyl chloride to a mixture of an alkene and water. Good yields of HCl addition products (Markownikoff orientation) are obtained.3 These conditions presumably involve generation of HCl from the silyl chloride, but it is unclear if the silicon plays any further role in the reaction. CH3 CH3CH

CCH2CH3

CH3 (CH3)3SiCl H2O

CH3CH2CCH2CH3

98%

Cl

In nucelophilic solvents, products that arise from reaction of the solvent with the cationic intermediate may be encountered. For example, reaction of cyclohexene with hydrogen bromide in acetic acid gives cyclohexyl acetate as well as cyclohexyl bromide. 1. A. Hassner, J. Org. Chem. 33:2684 (1968). 2. P. J. Kropp, K. A. Daus, M. W. Tubergen, K. D. Kepler, V. P. Wilson, S. L. Craig, M. M. Baillargeon, and G. W. Breton, J. Am. Chem. Soc. 115:3071 (1993). 3. P. Boudjouk, B.-K. Kim, and B.-H. Han, Synth. Commun. 26:3479 (1996); P. Boudjouk, B.-K. Kim, and B.-H. Han, J. Chem. Ed. 74:1223 (1997).

This occurs because acetic acid acts as a nucleophile in competition with the bromide ion. Br

+ HBr

SECTION 4.1. ADDITION OF HYDROGEN HALIDES

OAc

AcOH 40°C

Ref. 4

+ 85%

15%

Since carbocations are involved as intermediates, carbon skeleton rearrangement can occur during electrophilic addition reactions. Reaction of t-butylethylene with hydrogen chloride in acetic acid gives both rearranged and unrearranged chloride.5 (CH3)3CCH

CH2

AcOH HCl

(CH3)3CCHCH3 + (CH3)2CCH(CH3)2 + (CH3)3CCHCH3 Cl

Cl

35–40%

OAc

40–50%

15–20%

The stereochemistry of addition of hydrogen halides to alkenes is dependent on the structure of the alkene and also on the reaction conditions. Addition of hydrogen bromide to cyclohexene and to E- and Z-2-butene is anti.6 The addition of hydrogen chloride to 1-methylcyclopentene is entirely anti when carried out at 25 C in nitromethane.7 Me D

Me D

D

Cl

D

H

D

D

1,2-Dimethylcyclohexene is an example of an alkene for which the stereochemistry of hydrogen chloride addition is dependent on the solvent and temperature. At 78 C in dichloromethane, 88% of the product is the result of syn addition, whereas at 0 C in ether, 95% of the product results from anti addition.8 Syn addition is particulary common with alkenes having an aryl substituent. Table 4.1 lists examples of several alkenes for which the stereochemistry of addition of hydrogen chloride or hydrogen bromide has been studied. The stereochemistry of addition, depends on the details of the mechanism. The addition can proceed through an ion-pair intermediate formed by an initial protonation step. RCH

CH2 + HCl

RCHCH3 +

Cl–

RCHCH3 Cl

Most alkenes, however, react via a transition state that involves the alkene, hydrogen halide, and a third species which delivers the nucleophile. This termolecular mechanism is generally pictured as a nucleophilic attack on the alkene±hydrogen halide complex. This 4. 5. 6. 7. 8.

193

R. C. Fahey and R. A. Smith, J. Am. Chem. Soc. 86:5035 (1964). R. C. Fahey and C. A. MckPherson, J. Am. Chem. Soc. 91:3865 (1969). D. J. Pasto, G. R. Meyer, and S. Kang, J. Am. Chem. Soc. 91:4205 (1969). Y. Pocker and K. D. Stevens, J. Am. Chem. Soc. 91:4205 (1969). K. B. Becker and C. A. Grob, Synthesis 1973:789.

Table 4.1. Stereochemistry of Addition of Hydrogen Halides to Alkenes

194 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Alkene

Hydrogen halide

Stereochemistry

Reference

HBr HCl HBr DBr DBr HBr HCl HBr HCl HBr HBr DCl DCl

anti solvent- and temperature-dependent anti anti anti anti anti syn and rearrangement syn and rearrangement syn (9 : 1) syn (8 : 1) syn syn

a a b c c d e f g h h i j

1,2-Dimethylcyclohexene 1,2-Dimethylcyclohexene Cyclohexene Z-2-Butene E-2-Butene 1,2-Dimethylcyclopentene 1-Methylcyclopentene Norbornene Norbornene E-1-Phenylpropene Z-1-Phenylpropene Bicyclo[3.1.0]hex-2-ene 1-Phenyl-4-t-butylcyclohexene

a. G. S. Hammond and T. D. Nevitt, J. Am. Chem. Soc. 76:4121 (1954); R. C. Fahey and C. A. McPherson, J. Am. Chem. Soc. 93:2445 (1971); K. B. Becker and C. A. Grob, Synthesis 1973:789. b. R. C. Fahey and R. A. Smith, J. Am. Chem. Soc. 86:5035 (1964). c. D. J. Pasto, G. R. Meyer, and B. Lepeska, J. Am. Chem. Soc. 96:1858 (1974). d. G. S. Hammond and C. H. Collins, J. Am. Chem. Soc. 82:4323 (1960). e. Y. Pocker and K. D. Stevens, J. Am. Chem. Soc. 91:4205 (1969). f. H. Kwart and J. L. Nyce. J. Am. Chem. Soc. 86:2601 (1964). g. J. K. Stille, F. M. Sonnenberg, and T. H. Kinstle, J. Am. Chem. Soc. 88:4922 (1966). h. M. J. S. Dewar and R. C. Fahey, J. Am. Chem. Soc. 85:3645 (1963). i. P. K. Freeman, F. A. Raymond, and M. F. Grostic, J. Org. Chem. 32:24 (1967). j. K. D. Berlin, R. O. Lyerla, D. E. Gibbs, and J. P. Devlin, J. Chem. Soc., Chem. Commun. 1970:1246.

mechanism bypasses a discrete carbocation. H RCH

CHR + HX H

H

X CHR

...

RCH

RCH

X

CHR + HX

X

The major factor in determining which mechanism is followed is the stability of the carbocation intermediate. Alkenes that can give rise to a particularly stable carbocation are likely to react via the ion-pair mechanism. The ion-pair mechanism would not be expected to be stereospeci®c, because the carbocation intermediate permits loss of stereochemistry relative to the reactant alkene. It might be expected that the ion-pair mechanism would lead to a preference for syn addition, since at the instant of formation of the ion pair, the halide is on the same side of the alkene as the proton being added. Rapid collapse of the ion-pair intermediate leads to syn addition. If the lifetime of the ion pair is longer and the ion pair dissociates, a mixture of syn and anti addition products is formed. The termolecular mechanism is expected to give anti addition. Attack by the nucleophile occurs at the opposite side of the double bond from proton addition. H C Nu:

C

Cl

Section 6.1 of Part A gives further discussion of the structural features that affect the competition between the two possible mechanisms.

4.2. Hydration and Other Acid-Catalyzed Additions of Oxygen Nucleophiles Other nucleophilic species can be added to double bonds under acidic conditions. A fundamental example is the hydration of alkenes in strongly acidic aqueous solution: CH2 + H+

R2C

R2CCH3

H2O

+

R2CCH3

–H+

R2CCH3

+OH2

OH

Addition of a proton occurs to give the more substituted carbocation and addition is regioselective, in accord with Markownikoff's rule. A more detailed discussion of the reaction mechanism is given in Section 6.2 of Part A. The reaction is occasionally applied to the synthesis of tertiary alcohols: O (CH3)2C

O

CHCH2CH2CCH3

H2SO4 H2O

(CH3)2CCH2CH2CH2CCH3

Ref. 9

OH

Because of the strongly acidic and rather vigorous conditions required to effect hydration of most alkenes, these conditions are only applicable to molecules that have no acidsensitive functional groups. Also, because of the involvement of cationic intermediates, rearrangements can occur in systems where a more stable cation would result by aryl, alkyl, or hydrogen migration. A much milder and more general procedure for alkene hydration is discussed in the next section. Addition of nucleophilic solvents such as alcohols and carboxylic acids can be effected by use of strong acids as catalysts10: (CH3)2C CH3CH

CH2 + CH3OH CH2 + CH3CO2H

HBF4 HBF4

(CH3)3COCH3 (CH3)2CHO2CCH3

Tri¯uoroacetic acid is a suf®ciently strong acid to react with alkenes under relatively mild conditions.11 The addition is regioselective in the direction predicted by Markownikoff's rule. ClCH2CH2CH2CH

CH2

CF3CO2H ∆

ClCH2CH2CH2CHCH3 O2CCF3

9. J. Meinwald, J. Am. Chem. Soc. 77:1617 (1955). 10. R. D. Morin and A. E. Bearse, Ind. Eng. Chem. 43:1596 (1951); D. T. Dalgleish, D. C. Nonhebel, and P. L. Pauson, J. Chem. Soc., C 1971:1174. 11. P. E. Peterson, R. J. Bopp, D. M. Chevli, E. L. Curran, D. E. Dillard, and R. J. Kamat, J. Am. Chem. Soc. 89:5902 (1967).

195 SECTION 4.2. HYDRATION AND OTHER ACIDCATALYZED ADDITIONS OF OXYGEN NUCLEOPHILES

196 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Ring strain enhances alkene reactivity. Norbornene, for example, undergoes rapid addition at 0 C.12

4.3. Oxymercuration The addition reactions which were discussed in Sections 4.1 and 4.2 are initiated by interaction of a proton with the alkene, which causes nucleophilic attack on the double bond. The role of the initial electrophile can be played by metal cations as well. Mercuric ion is the reactive electrophile in several synthetically valuable procedures.13 The most commonly used reagent is mercuric acetate, but the tri¯uoroacetate, tri¯uoromethanesulfonate, or nitrate salts are preferable in some applications. A general mechanism depicts a mercurinium ion as an intermediate.14 Such species can be detected by physical measurements when alkenes react with mercuric ions in nonnucleophilic solvents.15 Depending on the structure of the particular alkene, the mercurinium ion may be predominantly bridged or open. The addition is completed by attack of a nucleophile at the more substituted carbon: 2+

+

Hg

Hg RCH

CH2 + Hg(II)

RCH

CH2 or RCH

CH2

Nu–

RCHCH2

Hg+

Nu

The nucleophiles that are used for synthetic purposes include water, alcohols, carboxylate ions, hydroperoxides, amines, and nitriles. After the addition step is complete, the mercury is usually reductively removed by sodium borohydride. The net result is the addition of hydrogen and the nucleophile to the alkene. The regioselectivity is excellent and is in the same sense as is observed for proton-initiated additions.16 Scheme 4.1 includes examples of these reactions. Electrophilic attack by mercuric ion can affect cyclization by intramolecular capture of a nucleophilic functional group, as illustrated by entries 9±11. Inclusion of triethylboron in the reduction has been found to improve yields (entry 9).17 The reductive replacement of mercury using sodium borohydride is a free-radical process.18 RHgX + NaBH4 RHgH R⋅ + RHgH

RHgH

R⋅ + Hg(I)H RH + Hg(II) + R⋅

12. H. C. Brown, J. H. Kawakami, and K.-T. Liu, J. Am. Chem. Soc. 92:5536 (1979). 13. R. C. Larock, Angew. Chem. Int. Ed. Engl. 17:27 (1978); W. Kitching, Organomet, Chem. Rev. 3:61 (1968). 14. S. J. Cristol, J. S. Perry, Jr., and R. S. Beckley, J. Org. Chem. 41:1912; D. J. Pasto and J. A. Gontarz, J. Am. Chem. Soc. 93:6902 (1971). 15. G. A. Olah and P. R. Clifford, J. Am. Chem. Soc. 95:6067 (1973); G. A. Olah and S. H. Yu, J. Org. Chem. 40:3638 (1975). 16. H. C. Brown and P. J. Geoghegan, Jr., J. Org. Chem. 35:1844 (1970); H. C. Brown, J. T. Kurek, M.-H. Rei, and K. L. Thompson, J. Org. Chem. 49:2551 (1984); H. C. Brown, J. T. Kurek, M.-H. Rei, and K. L. Thompson, J. Org. Chem. 50:1171 (1985). 17. S. H. Kang, J. H. Lee, and S. B. Lee, Tetrahedron Lett. 39:59 (1998). 18. C. L. Hill and G. M. Whitesides, J. Am. Chem. Soc. 96:870 (1974).

Scheme 4.1. Synthesis via Mercuration

197

A. Alcohols 1a (CH3)3CCH

1) Hg(OAc)2

CH2

SECTION 4.3. OXYMERCURATION

(CH3)3CCHCH3 + (CH3)3CCH2CH2OH

2) NaBH4

OH 97%

(CH2)8CH

2b

3%

CH2

(CH2)8CHCH3 OH

1) Hg(OAc)2

O

80%

O

2) NaBH4

O

O 3c 1) Hg(OAc)2 2) NaBH4

OH

CH2

99.5%

CH3

B. Ethers 4d

1) Hg(O2CCF3)2, (CH3)2CHOH

OCH(CH3)2

2) NaBH4

5e

CH3(CH2)3CH

CH2

Hg(O2CCF3)2

98%

CH3(CH2)3CHCH3

EtOH

OC2H5

97%

C. Amides 6f

CH3(CH2)3CH

CH2

1) Hg(NO3)2, CH3CN

CH3CH2CH2CH2CHCH3

2) NaBH4, H2O

92%

HNCOCH3 D. Peroxides 7g CH3(CH2)4CH

1) Hg(OAc)2, t-BuOOH

CHCH3

2) NaBH4

CH3(CH2)4CHCH2CH3

40%

OOC(CH3)3 E. Amines 8h CH3O

CH2CH

CH2 + PhCH2NH2

CH3O

1) Hg(ClO4)2

CH2CHCH3 HNCH2Ph

2) NaBH4

F. Cyclizations Ph

Ph 9i

10j

CH2

CHCH2CHCO2H

PhCH2OCH2CH

1) Hg(O2CCF3)2, K2CO3 2) (C2H5)3B 3) NaBH4

CH CH2

PhCH2O2CNCH2O H

93%

CH3

1) Hg(NO3)2

O

O

PhCH2OCH2CH2

2) NaBH4

N PhCH2O2C

O

81%

70%

Scheme 4.1. (continued )

198 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

11k

CH3

1) Hg(OAc)2 2) NaBr, NaHCO3

CbzNH

3) O2, NaBH4

H3C

CH2OH

N

67%

Cbz a. b. c. d. e. f. g. h. i. j.

H. C. Brown and P. J. Geoghegan, Jr., J. Org. Chem. 35:1844 (1970). H. L. Wehrmeister and D. E. Roberston, J. Org. Chem. 33:4173 (1968). H. C. Brown and W. J. Hammar, J. Am. Chem. Soc. 89:1524 (1967). H. C. Brown and M.-H. Rei, J. Am. Chem. Soc. 91:5646 (1969). H. C. Brown, J. T. Kurek, M.-H. Rei, and K. L. Thompson, J. Org. Chem. 50:1171 (1985). H. C. Brown and J. T. Kurek, J. Am. Chem. Soc. 91:5647 (1969). D. H. Ballard and A. J. Bloodworth, J. Chem. Soc. C. 1971:945. R. C. Grif®th, R. J. Gentile, T. A. Davidson, and F. L. Scott, J. Org. Chem. 44:3580 (1979). S. H. Kang, J. H. Lee, and S. B. Lee, Tetrahedron Lett. 39:59 (1998). K. E. Harding and D. R. Hollingsworth, Tetrahedron Lett. 29:3789 (1988).

The evidence for this mechanism includes the fact that the course of the reaction can be diverted by oxygen, an ef®cient radical scavenger. In the presence of oxygen, the mercury is replaced by a hydroxy group. Also consistent with occurrence of a free-radical intermediate is the formation of cyclic products when hex-5-enylmercury compounds are reduced with sodium borohydride.19 In the presence of oxygen, no cyclic product is formed, indicating that O2 trapping of the radical is much faster than cyclization. CH2

CH(CH2)4HgBr

NaBH4 THF, H2O NaBH4, O2

CH2 I–

THF, H2O

CH3

CH(CH2)3CH3 + CH2

CH(CH2)3CH2OH

The trapping of the radical intermediate by oxygen has been exploited as a method for introduction of a hydroxyl substituent. The example below and entry 11 in Scheme 4.1 illustrate this reaction. OCH2NCO2CH2Ph H

CH3CH

CH2CH

1) Hg(NO3)2 2) KBr

O

O2

NCO2CH2Ph 80%

NaBH4

CH2

Ref. 20

CH2OH

CH3

An alternative reagent for demercuration is sodium amalgam in a protic solvent. Here the evidence is that free radicals are not involved and the mercury is replaced with complete retention of con®guration21: OCH3 HgCl

Na–Hg D 2O

OCH3 D

19. R. P. Quirk and R. E. Lea, J. Am. Chem. Soc. 98:5973 (1976). 20. K. E. Harding, T. H. Marman and D. Nam, Tetrahedron Lett. 29:1627 (1988). 21. F. R. Jensen, J. J. Miller, S. J. Cristol, and R. S. Beckley, J. Org. Chem. 37:434 (1972); R. P. Quirk, J. Org. Chem. 37:3554 (1972); W. Kitching, A. R. Atkins, G. Wickham, and V. Alberts, J. Org. Chem. 46:563 (1981).

The stereochemistry of oxymercuration has been examined in a number of systems. Conformationally biased cyclic alkenes such as 4-t-butylcyclohexene and 4-t-butyl-1methylcyclohexene give exclusively the product of anti addition, which is consistent with a mercurinium ion intermediate.16,22

Hg(OAc)2

t-Bu

OH

OH

CH3

CH3

t-Bu

NaBH4

CH3

t-Bu

HgOAc

The reactivity of different alkenes toward mercuration spans a considerable range and is governed by a combination of steric and electronic factors.23 Terminal double bonds are more reactive than internal ones. Disubstituted terminal alkenes, however, are more reactive than monosubstituted ones, as would be expected for electrophilic attack. The differences in relative reactivities are large enough that selectivity can be achieved in certain dienes:

CH

CH2

HOCHCH3 1) Hg(O2CCF3)2 2) NaBH4

Ref. 23b

55%

The relative reactivity data for some pentene derivatives are given in Table 4.2. Diastereoselectivity has been observed in oxymercuration of alkenes with nearby oxygen substituents. Terminal allylic alcohols show a preference for formation of the anti Table 4.2. Relative Reactivity of Some Alkenes in Oxymercuration Alkene 1-Pentene 2-Methyl-1-pentene Z-2-Pentene E-2-Pentene 2-Methyl-2-pentene

Relative reactivitya 6.6 48 0.56 0.17 1.24

a. Relative to cyclohexene; data from H. C. Brown and P. J. Geoghegan, Jr., J. Org. Chem. 37:1937 (1972).

22. H. C. Brown, G. J. Lynch, W. J. Hammar, and L. C. Liu, J. Org. Chem. 44:1910 (1979). 23. H. C. Brown and J. P. Geoghegan, Jr., J. Org. Chem. 37:1937 (1972); H. C. Brown, P. J. Geoghegan, Jr., G. J. Lynch, and J. T. Kurek, J. Org. Chem. 37:1941 (1972); H. C. Brown, P. J. Geoghegan, Jr., and J. T. Kurek, J. Org. Chem. 46:3810 (1981).

199 SECTION 4.3. OXYMERCURATION

200 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

2,3-diols. OH 1) Hg(OAc)2

R

Et i-Pr t-Bu Ph

CH3

CH3 + R

R

2) NaBH4

R

OH

OH

OH

OH

anti

syn

76 80 98 88

24 20 2 12

This result can be explained in terms of a steric preference for transition state A over B. The approach of the mercuric ion is directed by the hydroxyl group. The selectivity increases with the size of the substituent R.24 H

Hg

OH H

H H A

HO

Hg H

H

R

H R

H B

H2O

H2O

When the hydroxyl group is acetylated, the syn isomer is preferred. This result is attributed to direct nucleophilic participation by the carbonyl oxygen of the ester.

O

R

R C

OH O

R

Hg2+

O

+

NaBH4 H2O

O CH2HgX

R

CH3

R OH

4.4. Addition of Halogens to Alkenes The addition of chlorine or bromine to alkenes is a very general reaction. Considerable insight has been gained into the mechanism of halogen addition by studies on the stereochemistry of the reaction. Most types of alkenes are known to add bromine in a stereospeci®c manner, giving the product of anti addition. Among the alkenes that are known to give anti addition products are maleic and fumaric acid, Z-2-butene, E-2-butene, and a number of cycloalkenes.25 Cyclic, positively charged bromonium ion intermediates provide an explanation for the observed stereospeci®city. H3C

+

CH3 + Br2

H

H

H3C H

Br

Br CH3 + Br– H

H3C

H

CH3 H Br

The bridging by bromine prevents rotation about the remaining bond and back-side nucleophilic opening of the bromonium ion by bromide ion leads to the observed anti 24. B. Giese and D. Bartmann, Tetrahedron Lett. 26: 1197 (1985). 25. J. H. Rolston and K. Yates, J. Am. Chem. Soc. 91:1469, 1477 (1969).

addition. Direct evidence for the existence of bromonium ions has been obtained from NMR measurements.26 A bromonium ion salt (with Br3 as the counterion) has been isolated from the reaction of bromine with the very hindered alkene adamantylideneadamantane.27 (See Part A, Section 6.3, for further mechanistic discussion.) Substantial amounts of syn addition have been observed for cis-1-phenylpropene (27± 80% syn addition), trans-1-phenylpropene (17±29% syn addition), and cis-stilbene (up to 90% syn addition in polar solvents). H

H

+ Br2 Ph

H Ph

CH3

H CH3

CH3 Br H + H Ph Br

Br

AcOH

Br

28%

H

CH3 + Br2

Ph

H Ph

H

H CH3

CH3 Br H + H Ph Br

Br

AcOH

72%

Ref. 28

Br

83%

17%

A common feature of the compounds that give extensive syn addition is the presence of at least one phenyl substituent on the double bond. The presence of a phenyl substituent diminishes the strength of bromonium ion bridging by stabilizing the cationic center. A weakly bridged structure in equilibrium with an open benzylic cation can account for the loss in stereospeci®city. δ+

H

δ+

Br

Ph

H CH3

δ+

Br

H

+

H

Ph

Ph

CH3

Br

δ+

H

H

CH3

The diminished stereospeci®city is similar to that noted for hydrogen halide addition to phenyl-substituted alkenes. Although chlorination of aliphatic alkenes usually gives anti addition, syn addition is often dominant for phenyl-substituted alkenes29: H3C

CH3 + Cl2

H Ph

+ Cl2 H

H

H3C

H

CH3

AcOH

H H CH3

Cl Ph

CH3 H

Cl

AcOH

H

Cl (major)

Cl

only dichloride formed

Cl CH3

Cl + Ph

H

H (minor)

These results, too, re¯ect a difference in the extent of bridging in the intermediates. With 26. G. A. Olah, J. M. Bollinger, and J. Brinich, J. Am. Chem. Soc. 90:2587 (1968); G. A. Olah, P. Schilling, P. W. Westerman, and H. C. Lin, J. Am. Chem. Soc. 96:3581 (1974). 27. J. Strating, J. H. Wierenga, and H. Wynberg, J. Chem. Soc., Chem. Commun. 1969:907. 28. J. H. Rolston and K. Yates, J. Am. Chem. Soc. 91:1469, 1477 (1969). 29. M. L. Poutsma, J. Am. Chem. Soc. 87:2161, 2172 (1965); R. C. Fahey, J. Am. Chem. Soc. 88:4681 (1966); R. C. Fahey and C. Shubert, J. Am. Chem. Soc. 87:5172 (1965).

201 SECTION 4.4. ADDITION OF HALOGENS TO ALKENES

202 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

unconjugated alkenes, there is strong bridging and high anti stereospeci®city. Phenyl substitution leads to greater cationic character at the benzylic site, and there is more syn addition. Because of its smaller size and lesser polarizability, chlorine is not as effective as bromine in maintaining bridging for any particular alkene. Bromination therefore generally gives a higher degree of anti addition than chlorination, all other factors being the same.30 Chlorination can be accompanied by other reactions that are indicative of carbocation intermediates. Branched alkenes can give products that are the result of elimination of a proton from a cationic intermediate.

H3C CH2

Cl2

+

(CH3)2C

CH2Cl

H2 C

H3C H3C

CH2Cl

80%

CH3 CH3

H3C

C

Cl

Cl Cl2

+

(CH3)2C

C(CH3)2

H2C

CH3

CC(CH3)2

99%

H3C

Skeletal rearrangements have also been observed in systems that are prone toward migration.

(CH3)3C

H

H2C

CH2

Br2

Cl

CH3CCHCHC(CH3)3

C(CH3)2

H Ph3CCH

Cl2

Ref. 31

CH3

Ph3CCHCH2Br + Ph2C CCH2Br Br

Ref. 32

Ph

Because halogenation involves electrophilic attack, substituents on the double bond that increase electron density increase the rate of reaction, whereas electron-withdrawing substituents have the opposite effect. Bromination of simple alkenes is an extremely fast reaction. Some speci®c rate data are tabulated and discussed in Section 6.3 of Part A. In nucleophilic solvents, the solvent can compete with halide ion for the cationic intermediate. For example, the bromination of styrene in acetic acid leads to substantial amounts of the acetoxybromo derivative.

PhCH

CH2 + Br2

AcOH

PhCHCH2Br + PhCHCH2Br Br 80%

30. 31. 32. 33.

OAc 20%

R. J. Abraham and J. R. Monasterios, J. Chem. Soc., Perkin Trans. 1 1973:1446. M. L. Poutsma, J. Am. Chem. Soc. 87:4285 (1965). R. O. C. Norman and C. B. Thomas, J. Chem. Soc. B 1967:598. J. H. Rolston and K. Yates, J. Am. Chem. Soc. 91:1469 (1969).

Ref. 33

The acetoxy group is introduced exclusively at the benzylic carbon, in accord with the intermediate being a weakly bridged species or a benzylic cation. δ+

H

Br

δ+

H

Br

Ph

Ph

O

H

AcO

H

H

Ac

The addition of bromide salts to the reaction mixture diminishes the amount of acetoxy compound formed by tipping the competition between acetic acid and bromide ion for the electrophile in favor of the bromide ion. Chlorination in nucleophilic solvents can also lead to solvent incorporation, as, for example, in the chlorination of phenylpropene in methanol:34 PhCH

CH3OH

CHCH3 + Cl2

PhCHCHCH3 + PhCH CH3O Cl

Cl

82%

CHCH3 Cl

18%

From a synthetic point of view, the participation of water in brominations, leading to bromohydrins, is the most important example of nucleophilic participation by solvent. In the case of unsymmetrical alkenes, water reacts at the more substituted carbon, which is the carbon with the greatest cationic character. To favor introduction of water, it is necessary to keep the concentration of the bromide ion as low as possible. One method for accomplishing this is to use N-bromosuccinimide (NBS) as the brominating reagent.35,36 High yields of bromohydrins are obtained by use of NBS in aqueous DMSO. The reaction is a stereospeci®c anti addition. As in bromination, a bromonium ion intermediate can explain the anti stereospeci®city. It has been shown that the reactions in DMSO involve initial nucleophilic attack by the sulfoxide oxygen. The resulting intermediate reacts with water to give the bromohydrin. Br+ RCH

CH2

Br+

R (CH3)2S

CH

R +

(CH3)2S

CH2

O

H2O

HOCHCH2Br

H+

H2O

O

R

CHCH2Br

In accord with the Markownikoff rule, the hydroxyl group is introduced at the carbon best able to support positive charge: CH3 (CH3)3CC

CH2

PhCH2CH

34. 35. 36. 37. 38.

CH3 NBS DMSO H2O

CH2

(CH3)3CC

CH2Br

Ref. 37

60%

OH NBS DMSO H2O

PhCH2CHCH2Br

89%

OH

M. L. Poutsma and J. L. Kartch, J. Am. Chem. Soc. 89:6595 (1967). A. J. Sisti and M. Meyers, J. Org. Chem. 38:4431 (1973). C. O. Guss and R. Rosenthal, J. Am. Chem. Soc. 77:2549 (1955). D. R. Dalton, V. P. Dutta, and D. C. Jones, J. Am. Chem. Soc. 90:5498 (1968). A. W. Langman and D. R. Dalton, Org. Synth. 59:16 (1979).

Ref. 38

203 SECTION 4.4. ADDITION OF HALOGENS TO ALKENES

204 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Another procedure which is useful for the preparation of both bromohydrins and iodohydrins involves in situ generation of the hypohalous acid from NaBrO3 and NaIO4 .39 Br 75%

NaBrO3 NaHSO3

OH

H2O, CH3CN HIO4 NaHSO3 H2O, CH3CN

I 80%

OH

These reactions show the same regioselectivity and stereoselectivity as other reactions which proceed through halonium ion intermediates. Because of its high reactivity, special precautions must be used in reactions of ¯uorine, and its use is somewhat specialized.40 Nevertheless, there is some basis for comparison with the less reactive halogens. Addition of ¯uorine to Z- and E-1-propenylbenzene is not stereospeci®c, but syn addition is somewhat favored.41 This result suggests formation of a cationic intermediate. F

F PhCH

CHCH3

F2

CH3

CH3 + Ph

Ph F

F

In methanol, the solvent incorporation product is formed, as would be expected for a cationic intermediate. PhCH

CHCH3

F2 MeOH

PhCHCHCH3 MeO F

These results are consistent with the expectation that ¯uorine would not be an effective bridging atom. There are other reagents, such as CF3 OF and CH3 CO2 F, which appear to transfer an electrophile ¯uorine to double bonds and form an ion pair that collapses to an addition product. PhCH

CHPh + CF3OF

Ref. 42

PhCHCHPh CF3O F

CH3(CH2)9CH

CH2 + CH3CO2F

CH3(CH2)9CHCH2F

Ref. 43 30%

CH3CO2 39. 40. 41. 42.

H. Masuda, K. Takase, M. Nishio, A. Hasegawa, Y. Nishiyama, and Y. Ishii, J. Org. Chem. 59:5550 (1994). H. Vypel, Chimia 39:305 (1985). R. F. Merritt, J. Am. Chem. Soc. 89:609 (1967). D. H. R. Barton, R. H. Hesse, G. P. Jackman, L. Ogunkoya, and M. M. Pechet, J. Chem. Soc., Perkin Trans. 1 1974:739. 43. S. Rozen, O. Lerman, M. Kol, and D. Hebel, J. Org. Chem. 50:4753 (1985).

The stability of hypo¯uorites is improved in derivatives having electron-withdrawing substituents, such as 2,2-dichloropropanoyl hypo¯uorite.44 Various other ¯uorinating agents have been developed and used. These include N ¯uoropyridinium salts such as the tri¯ate45 and hepta¯uorodiborate.46 The reactivity of these reagents can be ``tuned'' by variation of the pyridine ring substituents. In contrast to the hypo¯uorites, these reagents are storable.47 In nucleophilic solvents such as acetic acid or alcohols, the reagents give addition products whereas in nonnucleophilic solvents, alkene substitution products resulting from a carbocation intermediate are formed.

N+

Cl

CH3 Cl

PhCCH2F

F

PhC

CH2

(CH3)2CHOH

CH3

70%

OCH(CH3)2

CH2Cl2

PhCCH2F Cl

N+

Cl

73%

CH2

F

Addition of iodine to alkenes can be accomplished by a photochemically initiated reaction. Elimination of iodine is catalyzed by excess iodine radicals, but the diiodo compounds can be obtained if unreacted iodine is removed.48 RCH

CHR + I2

RCH I

CHR I

The diiodo compounds are very sensitive to light and have not been used very often in synthesis. Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exempli®ed by the iodolactonization reaction.49 Reaction of iodine with carboxylic acids having carbon±carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones.50 The reaction shows a preference for formation of ®ve-membered rings over six-membered ones51 and is a strictly anti stereospeci®c addition when carried out under basic conditions. O

CH2CO2H O CH

CH2

I2, I–

Ref. 52

NaHCO3

I CH

CH2

44. S. Rozen and D. Hebel, J. Org. Chem. 55:2621 (1990). 45. T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, and K. Tomita, J. Am. Chem. Soc. 112:8563 (1990). 46. A. J. Poss, M. Van Der Puy, D. Nalewajek, G. A. Shia, W. J. Wagner, and R. L. Frenette, J. Org. Chem. 56:5962 (1991). 47. T. Umemoto, K. Tomita, and K. Kawada, Org. Synth. 69:129 (1990). 48. P. S. Skell and R. R. Pavlis, J. Am. Chem. Soc. 86:2956 (1964); R. L. Ayres, C. J. Michejda, and E. P. Rack, J. Am. Chem. Soc. 93:1389 (1971). 49. G. Cardillo and M. Orena, Tetrahedron 46:3321 (1990). 50. M. D. Dowle and D. I. Davies, Chem. Soc. Rev. 8:171 (1979). 51. S. Ranganathan, D. Ranganathan, and A. K. Mehrota, Tetrahedron 33:807 (1977); C. V. Ramana, K. R. Reddy, and M. Nagarajan, Ind. J. Chem. B 35:534 (1996).

205 SECTION 4.4. ADDITION OF HALOGENS TO ALKENES

206 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

The anti addition is kinetically controlled and results from irreversible back-side opening of an iodonium ion intermediate by the carboxylate nucleophile. When iodolactonization is carried out under nonbasic conditions, the addition step becomes reversible and the product is then the thermodynamically favored one.53 This usually results in the formation of the stereoisomeric lactone which has adjacent substituents trans with respect to one another.

H

CH2 I2 CH3CN

R

CH2CO2H

ICH2 O H R

ICH2 O H

+

OH

R

H

ICH2 O H

+

+

OH

–H

R

H

O

H

Several other nucleophilic functional groups can be induced to participate in iodocyclization reactions. t-Butyl carbonate esters cyclize to diol carbonates54:

CH2

CHCH2CHCH2CH2CH

CH2

I2

OCOC(CH3)3 O (CH2)2CH

ICH2

CH2

(CH2)2CH

ICH2

CH2

+ O

O O

O

O O

(major)

(minor)

Enhanced stereoselectivity has been found using IBr, which reacts at a lower temperature.55 Lithium salts of carbonate monoesters can also be prepared and cyclized.56

CH2

CHCH2CHCH3 OH

1) RLi 2) CO2

CH2

I2

CHCH2CHCH3 OCO2– +Li

CH3

ICH2

CH3

ICH2 +

O

O O

52. 53. 54. 55. 56.

(major)

O

O O

(minor)

L. A. Paquette, G. D. Crouse, and A. K. Sharma, J. Am. Chem. Soc. 102:3972 (1980). P. A. Bartlett and J. Myerson, J. Am. Chem. Soc. 100:3950 (1978). P. A. Bartlett, J. D. Meadows, E. G. Brown, A. Morimoto, and K. K. Jernstedt, J. Org. Chem. 47:4013 (1982). J. J.-W. Duan and A. B. Smith III, J. Org. Chem. 58:3703 (1993). A. Bogini, G. Cardillo, M. Orena, G. Ponzi, and S. Sandri, J. Org. Chem. 47:4626 (1982).

Because the iodocyclization products have a potentially nucleophilic oxygen substituent b to the iodide, they are useful in stereospeci®c synthesis of epoxides and diols: CH2

CHCH2CH2

CH2I O

K2CO3

Ref. 54

O

MeOH

O

OH O CH3 CH3

CH3

CH3

CH3

I

I2

Na2CO3

HO2C

O

HO

CH3

MeO2C

Ref. 57

MeOH

O

OH

OH

O

Iodolactones can also be obtained form N -pentenoyl amides. These reactions occur by O-alkylation, followed by hydrolysis of the iminoether intermediate.58 O R2NCCH2CH2CH

CHR

R

O

R2N+

I2, H2O DME

H2O

O

O

I

R I

Use of a chiral amide can promote enantioselective cyclization.59 CH2OCH2Ph O O

I2

N CHCH CH3 CH2OCH2Ph

CH2

CH2I

O

THF, H2O

CH3

Lactams can be obtained by iodolactonization of O,N-trimethylsilyl imidates60: O CH2

CHCH2CH2CNH2

TMS–O3SCF3 Et3N

CH2

CHCH2CH2C

NTMS

1) I2

ICH2

H N O

2) Na2SO3

OTMS 86%

As compared with amides, where oxygen is the most nucleophilic atom, the silyl imidates are more nucleophilic at nitrogen. Examples of iodolactonization and related iodocyclizations can be found in Scheme 4.2. The elemental halogens are not the only source of electrophilic halogen atoms, and, for some synthetic purposes, other ``positive halogen'' compound may be preferable 57. C. Neukome, D. P. Richardson, J. H. Myerson, and P. A. Bartlett, J. Am. Chem. Soc. 108:5559 (1986). 58. Y. Tamaru, M. Mizutani, Y. Furukawa, S. Kawamura, Z. Yoshida, K. Yanagi, and M. Minobe, J. Am. Chem. Soc. 106:1079 (1984). 59. S. Najda, D. Reichlin, and M. J. Kurth, J. Org. Chem. 55:6241 (1990). 60. S. Knapp, K. E. Rodriquez, A. T. Levorse, and R. M. Ornat, Tetrahedron Lett. 26:1803 (1985).

207 SECTION 4.4. ADDITION OF HALOGENS TO ALKENES

Scheme 4.2. Iodolactonization and Other Cyclizations Induced by Iodine

208 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

O 1a

CH2CO2H

O

I2 NaHCO3

CH

CH2

I CH

2b

OSiR3

CH3

OSiR3

I2

CH3

NaHCO3

O

CH2

I

O

CH2CO2H

3c

CH3

CH3

1) I2, CH3CN

HO2C

85%

2) NaHCO3

O

4d

1) I2, CH3CN

O

CH2I

ICH2

ICH2

2) NaHCO3

O

OCO2C(CH3)3

O major (68%)

O

5e

IBr –80°C

O

ICH2

O

+

O O

O

O O

major

minor

95% (25.8:1)

6f

I2, NaHCO3 92%

CH2OH

O

1) RLi, CO2

7g

O

OH

CH2 HO H3C

O

major (80%)

CH2I

O

N-iodosuccinimide

OH CH3

OH H3C

CH3

ICH2

O O

8h

CH2I

CH3

ICH2

2) I2

minor

ICH2 O

O2COC(CH3)3

O

CH3

O O

minor

Scheme 4.2. (continued ) 9i CH2CNH2

CH2C Me3SiO3SCF3

O

209 I

NSiMe3 OSiMe3

Et3N

H N

1) I2, THF

O

2) Na2SO3 88%

a. b. c. d. e. f. g. h. i.

L. A. Paquette, G. D. Crouse, and A. K. Sharma, J. Am. Chem. Soc. 102:3972 (1980). A. J. Pearson and S.-Y. Hsu, J. Org. Chem. 51:2505 (1986). A. G. M. Barrett, R. A. E. Carr, S. V. Attwood, G. Richardson, and N. D. A. Walshe, J. Org. Chem. 51:4840 (1986). P. A. Bartlett, J. D. Meadows, E. G. Brown, A. Morimoto, and K. K. Jernstedt, J. Org. Chem. 47:4013 (1982). J. J.-W. Duan and A. B. Smith, III, J. Org. Chem. 58:3703 (1993). L. F. Tietze and C. Schneider, J. Org. Chem. 56:2476 (1991). A. Bongini, G. Cardillo, M. Orena, G. Porzi, and S. Sandri, J. Org. Chem. 47:4626 (1982). A. Murai, N. Tanimoto, N. Sakamoto, and T. Masamune, J. Am. Chem. Soc. 110:1985 (1988). S. Knapp and A. T. Levorse, J. Org. Chem. 53:4006 (1988).

sources of the desired electrophile. The utility of N-bromosuccinimide in formation of bromohydrins was mentioned earlier. Other compounds which are useful for speci®c purposes are indicated in Table 4.3. Pyridinium hydrotribromide (pyridinium hydrobromide perbromide), benzyltrimethyl ammonium tribromide, and dioxane±bromine complex of examples of complexes of bromine in which its reactivity is somewhat attenuated, resulting in increased selectivity. N-Chlorosuccinimide and N-bromosuccinimide transfer electrophile halogen, with the succinimide anion acting as the leaving group. This anion is subsequently protonated to give the weak nucleophile succinimide. These reagents therefore favor nucleophilic additions by solvent and cyclization reactions, because there is no competition from a nucleophilic anion. In tetrabromocyclohexadienone, the leaving group is 2,4,6-tribromophenoxide ion. This reagent is a very mild and selective source of electrophilic bromine. Br

Br Br O

“Br+” + Br

O–

Br Br

Br

Electrophilic iodine reagents have also been employed in iodocyclization. Several salts of pyridine complexes with I‡ such as bis(pyridinium)iodonium tetra¯uoroborate and bis(collidine)iodonium hexa¯uorophosphate have proven especially effective.61 gHydroxy- and d-hydroxyalkenes can be cyclized to tetrahydrofuran and tetrahydropyran derivatives, respectively, by positive halogen reagents.62 (see entries 6 and 8 in Scheme 4.2).

4.5. Electrophilic Sulfur and Selenium Reagents Compounds in which sulfur and selenium atoms are bound to more electronegative elements react with alkenes to give addition products. The mechanism is similar to that in 61. Y. Brunel and G. Rousseau, J. Org. Chem. 61:5793 (1996). 62. A. B. Reitz, S. O. Nortey, B. E. Maryanoff, D. Liotta, and R. Monahan III, J. Org. Chem. 52:4191 (1987).

SECTION 4.5. ELECTROPHILIC SULFUR AND SELENIUM REAGENTS

Table 4.3. Other Sources of Positive Halogen

210 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Synthetic applicationsa

Source A. Chlorinating agents Sodium hypochlorite solution N-Chlorosuccinimide Antimony pentachloride

Formation of chlorohydrins from alkenes Chlorination with solvent participation and cyclization Controlled chlorination of acetylenes

B. Brominating agents Pyridinium hydrotribromide (pyridinium hydrobromide perbromide) Dioxane±bromine complex N-Bromosuccinimide

Substitute for bromine when increased selectivity or mild reaction conditions are required Same as for pyridinium hydrotribromide Substitute for bromine when low Br concentration is required Selective bromination of polyole®ns and cyclization induced by Br‡ Selective bromination of alkenes and carbonyl compounds

2,4,4,6-Tetrabromocyclohexadienone Benzyltrimethylammonium tribromideb C. Iodinating Agents Bis(pyridine)iodonium tetra¯uoroboratec

Selective iodination and iodocyclization

a. For speci®c examples, consult M. Fieser and L. F. Fieser, Reagents for Organic Synthesis, Vols 1±8, John Wiley & Sons, New York, 1979. b. S. Kajgaeshi and T. Kakinami, Ind. Chem. Libr. 7:29 (1995). c. J. Barluenga, J. M. Gonzalez, M. A. Garcia-Martin, P. J. Campos, and G. Asensio, J. Org. Chem. 58:2058 (1993).

halogenation with a bridged cationic intermediate being involved. R′ S+ R′S

Cl + RCH

CHR

RCH

SR′ CHR

Cl–

RCHCHR Cl

R′ +Se

R′Se

Cl + RCH

CHR

RCH

SeR′ CHR

Cl–

R

CH

CHR Cl

In many synthetic applications, the sulfur or selenium substituent is subsequently removed by elimination, as will be discussed in Chapter 6. Arenesulfenyl halides, ArSCl, are the most commonly used of the sulfur reagents. A variety of electrophilic selenium reagents have been employed, and several examples are given in Scheme 4.3. Mechanistic studies have been most thorough with the sulfenyl halides.63 The reactions show moderate sensitivity to alkene structure, with electron-releasing groups on the alkene accelerating the reaction. The addition can occur in either the Markownikoff or anti-Markownikoff sense.64 The variation in regioselectivity can be understood by 63. W. A. Smit, N. S. Ze®rov, I. V. Bodrikov, and M. Z. Krimer, Acc. Chem. Res. 12:282 (1979); G. H. Schmid and D. G. Garratt, The Chemistry of Double-Bonded Functional Groups, S. Patai, ed., John Wiley & Sons, New York, 1977, Chapter 9; G. A. Jones, C. J. M. Stirling, and N. G. Bromby, J. Chem. Soc., Perkin Trans. 2 1983:385. 64. W. H. Mueller and P. E. Butler, J. Am. Chem. Soc. 90:2075 (1968); G. H. Schmid and D. I. Macdonald, Tetrahedron Lett. 25:157 (1984).

Scheme 4.3. Sulfur and Selenium Reagents for Electrophile Addition CH3S 1a,b

CH3SCl

RCHCHR Cl PhS

2a

PhSCl

RCHCHR Cl PhSe

3

c

PhSeCl

RCHCHR Cl PhSe

4

d

PhSeO2CCF3

RCHCHR O2CCF3

O PhSe 5e

PhSe

N

, H2O

RCHCHR OH

O PhSe 6f

PhSeO2H, H3PO2

RCHCHR OH PhSe

7g

PhSeCN, Cu(II), R′OH

RCHCHR OR′

O

8h

PhSe PhSe

N

, (CH3)3SiN3

R2CCHR N3

O PhSe 9i

PhSeCl, AgBF4, H2NCO2C2H5

RCHCHR HNCO2C2H5

a. W. M. Mueller and P. E. Butler, J. Am. Chem. Soc. 90:2075 (1968). b. W. A. Thaler, J. Org. Chem. 34:871 (1969). c. K. B. Sharpless and R. F. Lauer, J. Org. Chem. 39:429 (1974); D. Liotta and G. Zima, Tetrahedron Lett. 1978:4977. d. H. J. Reich, J. Org. Chem. 39:428 (1974); A. G. Kulateladze, J. L. Kice, T. G. Kutateladze, N. S. Ze®rov, and N. V. Zyk, Tetrahedron Lett. 33:1949 (1992). e. K. C. Nicolaou, D. A. Claremon, W. E. Barnette, and S. P. Seitz, J. Am. Chem. Soc. 101:3704 (1979). f. D. Labar, A. Krief, and L. Hevesi, Tetrahedron Lett. 1978:3967. g. A. Toshimitsu, T. Aoai, S. Uemura, and M. Okano, J. Org. Chem. 45:1953 (1980). h. R. M. Giuliano and F. Duarte, Synlett 1992:419. i. C. G. Francisco, E. I. LeoÂn, J. A. Salazar, and E. SuaÂrez, Tetrahedron Lett. 27:2513 (1986).

211 SECTION 4.5. ELECTROPHILIC SULFUR AND SELENIUM REAGENTS

212 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

focusing attention on the sulfur-bridged intermediate, which may range from being a sulfonium ion to being a less electrophilic chlorosulfurane.

R

R′

R′

S+

S

C

C

H

H

H

R

Cl

C

C

H

H

H

Compared to the C Br bonds in a bromonium ion, the C S bonds are stronger and the transition state for nucleophilic addition will be reached later. Steric interactions that dictate access by the nucleophile become a more important factor in determining the direction of addition. For reactions involving phenylsulfenyl chloride or methylsulfenyl chloride, the intermediate is a fairly stable species, and ease of approach by the nucleophile is the major factor in determining the direction of ring opening. In these cases, the product has the anti-Markownikoff orientation.65

CH2

CHCH(CH3)2

CH3SCl

ClCH2CHCH(CH3)2 + CH3SCH2CHCH(CH3)2 SCH3

Ref. 66

Cl 94%

6%

p-ClPhSCl

CH3CH2CH

CH2

ClCH2CHCH2CH3 + ArSCH2CHCH2CH3 SAr

Ref. 67

Cl 77%

23%

The stereospeci®c anti addition of phenylsulfenyl chloride to norbornene is a particularly interesting example of the stability of the intermediate. Neither rearrangement nor syn addition products, which are observed with many of the other electrophilic reagents, are formed.63 This result indicates that the intermediate must be quite stable and reacts only by nucleophilic attack.64

SPh

+ PhSCl Cl

When nonnucleophilic salts, for example LiClO4 , are included in the reaction medium, products indicative of a more reactive intermediate with carbocationic character are 65. G. H. Schmid, M. Strukelj, S. Dalipi, and M. D. Ryan, J. Org. Chem. 52:2403 (1987). 66. W. H. Mueller and P. E. Butler, J. Am. Chem. Soc. 90:2075 (1968). 67. G. H. Schmid, C. L. Dean, and D. G. Garratt, Can. J. Chem. 54:1253 (1976).

213

observed. SAr

ArS

SAr +

ArSCl LiClO4 CH3CO2H

+

O2CCH3

O2CCH3

Ref. 68

NO2 Ar = O2N

These contrasting results can be interpreted in terms of a relatively unreactive species, perhaps a chlorosulfurane, being the main intermediate in the absence of the salt. The presence of the lithium cation gives rise to a more reactive species such as the episulfonium ion, as the result of ion pairing with the chloride ion. Ar +

+ Li+

S

S

Ar

+ Li+ –Cl

Cl

Terminal alkenes react with selenenyl halides with anti-Markownikoff regioselectivity.69 However, the b-selenenyl halide addition product can readily rearrange to isomeric products70: ArSe R2C

CH2 + ArSeX

R2CCH2SeAr

R2CCH2X

X

X

When reactions with phenylselenenyl chloride are carried out in aqueous acetonitrile solution b-hydroxyselenides are formed as a result of solvolysis of the chloride.71 Electrophilic selenium reagents are very effective in promoting cyclization of unsaturated molecules containing potentially nucleophilic substituents.72 Unsaturated carboxylic acids, for example, give selenolactones, and this reaction has been termed selenolactonization73:

CH2CO2H

PhSeCl

93%

PhSe

O

O

68. N. S. Ze®rov, N. K. Sadovaja, A. M. Maggerramov, I. V. Bodrikov, and V. E. Karstashov, Tetrahedron 31:2949 (1975); see also S. Dalipi and G. H. Schmid, J. Org. Chem. 47:5027 (1982); N. S. Ze®rov and I. V. Bodrikov, J. Org. Chem. USSR Engl. Trans. 1983:1940. 69. D. Liotta and G. Zima, Tetrahedron Lett. 1978:4977; P. T. Ho and R. J. Holt, Can. J. Chem. 60:663 (1982). 70. S. Raucher, J. Org. Chem. 42:2950 (1977). 71. A. Toshmitsu, T. Aoai, H. Owada, S. Uemura, and M. Okano, Tetrahedron 41:5301 (1985). 72. K. Fujita, Rev. Hetereoatom. Chem. 16:101 (1997). 73. K. C. Nicolaou, S. P. Seitz, W. J. Sipio, and J. F. Blount, J. Am. Chem. Soc. 101:3884 (1979).

SECTION 4.5. ELECTROPHILIC SULFUR AND SELENIUM REAGENTS

214 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

N -Phenylselenenophthalimide is an excellent reagent for this process and permits the formation of large-ring lactones.74 The advantage of the reagent in this particular application is the low nucleophilicity of the phthalimide anion, which does not compete with the remote internal nucleophile. The reaction of phenylselenenyl chloride of N -phenylselenenophthalimide with unsaturated alcohols leads to formation of b-phenylselenenyl ethers: O O

PhSe

CH2CH2OH + PhSeN

Ref. 75

O

Another useful reagent for selenoncyclization is phenylselenenyl sulfate. This reagent is capable of cyclizing unsaturated acids76 and alcohols.77 This reagent can be prepared in situ by oxidation of diphenyl diselenide with ammonium peroxydisulfate.78 CH3CHCH2CH

C(CH3)2

(PhSe)2 (NH4+)2S2O82–

OH

O

90%

C(CH3)2 SePh

Chiral selenenylating reagents have been developed and shown to be capable of effecting enantiselective additions and cyclizations. For example the reagent show below (SeAr*) achieves > 90% enantioselectivity in typical reactions.79 SeAr* Ph Ph

O

CH3

Ph

CH3 95% d.e.

OCH3 O

Ar*Se

N Ph Se+ PF6–

O

CH2OH

O

94% d.e.

Ph

O SeAr*

Ph

CO2H

O O

95% d.e.

Scheme 4.4 gives some examples of cyclizations induced by selenium electrophiles. 74. K. C. Nicolaou, D. A. Claremon, W. E. Barnette, and S. P. Seitz, J. Am. Chem. Soc. 101:3704 (1979). 75. K. C. Nicolaou, R. L. Magolda, W. J. Sipio, W. E. Barnette, Z. Lysenko, and M. M. Joullie, J. Am. Chem. Soc. 102:3784 (1980). 76. S. Murata and T. Suzuki, Chem. Lett. 1987:849. 77. A. G. Kutateladze, J. L. Kice, T. G. Kutateladze, N. S. Ze®rov, and N. V. Zyk, Tetrahedron Lett. 33:1949 (1992). 78. M. Tiecco, L. Testaferri, M. Tingoli, D. Bartoli, and R. Balducci, J. Org. Chem. 55:429 (1990). 79. K. Fujita, K. Murata, M. Iwaoka, and S. Tomoda, Tetrahedron 53:2029 (1997); K. Fujita, Rev. Heteroatom Chem. 16:101 (1997); T. Wirth, Tetrahedron 55:1 (1999).

Scheme 4.4. Cyclizations Induced by Electrophilic Sulfur and Selenium Reagents 1a

PhSCl (i-Pr)2NEt

CH(CH2)4OH

CH2

CH2CH

O

CH2 PhSCl

CH2SPh

CCH2NCO2C2H5

CH2

35%

O

OH

3c

SECTION 4.5. ELECTROPHILIC SULFUR AND SELENIUM REAGENTS

85%

PhSCH2 2b

215

CH(CH3)2 N

PhSCl

H3C

CH3 CH(CH3)2

PhSCH2 4d

42%

O

O

HO

HO

H

PhCH2

H

PhSe PhSeCl

70–75%

CH2CO2H

PhCH2 H

5e

O

O

SePh OAc H3C

H

H HOCH2

OAc

O PhSeCl

52%

O

CH2OAc

H

H3C

O

CH2OAc

O

6f

H3C

OH PhSe

SePh

N 82%

H3C

O

CH3

CH2OH

7g

O

CH3

PhSeO2CCF3

O

CH3

SePh

8h

CH3O2CCH2CCH2CH2CH

CH2

(PhSe)2 (NH4+)2S2O52–

O

O CH3O2C

9i

HOCH2

CH3

PhSeCN

95%

Cu(O3SCF3)2

CH3

O

CH2SePh

CH2SePh

58%

Scheme 4.4. (continued )

216 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

10j

CH3CH2 CH2

CHCH2CHCNHPh

CH2CH3 PhSeCl

PhSeCH2

85%

O

O

NPh

11k O

N H

CH2CH2CH

CH2

PhSeBr

O a. b. c. d. e. f. g. h. i. j. k.

68%

N CH2SePh

S. M. Tuladhar and A. G. Fallis, Tetrahedron Lett. 28:523 (1987). M. Muehlstaedt, C. Schubert, and E. Kleinpeter, J. Prakt, Chem. 327:270 (1985). M. Muehlstaedt, R. Widera, and B. Olk, J. Prakt. Chem. 324:362 (1982). F. Bennett and D. W. Knight, Tetrahedron Lett. 29:4625 (1988). S. J. Danishefsky, S. DeNinno, and P. Lartey, J. Am. Chem. Soc. 109:2082 (1987). E. D. Mihelich and G. A. Hite, J. Am. Chem. Soc. 114:7318 (1992). G. Li and W. C. Still, J. Org. Chem. 56:6964 (1991). M. Ticocco, L. Testaferri, M. Tingoli, D. Bartoli, and R. Balducci, J. Org. Chem. 55:429 (1990). H. Inoue and S. Murata, Heterocycles 45:847 (1997). A. Toshimitsu, K. Terao, and S. Uemura, J. Org. Chem. 52:2018 (1987). A. Toshimitsu, K. Terao, and S. Uemura, J. Org. Chem. 51:1724 (1986).

4.6. Addition of Other Electrophilic Reagents Many other halogen-containing compounds react with alkenes to give addition products by mechanisms similar to halogenation. A complex is generated, and the halogen is transferred to the alkene to generate a cationic intermediate. This may be a symmetrically bridged ion or an unsymmetrically bridged species, depending on the ability of the reacting carbon atoms of the alkene to accommodate positive charge. The direction of opening of the bridged intermediate is usually governed by electronic factors. That is, the addition is completed by attack of the nucleophile at the more positive carbon atom of the bridged intermediate. The orientation of addition therefore follows Markownikoff's rule. The stereochemistry of addition is usually anti, because of the involvement of a bridged halonium intermediate.80 Several reagents of this type are listed in Scheme 4.5. In the case of thiocyanogen chloride and thiocyanogen, the formal electrophile is ‰NCSŠ‡ . The presumed intermediate is a cyanosulfonium ion. The thiocyanate anion is an ambident nucleophile, and both carbon±sulfur and carbon±nitrogen bond formation can be observed, depending upon the reaction conditions (see entry 9 in Scheme 4.5).

4.7. Electrophilic Substitution Alpha to Carbonyl Groups Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to that of electrophilic additions to alkenes. An enol or enolate derived from the carbonyl compound is the reactive species, and the electrophilic attack by the halogen is analogous to the attack on alkenes. The reaction is completed by deprotonation and restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and 80. A. Hassner and C. Heathcock, J. Org. Chem. 30:1748 (1965).

Scheme 4.5. Addition Reactions of Other Electrophilic Reagents Reagent

1a

2b

I

Preparation

N

Br

C +

N

N–

N

Product

AgCNO, I2

O

HN3, Br2

RCH

CHR

I

NCO

RCH

CHR

Br 3c

I

+

N

N–

N

NaN3, ICl

I

S

C

RCH

(NCS)2, I2

N

CHR N3

RCH

CHR

I 5e

6f

I

O

AgNO3, ICl

ONO2

N

Cl

S

8

h

9i

O

Cl

N

N

CHR

I

ONO2

RC

(CH3)2CHCH2CH2ON HCO2H

CO2H

SC

CHR

CHR

HON O2CH

Pb(SCN)2, Br2

N

N

Cl

RC

Pb(SCN)2, Cl2

SCN

CS

O,

C

RCH

HON 7g

SECTION 4.7. ELECTROPHILIC SUBSTITUTION ALPHA TO CARBONYL GROUPS

N3

I 4d

217

N

N

RCH

CHR

Cl

SCN

RCH

CHR

CS

SC

and N

RCH

CHR

CS

N

C

S

a. A. Hassner, R. P. Hoblitt, C. Heathcock, J. E. Kropp, and M. Lorber, J. Am. Chem. Soc. 92:1326 (1970); A. Hassner, M. E. Lorber, and C. Heathcock, J. Org. Chem. 32:540 (1967). b. A. Hassner, F. P. Boerwinkle, and A. B. Levy, J. Am. Chem. Soc. 92:4879 (1970). c. F. W. Fowler, A. Hassner, and L. A. Levy, J. Am. Chem. Soc. 89: 2077 (1967). d. R. J. Maxwell and L. S. Silbert, Tetrahedron Lett. 1978:4991. e. J. W. Lown and A. V. Joshua, J. Chem. Soc., Perkin Trans. 1 1973:2680. f. J. Meinwald, Y. C. Meinwald, and T. N. Baker III, J. Am. Chem. Soc. 86:4074 (1964). g. H. C. Hamann and D. Swern, J. Am. Chem. Soc. 90:6481 (1968). h. R. G. Guy and I. Pearson, J. Chem. Soc., Perkin Trans. 1 1973:281; J. Chem. Soc., Perkin Trans. 2 1973:1359. i. R. J. Maxwell, L. S. Silbert, and J. R. Russell, J. Org. Chem. 42:1510 (1977).

base-catalyzed halogenation of ketones, which were discussed brie¯y in Part A, Chapter 7, are the most studied examples of the reaction. O R2CHCR′

OH H+

R2C

CR′

OH Br2

R2C Br

–OH

R2CHCR′

Br

O–

O R2C

CR′

CR′

Br O–

Br2

R2C Br

Br

O R2CCR′

CR′

O R2CCR′ Br

218 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

The most common preparative procedures involve use of the halogen, usually bromine, in acetic acid. Other suitable halogenating agents include N -bromosuccinimide, sulfuryl chloride and tetrabromocyclohexadienone. O

O Br

CCH3

Br2

Br

CH3CO2H

CCH2Br

O

Ref. 81

69–72%

O Br N-bromosuccinimide

Ref. 82

CCl4

O

O CH3

CH3 SO2Cl2

83–85%

Ref. 83

Cl Br

O CH

Br

Br

Br O

CHCCH3

O CH

CHCCH2Br

91%

Ref. 84

The reactions involving bromine or chlorine generate hydrogen halide and are autocatalytic. Reactions with N -bromosuccinimide or tetrabromocyclohexadienone form no hydrogen bromide, and these reagents may therefore be preferable in the case of acidsensitive compounds. As was pointed out in Part A, Section 7.3, under many conditions halogenation is faster than enolization. When this is true, the position of substitution in unsymmetrical ketones is governed by the relative rates of formation of the isomeric enols. In general, mixtures are formed with unsymmetrical ketones. The presence of a halogen substituent decreases the rate of acid-catalyzed enolization and therefore retards the introduction of a second halogen at the same site. Monohalogenation can therefore usually be carried out satisfactorily. A preparatively useful procedure for monohalogenation of ketones involves reaction with cupric chloride or cupric bromide.85 O

O CuBr2 HCCl3 CH3CO2C2H5

Ref. 86 Br

In contrast, in basic solution halogenation tends to proceed to polyhalogenated products. This is because the inductive effect of a halogen accelerates base-catalyzed 81. 82. 83. 84. 85.

W. D. Langley, Org. Synth. 1:122 (1932). E. J. Corey, J. Am. Chem. Soc. 75:2301 (1953). E. W. Warnhoff, D. G. Martin, and W. S. Johnson, Org. Synth. IV:162 (1963). V. Calo, L. Lopez, G. Pesce, and P. E. Todesco, Tetrahedron 29:1625 (1973). E. M. Kosower, W. J. Cole, G-S. Wu, D. E. Cardy, and G. Meisters, J. Org. Chem. 28:630 (1963); E. M. Kosower and G.-S. Wu, J. Org. Chem. 28:633 (1963). 86. D. P. Bauer and R. S. Macomber, J. Org. Chem. 40:1990 (1975).

enolization. With methyl ketones, base-catalyzed reaction with iodine or bromine leads eventually to cleavage to a carboxylic acid.87 The reaction can also be effected with hypochlorite ion. O (CH3)2C

CHCCH3 + –OCl

(CH3)2C

CHCO2H

Ref. 88

49–53%

Instead of direct halogenation of ketones, reactions with more reactive ketone derivatives such as silyl enol ethers and enamines have advantages in certain cases. OSi(CH3)3

O I

1) I2, AgOAc

Ref. 89

84%

R4N –F

Cl N

Cl2

+

N

–78°C

Cl H2O

O

65%

Ref. 90

There are also procedures in which the enolate is generated and allowed to react with a halogenating agent. Among the sources of halogen that have been used under these conditions are bromine,91 N -chlorosuccinimide,92 tri¯uoromethanesulfonyl chloride,93 and hexachloroethane.94 CH3

CH3 O

O 1) LDA 2) CF3SO2Cl

Cl CH3

C

CH3

OCH3

CH3

C

CH3

OCH3

a-Fluoroketones have been made primarily by reactions of enol acetates or silyl enol ethers with ¯uorinating agents such as CF3 OF,95 XeF2 ,96 and dilute F2 .97 Other ¯uorinating reagents which can be used include N -¯uoropyridinium salts,98 1-¯uoro-487. S. J. Chakabartty, in Oxidations in Organic Chemistry, Part C, W. Trahanovsky, ed., Academic Press, New York, 1978, Chapter V. 88. L. J. Smith, W. W. Prichard, and L. J. Spillane, Org. Synth. III:302 (1955). 89. G. M. Rubottom and R. C. Mott, J. Org. Chem. 44:1731 (1979); G. A. Olah, L. Ohannesian, M. Arvanaghi, and G. K. S. Prakash, J. Org. Chem. 49:2032 (1984). 90. W. Seufert and F. Effenberger, Chem. Ber. 112:1670 (1979). 91. T. Woolf, A. Trevor, T. Baille, and N. Castagnoli, Jr., J. Org. Chem. 49:3305 (1984). 92. A. D. N. Vaz and G. Schoellmann, J. Org. Chem. 49:1286 (1984). 93. P. A. Wender and D. A. Holt, J. Am. Chem. Soc. 107:7771 (1985). 94. M. B. Glinski, J. C. Freed, and T. Durst, J. Org. Chem. 52:2749 (1987). 95. W. J. Middleton and E. M. Bingham, J. Am. Chem. Soc. 102:4845 (1980). 96. B. Zajac and M. Zupan, J. Chem. Soc., Chem. Commun. 1980:759. 97. S. Rozen and Y. Menahem, Tetrahedron Lett. 1979:725. 98. T. Umemoto, M. Nagayoshi, K. Adachi, and G. Tomizawa, J. Org. Chem. 63:3379 (1998).

219 SECTION 4.7. ELECTROPHILIC SUBSTITUTION ALPHA TO CARBONYL GROUPS

220 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

hydroxy-1,4-diazabicyclo[2.2.2]octane,99 and 1,4-di¯uoro-1,4-diazabicyclooctane.100 These reagents ¯uorinate readily enolizable carbonyl compounds and silyl enol ethers.

O

O +

N+OH

PhCCH2CH3 + F N

PhCCHCH3

Ref. 101

88%

F

Another example of a-halogenation which has synthetic utility is the a-halogenation of acyl chlorides. The mechanism is presumed to be similar to that of ketone halogenation and to proceed through an enol. The reaction can be effected in thionyl chloride as solvent to give a-chloro, a-bromo, or a-iodo acyl chlorides using, respectively, N -chlorosuccinimide, N -bromosuccinimide, or molecular iodine as the halogenating agent.102 Because thionyl chloride rapidly converts carboxylic acids to acyl chlorides, the acid can be used as the starting material.

CH3(CH2)3CH2CO2H

N-chlorosuccinimide SOCl2

CH3(CH2)3CHCOCl

87%

Cl PhCH2CH2CO2H

I2 SOCl2

PhCH2CHCOCl

95%

I

The a-sulfenylation103 and a-selenation104 of carbonyl compounds have become very important reactions, because these derivatives can subsequently be oxidized to sulfoxides and selenoxides. The sulfoxides and selenoxides readily undergo elimination (see Section 6.8.3), generating the corresponding a,b-unsaturated carbonyl compound. Sulfenylations and selenations are usually carried out under conditions in which the enolate of the carbonyl compound is the reactive species. Scheme 4.6 gives some speci®c examples of these types of reactions. The most general procedure involves generating the enolate by deprotonation, or one of the alternative methods, followed by reaction with the sulfenylation or selenation reagent, Disul®des are the most common sulfenylation reagents, whereas diselenides or selenenyl halides are used for selenation. As entries 7 and 8 in Scheme 4.6 indicate, the selenation of ketones can also be effected by reactions of enol acetates or silyl enol ethers. If a speci®c enolate is generated by one of the methods described in Chapter 1, the position of sulfenylation of selenation can be controlled.105

99. 100. 101. 102.

S. Stavber, M. Zupan, A. J. Poss, and G. A. Shia, Tetrahedron Lett. 36:6769 (1995). T. Umemoto and M. Nagayoshi, Bull. Chem. Soc. Jpn. 69:2287 (1996). S. Stavber and M. Zupan, Tetrahedron Lett. 37:3591 (1996). D. N. Harpp, L. Q. Bao, C. J. Black, J. G. Gleason, and R. A. Smith, J. Orgn. Chem. 40:3420 (1975); Y. Ogata, K. Adachi, and F.-C. Chen, J. Org. Chem. 48:4147 (1983). 103. B. M. Trost, Chem. Rev. 78:363 (1978). 104. H. J. Reich, Acc. Chem. Res. 12:22 (1979); H. J. Reich, J. M. Renga, and I. L. Reich, J. Am. Chem. Soc. 97:5434 (1975). 105. P. G. Gassman, D. P. Gilbert, and S. M. Cole, J. Org. Chem. 42:3233 (1977).

Scheme 4.6. a-Sulfenylation and a-Selenenylation of Carbonyl Compounds

221

1a CO2C2H5

1) LiNR2

CO2C2H5

2) PhSSPh

2b

O

1) NaIO4

CO2C2H5

84%

2) H2O2

SPh

O SCH3 1) Li, NH3

62%

2) CH3SSCH3

3c

O

O N

4d

CH3S

1) LDA

CH3

O

PhCCH2SPh

PhS

69%

83%

O

N

5e

OSiR3

H

O

2) (PhSe)2

CH2OSiR3

O

O

O

Ph

O

O2CCH3 PhSeBr

PhCCHCH2CH3

H2O2

PhCCH

CHCH3

83%

80%

O PhSeBr

8h

CH3C

9i

PhCH2CH2CO2C2H5

CH2

87%

O

SePh OSi(CH3)3

H

O

O

CHCH2CH3

O

H2O2

SePh Ph

2) PhSeSePh

Ph

CH2OSiR3

O

H

1) LiNR2

6f

OSiR3

H

PhSe

1) KN(SiMe3)2

O

PhC

CH3

O t-BuOK

PhCCH3

7g

N

2) CH3SSCH3

CH3CCH2SePh 1) LiNR2 2) PhSeCl

PhCH2CHCO2C2H5

H2O2

PhCH

CHCO2C2H5

SePh 10f

O

O

O CH3

1) NaH 2) PhSeCl

O CH3 SePh

O H2O2

O CH3

80%

82%

SECTION 4.7. ELECTROPHILIC SUBSTITUTION ALPHA TO CARBONYL GROUPS

Scheme 4.6. (continued )

222 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

11j

1) LiNR2

O CH3 a. b. c. d. e. f. g. h. i. j.

82%

O

2) PhSeBr 3) H2O2

O

O

B. M. Trost, T. N. Salzmann, and K. Hiroi, J. Am. Chem. Soc. 98:4887 (1976). P. G. Gassman, D. P. Gilbert, and S. M. Cole, J. Org. Chem. 42:3233 (1977). P. G. Gassman and R. J. Balchunis, J. Org. Chem. 42:3236 (1977). G. Foray, A. Penenory, and A. Rossi, Tetrahedron Lett. 38:2035 (1997). A. B. Smith III and R. E. Richmond, J. Am. Chem. Soc. 105:575 (1983). H. J. Reich, J. M. Renga, and I. L. Reich, J. Am. Chem. Soc. 97:5434 (1975). H. J. Reich, I. L. Reich, and J. M. Renga, J. Am. Chem. Soc. 95:5813 (1973). I. Ryu, S. Murai, I. Niwa, and N. Sonoda, Synthesis 1977:874. J. M. Renga and H. J. Reich, Org. Synth. 59:58 (1979). T. Wakamatsu, K. Akasaka, and Y. Ban, J. Org. Chem. 44:2008 (1979).

4.8. Additions to Allenes and Alkynes Both allenes106 and alkynes107 require special consideration with regard to mechanisms of electrophilic addition. The attack by a proton on allene can conceivably lead to the allyl cation or the 2-propenyl cation: +CH

2

CH

CH2

H+

CH2

C

CH2

H+

+

C

CH3

CH2

An immediate presumption that the more stable allyl ion will be formed overlooks the stereoelectronic aspects of the reaction. Protonation at the center carbon without rotation of one of the terminal methylene groups leads to a primary carbocation which is not stabilized by resonance, because the the adjacent p bond is orthogonal to the empty p orbital. H H

H C H

C

H

H C

C H

H

C

C H

The addition of HCl, HBr, and HI to allene has been studied in some detail.108 In each case, a 2-halopropene is formed, corresponding to protonatin at a terminal carbon. The initial product can undergo a second addition, giving rise to 2,2-dihalopropanes. Dimers are also formed, but we will not consider them. X CH2

C

CH2 + HX

CH3C

X CH2 + H3CCCH3 X

106. H. F. Schuster and G. M. Coppola, Allenes in Organic Synthesis, John Wiley & Sons, New York. 107. W. Drenth, in: The Chemistry of Triple Bonded Functional Groups, Supplement C2, Vol. 2, S. Patai, ed., John Wiley & Sons, New York, 1994, pp. 873±915. 108. K. Griesbaum, W. Naegele, and G. G. Wanless, J. Am. Chem. Soc., 87:3151 (1965).

The presence of a phenyl group results in the formation of products from protonation at the sp carbon109: PhCH

C

CH2

HCl HOAc

PhCH

CHCH2Cl

Two alkyl substituents, as in 1,1-dimethylallene, also lead to protonation at the sp carbon110: (CH3)2C

C

CH2

(CH3)2C

CHCH2Cl

These substituent effects are due to the stabilization of the carbocation resulting from protonation at the center carbon. Even if allylic conjugation is not available in the transition state, the aryl and alkyl substituents make the terminal carbocation more stable than the alternative, a secondary vinyl cation. Alkynes, although not as prevalent as alkenes, have a number of important uses in synthesis. In general, alkynes are somewhat less reactive than alkenes toward many electrophiles. A major reason for this difference in reactivity is the substantially higher energy of the vinyl cation intermediate that is formed by an electrophilic attack on an alkyne. It is estimated that vinyl cations are about 10 kcal=mol less stable than an alkyl cation with similar substitution. The observed differences in rate of addition in direct comparisons between alkenes and alkynes depend upon the speci®c electrophile and the reaction conditions.111 Table 4.4 summarizes some illustrative rate comparisons. A more complete discussion of the mechanistic aspects of addition to alkynes can be found in Section 6.5 of Part A. Acid-catalyzed additions to alkynes follow the Markownikoff rule. CH3(CH2)6C

CH

Et4N+HBr2

CH3(CH2)6C

CH2

Ref. 112

77%

Br

The rate and selectivity of the reactions can be considerably enhanced by using an added quaternary bromide salt in 1 : 1 tri¯uoroacetic acid (TFA) : CH2 Cl2 . Clean formation of the anti addition product occurs under these conditions.113 Br CH3CH2CH2C

CCH2CH2CH3

1.0 M Bu4N+Br– 1:4 TFA:CH2Cl2 144 h

CH3CH2CH2

CH2CH2CH3

100%

H HC

C(CH2)5CH3

1.0 M Bu4N+Br– 1:4 TFA:CH2Cl2 336 h

CH2

C(CH2)5CH3

98%

Br

109. T. Okuyama, K. Izawa, and T. Fueno, J. Am. Chem. Soc. 95:6749 (1973). 110. T. L. Jacobs and R. N. Johnson, J. Am. Chem. Soc. 82:6397 (1960). 111. K. Yates, G. H. Schmid, T. W. Regulski, D. G. Garratt, H. W. Leung, and R. McDonald, J. Am. Chem. Soc. 95:160 (1973). 112. J. Cousseau, Synthesis 1980:805. 113. H. W. Weiss and K. M. Touchette, J. Chem. Soc., Perkin Trans. 2 1998:1523.

223 SECTION 4.8. ADDITIONS TO ALLENES AND ALKYNES

Table 4.4. Relative Reactivity of Alkenes and Alkynesa

224 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Ratio of second-order rate constants (alkene=alkyne) Bromination, acetic acid

Chlorination, acetic acid

Acid-catalyzed hydration, water

CH3 CH2 CH2 CH2 CHˆCH2 CH3 CH2 CH2 CH2 CCH

1:8  105

5:3  105

3.6

trans-CH3 CH2 CHˆCHCH2 CH3 CH3 CH2 CCCH2 CH3

3:4  105

 1  105

16.6

PhCHˆCH2 PhCCH

2:6  103

7:2  102

Alkene and alkyne

0.65

a. From data tabulated in Ref. 111.

Surface-mediated addition of HCl or HBr can be carried out in the presence of silica or alumina.114 The hydrogen halides can be generated from thionyl chloride, oxalyl chloride, oxalyl bromide, phosphorus tribromide, or acetyl bromide. H

Cl PhC

CCH3

SOCl2

C

SiO2

Cl

C

Ph

CH3 C

CH3

Ph

C H

The kinetic products from HCl results from syn addition, but isomerization to the more stable Z-isomer occurs on continued exposure to the acid halide. The initial products of addition to alkynes are not always stable. Addition of acetic acid, for example, results in the formation of enol acetates, which are easily converted to the corresponding ketone under the reaction conditions115: H5C2C

CC2H5

H+ CH3CO2H

H5C2C

CHCH2CH3

O2CCH3

H5C2CCH2CH2CH3 O

The most synthetically valuable method for converting alkynes to ketones is by mercuric ion-catalyzed hydration. Terminal alkynes give methyl ketones, in accordance with the Markownikoff rule. Internal alkynes will give mixtures of ketones unless some structural feature promotes regioselectivity. Reactions with Hg…OAc†2 in other nucleophilic solvents such as acetic acid or methanol proceed to b-acetoxy- or b-methoxyalkenylmercury intermediates.116 These intermediates can be reduced to alkenyl acetates or solvolyzed to ketones. The regiochemistry is indicative of a mercurinium ion intermediate which is opened by nucleophilic attack at the more positive carbon; that is, the additions follow the Markownikoff rule. Scheme 4.7 gives some examples of alkyne addition reactions. 114. P. J. Kropp and S. D. Crawford, J. Org. Chem. 59:3102 (1994). 115. R. C. Fahey and D.-J. Lee, J. Am. Chem. Soc. 90:2124 (1968). 116. S. Uemura, H. Miyoshi, and M. Okano, J. Chem. Soc., Perkin Trans. 1 1980:1098; R. D. Bach, R. A. Woodard, T. J. Anderson, and M. D. Glick, J. Org. Chem. 47:3707 (1982); M. Bassetti, B. Floris, and G. Spadafora, J. Org. Chem. 54:5934 (1989).

Scheme 4.7. Ketones by Hydration of Alkynes 1a

225

O CH3(CH2)3C

H2SO4

CH

CH3(CH2)3CCH3

HgSO4

SECTION 4.8. ADDITIONS TO ALLENES AND ALKYNES

79%

O

2b C

CH

H2SO4

CCH3

HOAc–H2O

3c

O HO

C

CH

HO

CCH3

HgSO4, H2SO4

65–67%

H2O

4d O

O CH

O

3

CH2C

CH

O CH

3

Hg2+, Dowex 50

O

CH2CCH3

H2SO4

O

100%

O

5e H

CH3 OH

H

CH3 OH

1) Hg2+, H2SO4, H2O ~60%

2) H2S

CH3CO2

C

H

CH3CO2 H H CH3C CH(CH3)2 O

H CH(CH3)2

C H a. b. c. d. e.

R. J. Thomas, K. N. Campbell, and G. F. Hennion, J. Am. Chem. Soc. 60:718 (1938). R. W. Bott, C. Eaborn, and D. R. M. Walton, J. Chem. Soc. 1965:384. G. N. Stacy and R. A. Mikulec, Org. Synth. IV:13 (1963). W. G. Dauben and D. J. Hart, J. Org. Chem. 42:3787 (1977). D. Caine and F. N. Tuller, J. Org. Chem. 38:3663 (1973).

Addition of chlorine to 1-butyne is slow in the absence of light. When addition is initiated by light, the major product is E-1,2-dichlorobutene when butyne is in large excess117: CH3CH2 CH3CH2C

CH + Cl2

Cl C

Cl

C H

In acetic acid, both 1-pentyne and 1-hexyne give the syn addition product. With 2-butyne and 3-butyne, the major products are b-chlorovinyl acetates of E-con®guration.118 Some of the dichloro compounds are also formed, with more of the E- than the Z-isomer being 117. M. L. Poutsma and J. L. Kartch, Tetrahedron 22:2167 (1966). 118. K. Yates and T. A. Go, J. Org. Chem. 45:2385 (1980).

226

observed.

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

RC

CR

O2CCH3

R

Cl2

C

CH3CO2H

R +

C

Cl

R C

Cl

R

R +

C Cl

Cl C

C

Cl

R

The reactions of the internal alkynes are considered to involve a cyclic halonium ion intermediate, whereas the terminal alkynes seem to react by a rapid collapse of a vinyl cation. Alkynes react with bromine via an electrophilic addition mechanism. A bridged bromonium ion intermediate has been postulated for alkyl-substituted acetylenes, while vinyl cations are suggested for aryl-substituted examples.119 1-Phenylpropyne gives mainly the anti addition product in acetic acid, but some of the syn isomer is formed.120 The proportion of dibromide formed and stereoselectivity are enhanced when lithium bromide is added to the reaction mixture.

PhC

CCH3

Br

Br2 CH3CO2H

Ph no LiBr LiBr added

+

C

C

59% 98%

+ PhC

C

Ph

Br

AcO

Br

Br

CH3 C

Br CCH3

CH3

(both isomers)

14% 0.2%

21% 1.5%

Some of the most useful reactions of alkynes are with organometallic reagents. These reactions, which can lead to carbon±carbon bond formation, will be discussed in Chapter 8.

4.9. Addition at Double Bonds via Organoborane Intermediates 4.9.1. Hydroboration Borane, BH3 ; is an avid electron-pair acceptor, having only six valence electrons on boron. Pure borane exists as a dimer in which two hydrogens bridge the borons. In aprotic solvents that can act as electron donors such as ethers, tertiary amines, and sul®des, borane forms Lewis acid±base adducts. +

R2O



BH3

+

R3N



BH3

+

R2S



BH3

Borane dissolved in THF or dimethyl sul®de undergoes addition reactions rapidly with most alkenes. This reaction, which is known as hydroboration, has been extensively studied, and a variety of useful synthetic processes have been developed, largely through the work of H. C. Brown and his associates. Hydroboration is highly regioselective and is stereospeci®c. The boron becomes bonded primarily to the less substituted carbon atom of the alkene. A combination of steric and electronic effects work together to favor this orientation. Borane is an electrophilic reagent. The reaction with substituted styrenes exhibits a weakly negative r value 119. G. H. Schmid, A. Modro, and K. Yates, J. Org. Chem. 45:665 (1980). 120. J. A. Pinock and K. Yates, J. Am. Chem. Soc. 90:5643 (1968).

… 0:5†.121 Compared with bromination …r‡ ˆ 4:3†,122 this is a small substituent effect, but it does favor addition of the electrophilic boron at the less substituted end of the double bond. In contrast to the case of addition of protic acids to alkenes, it is the boron atom, not hydrogen, which is the more electrophilic atom. This electronic effect is reinforced by steric factors. Hydroboration is usually done under conditions in which the borane eventually reacts with three alkene molecules to give a trialkylborane. The second and third alkyl groups would result in severe steric repulsion if the boron were added at the internal carbon. H

CH3 H3C

C

H3C H3C

C

H3C

CH3 H

CH3 B

H3C

C

CH3

H3C

CH3

C

CH2

C

CH3

CH2

H

B

C

CH2

CH3

severe nonbonded repulsions

CH3

CH3 nonbonded repulsions reduced

Table 4.5 provides some data on the regioselectivity of addition of diborane and several of its derivatives to representative alkenes. The table includes data for some monoand dialkylboranes which show even higher regioselectivity than diborane itself. These derivatives have been widely used in synthesis and are frequently referred to by the shortened names shown with the structures. CH3 (CH3)2CHCH

CH3 2BH

(CH3)2CHC

BH

BH2

CH3 disiamylborane bis(3-methyl-2-butyl)borane

thexylborane 1,1,2-trimethylpropylborane

9-BBN 9-borabicyclo[3.3.1]nonane

These reagents are prepared by hydroboration of the appropriate alkene, using control of stoichiometry to terminate the hydroboration at the desired degree of alkylation: CH3 2 (CH3)2C

CHCH3 + BH3

(CH3)2CHCH

2BH

CH3 (CH3)2C

C(CH3)2 + BH3

(CH3)2CHC

BH2

CH3

Hydroboration is a sterospeci®c syn addition. The addition occurs through a fourcenter transition state with essentially simultaneous bonding to boron and hydrogen. Both the new C B and C H bonds are, therefore, formed from the same side of the double bond. In molecular orbital terms, the addition is viewed as taking place by interaction of the ®lled alkene p orbital with the empty p orbital on boron, accompanied by concerted 121. L. C. Vishwakarma and A. Fry, J. Org. Chem. 45:5306 (1980). 122. J. A. Pincock and K. Yates, Can. J. Chem. 48:2944 (1970).

227 SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

228

Table 4.5. Regioselectivity of Diborane and Alkylboranes toward Representative Alkenes Percent of boron added at less substituted carbon

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Hydroborating reagent

1-Hexene

Diboranea Chloroborane±dimethyl sul®deb Disiamylboranea Thexylboranec Thexylchloroborane± dimethyl sul®ded 9-BBNe

2-Methyl-1-butene

4-Methyl-2-pentene

Styrene

94 99

99 99.5

57 Ð

80 98

99 94 99

Ð Ð 99

97 66 97

98 95 99

99.9

99.8f

99.8

98.5

a. G. Zweifel and H. C. Brown, Org. React. 13:1 (1963). b. H. C. Brown, N. Ravindran, and S. U. Kulkari, J. Org. Chem. 44:2417 (1969); H. C. Brown and U. S. Racherla, J. Org. Chem. 51:895 (1986). c. H. C. Brown and G. Zweifel, J. Am. Chem. Soc. 82:4708 (1960). d. H. C. Brown, J. A. Sikorski, S. U. Kulkarni, and H. D. Lee, J. Org. Chem. 45:4540 (1980). e. H. C. Brown, E. F. Knights, and C. G. Scouten, J. Am. Chem. Soc. 96:7765 (1974). f. Data for 2-methyl-1-pentene.

C H bond formation.123

H H

B

B H

B

H B

As is true for most reagents, there is a preference for approach of the borane from the less hindered side of the molecule. Because diborane itself is a relatively small molecule, the stereoselectivity is not high for unhindered molecules. Table 4.6 gives some data comparing the direction of approach for three cyclic alkenes. The products in all cases result from syn addition, but the mixtures result both from the low regioselectivity and from addition to both faces of the double bond. Even the quite hindered 7,7-dimethylnorbornene shows only modest preference for endo addition with diborane. The selectivity is enhanced with the bulkier reagent 9-BBN. The haloboranes BH2 Cl, BH2 Br, BHCl2 , and BHBr2 are also useful hydroborating reagents.124 These compounds are somewhat more regioselective than borane itself but otherwise show similar reactivity. The most useful aspects of the chemistry of the haloboranes is their application in sequential introduction of substituents at boron. The 123. D. J. Pasto, B. Lepeska, and T.-C. Cheng, J. Am. Chem. Soc. 94:6083 (1972); P. R. Jones, J. Org. Chem. 37:1886 (1972); S. Nagase, K. N. Ray, and K. Morokuma, J. Am. Chem. Soc. 102:4536 (1980); X. Wang, Y. Li, Y.-D. Wu, M. N. Paddon-Row, N. G. Rondan, and K. N. Houk, J. Org. Chem. 55:2601 (1990); N. J. R. van Eikema Hommes and P. v. R. Schleyer, J. Org. Chem. 56:4074 (1991). 124. H. C. Brown and S. U. Kulkarni, J. Organomet. Chem. 239:23 (1982).

Table 4.6. Stereoselectivity of Hydroboration of Cyclic Alkenesa

229

b

Product composition Hydroborating reagent Borane Disiamylborane 9-BBN

3-Methylcyclopentene trans-2 45 40 25

cis-3

3-Methylcyclohexene

trans-3

|‚‚‚{z‚‚‚} 55 |‚‚‚{z‚‚‚} 60 50 25

7,7-Dimethylnorbornene

cis-2

trans-2

cis-3

trans-3

exo

endo

16 18 0

34 30 20

18 27 40

32 25 40

22 Ð 3

78c Ð 97

a. Data from H. C. Brown, R. Liotta, and L. Brener, J. Am. Chem. Soc. 99:3427 (1977), except where noted otherwise. b. Product composition refers to methylcycloalkanol formed by subsequent oxidation. c. H. C. Brown, J. H. Kawakami, and K.-T. Liu, J. Am. Chem. Soc. 95:2209 (1973).

halogens can be replaced by alkoxide or by hydride. When halogen is replaced by hydride, a second hydroboration step can be carried out. R2BX + NaOR′

R2BOR′

R2BX + LiAlH4

R2BH

RBX2 + LiAlH4

RBH2

X = Cl, Br

Application of these transformations will be discussed in Chapter 9, where carbon±carbon bond-forming reactions of organoboranes are covered. Catecholborane and pinacoloborane, in which the boron has two oxygen substituents, are much less reactive hydroborating reagents than alkyl- or haloboranes. Nevertheless, they are useful reagents for certain applications. The reactivity of catecholborane has been found to be substantially enhanced by addition of 10±20% of N,N-dimethylacetamide to CH2 Cl2 .125 Hydroboration by catecholborane and pinacolborane is also catalyzed by transition metals.126 H3C

CH3

H3C O

O B

CH3 O

O B

H

H

catecholborane

pinacolborane

One frequently used catalyst is Wilkinson's catalyst Rh…PPh3 †3 Cl.127 The general mechanism for catalysis is believed to involve addition of the borane to the metal by oxidative addition128 (see Section 8.2.3.3). Catalyzed hydroboration has proven to be valuable in 125. C. E. Garrett and G. C. Fu, J. Org. Chem. 61:3224 (1996). 126. I. Beletskaya and A. Pelter, Tetrahedron 53:4957 (1997); H. Wadepohl, Angew. Chem. Int. Ed. Engl. 36:2441 (1997); K. Burgess and M. J. Ohlmeyer, Chem. Rev. 91:1179 (1991). 127. D. A. Evans, G. C. Fu, and A. H. Hoveyda, J. Am. Chem. Soc. 110:6917 (1988); D. MaÈnnig and H. NoÈth, Angew. Chem. Int. Ed. Engl. 24:878 (1985). 128. D. A. Evans, G. C. Fu, and B. A. Anderson, J. Am. Chem. Soc. 114:6679 (1992).

SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

230

controlling the stereoselectivity of hydroboration of functionalized alkenes.129

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

C Cl L2Rh H

C

O

C

C

C

L2Rh

B O

H

H

O

C

O

L2Rh

B

B O

O

O

H L2RhCl +

C

C

B O

Several other catalysts have been described, including, for example, dimethyltitanocene.130 O HB

RCH

CH2

O

O (Cp)2Ti(CH3)2 (Cp =

RCH2CH2

B

NaOH H2O2

RCH2CH2OH

O

η5-C

5H5)

The use of chiral ligands in catalysis can lead to enantioselective hydroboration. RhBINAP131 and the related structure D132 have shown good enantioselectivity in the hydroboration of styrene and related compounds.

Ph P

Ph

N

Rh

P Ph

Rh P

Ph

Ph

C

Ph

D

styrene

indene

C

96% e.e.

13% e.e.

(Ref. 131)

D

67% e.e.

84% e.e.

(Ref. 132)

Hydroboration is thermally reversible. At 160 C and above, B H moieties are eliminated from alkylboranes, but the equilibrium is still in favor of the addition products. This provides a mechanism for migration of the boron group along the carbon chain by a 129. 130. 131. 132.

D. A. Evans, G. C. Fu, and A. H. Hoveyda, J. Am. Chem. Soc. 114:6671 (1992). X. He and J. F. Hartwig, J. Am. Chem. Soc. 118:1696 (1996). T. Hayashi, Y. Matsumoto, and Y. Ito Tetrahedron Asymmetry 2:601 (1991). J. M. Valk, G. A. Whitlock, T. P. Layzell, and J. M. Brown, Tetrahedron Asymmetry 6:2593 (1995).

231

series of eliminations and additions. R R

R

C

CH

H

B

CH3

R

C

CH

H

B

CH3 + R

R

H

C

C

CH2

H

B

R R

H

C

CH2

CH2

B

H

Migration cannot occur past a quaternary carbon, however, since the required elimination is blocked. At equilibrium, the major trialkylborane is the least substituted terminal isomer that is accessible, because this is the isomer which minimizes unfavorable steric interactions. H3C

H

H B

CH2

160°C

3

3

CH3(CH2)13CH

CH(CH2)13CH3

Ref. 133

B

1) B2H6 2) 80°C, 14 h

[CH3(CH2)29]3B

Ref. 134

More bulky substituents on boron faciliate the migration. Bis-Bicyclo[2.2.2]octanylborane, in which there are no complications from migrations in the bicylic substituent, have been found to be particularly useful.

B

H + (CH3)2C



CHCH3

BCH2CH2CH(CH3)2

Ref. 135

There is also evidence that boron migration can occur intramolecularly.136 A transition state that could describe this process has been located computationally.137 It involves an electron-de®cient p-complex about 20±25 kcal above the trialkylborane.

B C

H C H

133. 134. 135. 136. 137.

B H

C

H

H C H

H

C

B C

H

H

G. Zweifel and H. C. Brown, J. Am. Chem. Soc. 86:393 (1964). K. Maruyama, K. Terada, and Y. Yamamoto, J. Org. Chem. 45:737 (1980). H. C. Brown and U. S. Racherla, J. Am. Chem. Soc. 105:6506 (1983). S. E. Wood and B. Rickborn, J. Org. Chem. 48:555 (1983). N. J. R. van Eikema Hommes and P. v. R. Schleyer, J. Org. Chem. 56:4074 (1991).

SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

232 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Migration of boron to terminal positions is observed under much milder conditions in the presence of transition metal catalysts. For example, catalytic hydroboration of 2methyl-3-hexene by pinacolborane leads to the terminal boronic ester.

O H

B O

(CH3)2CHCH

CHCH2CH3

O (CH3)2CH(CH2)4

Rh(PPh3)3Cl

Ref. 138

B O

4.9.2. Reactions of Organoboranes The organoboranes have proven to be very useful intermediates in organic synthesis. In this section, we will discuss methods by which the boron atom can ef®ciently be replaced by hydroxyl, halogen, or amino groups. There are also important processes which use alkyboranes in the formation of new carbon±carbon bonds. These reactions will be discussed in Section 9.1. The most widely used reaction of organoboranes is the oxidation to alcohols. Alkaline hydrogen peroxide is the reagent usually employed to effect the oxidation. The mechanism is outlined below. R R3B +

HOO–

R

R –

B

O

OH

R

B

OR + –OH

R R R2BOR +

HOO–

R

O

RO



B

O

O

R

H

R (RO)2BR + HOO–

B + –OH RO

(RO)2B



O

O

H

(RO)3B + –OH

R (RO)3B + 3 H2O

3 ROH + B(OH)3

The R O B bonds are hydrolysed in the alkaline aqueous solution, generating the alcohol. The oxidation mechanism involves a series of B-to-O migrations of the alkyl groups. The stereochemical outcome is replacement of the C B bond by a C O bond with retention of con®guration. In combination with the stereospeci®c syn hydroboration, this allows the structure and stereochemistry of the alcohols to be predicted with con®dence. The preference for hydroboration at the least substituted carbon of a double bond results in the alcohol being formed with regiochemistry which is complementary to that observed in the case of direct hydration or oxymercuration, that is, anti-Markownikoff. 138. S. Pereira and M. Srebnik, J. Am. Chem. Soc. 118:909 (1996); S. Pereira and M. Srebnik, Tetrahedron Lett. 37:3283 (1996).

Conditions that permit oxidation of organoboranes to alcohols using molecular oxygen,139 sodium peroxycarbonate,140 or amine oxides141 as oxidants have also been developed. The reaction with molecular oxygen is particularly effective in per¯uoroalkane solvents.142

1) HB(C2H5)2

OH

82%

2) O2, Br(CF2)7CF3

The oxidation by amine oxides provides a basis for selection among non-equivalent groups on boron. In acyclic organoboranes, the order of reaction is tertiary > secondary > primary. In cyclic boranes, stereoelectronic factors dominate. With 9-BBN derivatives, for example, preferential migration of a C B bond which is part of the bicylic ring structure occurs. +

N(CH3)3

O

R B



+ (CH3)3N

R

R B

B

O–

O

This is attributed to the unfavourable steric interactions which arise in the transition state that is required for antiperiplanar migration of the exocyclic substituent.143 Some examples of synthesis of alcohols by hydroboration±oxidation are included in Scheme 4.8. More vigorous oxidizing agents such as Cr(VI) reagents effect replacement of boron and oxidation to the carbonyl level.144 Ph

Ph O 1) B2H6 2) K2Cr2O7

An alternative procedure for oxidation to ketones involves treatment of the alkylborane with a quaternary ammonium perruthenate salt and an amine oxide.145 (see entry 6, in Scheme 4.8). Use of the dibromoborane±dimethyl sul®de complex for hydroboration of terminal alkenes, followed by hydrolysis and Cr(VI) oxidation, gives carboxylic acids.146 RCH

CH2

1) BHBr2S(CH3)2 2) H2O

RCH2CH2B(OH)2

Cr(VI) HOAc, H2O

RCH2CO2H

139. H. C. Brown, and M. M. Midland, and G. W. Kalbalka, J. Am. Chem. Soc. 93:1024 (1971). 140. G. W. Kabalka, P. P. Wadgaonkar, and T. M. Shoup, Tetrahedron Lett. 30:5103 (1989). 141. G. W. Kabalka and H. C. Hedgecock, Jr., J. Org. Chem. 40:1776 (1975); R. Koster and Y. Monta, Justus Liebigs Ann. Chem. 704:70 (1967). 142. I. Klement and P. Knochel, Synlett 1996:1004. 143. J. A. Soderquist and M. R. Naja®, J. Org. Chem. 51:1330 (1986). 144. H. C. Brown and C. P. Garg, J. Am. Chem. Soc. 83:2951 (1961); H. C. Brown, C. Rao and S. Kulkarni, J. Organomet. Chem. 172:C20 (1979). 145. M. H. Yates, Tetrahedron Lett. 38:2813 (1997). 146. H. C. Brown, S. V. Kulkarni, V. V. Khanna, V. D. Patil, and U. S. Racherla, J. Org. Chem. 57:6173 (1992).

233 SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

234 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Scheme 4.8. Alcohols, Ketones, Aldehydes, and Amines from Organoboranes A. Alcohols 1a

CH3

H3C

H

OH

1) B2H6

85%



2) H2O2, OH

2b

H CH2

1) B2H6

CH2OH CH3

2) H2O2, –OH

CH3 CH3 3c

CH3 CH3 H

CH3

OH

1) B2H6 2) H2O2,

4d

85%

–OH

CH2OCH2Ph

H C O

76%

C

C

OH 1) B2H6, THF

CH3

H

C

2) H2O2, –OH

O

H CH 3

C

CH2OCH2Ph C

H CH CH H 3 3

B. Ketones and aldehydes 5e

Ph

H3C

1) B2H6

C H3C

2) CrO3

H

Ph

H3C

50%

H3C

O

6f

O

1) BH3/S(CH3)2 2) N-methylmorpholineN-oxide, R4N+RuO4–

7g

H3C

H

H

H3C CH2OAc CH

CH2

H

CH3

CH3 1) B2H6 2) H2NOSO3H

CH2OAc 80%

pyridinium chlorochromate

C. Amines 8h

H

disiamylborane

NH2 42%

CH2CH

O

85%

Scheme 4.8. Alcohols, Ketones, Aldehydes, and Amines from Organoboranes 9i

1) BHCl2

NHPh

2) PhN3, H2O

84%

a. b. c. d. e. f. g.

H. C. Brown and G. Zweifel, J. Am. Chem. Soc. 83:2544 (1961). R. Dulou, Y. Chretien-Bessiere, Bull. Soc. Chim. France, 1362 (1959). G. Zweifel and H. C. Brown, Org. Synth. 52:59 (1972). G. Schmid, T. Fukuyama, K. Akasaka, and Y. Kishi, J. Am. Chem. Soc. 101:259 (1979). W. B. Farnham, J. Am. Chem. Soc. 94:6857 (1972). M. H. Yates, Tetrahedron Lett. 38:2813 (1997). H. C. Brown, S. U. Kulkarni, and C. G. Rao, Synthesis, 151 (1980); T. H. Jones and M. S. Blum, Tetrahedron Lett. 22:4373 (1981). h. M. W. Rathke and A. A. Millard, Org. Synth. 58:32 (1978). i. H. C. Brown, M. M. Midland, and A. B. Levy, J. Am. Chem. Soc. 95:2394 (1973).

The boron atoms can also be replaced by an amino group.147 The reagents that effect this conversion are chloramine or hydroxylamine-O-sulfonic acid. The mechanism of these reactions is very similar to that or the hydrogen peroxide oxidation of organoboranes. The nitrogen-containing reagent initially reacts as a nucleophile by adding at boron, and then rearrangement with expulsion of chloride or sulfate ion follows. As in the oxidation, the migration step occurs with retention of con®guration. The amine is freed by hydrolysis. –

R3B + NH2X

R2B

NH

X

R2B

R

NH

H2O

RNH2

R

X = Cl or OSO3

Secondary amines are formed by reaction of trisubstituted boranes with alkyl or aryl azides. The most ef®cient borane intermediates to use are monoalkyldichloroboranes, which are generated by reaction of an alkene with BHCl2  Et2 O.148 The entire sequence of steps and the mechanism of the ®nal stages are summarized by the equations below. BHCl2 . Et2O + RCH CH2

RCH2CH2BCl2 R′

RCH2CH2BCl2 + R′

N3

B–

Cl2

N

R′ +

N

N

Cl2BNCH2CH2R

RCH2CH2 R′ Cl2BNCH2CH2R

H2O

R′NHCH2CH2R

Secondary amines can also be made using the N -chloro derivatives of primary amines149: Cl (CH3CH2)3B + HN(CH2)7CH3

H CH3CH2N(CH2)7CH3

90%

147. M. W. Rathke, N. Inoue, K. R. Varma, and H. C. Brown, J. Am. Chem. Soc. 88:2870 (1966); G. W. Kabalka, K. A. R. Sastry, G. W. McCollum, and H. Yoshioka, J. Org. Chem. 46:4296 (1981). 148. H. C. Brown, M. M. Midland, and A. B. Levy, J. Am. Chem. Soc. 95:2394 (1973). 149. G. W. Kabalka, G. W. McCollum, and S. A. Kunda, J. Org. Chem. 49:1656 (1984).

235 SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

236 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

Organoborane intermediates can also be used to synthesize alkyl halides. Replacement of boron by iodine is rapid in the presence of base.150 The best yields are obtained with sodium methoxide in methanol.151 If less basic conditions are desirable, the use of iodine monochloride and sodium acetate gives good yields.152 As is the case in hydroboration±oxidation, the regioselectivity of hydroboration±halogenation is opposite to that observed for direct ionic addition of hydrogen halides to alkenes. Terminal alkenes give primary halides. RCH

CH2

1) B2H6

RCH2CH2Br

2) Br2, NaOH

4.9.3. Enantioselective Hydroboration Several alkylboranes are available in enantiomerically enriched or enantiomerically pure form, and they can be used to prepare enantiomerically enriched alcohols and other compounds available via organoborane intermediates.153 One route to enantiopure boranes is by hydroboration of readily available terpenes that occur naturally in enantiomerically enriched or enantiomerically pure form. The most thoroughly investigated of these is bis(isopinocampheyl)borane […Ipc†2 BH], which can be prepared in 100% enantiomeric purity from the readily available terpene a-pinene.154 Both enantiomers are available. BH + BH3 2

Other examples of chiral organoboranes derived from terpenes are E; F, and G, which are derived from longifolene,155 2-carene,156 and limonene,157 respectively. Me

Me

Me

Me

HB 2

HB

Me HB Me E 150. 151. 152. 153. 154. 155. 156. 157.

2

Me

Me F

G

H. C. Brown, M. W. Rathke, and M. M. Rogic, J. Am. Chem. Soc. 90:5038 (1968). N. R. De Lue and H. C. Brown, Synthesis 1976:114. G. W. Kabalka and E. E. Gooch III, J. Org. Chem. 45:3578 (1980). H. C. Brown and B. Singaram, Acc. Chem. Res. 21:287 (1988); D. S. Matteson, Acc. Chem. Res. 21:294 (1988). H. C. Brown, P. K. Jadhav, and A. K. Mandal, Tetrahedron 37:3547 (1981); H. C. Brown and P. K. Jadhav, in Asymmetric Synthesis, Vol. 2, J. D. Morrison, ed., Academic Press, New York, 1983, Chapter 1. P. K. Jadhav and H. C. Brown, J. Org. Chem. 46:2988 (1981). H. C. Brown, J. V. N. Vara Prasad, and M. Zaidlewics, J. Org. Chem. 53:2911 (1988). P. K. Jadhav and S. U. Kulkarni, Heterocycles 18:169 (1982).

…Ipc†2 BH adopts a conformation which minimizes steric interactions. This conformation results in transition states H and I, where the S, M, and L substituents are, respectively, the 3-H, 4-CH2 , and 2-CHCH3 groups of the carbocyclic structure. The steric environment at boron in this conformation is such that Z-alkenes encounter less steric encumbrance in transition state I than in H. S 2

B

3

M M S

4

L B

M M

H

C

S

L

R

L

S

C

R C

C

B H C H

C H

S M M S

L

H

L

H

C

C

C

B H R

C R

L

H

I

The degree of enantionselectivity of …Ipc†2 BH is not high for all simple alkenes. ZDisubstituted alkenes give good enantioselectivity (75±90%), but E-alkenes and simple cycloalkenes give low enantioselectivity (5±30%). Monoisopinocampheylborane …IpcBH2 † can be prepared in enantiomerically pure form by puri®cation of a TMEDA adduct.158 When this monoalkylborane reacts with a prochiral alkene, one of the diastereomeric products is normally formed in excess and can be obtained in high enatiomeric purity by an appropriate separation.159 Oxidation of the borane then provides the corresponding alcohol in the same enantiomeric purity achieved for the borane. BH2

R1

R3 +

C H

C

H IpcB

R2

R1

R3 C H

R3 H C H or IpcB C R2 H

R1 C

H R2

Because oxidation also converts the original chiral terpene-derived group to an alcohol, it is not directly reusable as a chiral auxillary. Although this is not a problem with inexpensive materials, the overall ef®ciency of generation of enantiomerically pure product is improved by procedures that can regenerate the original terpene. This can be done by heating the dialkylborane intermediate with acetaldehyde. The a-pinene is released and a diethoxyborane is produced.160 Me

CH3 BH2 +

CH3

CH3 H IpcB

CH3CH O

(EtO)2B

+

The usual oxidation conditions then convert this boronate ester to an alcohol.161 The corresponding haloboranes are also useful for enantioselective hydroboration. Isopinocampheylchloroborane can achieve 45±80% e.e. with representative alkenes.162 The corresponding dibromoborane achieves 65±85% enantioselectivity with simple 158. H. C. Brown, J. R. Schwier, and B. Singaram, J. Org. Chem. 43:4395 (1978); H. C. Brown, A. K. Mandal, N. M. Yoon, B. Singaram, J. R. Schwier, and P. K. Jadhav, J. Org. Chem. 47:5069 (1982). 159. H. C. Brown and B. Singaram, J. Am. Chem. Soc. 106:1797 (1984); H. C. Brown, P. K. Jadhav, and A. K. Mandal, J. Org. Chem. 47:5074 (1982). 160. H. C. Brown, B. Singaram, and T. E. Cole, J. Am. Chem. Soc. 107:460 (1985); H. C. Brown, T. Imai, M. C. Desai, and B. Singaram, J. Am. Chem. Soc. 107:4980 (1985). 161. D. S. Matteson and K. M. Sadhu, J. Am. Chem. Soc. 105:2077 (1983). 162. U. P. Dhokte, S. V. Kulkarni, and H. C. Brown, J. Org. Chem. 61:5140 (1996).

237 SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

238

78 C.163

alkenes when used at

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

BHCl

H

OH

CH3

–OH

+

BBr2

CH3

H

CH3

CH3

H

CH3

+

64% e.e.

H2O2

OH (CH3)3SiH

–OH

H2O2

65% e.e.

Procedures for synthesis of chiral amines164 and halides165 based on chiral alkylboranes have been developed by applying the methods discussed earlier to the homochiral organoborane intermediates. For example, enantiomerically pure terpenes can be converted to trialkylboranes and then aminated with hydroxylaminesulfonic acid. BCH3 1) BHCl2⋅S(CH3)2

1) NH2OSO3H

2) (CH3)3AI

2) HCl 3) NaOH

NH2 Ref. 166

2

Combining catalytic enantioselective hydroboration (see p. 230) with amination has provided certain amines with good enantioselectivity.

catalyst N +

O

1%

BH

+

PPh2

Rh(COD)

O

CH3O

NH2 O

O B

1) CH3MgBr

CH3

2) NH2OSO3H

CH3

Ref. 167

CH3O

CH3O 163. U. P. Dhokte and H. C. Brown, Tetrahedron Lett. 37:9021 (1996). 164. L. Verbit and P. J. Heffron, J. Org. Chem. 32:3199 (1967); H. C. Brown, K.-W. Kim, T. E. Cole, and B. Singaram, J. Am. Chem. Soc. 108:6761 (1986); H. C. Brown, A. M. Sahinke, and B. Singaram, J. Org. Chem. 56:1170 (1991). 165. H. C. Brown, N. R. De Lue, G. W. Kabalka, and H. C. Hedgecock, Jr., J. Am. Chem. Soc. 98:1290 (1976). 166. H. C. Brown, S. V. Malhotra, and P. V. Ramachandran, Tetrahedron Asymmetry 7:3527 (1996). 167. E. Fernandez, M. W. Hooper, F. I. Knight, and J. M. Brown, J. Chem. Soc., Chem. Commun. 1997:173.

239

4.9.4. Hydroboration of Alkynes Alkynes are reactive toward hydroboration reagents. The most useful procedures involve addition of a disubstituted borane to the alkyne. This avoids the complications which occur with borane that lead to polymeric structures. Catecholborane is a particularly useful reagent for hydroboration of alkynes.168 Protonolysis of the adduct with acetic acid results in reduction of the alkyne to the corresponding Z-alkene. Oxidative workup with hydrogen peroxide gives ketones via enol intermediates.

D

H C

CH3CO2D

O BH + RC

H2O2, –OH

O

CR′

O

O

B

R′

HO

H C

O RCCH2R′

C R′

Br2

C

R

R

R

H C

C

R′

Br

–OCH 3

R′ C

C

R

H

Treatment of the vinylborane with bromine and base leads to vinyl bromides. The reaction occurs with net anti addition. The stereoselectivity is explained on the basis of anti addition of bromine followed by a second anti elimination of bromide and boron:

L2B

H

Br

Br2

H

L2B R

R

R

L2B R

H

Br

R

R

R Br

Br

R

H Br

Exceptions to this stereoselectivity have been noted.169 The adducts derived from catecholborane are hydrolysed to vinylboronic acids. These materials are useful intermediates for preparation of terminal vinyl iodides. Because the hydroboration is a syn addition and the iodinolysis occurs with retention of the alkene geometry, the iodides have the E-con®guration.170

O O

H2O

B

H C

H

C

(HO2)B

H C

H

C R

I2

I

H C

H

C R

R

168. H. C. Brown, T. Hamaoka, and N. Ravindran, J. Am. Chem. Soc. 95:6456 (1973); C. F. Lane and G. W. Kabalka, Tetrahedron 32:981 (1976). 169. J. R. Wiersig, N. Waespe-Sarcevic, and C. Djerassi, J. Org. Chem. 44:3374 (1979). 170. H. C. Brown, T. Hamaoka, and N. Ravindran, J. Am. Chem. Soc. 95:5786 (1973).

SECTION 4.9. ADDITION AT DOUBLE BONDS VIA ORGANOBORANE INTERMEDIATES

240 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

The dimethyl sul®de complex of dibromoborane171 and pinacolborane172 are also useful for synthesis of E-vinyl iodides from terminal alkynes. –

Br2BH

Br2B

+

S(CH3)2 + HC

CR

H C

C

H

R

1) OH, H2O 2) –OH, I2

I

H C

H

C R

Other disubstituted boranes have also been used for selective hydroboration of alkynes. 9-BBN can be used to hydroborate internal alkynes. Protonlysis can be carried out with methanol, and this provides a convenient method for formation of a disubstituted Z-alkene173. R R

C

C

R C

R + 9-BBN H

C B

MeOH

R

R C

H

C H

A large number of procedures which involve carbon±carbon bond formation have developed around organoboranes. These reactions are considered in Chapter 9.

General References Addition of Hydrogen Halide, Halogens, and Related Electrophiles P. B. De la Mare and R. Bolton, Electrophilic Addition to Unsaturated Systems, Elsevier, Amsterdam, 1982. R. C. Fahey, Top Stereochem. 2:237 (1968).

Solvomercuration W. Kitching, Organomet. Chem. Rev. 3:61 (1968). R. C. Larock, Angew. Chem. Int. Ed. Engl. 12:27 (1978).

Addition of Sulfur and Selenium Reagents D. J. Clive, Tetrahedron 34:1049 (1978). D. Liotta, ed., Organoselenium Chemistry, John Wiley & Sons, New York, 1987. S. Patai and Z. Rappoport, ed., The Chemistry of Organic Selenium and Tellurium Compounds, Johnn Wiley & Sons, New York, 1986. C. Paulmier, Selenium Reagents and Intermediates in Organic Synthesis, Pergamon, Oxford, 1986.

Additions to Acetylenes and Allenes T. F. Rutledge, Acetylenes and Allenes, Reinhold, New York, 1969. G. H. Schmid, in The Chemistry of the Carbon±Carbon Triple Bond, S. Patai, ed., John Wiley & Sons, New York, 1978, Chapter 8. L. Brandsma, Preparative Acetylenic Chemistry, 2nd ed. Elsevier, Amsterdam, 1988. 171. H. C. Brown and J. B. Campbell, Jr., J. Org. Chem. 45:389 (1980); H. C. Brown, T. Hamaoka, N. Ravindran, C. Subrahmanyam, V. Somayaji, and N. G. Bhat, J. Org. Chem. 54:6075 (1989). 172. C. E. Tucker, J. Davidson, and P. Knochel, J. Org. Chem. 57:3482 (1992).

Organoboranes as Synthetic Intermediates H. C. Brown, Organic Synthese via Boranes, John Wiley & Sons, New York, 1975. G. Cragg, Organoboranes in Organic Synthesis, Marcel Dekker, New York, 1973. A. Pelter, K. Smith, and H. C. Brown, Borane Reagents, Academic Press, New York, 1988.

Problems (References for these problems will be found on page 927.) 1. Predict the direction of addition and structure of the product for each of the following reactions. (a) CH3CH

CH2 + O2N

SCl NO2

(b)

(CH3)2CC

1) H+, H2O

COCH2CH3

2) KOH

OH

(c) CH2

HOBr

1) disiamylborane

(d)

(CH3)2C

(e)

CH3CH2CH2CH2CH

(f)

(CH3)3CCH

(g)

C6H5CH

CHCH3

2) H2O2, HO–

CH2

CHCH3

IN3

CHCH(OCH3)2

(h) OSi(CH3)3

(i)

HC

(j)

H2C

(k)

CCH2CH2CO2H

CHCl3, crown ether

(l)

NOCl

PhSCl, Hg(OAc)2 LiClO4, CH3CN

(n)

PhCHCH2CO2H CH

IN3

PhSeBr ether, –78°C

CH2

I2 CH3CN

NaHCO3 H 2O

Hg(OAc)2

H2O, NaHCO3

CH2Cl2

10 min

CHCH2CH2CH2CH2OH I2, NaN3

(m)

IN3

1) Hg(OAc)2 2) NaBH4

241 PROBLEMS

242 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

2. Bromination of 4-t-butylcyclohexene in methanol gives a 45 : 55 mixture of two compounds, each of compositions C11 H21 BrO. Predict the structure and stereochemistry of these two products. How would you con®rm your prediction? 3. Hydroboration±oxidation of PhCHˆCHOC2 H5 gives A as the major product if the hydroboration step is of short duration (7 s), but B is the major product if the hydroboration is allowed to proceed for a longer time (2 h). Explain. PhCHCH2OC2H5

PhCH2CH2OH

OH A

B

4. Oxymercuration of 4-t-butylcyclohexene, followed by NaBH4 reduction, gives cis-4-tbutylcyclohexanol and trans-3-t-butylcyclohexanol in approximately equal amounts. 1-Methyl-4-t-butylcyclohexene under similar conditions gives only cis-4-t-butyl-1methylcyclohexanol. Formulate a mechanism for the oxymercuration±reduction process that is consistent with this stereochemical result. 5. Treatment of compound C with N -bromosuccinimide in acetic acid containing sodium acetate gives a product C13 H19 BrO3 . Propose the structure, including stereochemistry, of the product and explain the basis for your proposal. H

O

H C

6. The hydration of 5-undecyn-2-one with mercuric sulfate and sulfuric acid in methanol is regioselective, giving 2,5-undecadione in 85% yield. Suggest an explanation for the high selectivity. 7. A procedure for the preparation of allylic alcohols has been devised in which the elements of phenylselenenic acid are added to an alkene, and then the reaction mixture is treated with t-butyl hydroperoxide. Suggest a mechanistic rationale for this process.

CH3CH2CH2CH

CHCH2CH2CH3

1) “C6H5SeOH” 2) t-BuOOH

CH3CH2CH2CHCH

CHCH2CH3

88%

OH

8. Suggest synthetic sequences that could accomplish each of the following transformations.

243

O

(a) O

(b)

PROBLEMS

CO2C2H5

OTHP

CH3

CH3

OTHP

O O

CH3C

CH3

(c)

CH3

CH3

CH3 CH3 C(CH3)2

(d)

COH

H

CH3

OH

CH3

CH3

(e)

CH3CH2CH2CH2 CH3CH2CH2CH2C

CH

H C

C

H

(f)

CH3 O

H3C

(g)

C

I

CH3 O

HC(CH3)2

CH3

O

O CH3CCH2CH2CH

C(CH3)2 (CH3)2CH

(h)

H3C

H3C C

CH2

CH

C

CH2CH2OH

CH2

CH3

(i)

CH3 CH2CH

O

CH2

O

(j)

(CH2)3I

O O CH3

CH3

O

CH2

C

CH

O

CH2CH

O

244 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

OH

OH C

CH

CH

CHI

(k)

MeO

MeO

(l)

CH3CH2CHCH2CH

(m)

HC(OCH3)2

HC(OCH3)2

CH3(CH2)5C

CH2

CH

CH3CH2CHCH2CH2CH2Br

CH3(CH2)5

H C

C

H

(n)

Br

CH2 O

O NHCO2C(CH3)3 O

N

HOCH2

O

CO2C(CH3)3 CH2OCH3

(o) O

H3C

O

CH2OCH3 O

N

N

H3C

HOCH2

N

O N

O

9. Three methods for the preparation of nitroalkenes are outlined as shown. Describe in mechanistic terms how each of these transformations might occur. (a)

1) HgCl2, NaNO2

NO2

2) NaOH

(b)

Sn(CH3)3

NO2 + C(NO2)4

(c)

NO2+BF4–

NO2

10. Hydroboration±oxidation of 1,4-di-t-butylcyclohexene gave three alcohols: C (77%), D (20%), and E (3%). Oxidation of C gave ketone F, which was readily converted in either acid or base to an isomeric ketone G. Ketone G was the only oxidation product of alcohols D and E. What are the structures of compounds C±G?

11. Show how, using enolate chemistry and organoselenium reagents, you could convert 2-phenylcyclohexanone regiospeci®cally to either 2-phenyl-2-cyclohexen-1-one or 6phenyl-2-cyclohexen-1-one.

12. On the basis of the mechanistic picture of oxymercuration involving a mercurinium ion, predict the structure and stereochemistry of the major alcohols to be expected by application of the oxymercuration±demercuration sequence to each of the following substituted cyclohexenes. (a)

(b)

C(CH3)3

CH3

(c)

CH3

13. Reaction of the unsaturated acid A and I2 in acetonitrile (no base) gives rise in 89% yield to a 20 : 1 mixture of two stereoisomeric iodolactones. Formulate the complete stereochemistry of both the major and the minor product to be expected under these conditions.

H3C

H3C

A

CH2

CH C

CO2H C

H

H

CH3

14. Give the structure, including stereochemistry, of the expected product. (a)

CH2CH2CH2OH N I2, NaHCO3

CH3O2C

(b)

H O O H

(c)

CH3CONHBr H2O

OH

(PhCH2)2C(CH2)3CH

CH2

1) Hg(O3SCF3)2 CH3CN 2) NaCl

OH

(d)

CH3 CO2H

I2, KI NaHCO3

CH2CH2OCH3 CH3

(e)

Si(CH3)2Ph C11H23 C H

C

OTBDMS H

C6H13

1) 9-BBN 2) –OH, H2O2

245 PROBLEMS

246

(f)

CH2OC16H33 H2C

CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

1) (+)-(Ipc)2BH 2) –OH, H2O2

CH2OCH3

15. Some synthetic transformations are shown in the retrosynthetic format. Propose a short series of reactions (no more than three steps should be necessary) which could effect the synthetic conversion. (a)

O

O

O N

O

C

CH(CH3)2

O N

O

NH2 CH2Ph

CH2CH(CH3)2

CH2Ph

(enantioselective)

CH2OH

(b) O

(c)

CHCH2CH2CH2CO2CH3

I

HO

S

CH2 CH2CH2CH2CO2CH3 C C H H H C C CH(CH2)4CH3

H C

C RO

H

CH(CH2)4CH3

RO

O

(d)

H

OR O CH3

CH3 O

PhCHN

CNCHPh H

O

Br

(e)

CH3

CH3 CH2O2CCH3

C

CH2

CH2O2CCH3 CH3CHCH

O

CH3

16. Write detailed mechanisms for the following reactions. (a)

O CH3

H3C

NaOCl

H3C

HO2CCH2CCH2CO2H CH3

O

OR

(b)

CH2

CHCH2CHOCH2NCO2CH2Ph H CH3

O

NaBH4

1) Hg(NO3)2 2) KBr

NCO2CH2Ph

O2

H3C

CH2OH 3:1 cis:trans

(c) N

CO2H 1) NBS

O

2) NaOCH3

Ph

N

CO2CH3 >90% enantiomerically pure

Ph CH3

CH3

17. It has been observed that 4-pentenyl amides such as 1 cyclize to lactams 2 on reaction with phenylselenenyl bromide. The 3-butenyl compound 3, on the other hand, cyclizes to an imino ether, 4. What is the basis for the different course of these reactions? R CH2

R

O

CHCH2CHCH2NHCCH3

PhSeBr

PhSeCH2

1

N 2 CCH3

O PhSeCH2

O CH2

CHCH2CH2NHCCH3

PhSeBr

O

N

3

4

CH3

18. Procedures for enantioselective synthesis of derivatives of a-bromoacids based on reaction of compounds A and B with N-bromosuccinimide have been developed. Predict the absolute con®guration at the halogenated carbon in each product. Explain the basis of your prediction. Bu R

O

C

C H

O

Bu B

O R

NBS

N

O

OTMS

(C6H13)2NSO2CH2 A

B

NBS

H CH2Ph

19. The stereochemical outcome of the hydroboration±oxidation of 1,10 -bicyclohexenyl depends on the amount of diborane used in the hydroboration. When 1.1 equiv is used, the product is a 3 : 1 mixture of C and D. When 2.1 equiv is used, C is formed nearly exclusively. Offer an explanation of these results. 1) B2H6

HH

HH +

2) –OH, H2O2

OH HO C

OH HO D

247 PROBLEMS

248 CHAPTER 4 ELECTROPHILIC ADDITIONS TO CARBON±CARBON MULTIPLE BONDS

20. Predict the absolute con®guration of the product obtained from the following reactions based on enantioselective hydroboration. (a)

CH3

CH3 H2B

CH3CH

O

H2O2 –OH

CH3

(b) CH3

B

CH3

H2O2

H



OH

CH3

21. The regioselectivity and stereoselectivity of electrophilic additions to 2-benzyl-2azabicyclo[2.2.1]hept-5-en-3-one are quite dependent on the speci®c electrophile. Discuss the factors which could in¯uence the differing selectivity patterns and compare this system to norbornene. Br

PhS

Br N CH2Ph

Cl

Br2

O

N CH2Ph

PhSCl

N O

CH2Ph

PhSeBr

O 1) Hg(OAc)2 2) NaBH4

Br O PhSe

HO O

N

O

HO

+

N

CH2Ph

O

+ HO

N CH2Ph

N CH2Ph

CH2Ph

22. Offer a mechanistic explanation of the following observations. (a) In the cyclization shown, A is the preferred product for RˆH, but endo cyclization to B is preferred for Rˆphenyl or methyl. O

O N

CH2C

N NHPh

CR

O I

N

I2

N

N

R

N

N

Ph A

I

N

or

R

Ph B

(b) The pent-4-enoyl group has been developed as a protecting group for amines. The conditions for cleavage involve treatment with iodine and an mixed aqueous solution with THF or acetonitrile. Give a mechanism which accounts for the mild deprotection under these conditions.

5

Reduction of Carbonyl and Other Functional Groups Introduction The topic of this chapter is reduction reactions that are especially important in synthesis. Reduction can be accomplished by several broad methods, including addition of hydrogen and=or electrons to a molecule or removal of oxygen or other electronegative substituents. The most important reducing agents from a synthetic point of view are molecular hydrogen and hydride derivatives of boron and aluminum. Other important procedures use metals such as lithium, sodium, or zinc as electron donors. Certain reductions that proceed via a free-radical mechanism involve hydrogen atom donors such as the trialkyl tin hydrides. Reductive removal of oxygen from functional groups such as alcohols, benzylic carbonyls, a-oxycarbonyls, and diols is also important in synthesis, since these reactions provide important methods for interconversion of functional groups. There are also reductive procedures which involve formation of carbon±carbon bonds. Most of these begin with an electron transfer that generates a radical intermediate which then undergoes a coupling or addition reaction.

5.1. Addition of Hydrogen 5.1.1. Catalytic Hydrogenation The most widely used method for adding the elements of hydrogen to carbon±carbon double bonds is catalytic hydrogenation. Except for very sterically hindered alkenes, this reaction usually proceeds rapidly and cleanly. The most common catalysts are various forms of transition metals, particularly platinum, palladium, rhodium, ruthenium, and nickel. Both the metals, as ®nely dispersed solids or adsorbed on inert supports such as

249

250 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

carbon or alumina, and certain soluble complexes of these metals exhibit catalytic activity. Depending upon conditions and catalyst, other functional groups are also subject to catalytic hydrogenation. RCH

CHR + H2

catalyst

RCH2CH2R

The mechanistic description of alkene hydrogenation is somewhat vague, partly because the reactive sites on the metal surface are not as easily described as smallmolecule reagents in solution. As understanding of the chemistry of soluble hydrogenation catalysts has developed, it has become possible to extrapolate some mechanistic concepts to heterogeneous catalysts. It is known that hydrogen is adsorbed onto the metal surface, presumably forming metal±hydrogen bonds similar to those in transition-metal hydride complexes. Alkenes are also adsorbed on the catalyst surface, and at least three types of intermediates have been implicated in the process of hydrogenation. The initially formed intermediate is pictured as attached at both carbon atoms of the double bond by p-type bonding, as shown in A. The bonding is regarded as an interaction between the alkene p and p* orbitals and acceptor and donor orbitals of the metal. A hydrogen can be added to the adsorbed group, leading to B, which involves a s-type carbon±metal bond. This species can react with another hydrogen to give the alkane, which is desorbed from the surface. A third intermediate species, shown as C, accounts for double-bond isomerization and the exchange of hydrogen which sometimes accompanies hydrogenation. This intermediate is equivalent to an allyl group bound to the metal surface by p bonds. It can be formed from adsorbed alkene by abstraction of an allylic hydrogen atom by the metal. In Chapter 8, the reactions of transition metals with organic compounds will be discussed. There are well-characterized examples of structures corresponding to each of the intermediates A, B, and C that are involved in hydrogenation. R R C H H

C A

R R H

R C

CH2R C

H

π-complex R

H H

B

R CH2R H H

σ-bond

R C H H

R C

C

R H H

C

H

π-allyl complex

In most cases, both hydrogen atoms are added to the same side of the reactant (syn addition). If hydrogenation occurs by addition of hydrogen in two steps, as implied by the mechanism above, the intermediate must remain bonded to the metal surface in such a way that the stereochemical relationship is maintained. Adsorption to the catalyst surface normally involves the less sterically congested side of the double bond, and, as a result, hydrogen is added from the less hindered face of the double bond. Scheme 5.1 illustrates some hydrogenations in which the syn addition from the less hindered side is observed. Some exceptions are also included. There are many hydrogenations in which hydrogen addition is not entirely syn, and independent corroboration of the stereochemistry is normally necessary.

Scheme 5.1. Stereochemistry of Hydrogenation of Some Alkenes A. Examples of preferential syn addition from less hindered side 1a

H3C

H3C

H CH2

H3C

H CH3

Pt H2

H

+

CH3

70%

2b

CH3

30%

CH3

CH3

Pt H2

+

CH3

CH3

CH3

70–85%

3c

SECTION 5.1. ADDITION OF HYDROGEN

H

H

CH3

15–30%

H H

CH3 4b

H3C

CH2

CH3

CH3 H Pt(BH4–)—C H2

B. Exceptions 5a

CH3

CH3

CH3

Pd H2

+

CH3

CH3

CH3

75%

6d

25%

CH2CH2CO2CH3

CH2CH2CO2CH3 Pt H2

H

CO2CH3

7e

H

CO2CH3 H

Ni, H2

+ H

OH

OH

OH

95%

8f

5%

Pt, H2 acetic acid

+ H

H

CH3

CH3 80%

a. b. c. d. e. f.

251

S. Siegel and G. V. Smith, J. Am. Chem. Soc. 82:6082, 6087 (1960). C. A. Brown, J. Am. Chem. Soc. 91:5901 (1969). K. Alder and W. Roth, Chem. Ber. 87:161 (1954). J. P. Ferris and N. C. Miller, J. Am. Chem. Soc. 88:3522 (1966). S. Mitsui, Y. Senda, and H. Saito, Bull. Chem. Soc. Jpn. 39:694 (1966). S. Siegel and J. R. Cozort, J. Org. Chem. 40:3594 (1975).

CH3 20%

252 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

The facial stereoselectivity of hydrogenation is affected by the presence of polar functional groups that can in¯uence the mode of adsorption to the catalyst surface. For instance, there are many examples where the presence of a hydroxyl group results in the hydrogen being introduced from the side of the molecule occupied by the hydroxyl group. This implies that the hydroxyl group is involved in the interaction with the catalyst surface. This behavior can be illustrated with the alcohol 1a and the ester 1b.1 Although the overall shapes of the two molecules are similar, the alcohol gives mainly the product with a cis ring juncture (2a), whereas the ester gives a product with trans stereochemistry (3b). The stereoselectivity of hydroxyl-directed hydrogenation is a function of solvent and catalyst. The cis isomer is the main product in hexane. This suggests that the hydroxyl group directs the molecule to the catalyst surface. In ethanol, the competing interaction of the solvent molecules evidently swamps out the effect of the hydroxymethyl group in 4. O

O

H

O X

CH3O 1a 1b

+

O 2a 2b

X = CH2OH X = CO2CH3

94% 15%

O X

CH3O 3a 3b

CH2OH CH3O

O

H

X

CH3O

Solvent

% cis

% trans

Hexane DME EtOH

61 20 6

39 80 94

6% 85%

4

Catalytic hydrogenations are usually extremely clean reactions with little by-product formation, unless reduction of other groups is competitive. Careful study, however, sometimes reveals that double-bond migration can take place in competition with reduction. For example, hydrogenation of 1-pentene over Raney nickel is accompanied by some isomerization to both E- and Z-2-pentene.2 The isomerized products are converted to pentane, but at a slower rate than 1-pentene. Exchange of hydrogen atoms between the reactant and adsorbed hydrogen can be detected by exchange of deuterium for hydrogen. Allylic positions undergo such exchange particularly rapidly.3 Both the isomerization and allylic hydrogen exchange can be explained by the intervention of the p-allyl intermediate C in the general mechanism for hydrogenation. If this intermediate adds a hydrogen at the alternative end of the allyl system, an isomeric alkene is formed. Hydrogen exchange occurs if a hydrogen from the metal surface, rather than the original hydrogen, is transferred prior to desorption.

1. H. W. Thompson, J. Org. Chem. 36:2577 (1971); H. W. Thompson, E. McPherson, and B. L. Lences, J. Org. Chem. 41:2903 (1976). 2. H. C. Brown and C. A. Brown, J. Am. Chem. Soc. 85:1005 (1963). 3. G. V. Smith and J. R. Swoap, J. Org. Chem. 31:3904 (1966).

Besides solid transition metals, certain soluble transition-metal complexes are active hydrogenation catalysts.4. The most commonly used example is tris(triphenylphosphine)chlororhodium, which is known as Wilkinson's catalyst.5 This and related homogeneous catalysts usually minimize exchange and isomerization processes. Hydrogenation by homogeneous catalysts is believed to take place by initial formation of a p-complex, followed by transfer of hydrogen from rhodium to carbon. Rh

H + RCH

CHR

Rh RCH

CHR

H2

Rh

H

Rh

RCH2CHR

H

RCH2CHR

RCH2CHR

The phosphine ligands serve both to provide a stable soluble, complex and to adjust the reactivity of the metal center. Scheme 5.2 gives some examples of hydrogenations carried out with homogeneous catalysts. One potential advantage of homogeneous catalysts is the ability to achieve a high degree of selectivity among different functional groups. Entries 3 and 5 in Scheme 5.2 are examples of such selectivity. The stereochemistry of reduction by homogeneous catalysts is often controlled by functional groups in the reactant. Homogeneous iridium catalysts have been found to be in¯uenced not only by hydroxyl groups, but also by amide, ester, and ether substituents.6 CH3

OH

CH3

OH

[R3P—Ir(COD)py]PF4 H2

O

O

Ref. 7 O

N

H

O

N Ref. 8

[R3P—Ir(COD)py]PF4 H2

CH3

H

CH3

Delivery of hydrogen occurs syn to the polar functional group. Presumably, the stereoselectivity is the result of coordination of iridium by the functional group. The crucial property required for a catalyst to be stereodirective is that it be able to coordinate with both the directive group and the double bond and still accommodate the metal hydride bond necessary for hydrogenation. In the iridium catalyst illustrated above, the cyclooctadiene (COD) ligand in the catalyst is released upon coordination of the reactant. A number of chiral ligands, especially phosphines, have been explored in order to develop enantioselective hydrogenation catalysts.9 Some of the most successful catalysts 4. A. J. Birch and D. H. Williamson, Org. React. 24:1 (1976); B. R. Jones, Homogeneous Hydrogenation, John Wildey & Sons, New York, 1973. 5. J. A. Osborn, F. H. Jardine, J. F. Young, and G. Wilkinson, J. Chem. Soc. A. 1966:1711. 6. R. H. Crabreee and M. W. Davis, J. Org. Chem. 51:2655 (1986); P. J. McCloskey and A. G. Schultz, J. Org. Chem. 53:1380 (1988). 7. G. Stork and D. E. Kahne, J. Am. Chem. Soc. 105:1072 (1983). 8. A. G. Schultz and P. J. McCloskey, J. Org. Chem. 50:5905 (1985). 9. B. Bosnich and M. D. Fryzuk, Top. Stereochem. 12:119 (1981); W. S. Knowles, W. S. Chrisopfel, K. E. Koenig, and C. F. Hobbs, Adv. Chem. Ser. 196:325 (1982); W. S. Knowles, Acc. Chem. Res. 16:106 (1983).

253 SECTION 5.1. ADDITION OF HYDROGEN

Scheme 5.2. Homogeneous Catalytic Hydrogenation

254 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

O

1a

H3C

H+, H2O

(Ph3P)3RhBr D2

CH3

O

56%

D

O

D 2b H3C

O

THP H3C

O

THP

(Ph3P)3RhCl H2

H3C CH3CO2 3c

90%

H3C

CH3

CH2

CH3CO2

H3C

CH3

CH3 (CH3)2CH

H3C

94%

O

4d CH3O

CH

CHNO2

CH3

(Ph3P)3RhCl H2

CH2CH2NO2

90%

O (Ph3P)3RhCl H2

6f

CH3O

CH3 O

H2C

CH3

(Ph3P)3RhCl H2

O

5e

H3C

CCH3 CH3 CO2CH3

90–94%

CH(CH3)2 CH3 CO2CH3

[R3P—Ir(COD)py]BF4

67%

H

CH3 7g

CH3

CH3

CH3 [Rh(NBD)(diphosp)]BF4

OH

CH3

OH

(CH3)2CH H

(CH3)2CH 8h

95%

CH3

H

[R3P—Ir(COD)py]PF6 100%

CH3O a. b. c. d. e. f. g. h.

CH(CH3)2

CH3O

CH(CH3)2

W. C. Agosta and W. L. Schreiber, J. Am. Chem. Soc. 93:3947 (1971). E. Piers, W. de Waal, and R. W. Britton, J. Am. Chem. Soc. 93:5113 (1971). M. Brown and L. W. Piszkiewicz, J. Org. Chem. 32:2013 (1967). R. E. Harmon, J. L. Parsons, D. W. Cooke, S. K. Gupta, and J. Schoolenberg, J. Org. Chem. 34:3684 (1969). R. E. Ireland and P. Bey, Org. Synth. 53:63 (1973). A. G. Schulz and P. J. McCloskey, J. Org. Chem. 50:5905 (1985). D. A. Evans and M. M. Morrissey, J. Am. Chem. Soc. 106:3866 (1984). R. H. Crabtree and M. W. Davies, J. Org. Chem. 51:2655 (1986).

are derived from chiral 1,10 -binaphthyldiphosphines (BINAP).10 These ligands are chiral by virtue of the sterically restricted rotation of the two naphthyl rings.

PPh2 PPh2

Ruthenium complexes containing this phosphine ligand are able to reduce a variety of double bonds with enantiomeric excesses above 95%. In order to achieve high enantioselectivity, the compound to be reduced must show a strong preference for a speci®c orientation when complexed with the catalyst. This ordinarily requires the presence of a functional group that can coordinate with the metal. The ruthenium binaphthyldiphosphine catalyst has been used successfully with unsaturated amides,11 allylic and homoallylic alcohols,12 and unsaturated carboxylic acids.13

Ru(S-BINAP)(OAc)2

OH

OH

99% e.e.

Ref. 12

An especially important case is the enantioselective hydrogenation of a-amidoacrylic acids, which leads to a-amino acids.14 A particularly detailed study has been carried out on the mechanism of reduction of methyl Z-a-acetamidocinnamate by a rhodium catalyst with a chiral disphosphine ligand.15 It has been concluded that the reactant can bind reversibly to the catalysts to give either of two complexes. Addition of hydrogen at rhodium then leads to a reactive rhodium hybride and eventually to product. Interestingly, the addition of hydrogen occurs most rapidly in the minor isomeric complex, and the enantioselectivity is 10. R. Noyori and H. Takaya, Acc. Chem. Res. 23:345 (1990). 11. R. Noyori, M. Ohta, Y. Hsiao, M. Kitamura, T. Ohta, and H. Takaya, J. Am. Chem. Soc. 108:7117 (1986). 12. H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S. Inoue, I. Kasahara, and R. Noyori, J. Am. Chem. Soc. 109:1596 (1987). 13. T. Ohta, H. Takaya, M. Kitamura, K. Nagai, and R. Noyori, J. Org. Chem. 52:3176 (1987). 14. A. Pfaltz and J. M. Brown, in Stereoselective Synthesis, G. Helmchen, R. W. Hoffmann, J. Mulzer, and E. Schauman, eds., Thieme, New York, 1996, Part D, Sect. 2.5.1.2; U. Nagel and J. Albrecht, Top. Catal. 5:3 (1998). 15. C. R. Landis and J. Halpern, J. Am. Chem. Soc. 109:1746 (1987).

255 SECTION 5.1. ADDITION OF HYDROGEN

256

due to this kinetic preference.

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

OMe

P

P Rh MeO CO2Me

PhCH

C NHAc

H2 slower

H2 faster

minor complex

major complex Rh

Rh-hydride complex

Rh-hydride complex

minor (R) product

major (S) product

a,b-Unsaturated acids can be reduced enantioselectively with ruthenium and rhodium catalysts having chiral phosphine ligands. The mechanism of such reactions using Ru…BINAP†…O2 CCH3 †2 has been studied and is consistent with the idea that coordination of the carboxy group establishes the geometry at the metal ion.16

P * P

H+

H2 O

Ru O



R

R O

O P * P

k

O Ru O

O

R



H

O CO2H * K CO2H R O P * P

O O

P * P

Ru O

O Ru

O

H+

O *

O *

Table 5.1 gives the enantioselectivity of some hydrogenations of substituted acrylic acids. 16. M. T. Ashby and J. T. Halpern, J. Am. Chem. Soc. 113:589 (1991).

Ph

H

Ph

H

Ph

H

C

C

C

CH2

C

C

C

C

Substrate

O

NHCPh

CO2H

O

NHCCH3

CO2H

O

NHCCH3

CO2H

O

NHCCH3

CO2H

H

H

CH3O

PH Rh PH

CH3 CH3

PPh2

PPh2

Same as above

Ph2 P Rh P Ph2

Catalyst

Rh

OCH3

O

NHCPh

PhCH2CHCO2H

O

NHCCH3

PhCH2CHCO2H

O

NHCCH3

PhCH2CHCO2H

O

NHCCH3

CH3CHCO2H

Product

S

R

R

R

Con®guration % e.e.

c

b

a

a

(continued )

100

94

95

90

Reference

Table 5.1. Enantiomeric Excess (e.e.) for Asymmetric Catalytic Hydrogenation of Substituted Acrylic Acids

257

SECTION 5.1. ADDITION OF HYDROGEN

C

C

C

CH3O2C

CH

CO2H

O

NHCCH3

CO2CH3

CH2CO2CH3

CO2CH3

O2CCH3

CO2C2H5

(CH3)2CH

3

C H

CH2

Ph

H

Substrate

PH Rh PH

P

P

Same as above

H5C2

Rh

OCH3

C2H5

C2H5

Same as above

H5C2

CH3O

Catalyst

Table 5.1. (continued )

CH3O2C

(CH3)2CH

CH3

CH2 CO2H

O

NHCCH3

CO2CH3

CH2CO2CH3

CH3CH2CO2CH3

O2CCH3

R

R

R

S

Con®guration % e.e.

PhCH2CHCO2C2H5

Product

99

99.2

88

90

d

b

f

e

Reference

258

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

a. b. c. d. e. f. g. h.

CH2

CO2H

CO2H

Ph

(C6H11)2

Rh

(C6H11)2

P

P

Ph2PCH2

Rh

O

CNHPh

N

PPh2

CH3 CH3

HO2C

HO2C

CH3

PhCH2

CO2H

CO2H

M. D. Fryzuk and B. Bosnich, J. Am. Chem. Soc. 99:6262 (1977). B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman, and D. J. Weinkauff, J. Am. Chem. Soc. 99:5946 (1977). A. Miyashita, H. Takaya, T. Souchi, and R. Noyori, Tetrahedron 40:1245 (1984). W. C. Christopfel and B. D. Vineyard, J. Am. Chem. Soc. 101:4406 (1979). M. J. Burk, J. G. Allen, and W. F. Kiesman, J. Am. Chem. Soc. 120:657 (1998). M. J. Burk, F. Bienewald, M. Harris, and A. Zanotti-Gerosa, Angew. Chem. Int. Ed. Engl. 37:1931 (1998). H. Jendralla, Tetrahedron Lett. 32:3671 (1991). T. Chiba, A. Miyashita, H. Nohira, and H. Takaya, Tetrahedron Lett. 32:4745 (1991).

CH3O2C

CH3O2C

HC

S

S

96

>95

h

g

259

SECTION 5.1. ADDITION OF HYDROGEN

260 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Partial reduction of alkynes to Z-alkenes is another important application of selective hydrogenation catalysts. The transformation can be carried out under heterogeneous or homogeneous conditions. Among heterogeneous catalysts, the one which is most successful is Lindlar's catalyst, which is a lead-modi®ed palladium±CaCO3 catalyst.17 A nickel± boride catalyst prepared by reduction of nickel salts with NaBH4 is also useful.18 Rhodium catalysts have also been reported to show good selectivity.19 Many other functional groups are also reactive under conditions of catalytic hydrogenation. The reduction of nitro compounds to amines, for example, usually proceeds very rapidly. Ketones, aldehydes, and esters can all be reduced to alcohols, but in most cases these reactions are slower than alkene reductions. For most synthetic applications, the hydride-transfer reagents to be discussed in Section 5.2 are used for reduction of carbonyl groups. Amides and nitriles can be reduced to amines. Hydrogenation of amides requires extreme conditions and is seldom used in synthesis, but reduction of nitriles is quite useful. Table 5.2 gives a summary of the approximate conditions for catalytic hydrogenation of some common functional groups. Certain functional groups can be entirely removed and replaced by hydrogen. This is called hydrogenolysis. For example, aromatic halogen substituents are frequently removed by hydrogenation over transition-metal catalysts. Aliphatic halogens are somewhat less reactive, but hydrogenolysis is promoted by base.20 The most useful type of hydrogeolysis reactions involves removal of functional groups at benzylic and allylic positions.21 CH2OR

H2, Pd

CH3 + HOR

Hydrogenolysis of halides and benzylic groups presumably involves intermediates formed by oxidative addition to the active metal catalysts to generate intermediates similar to those involved in hydrogenation. H CH2X + Pd0

CH2PdX

H2

CH2PdX

CH3 + Pd0

H

Many other examples of this pattern of reactivity will be discussed in Chapter 8. The facile cleavage of the benzyl±oxygen bond has made the benzyl group a useful ``protecting group'' in multistep synthesis. A particularly important example is the use of the carbobenzyloxy group in peptide synthesis. The protecting group is removed by hydrogenolysis. The substituted carbamic acid generated by the hydrogenolysis decarboxylates spontaneously to provide the amine. O PhCH2OCNHR

O PhCH3 + HOCNHR

CO2 + H2NR

17. H. Lindlar and R. Dubuis, Org. Synth. V:880 (1973). 18. H. C. Brown and C. A. Brown, J. Am. Chem. Soc. 85:1005 (1963); E. J. Corey, K. Achiwa, and J. A. Katzenellenbogen, J. Am. Chem. Soc. 91:4318 (1969). 19. R. R. Schrock and J. A. Osborn, J. Am. Chem. Soc. 98:2143 (1976); J. M. Tour, S. L. Pendalwar, C. M. Kafka, and J. P. Cooper, J. Org. Chem. 57:4786 (1992). 20. A. R. Pinder, Synthesis 1980:425. 21. W. H. Hartung and R. Simonoff, Org. React. 7:263 (1953); P. N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press, New York, 1967, Chapter 25; P. N. Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press, New York, 1979, Chapter 15; P. N. Rylander, Hydrogenation Methods, Academic Press, Orlando, Florida, 1985, Chapter 13.

Table 5.2. Conditions for Catalytic Reduction of Various Functional Groupsa Functional group

Reduction product

C

C

H

H

C

C

Common catalysts

Typical reaction conditions

Pd, Pt, Ni, Ru, Rh

Rapid at room temperature (R.T.) and 1 atm except for highly substituted or hindered cases

Lindlar

R. T. and low pressure, quinoline or lead added to deactivate catalyst

Rh, Pt

Moderate pressure (5–10 atm), 50–100°C

Ni, Pd

High pressure (100–200 atm), 100–200°C

Pt, Ru

Moderate rate at R. T. and 1–4 atm. acid-catalyzed

Cu–Cr, Ni

High pressure, 50–100°C

Pd

R. T., 1–4 atm. acid-catalyzed

Pd, Ni

50–100°C, 1–4 atm

Pd

R. T., 1 atm. quinoline or other catalyst moderator used

RCH2OH

Pd, Ni, Ru

Very strenuous conditions required

RCOR

RCH2OH

Cu–Cr, Ni

200°C, high pressure

RC

N

RCH2NH2

Ni, Rh

50–100°C, usually high pressure, NH3 added to increase yield of primary amine

RCNH2

RCH2NH2

Cu–Cr

Very strenuous conditions required

Pd, Ni, Pt

R. T., 1–4 atm

Pd, Pt

R. T., 4–100 atm

Pd

Order of reactivity: 1 > Br > Cl > F, bases promote reactions for R = alkyl

Pt, Pd

Proceeds slowly at R. T., 1–4 atm, acid-catalyzed

C

C

C

C H

H

O

RCHR

RCR

OH

O

RCHR

RCR

OH O CR CH2R

or OR CHR NR2

CH2R

CHR O

O

RCCl

RCH

O RCOH O

O

RNH2

RNO2 NR

R2CHNHR

RCR R R R

Cl Br I O C

C

R

H

H

OH

C

C

a. General references: M. Freifelder, Catalytic Hydrogenation in Organic Synthesis: Procedures and Commentary, John Wiley & Sons, New York, 1978; P. N. Rylander, Hydrogenation Methods, Academic Press, Orlando, Florida, 1985.

261 SECTION 5.1. ADDITION OF HYDROGEN

262

5.1.2. Other Hydrogen-Transfer Reagents

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Catalytic hydrogenation transfers the elements of molecular hydrogen through a series of complexes and intermediates. Diimide, HNˆNH, an unstable hydrogen donor that can only be generated in situ, ®nds some specialized application in the reduction of carbon± carbon double bonds. Simple alkenes are reduced ef®ciently by diimide, but other easily reduced functional groups, such as nitro and cyano, are unaffected. The mechanism of the reaction is pictured as a transfer of hydrogen via a nonpolar cyclic transition state. C HN

NH +

C

C

H

C

H

C

C

N

N

H N

N

H

In agreement with this mechanism is the fact that the stereochemistry of addition is syn.22 The rate of reaction with diimide is in¯uenced by torsional and angle strain in the alkene. More strained double bonds react more rapidly.23 For example, the more strained trans double bond is selectively reduced in Z,E-1,5-cyclodecadiene. NH2NH2 Cu2+, O2

Ref. 24

Diimide selectively reduces terminal over internal double bonds in polyunsaturated systems.25 There are several methods for generation of diimide and they are illustrated in Scheme 5.3.

5.2. Group III Hydride-Donor Reagents 5.2.1. Reduction of Carbonyl Compounds Most reductions of carbonyl compounds are done with reagents that transfer a hydride from boron or aluminum. The numerous reagents of this type that are available provide a considerable degree of chemoselectivity and stereochemical control. Sodium borohydride and lithium aluminum hydride are the most widely used of these reagents. Sodium borohydride is a mild reducing agent that reacts rapidly with aldehydes and ketones but quite slowly with esters. Lithium aluminum hydride is a much more powerful hydridedonor reagent. It will rapidly reduce esters, acids, nitriles, and amides, as well as aldehydes and ketones. Neither sodium borohydride nor lithium aluminum hydride reacts with isolated carbon±carbon double bonds. The reactivity of these reagents and some related reducing reagents is summarized in Table 5.3. 22. E. J. Corey, D. J. Pasto, and W. L. Mock, J. Am. Chem. Soc. 83:2957 (1961). 23. E. W. Garbisch, Jr., S. M. Schildcrout, D. B. Patterson, and C. M. Sprecher, J. Am. Chem. Soc. 87:2932 (1965). 24. J. G. Traynham, G. R. Franzen, G. A. Kresel, and D. J. Northington, Jr., J. Org. Chem. 32:3285 (1967). 25. E. J. Corey, H. Yamamoto, D. K. Herron, and K. Achiwa, J. Am. Chem. Soc. 92:6635 (1970); E. J. Corey and H. Yamamoto, J. Am. Chem. Soc. 92:6636, 6637 (1970).

Scheme 5.3. Reductions with Diimide +

Na –O2CN NCO2– Na

1a CH2

CHCH2OH

2b (CH2

CHCH2)2S

263

+

CH3CH2CH2OH

RCO2H, 25°C C7H7SO2NHNH2, heat

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

78%

(CH3CH2CH2)2S

93–100%

3c NH2NH2, O2, Cu(II)

4d

O2N

CH

CHCO2H

NH2OSO3– NH2OH

O2N

CH2CH2CO2H

5e NH2NH2 46%

H2O2

O

6f

O O

K+ –O2CN

O

NCO2– K+

87%

Br 7g

Br O

O CO2C2H5

K+ –O

2CN

CO2C2H5

– K+

NCO2

95%

MeOH, HOAc

NO2

NO2

O

8h PhS

O PhS

N

N

C7H7SO2NHNH2 99%

THF, H2O, NaOAc

N ArSO2 9i

N ArSO2 O

H N N

S

H O hν

a. b. c. d. e. f. g. h. i.

E. E. van Tamelen, R. S. Dewey, and R. J. Timmons, J. Am. Chem. Soc. 83:3725 (1961). E. E. van Tamelen, R. S. Dewey, M. F. Lease, and W. H. Pirkle, J. Am. Chem. Soc. 83:4302 (1961). M. Ohno and M. Okamoto, Org. Synth. 49:30 (1969). W. Durckheimer, Justus Liebigs Ann. Chem. 721:240 (1969). L. A. Paquette, A. R. Browne, E. Chamot, and J. F. Blount, J. Am. Chem. Soc. 102:643 (1980). J.-M. Durgnat and P. Vogel, Helv. Chim. Acta 76:222 (1993). P. A. Grieco, R. Lis, R. E. Zelle, and J. Finn, J. Am. Chem. Soc. 108:5908 (1986). P. Magnus, T. Gallagher, P. Brown, and J. C. Huffman, J. Am. Chem. Soc. 106:2105 (1984). M. Squillacote, J. DeFelipppis, and Y. L. Lai, Tetrahedron Lett. 34:4137 (1993).

87%

Table 5.3. Relative Reactivity of Hydride-Donor Reducing Agents

264 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Reduction productsa

Hydride donor b

LiAlH4 LiAlH2 …OCH2 CH2 OCH3 †2 c LiAlH‰…OC…CH3 †Š3 d NaBH4 b NaBH3 CNg B 2 H6 h AlHj3

Iminium ion

Acyl halide

Amine

Alcohol Alcohol Aldehydee

Amine Amine

Alcohol

CH3 [(CH3)2CHCH]2BHk ‰…CH3 †2 CHCH2 Š2 AlHl

Carboxylate salt

Aldehyde

Ketone

Ester

Amide

Alcohol Alcohol Alcohol Alcohol Alcohol Alcohol Alcohol

Alcohol Alcohol Alcohol Alcohol

Alcohol Alcohol Alcoholf Alcoholf

Amine Amine Aldehydef

Alcohol Alcohol

Alcohol Alcohol

Alcohol

Amine Amine

Alcoholf Alcohol

Alcohol

Alcohol

Alcohol

Alcohol Aldehydee Aldehydee

Aldehydee Alcohol

a. Products shown are the usual products of synthetic operations. Where no entry is given, the combination has not been studied or is not of major synthetic utility. b. See the general references at the end of the chapter. c. J. MaleÂk, Org. React. 34:1 (1985); 36:249 (1989). d. H. C. Brown and R. F. McFarlin, J. Am. Chem. Soc. 78:752 (1956); 80:5372 (1958); H. C. Brown and B. C. Subba Rao, J. Am. Chem. Soc. 80:5377 (1958); H. C. Brown and A. Tsukamoto, J. Am. Chem. Soc. 86:1089 (1964). e. Reaction must be controlled by use of a stoichiometric amount of reagent and low temperature. f. Reaction occurs slowly. g. C. F. Lane, Synthesis 1975:135. h. H. C. Brown, P. Heim, and N. M. Yoon, J. Am. Chem. Soc. 92:1637 (1970); N. M. Yoon, C. S. Park, H. C. Brown, S. Krishnamurthy, and T. P. Stocky, J. Org. Chem. 38:2786 (1973); H. C. Brown and P. Heim, J. Org. Chem. 38:912 (1973). i. Reaction occurs via the triacyl borate. j. H. C. Brown and N. M. Yoon, J. Am. Chem. Soc. 88:1464 (1966). k. H. C. Brown, D. B. Bigley, S. K. Arora, and N. M. Yoon, J. Am. Chem. Soc. 92:7161 (1970); H. C. Brown and V. Varma, J. Org. Chem. 39:1631 (1974). l. E. Winterfeldt, Synthesis 1975:617; H. Reinheckel, K. Haage, and D. Jahnke, Organomet. Chem. Res. 4:47 (1969); N. M. Yoon and Y. S. Gyoung, J. Org. Chem. 50:2443 (1985).

The mechanism by which the group III hydrides effect reduction involves nucleophilic transfer of hydride to the carbonyl group. Activation of the carbonyl group by coordination with a metal cation is probably involved under most conditions. As reduction proceeds and hydride is transferred, the Lewis acid character of boron and aluminum can also be involved. M+

H H H

H O

B–

R H

R

H

B– H

R

O C H

M+

H

M+ H H R

Al– H

H O R R

H

M+

Al– O H

R C

H

R

Because all four of the hydrides can eventually be transferred, there are actually several distinct reducing agents functioning during the course of the reaction.26 Although this somewhat complicates interpretation of rates and stereoselectivity, it does not detract from the synthetic utility of these reagents. Reduction with NaBH4 is usually done in aqueous or 26. B. Rickborn and M. T. Wuesthoff, J. Am. Chem. Soc. 92:6894 (1970).

alcoholic solution, and the alkoxyboranes formed as intermediates are rapidly solvolyzed.

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS



BH4– + R2CO

R2CHOBH3





[R2CHO]2BH2

R2CHOBH3 + R2CO –



[R2CHO]2BH2 + R2CO

[R2CHO]3BH





[R2CHO]3BH + R2CO

[R2CHO]4B



4 R2CHOH + B(OS)4–

[R2CHO]4B + 4 SOH

The mechanism for reduction by LiAlH4 is very similar. However, because LiAlH4 reacts very rapidly with protic solvents to form molecular hydrogen, reductions with this reagent must be carried out in aprotic solvents, usually ether or THF. The products are liberated by hydrolysis of the aluminum alkoxide at the end of the reaction. Hydride reduction of esters to alcohols involves elimination steps, in addition to hydride transfer. –

O

AlH3

RC



O

H

AlH3

RC

OR

O –

OR

RCH + ROAlH3

H –

O

AlH2OR

RC

RCH2O

H



AlH2OR

H2O

RCH2OH

H

Amides are reduced to amines because the nitrogen is a poorer leaving group than oxygen at the intermediate stage of the reduction. Primary and secondary amides are rapidly deprotonated by the strongly basic LiAlH4 , so the addition step involves the conjugate base. O RC NH –



AlH3 H



AlH3

O

R

H

RCH

C

NH –

HN



RCH2NAlH2O–

H AlH2O–

H2O

RCH2NH2

H

Reduction of amides by LiAlH4 is an important method for synthesis of amines: CON(CH3)2

H3C H3C

LiAlH4

LiAlH4

N H

O

CH2N(CH3)2

ether 35°C, 15 h

THF 65°C, 8 h

H3C 67–79%

H3C

88%

Ref. 27

Ref. 28

N H

Several factors affect the reactivity of the boron and aluminum hydrides. These include the metal cation present and the ligands, in addition to hydride, in the metallo 27. A. C. Cope and E. Ciganek, Org. Synth. IV:339 (1963). 28. R. B. Moffett, Org. Synth. IV:354 (1963).

265

266 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

hydride. Some of these effects can be illustrated by considering the reactivity of ketones and aldehydes toward various hydride-transfer reagents. Comparison of LiAlH4 and NaAlH4 has shown the former to be more reactive.29 This can be attributed to the greater Lewis acid strength and hardness of the lithium cation. Both LiBH4 and Ca…BH4 †2 are more reactive than sodium borohydride. This enhanced reactivity is due to the greater Lewis acid strength of Li‡ and Ca2‡, compared with Na‡ . Both of these reagents can reduce esters and lactones ef®ciently. CO2C2H5

CH2OH Ca(BH4)2

Ref. 30

70%

CN

CN LiBH4

C7H15

O

O

C7H15CHCH2CH2CH2OH

45%

Ref. 31

OH

Zinc borohydride is also a useful reagent.32 It is prepared by reaction of ZnCl2 with NaBH4 in THF. Because of the stronger Lewis acid character of Zn2‡ , Zn…BH4 †2 is more reactive than NaBH4 toward esters and amides and reduces them to alcohols and amines, respectively.33 The reagent also smoothly reduces a-amino acids to b-amino alcohols.34 PhCHCO2H + Zn(BH4)2 NH2

PhCHCH2OH

87%

NH2

An extensive series of aluminum hydrides in which one or more of the hydrides is replaced by an alkoxide ion can be prepared by addition of the correct amount of the appropriate alcohol. LiAlH4 + 2 ROH

LiAlH2(OR)2 + 2 H2

LiAlH4 + 3 ROH

LiAlH(OR)3 + 3 H2

These reagents generally show increased solubility, particularly at low temperatures, in organic solvents and are useful in certain selective reductions.35 Lithium tri-t-butoxyaluminum hydride and lithium or sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al)36 are examples of these types of reagents which have wide synthetic use. Their reactivity toward typical functional groups is included in Table 5.3. Sodium cyanoborohydride37 is a useful derivative of sodium borohydride. The electron-attracting cyano substituent reduces reactivity, and only iminum groups are rapidly reduced by this reagent. 29. E. C. Ashby and J. R. Boone, J. Am. Chem. Soc. 98:5524 (1976); J. S. Cha and H. C. Brown, J. Org. Chem. 58:4727 (1993). 30. H. C. Brown, S. Narasimhan, and Y. M. Choi, J. Org. Chem.47:4702 (1982). 31. K. Soai and S. Ookawa, J. Org. Chem. 51:4000 (1986). 32. S. Narasimhan and R. Balakumar, Aldrichimica Acta 31:19 (1998). 33. S. Narasimhan, S. Madhavan, R. Balakumar, and S. Swarnalakshmi, Synth. Commun. 27:391 (1997). 34. S. Narasimhan, S. Madhavan, and K. G. Prasad, Synth. Commun. 26:703 (1996). 35. J. Malek and M. Cerny, Synthesis 1972:217; J. Malek, Org. React. 34:1 (1985). 36. Red-Al is a trademark of Aldrich Chemical Company. 37. C. F. Lane, Synthesis 1975:135.

Alkylborohydrides are also used as reducing agents. These compounds have greater steric demands than the borohydride ion and therefore are more stereoselective in situations in which steric factors are controlling.38 They are prepared by reaction of trialkylboranes with lithium, sodium, or potassium hydride.39 Several of the compounds are available commercially under the trade name Selectrides.40 –

Li+HB(

CHCH2CH3)3



Li+HB[

CH3 L-selectride



Na+HB(

CHCH(CH3)2]3 CH3 LS-selectride

CHCH2CH3)3

CH3 N-selectride



K+HB( CHCH2CH3)3 CH3 K-selectride

Closely related to, but distinct from, the anionic boron and aluminum hydrides are the neutral boron (borane, BH3 ) and aluminum (alane, AlH3 ) hydrides. These molecules also contain hydrogen that can be transferred as hydride. Borane and alane differ from the anionic hydrides in being electrophilic species by virtue of a vacant p orbital at the metal. Reduction by these molecules occurs by an intramolecular hydride transfer in a Lewis acid±base complex of the reactant and reductant.

R2MH +

C R

+



C

H R

O MR2

O MR2

O R

R

R

C

H

R

Alkyl derivatives of borane and alane can function as reducing agents in a similar fashion. Two reagents of this group, disiamylborane and diisobutylaluminum hydride (DIBAlH), are included in Table 5.3. The latter is an especially useful reagent. In synthesis, the principal factors affecting the choice of a reducing agent are selectivity among functional groups (chemoselectivity) and stereoselectivity. Chemoselectivity can involve two issues. It may be desired to effect a partial reduction of a particular functional group, or it may be necessary to reduce one group in preference to another. The reagents in Table 5.3 are arranged in approximate order of decreasing reactivity as hydride donors.41 The relative ordering of reducing agents with respect to particular functional groups can permit selection of the appropriate reagent. One of the more dif®cult partial reductions to accomplish is the conversion of a carboxylic acid derivative to an aldehyde without over-reduction to the alcohol. Aldehydes are inherently more reactive than acids or esters so the challenge is to stop the reduction at the aldehyde stage. Several approaches have been used to achieve this objective. One is to replace some of the hydrogens in a group III hydride with more bulky groups, thus modifying reactivity by steric factors. Lithium tri-t-butoxyaluminum hydride is an example of this approach.42 Sodium tri-t-butoxyaluminum hydride can also be used to reduce acyl chlorides to aldehydes without over-reduction to the alcohol.43 The excellent solubility of sodium bis(2-methoxyethoxy)aluminum hydride makes it a useful reagent for selective 38. H. C. Brown and S. Krishnamurthy, J. Am. Chem. Soc. 94:7159 (1972); S. Krishnamurthy and H. C. Brown, J. Am. Chem. Soc. 98:3383 (1976). 39. H. C. Brown, S. Krishnamurthy, and J. L. Hubbard, J. Am. Chem. Soc. 100:3343 (1978). 40. Selectride is a trade name of the Aldrich Chemical Company. 41. For more complete discussion of functional group selectivity of hydride reducing agents, see E. R. H. Walter, Chem. Soc. Rev. 5:23 (1976). 42. H. C. Brown and B. C. SubbaRao, J. Am. Chem. Soc. 80:5377 (1958). 43. J. S. Cha and H. C. Brown, J. Org. Chem. 58:4732 (1993).

267 SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

268 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

reductions. The reagent is soluble in toluene even at 70 C. Selectivity is enhanced by the low temperature. It is possible to reduce esters to aldehydes and lactones to lactols with this reagent.

CH3O

CH2CH2CO2CH3

NaAlH2(OCH2CH2OCH3)2 HN

CH3O

CH2CH2CH

NCH3

O

OH

O

NaAlH2(OCH2CH2OCH3)2

O Ref. 45

(CH2)4CO2C(CH3)3 THPO

O Ref. 44

(CH2)4CO2C(CH3)3 THPO

OTHP

OTHP

Probably the most widely used reagent for partial reduction of esters and lactones at the present time is diisobutylaluminum hydride.46 By use of a controlled amount of the reagent at low temperature, partial reduction can be reliably achieved. The selectivity results from the relative stability of the hemiacetal intermediate that is formed. The aldehyde is not liberated until the hydrolytic workup and is therefore not subject to overreduction. At higher temperatures, at which the intermediate undergoes elimination, diisobutylaluminum hydride reduces esters to primary alcohols.

CH3O CH3O

CH3O (i-Bu)2AlH, toluene –60°C

N

CH3O

N

83%

C2H5

C2H5 CH2CO2C2H5 CO2C2H5 CH3SCH2O

Ref. 47

CH2CH (i-Bu)2AlH

CH

–90°C

O

O

Ref. 48

CH3SCH2O

Selective reduction to aldehydes can also be achieved using N-methoxy-N-methylamides.49 Lithium aluminum hydride and diisobutylaluminum hydride have both been used as the hydride donor. The partial reduction is believed to be the result of the stability of the initial reduction product. The N-methoxy substituent permits a chelated structure which is 44. 45. 46. 47. 48. 49.

R. Kanazawa and T. Tokoroyama, Synthesis 1976:526. H. DisselnkoÈtter, F. Liob, H. Oedinger, and D. Wendisch, Liebigs Ann. Chem. 1982:150. F. Winterfeldt, Synthesis 1975:617; N. M. Yoon and Y. G. Gyoung, J. Org. Chem. 50:2443 (1985). C. Szantay, L. Toke, and P. Kolonits, J. Org. Chem. 31:1447 (1966). G. E. Keck, E. P. Boden, and M. R. Wiley, J. Org. Chem. 54:896 (1989). S. Nahm and S. M. Weinreb, Tetrahedron Lett. 22:3815 (1981).

269

stable until acid hydrolysis occurs during workup. O R

RCNOCH3 + M H CH3

O M

H

H+ H2O

OCH3

RCH

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

O

N CH3

Another useful approach to aldehydes is by partial reduction of nitriles to imines. The imines are then hydrolyzed to the aldehyde. Diisobutylaluminum hydride seems to be the best reagent for this purpose.50,51 The reduction stops at the imine stage because of the low electrophilicity of the deprotonated imine intermediate. CH3CH

CHCH2CH2CH2C

N

1) (i-Bu)2AlH 2) H+, H2O

CH3CH

CHCH2CH2CH2CH

O

64%

A second type of chemoselectivity arises in the context of the need to reduce one functional group in the presence of another. If the group to be reduced is more reactive than the one to be left unchanged, it is simply a matter of choosing a reducing reagent with the appropriate reactivity. Sodium borohydride, for example, is very useful in this respect because it reduces ketones and aldehydes much more rapidly than esters. Sodium cyanoborohydride is used to reduce imines to amines. This reagent is only reactive toward protonated imines. At pH 6±7, NaBH3 CN is essentially unreactive toward carbonyl groups. When an amine and a ketone are mixed together, equilibrium is established with the imine. At mildly acidic pH, NaBH3 CN is reactive only toward the protonated imine.52 H R2C

O + R′NH2 + H+

R2C

NR′ +

H R2C

NR′ + BH3CN– +

R2CHNHR′

Reductive animation by NaBH3 CN can also be carried out in the presence of Ti…O-i-Pr†4 . These conditions are especially useful for situations in which it is not practical to use the amine in excess (as is typically the case under acid-catalyzed conditions) or for acidsensitive compounds. The Ti…O-i-Pr†4 may act as a Lewis acid in generation of a tetrahedral adduct, which then may be reduced directly or via a transient iminium intermediate.53 OTi(O-i-Pr)3 R2C

O + HNR′2

Ti(O-i-Pr)4

R2C

NR′2

R2C

N+R′2

NaBH3CN

R2CHNR′2

Sodium triacetoxyborohhydride is an alternative to NaBH3 CN for reductive amination. This reagent can be used with a wide variety of aldehydes and ketones mixed with primary and secondary amines, including aniline derivatives.54 This reagent has been used 50. 51. 52. 53. 54.

N. A. LeBel, M. E. Post, and J. J. Wang, J. Am. Chem. Soc. 86:3759 (1964). R. V. Stevens and J. T. Lai, J. Org. Chem. 37:2138 (1972); S. Tro®menko, J. Org. Chem. 29:3046 (1964). R. F. Borch, M. D. Bernstein, and H. D. Durst, J. Am. Chem. Soc. 93:2897 (1971). R. J. Mattson, K. M. Pham, D. J. Leuck, and K. A. Cowen, J. Org. Chem. 55:2552 (1990). A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff, and R. D. Shah, J. Org. Chem. 61:3849 (1996).

270

successfully to alkylate amino acid esters.55

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

R2C

O + HNR′2

NaBH(OAc)3

PhCH2CHCO2CH3 + CH3(CH2)4CH

O

R2CHNR′2

NaBH(OAc)3

PhCH2CHCO2CH3

+Cl–

NH3

79%

NH(CH2)5CH3

Zinc borohydride has been found to effect very ef®cient reductive amination in the presence of silica. The amine and the carbonyl compound are mixed with silica, and the powder is then treated with a solution of Zn…BH4 †2 . Excellent yields are reported and the procedure works well for unsaturated aldehydes and ketones.56

1) SiO2

O + H2N

80%

NH

2) Zn(BH4)2

Aromatic aldehydes can be reductively aminated with the combination Zn…BH4 †2 ZnCl2 .57

F

CH

O + H

N

1) ZnCl2 2) Zn(BH4)2

F

CH2

N

77%

The ZnCl2 assists in imine formation in this procedure. Diborane also has a useful pattern of selectivity. It reduces carboxylic acids to primary alcohols under mild conditions which leave esters unchanged.58 Nitro and cyano groups are also relatively unreactive toward diborane. The rapid reaction between carboxylic acids and diborane is the result of formation of triacyloxyborane intermediate by protonolysis of the B H bonds. This compound is essentially a mixed anhydride of the carboxylic acid and boric acid in which the carbonyl groups have enhance reactivity 3 RCO2H + BH3 O RC

(RCO2)3B + 3 H2 O

O

B(O2CR)2

RC

+

O



B(O2CR)2

Diborane is also a useful reagent for reducing amides. Tertiary and secondary amides are easily reduced, but primary amides react only slowly.59 The electrophilicity of diborane is involved in the reduction of amides. The boron coordinates at the carbonyl oxygen, 55. 56. 57. 58. 59.

J. M. Ramanjulu and M. M. Joullie, Synth. Commun. 26:1379 (1996). B. C. Ranu, A. Majee, and A. Sarkar, J. Org. Chem. 63:370 (1998). S. Bhattacharyya, A. Chatterjee, and J. S. Williamson, Synth. Commun. 27:4265 (1997). M. N. Yoon, C. S. Pak, H. C. Brown, S. Krishnamurthy, and T. P. Stocky, J. Org. Chem. 38:2786 (1973). H. C. Brown and P. Heim, J. Org. Chem. 38:912 (1973).

271

enhancing the reactivity of the carbonyl center. O R

C



+ BH3

O

R

C NR R

NR R

OBH2

BH2 R

H

C

R

H C

H

N R R

B

H +

N R R

R

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

H C

RN R

H

Amides require vigorous reaction conditions for reduction by LiAlH4 so that little selectivity can be achieved with this reagent. Diborane, however, permits the reduction of amides in the presence of ester and nitro groups. Alane is also a useful group for reducing amides, and it too can be used to reduce amides to amines in the presence of ester groups. O

H

PhCH2N

C2H5 O2CCHC4H9

C2H5

H AlH3

O2CCHC4H9

PhCH2N

Ref. 60

–70°C

H

OCH3

OCH3

H

COCH3

COCH3

Again, the electrophilicity of alane is the basis for the selective reaction with the amide group. Alane is also useful for reducing azetidinones to azetidines. Most nucleophilic hydride reducing agents lead to ring-opened products. DiBAlH, AlH2 Cl, and AlHCl2 can also reduce azetidinones to azetidines.61 CH3

Ph

CH3

CH3

Ph

CH3

AlH3

(CH3)3CN

Ref. 62

(CH3)3CN O

Another approach to reduction of an amide group in the presence of more easily reduced groups is to convert the amide to a more reactive species. One such method is conversion of the amide to an O-alkyl imidate with a positive charge on nitrogen.63 This method has proven successful for tertiary and secondary, but not primary, amides. Other compounds which can be readily derived from amides and that are more reactive than amides toward hydride reducing agents are a-alkylthioimmonium ions64 and a-chloroimmonium ions.65 O

OEt

RCNR2 + Et3O+

RC

NR2 +

OEt RC

60. 61. 62. 63. 64.

NR2 + NaBH4 +

RCH2NR2

S. F. Martin, H. RuÈeger, S. A. Williamson, and S. Grejszczak, J. Am. Chem. Soc. 109:6124 (1987). I. Ojima, M. Zhao, T. Yamato, K. Nakahashi, M. Yamashita, and R. Abe, J. Org. Chem. 56:5263 (1991). M. B. Jackson, L. N. Mander, and T. M. Spotswood, Aust. J. Chem. 36:779 (1983). R. F. Borch, Tetrahedron Lett. 1968:61. S. Raucher and P. Klein, Tetrahedron Lett. 1980:4061; R. J. Sundberg, C. P. Walters, and J. D. Bloom, J. Org. Chem. 46:3730 (1981). 65. M. E. Kuehne and P. J. Shannon, J. Org. Chem. 42:2082 (1977).

272 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

An important case of chemoselectivity arises in the reduction of a,b-unsaturated carbonyl compounds. Reduction can occur at the carbonyl group, giving an allylic alcohol, or at the double bond, giving a saturated ketone. If a hydride is added at the b position, the initial product is an enolate. In protic solvents, this leads to the ketone, which can be reduced to the saturated alcohol. If hydride is added at the carbonyl group, the allylic alcohol is usually not susceptible to further reduction. These alternative reaction modes are called 1,2- and 1,4-reduction, respectively. Both NaBH4 and LiAlH4 have been observed to give both types of product, although the extent of reduction to saturated alcohol is usually greater with NaBH4 .66 O–

O

1,2-reduction

R2C

[H–]

CHCR′ +

R2C

CHCR′

OH H+

R2C

CHCHR′

H 1,4-reduction leading to saturated alcohol

O–

O R2C

CHCR′ + [H–]

R2CH

CH

O H+

CR′

O–

O R2CHCH2CR′ +

[H–]

R2CHCH2CR′ OH

H+

R2CHCH2CHR′

R2CHCH2CHR′

Several reagents have been developed which lead to exclusive 1,2- or 1,4-reduction. Use of NaBH4 in combination with cerium chloride results in clean 1,2-reduction.67 Diisobutylaluminum hydride68 and the dialkylborane 9-BBN69 also give exclusive carbonyl reduction. In each case, the reactivity of the carbonyl group is enhanced by a Lewis acid complexation at oxygen. Selective reduction of the carbon±carbon double bond can usually be achieved by catalytic hydrogenation. A series of reagents prepared from a hydride reducing agent and copper salts also give primarily the saturated ketone.70 Similar reagents have been shown to reduce a,b-unsaturated esters71 and nitriles72 to the corresponding saturated compounds. The mechanistic details are not known with certainty, but it is likely that ``copper hydrides'' are the active reducing agents and that they form an organocopper intermediate by conjugate addition. O “H

Cu

H” + RCH

CHCR

H

R

Cu

CH

O CH2CR

O RCH2CH2CR

Combined use of cobalt(II) acetylacetonate [Co…acac†2 ] and DiBAlH also gives selective 1,4-reduction for a,b-unsaturated ketones, esters, and amides.73 66. M. R. Johnson and B. Richborn, J. Org. Chem. 35:1041 (1970); W. R. Jackson and A. Zurqiyah, J. Chem. Soc., 5280 (1965). 67. J.-L. Luche, J. Am. Chem. Soc., 100:2226 (1978); J.-L. Luche, L. Rodriquez-Hahn, and P. Crabbe, J. Chem. Soc. Chem. Commun. 1978:601. 68. K. E. Wilson, R. T. Seidner, and S. Masamune, J. Chem. Soc., Chem. Commun. 1970:213. 69. K. Krishnamurthy and H. C. Brown, J. Org. Chem. 42:1197 (1977). 70. S. Masamune, G. S. Bates, and P. E. Georghiou, J. Am. Chem. Soc. 96:3686 (1974); E. C. Ashby, J.-J. Lin, and R. Kovar, J. Org. Chem. 41:1939 (1976); E. C. Ashby, J.-J. Lin, and A. B. Goel, J. Org. Chem. 43:183 (1978); W. S. Mahoney, D. M. Brestensky, and J. M. Stryker, J. Am. Chem. Soc. 110:291 (1988); D. S. Brestensky, D. E. Huseland, C. McGettigan, and J. M. Stryker, Tetrahedron Lett. 29:3749 (1988); T. M. Koenig, J. F. Daeuble, D. M. Brestensky, and J. M. Stryker, Tetrahedron Lett. 31:3237 (1990). 71. M. F. Semmelhack, R. D. Stauffer, and A. Yamashita, J. Org. Chem. 42:3180 (1977). 72. M. E. Osborn, J. F. Pegues, and L. A. Paquette, J. Org. Chem. 45:167 (1980). 73. T. Ikeno, T. Kimura, Y. Ohtsuka, and T. Yamada, Synlett 1999:96.

Another reagent combination that selectively reduces the carbon±carbon double bond is Wilkinson's catalyst and triethylsilane. The initial product is the silyl enol ether.74 CH3 (CH3)2C

CH(CH2)2C

CH3

CHCH

O

Et3SiH

(CH3)2C

(Ph3P)3RhCl

CH(CH2)2CHCH

CHOSiEt3

H2O

CH3 (CH3)2C

CH(CH2)2CHCH2CH

O

Unconjugated double bonds are unaffected by this reducing system.75 The enol ethers of b-dicarbonyl compounds are reduced to a,b-unsaturated ketones by LiAlH4, followed by hydrolysis.76 Reduction stops at the allylic alcohol, but subsequent acid hydrolysis of the enol ether and dehydration lead to the isolated product. This reaction is a useful method for synthesis of substituted cyclohexenones. OC2H5

OC2H5 Ph

O

O Ph

LiAlH4 –O

Ph

Ph

H+

Ph

H

Ph

5.2.2. Stereoselectivity of Hydride Reduction A very important aspect of reductions by hydride-transfer reagents is their stereoselectivity. The stereochemistry of hydride reduction has been studied most thoroughly with conformationally biased cyclohexanone derivatives. Some reagents give predominantly axial cyclohexanols whereas others give the equatorial isomer. Axial alcohols are likely to be formed when the reducing agent is a sterically hindered hydride donor. This is because the equatorial direction of approach is more open and is preferred by bulky reagents. This is called steric approach control.77

H

O

H R

H



B

H

R R R

H R

favorable

H

R R R – B H O

unfavorable

OH

H

H R

H H

H

R

major product

OH minor product

Steric Approach Control

74. I. Ojima, T. Kogure, and Y. Nagai, Tetrahedron Lett. 1972:5035; I. Ojima, M. Nihonyanagi, T. Kogure, M. Kumagai, S. Horiuchi, K. Nakatsugawa, and Y. Nogai, J. Organomet. Chem. 94:449 (1973). 75. H.-J. Liu and E. N. C. Browne, Can. J. Chem. 59:601 (1981); T. Rosen and C. H. Heathcock, J. Am. Chem. Soc. 107:3731 (1985). 76. H. E. Zimmerman and D. I. Schuster, J. Am. Chem. Soc. 84:4527 (1962); W. F. Gannon and H. O. House, Org. Synth. 40:14 (1960). 77. W. G. Dauben, G. J. Fonken, and D. S. Noyce, J. Am. Chem. Soc. 78:2579 (1956).

273 SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

274 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

With less hindered hydride donors, particularly NaBH4 and LiAlH4, cyclohexanones give predominantly the equatorial alcohol. The equatorial alcohol is normally the more stable of the two isomers. However, hydride reductions are exothermic reactions with low activation energies. The transition state should resemble starting ketone, so product stability should not control the stereoselectivity. One explanation of the preference for formation of the equatorial isomer involves the torsional strain that develops in formation of the axial alcohol.78 H

O H H

H

M+

H

BH3

M

O

H

OH

BH3

H H

H

H

H

H H

H

minor product

H

Torsional strain as oxygen passes through an eclipsed conformation

H H

BH O

H

H H

BH3

H M+

O

H

M

H

OH

H

H

H

H

H

H

major product

H

Oxygen moves away from equatorial hydrogens; no torsional strain

An alternative suggestion is that the carbonyl group p-antibonding orbital which acts as the lowest unoccupied molecular orbital (LUMO) in the reaction has a greater density on the axial face.79 It is not entirely clear at the present time how important such orbital effects are. Most of the stereoselectivities which have been reported can be reconciled with torsional and steric effects being dominant.80 See Section 3.10 of Part A for further discussion of this issue. When a ketone is relatively hindered, as for example in the bicyclo[2.2.1]heptan-2one system, steric factors govern stereoselectivity even for small hydride donors.

NaBH4

H +

O

OH

H

86%

H3C

OH

H3C

CH3

H3C

14%

H3C

CH3

H3C

CH3

H3C

NaBH4

H +

O 14%

OH H

OH 86%

78. M. Cherest, H. Felkin, and N. Prudent, Tetrahedron Lett. 1968:2205; M. Cherest and H. Felkin, Tetrahedron Lett. 1971:383. 79. J. Klein, Tetrahedron Lett. 1973:4307; N. T. Ahn, O. Eisenstein, J.-M. Lefour, and M. E. Tran Huu Dau, J. Am. Chem. Soc. 95:6146 (1973). 80. W. T. Wipke and P. Gund, J. Am. Chem. Soc. 98:8107 (1976); J.-C. Perlburger and P. MuÈller, J. Am. Chem. Soc. 99:6316 (1977); D. Mukherjee, Y.-D. Wu, F. R. Fornczek, and K. N. Houk, J. Am. Chem. Soc. 110:3328 (1988).

Table 5.4. Stereoselectivity of Hydride Reducing Agentsa

275

Percentage of the alcohol favored by steric approach control O

O

(CH3)3C

CH3

CH3 H 3C

H3C

O

CH3

Reducing agent

% axial b

NaBH4 LiAlH4 LiAl…OMe†3 H LiAl…t-BuO†3 H 7 ‰CH3 CH2 CHŠ 3 BHLi‡ j CH3 CH3 j 7 ‰…CH3 †2 CHCHŠ3 BHLi‡

% axial c

20 8 9 9e 93g

25 24 69 36f 98g

>99h

>99h

O

% axial c

58 83

95 99.8g

% endo

CH3

CH3

O

% exo

d

86 89 98 94f 99.6g

86d 92 99 94f 99.6g

>99h

NRh

a. Except where otherwise noted, data are those given by H. C. Brown and W. D. Dickason, J. Am. Chem. Soc. 92:709 (1970). Data for many other cyclic ketones and reducing agents are given by A. V. Kamernitzky and A. A. Akhrem, Tetrahedron 18:705 (1962) and W. T. Wipke and P. Gund, J. Am. Chem. Soc. 98:8107 (1976). b. P. T. Lansbury and R. E. MacLeay, J. Org. Chem. 28:1940 (1963). c. B. Rickborn and W. T. Wuesthoff, J. Am. Chem. Soc. 92:6894 (1970). d. H. C. Brown and J. Muzzio, J. Am. Chem. Soc. 88:2811 (1966). e. J. Klein, E. Dunkelblum, E. L. Eliel, and Y. Senda, Tetrahedron Lett. 1968:6127. f. E. C. Ashby, J. P. Sevenair, and F. R. Dobbs, J. Org. Chem. 36:197 (1971). g. H. C. Brown and S. Krishnamurthy, J. Am. Chem. Soc. 94:7159 (1972). h. S. Krishnamurthy and H. C. Brown, J. Am. Chem. Soc. 98:3383 (1976).

A large amount of data has been accumulated on the stereoselectivity of reduction of cyclic ketones.81 Table 5.4 compares the stereochemistry of reduction of several ketones by hydride donors of increasing seric bulk. The trends in the table illustrate the increasing importance of steric approach control as both the hydride reagent and the ketone become more highly substituted. The alkyl-substituted borohydrides have especially high selectivity for the least hindered direction of approach. The stereochemistry of reduction of acylic aldehydes and ketones is a function of the substitution on the adjacent carbon atom and can be predicted on the basis of a conformational model of the transition state.78 H– preferred direction S of approach R S, M, L = relative size of substituents

M O L

This model is rationalized by a combination of steric and stereoelectronic effects. From a purely steric standpoint, an approach from the direction of the smallest substituent, involving minimal steric interaction with the groups L and M, is favorable. The stereoelectronic effect involves the interaction between the approaching hydride ion and the LUMO of the carbonyl group. This orbital, which accepts the electrons of the incoming 81. D. C. Wig®eld, Tetrahedron 35:449 (1979); D. C. Wig®eld and D. J. Phelps, J. Org. Chem. 41:2396 (1976).

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

276 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

nucleophile, is stabilized when the group L is perpendicular to the plane of the carbonyl group.82 This conformation permits a favourable interaction between the LUMO and the antiboding s* orbital associated with the C L bond. H– C

S C

O

M

L

Steric factors arising from groups which are more remote from the center undergoing reduction can also in¯uence the stereochemical course of reduction. Such steric factors are magni®ed with the use of bulky reducing agents. For example, a 4.5 : 1 preference for stereoisomer E over F is achieved by using the trialkylborohydride D as the reducing agent in the reduction of a prostaglandin intermediate.83 CH3

O O

H3C

B– H

+

O O

CH3 CH(CH3)2

O ArCO

CH

CH3 D

CHCC5H11 O

ArCO

CH

O

CHCC5H11 X

Y

E X = H, Y = OH 82% F X = OH, Y = H 18%

The stereoselectivity of reduction of carbonyl groups is effected by the same combination of steric and stereoelectronic factors which control the addition of other nucleophiles, such as enolates and organometallic reagents to carbonyl groups. A general discussion of these factors on addition of hydride is given in Section 3.10 of Part A. The stereoselectivity of reduction of carbonyl groups can also be controlled by chelation effects when there is a nearby donor substituent. In the presence of such a group, speci®c complexation between the substituent, the carbonyl oxygen, and the Lewis acid can establish a preferred conformation for the reactant which then controls reduction. Usually, hydride is then delivered from the less sterically hindered face of the chelate. O R

O R′

R

OH M

“H– ”

R′′

OR′′

O

R

O

R′′

R′

R′

a-Hydroxy ketones84 and a-alkoxy ketones85 are reduced to anti 1,2-diols by Zn…BH4 †2, 82. 83. 84. 85.

N. T. Ahn, Top. Curr. Chem. 88:145 (1980). E. J. Corey, S. M. Albonico, U. Koelliker, T. K. Shaaf, and R. K. Varma, J. Am. Chem. Soc. 93:1491 (1971). T. Nakata, T. Tanaka, and T. Oishi, Tetrahedron Lett. 24:2653 (1983). G. J. McGarvey and M. Kimura, J. Org. Chem. 47:5420 (1982).

which reacts through a chelated transition state. This stereoselectivity is consistent with the preference for transition state G over H. The stereoselectivity increases with the bulk of substituent R2 .

HO OH R1

OH R2

Zn(BH4)2 ether, 0°C

R1

O

OH 1 + R

R2 OH

R2MM OH

anti

H

R2

H R

syn

H H

H

B

Zn H

OH O

H R2

H

1

R1 G

R2

Zn…BH4 †2 anti : syn

LiAlH4 anti : syn

CH3 n-C5 H11 CH3 i-C3 H7 CH3 Ph

77 : 23 85 : 15 85 : 15 96 : 4 98 : 2 90 : 10

64 : 36 70 : 30 58 : 42 73 : 27 87 : 13 80 : 20

R1 n-C5 H11 CH3 i-C3 H7 CH3 Ph CH3

Zn H O H B

H

Reduction of b-hydroxyketones through chelated transitions states fovors syn-1,3diols. Boron chelates have been exploited to achieve this stereoselectivity.86 One procedure involves in situ generation of diethylmethoxyboron, which then forms a chelate with the b-hydroxy ketone. Reduction with NaBH4 leads to the syn diol.87 OH

H

O

R

R1 R

+

–R2OH

OR2

B

+R2OH

R1

R

C R

+

O O

1 R _

B R1

NaBH4

OH

OH

R

R1 R

+

+R2OH

OR2

B

–R

R1

H H R

2OH

R

R1 – O B R1 O + H

b-Hydroxy ketones also give primarily syn 1,3-diols when chelates prepared with BCl3 are reduced with quaternary ammonium salts of BH4 or BH3 CN .88 O

OH

OH

OH

1) BCl3

CH3

Ph

2) Bu4

N+

BH4



CH3

Ph 78%, 90:10 syn:anti

86. K. Narasaka and F.-C. Pai, Tetrahedron 40:2233 (1984); K.-M. Chen, G. E. Hardtmann, K. Prasad, O. Repic, and M. J. Shapiro, Tetrahedron Lett. 28:155 (1987). 87. K.-M. Chen, K. G. Gunderson, G. E. Hardtmann, K. Prasad, O. Repic, and M. J. Shapiro, Chem. Lett. 1987:1923. 88. C. R. Sarko, S. E. Collibee, A. L. Knorr, and M. DiMare, J. Org. Chem. 61:868 (1996).

277 SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

278 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Similar results are obtained with b-methoxyketones using TiCl4 as the chelating reagent.89 A survey of several alkylborohydrides found that LiBu3 BH in ether±pentane gave the best ratio of chelation-controlled reduction products from a- and b-alkoxyketones.90 In this case, the Li‡ cation must act as the Lewis acid. The alkylborohydride provides an added increment of steric discrimination.

O PhCH2O

OH CH3

Li+ Bu3BH– ether–pentane

PhCH2O

CH3

CH3

CH3

Syn 1,3-diols also can be obtained from b-hydroxyketones using LiI LiAlH4 at low temperatures.91 The reduction of an unsymmetrical ketone creates a new stereo center. Because of the importance of hydroxy groups both in synthesis and in relation to the properties of molecules, including biological activity, there has been a great deal of effort directed toward enantioselective reduction of ketones. One approach is to use chiral borohydride reagents.92 Boranes derived from chiral alkenes can be converted to borohydrides, and there has been much study of the enantioselectivity of these reagents. Several of the reagents are commercially available.

PhCH2O B–

B– H

Alpine-Hydride*

H

NB-Enantride*

Chloroboranes have also been found to be useful for enantioselective reduction. Diisopinocampheylchloroborane,93 …Ipc†2 BCl, and t-butylisopinocampheylchloroborane94 achieve high enantioselectivity for aryl and hindered dialkyl ketones. Diiso-2-ethylapopinocampheylchloroborane,95 …Eap†2 BCl, shows good enantioselectivity with a wider range * The names are trademarks of Aldrich Chemical Company. 89. C. R. Sarko, I. C. Guch, and M. DiMare, J. Org. Chem. 59:705 (1994); G. Bartoli, M. C. Bellucci, M. Bosco, R. Dalpozzo, E. Marcantoni, and L. Sambri, Tetrahedron Lett. 40:2845 (1999). 90. A.-M. Faucher, C. Brochu, S. R. Landry, I. Duchesne, S. Hantos, A. Roy, A. Myles, and C. Legault, Tetrahedron Lett. 39:8425 (1998). 91. Y. Mori, A. Takeuchi, H. Kageyama, and M. Suzuki, Tetrahedron Lett. 29:5423 (1988). 92. M. M. Midland, Chem. Rev. 89:1553 (1989). 93. H. C. Brown, J. Chandrasekharan, and P. V. Ramachandran J. Am. Chem. Soc. 110:1539 (1988); M. Zhao, A. O. King, R. D. Larsen, T. R. Verhoeven, and P. J. Reider, Tetrahedron Lett. 38:2641 (1997). 94. H. C. Brown, M. Srebnik, and P. V. Ramachandran, J. Org. Chem. 54:1577 (1989). 95. H. C. Brown, P. V. Ramachandran, A. V. Teodorovic, and S. Swaminathan, Tetrahedron Lett. 32:6691 (1991).

Table 5.5. Enantioselective Reduction of Ketones Reagent Alpine-Borane NB-Enantridea …Ipc†2 BCl …IpcB…t-Bu†Cl …Ipc†2 BCl …Eap†2 BCl a. b. c. d. e. f. g.

a

279

Ketone

% e.e.

Con®g.

Reference

3-Methyl-2-butanone 2-Octanone 2-Acetylnaphthalene Acetophenone 2,2-Dimethycyclohexanone 3-Methyl-2-butanone

62 79 94 96 91 95

S S S R S R

b c d e f g

Trademark of Aldrich Chemical Company. H. C. Brown and G. G Pai, J. Org. Chem. 50:1384 (1985). M. M. Midland and A. Kozubski, J. Org. Chem. 47:2495 (1982). M. Zhao, A. O. King, R. D. Larsen, T. R. Verhoeven, and A. J. Reider, Tetrahedron Lett. 38:2641 (1997). H. C. Brown, M. Srebnik, and P. V. Ramachandran, J. Org. Chem. 54:1577 (1989). H. C. Brown, J. Chandrasekharan, and P. V. Ramachandran, J. Am. Chem. Soc. 110:1539 (1988). H. C. Brown, P. V. Ramachandran, A. V. Teodorovic, and S. Swaminathan, Tetrahedron Lett. 32:6691 (1991).

of alcohols. Cl

R B

H CH3

OBClR

O

+

C

R

H R′

C R′

CH3

OH

R

H

C R′

R

Table 5.5 give some typical results for enantioselective reduction of ketones. An even more ef®cient approach to enantioselective reduction is to use a chiral catalyst. One of the most promising is the oxazaborolidine I, which is ultimately derived from the amino acid proline.96 The enantiomer is also available. A catalytic amount (5± 20 mol %) of this reagent along with BH3 as the reductant can reduce ketones such as acetophone and pinacolone in > 95% e.e. An adduct of borane and I is the active reductant. Ph B H3C

Ph + BH3

N O

Ph

I

N+ H3B– B H3C

O

Ph

This adduct can be prepared, stored, and used as a stoichiometric reagent if so desired.97 Catecholborane can also be used as the reductant.98 Ph N

O PhCH

B

O

CHCCH3 +

B O

H

O

Ph

OH

CH3(CH2)3

Ph

CH3 92% e.e.

96. E. J. Corey, R. K. Bakshi, S. Shibata, C. P. Chen, and V. K. Singh, J. Am. Chem. Soc. 109:7925 (1987); E. J. Corey and C. J. Helal, Angew, Chem. Int. Ed. Engl. 37:1987 (1998). 97. D. J. Mathre, A. S. Thompson, A. W. Douglas, K. Hoogsteen, J. D. Carroll, E. G. Corley, and E.-J. J. Grabowski, J. Org. Chem. 58:2880 (1993). 98. E. J. Corey and R. K. Bakshi, Tetrahedron Lett. 31:611 (1990).

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

280 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

The enantioselectivity and reactivity of these catalysts can be modi®ed by changes in substituent groups to optimize selectivity toward a particular ketone.99 The enantioselectivity in these reductions is proposed to arise from a chairlike transition state in which the governing steric interaction is with the alkyl substituent on boron.100 There are data indicating that the steric demand of this substituent in¯uences enantioselectivity.101 Ph B RS

Ph

O

O RL H

H N+

B H

H

Scheme 5.4 shows some examples of enantioselective reduction of ketones using I. Adducts of borane with several other chiral b-aminoalcohols are being explored as chiral catalyst for reduction of ketones.102 Table 5.6 shows the enantioselectivity of several of these catalysts toward acetophenone. 5.2.3. Reduction of Other Functional Groups by Hydride Donors Although reductions of the common carbonyl and carboxylic acid derivatives are the most prevalent uses of hydride donors, these reagents can reduce a number of other groups in ways that are of synthetic utility. Scheme 5.5 illustrates some of these other applications of the hydride donors. Halogen and sulfonate leaving groups can undergo replacement by hydride. Both aluminum and boron hydrides exhibit this reactivity. Lithium trialkylborohydrides are especially reactive.103 The reduction is particularly rapid and ef®cient in polar aprotic solvents such as DMSO, DMF, and HMPA. Table 5.7 gives some indication of the reaction conditions. The normal factors in susceptibility to nucleophilic attack govern reactivity, with the order of reactivity being I > Br > Cl in terms of the leaving group and benzyl  allyl > primary > secondary > tertiary in terms of the substitution site.104 For alkyl groups, it is likely that the reaction proceeds by an SN 2 mechanism. However, the range of halides that can be reduced includes aryl halides and bridgehead halides, which cannot react by the SN 2 mechanism.105 There is loss of stereochemical integrity in the reduction of vinyl halides, suggesting the involvement of radical intermediates.106 Formation and subsequent dissociation of a radical anion by one-electron transfer is a likely mechanism for reductive dehalogenation of compounds that cannot react 99. A. W. Douglas, D. M. Tschaen, R. A. Reamer, and Y.-J. Shi, Tetrahedron Asymmetry 7:1303 (1996). 100. D. K. Jones, D. C. Liotta, I. Shinkai, and D. J. Mathre, J. Org. Chem. 58:799 (1993). 101. E. J. Corey and R. K. Bakshi, Tetrahedron Lett. 31:611 (1990); T. K. Jones, J. J. Mohan, L. C. Xavier, T. J. Blacklock, D. J. Mathre, P. Sohar, E. T. T. Jones, R. A. Beamer, F. E. Roberts, and E. J. J. Grabowski, J. Org. Chem. 56:763 (1991). 102. G. J. Qaullich and T. M. Woodall, Tetrahedron Lett. 34:4145 (1993); J. Martens, C. Dauelsberg, W. Behnen, and S. Wallbaum, Tetrahedron Asymmetry 3:347 (1992); Z. Shen, W. Huang, J. W. Feng, and Y. W. Zhang, Tetrahedron Asymmetry 9:1091 (1998); N. Hashimot, T. Ishizuko, and T. Kunieda, Heterocycles 46:189 (1997). 103. S. Krishnamurthy and H. C. Brown, J. Org. Chem. 45:849 (1980). 104. S. Krishnamurthy and H. C. Brown, J. Org. Chem. 47:276 (1982). 105. C. W. Jefford, D. Kirkpatrick, and F. Delay, J. Am. Chem. Soc. 94:8905 (1972). 106. S.-K. Chung, J. Org. Chem. 45:3513 (1980).

Scheme 5.4. Enantionselective Reduction of Ketones Using Oxazaborolidine Catalyst Ph

1a

Ph

O N

CH3O2C

N

B

CCH2Br

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

OH

O

CH3O2C

CH3

N

CHCH2Br 80%

BH3

2b

O

O

Ph

O

Ph

B CH3

C5H11 ArCO2

O

O

N

C5H11

BH3

ArCO2

O

90% d.e.

OH

Ar = 4-biphenyl

3c

O + H3B Ph

O

4d

N

Ph

N+ B

O

98.8% e.e.

CH3 OH

Ph O B

98% e.e.

H

S

S

S

S

BH3, S(CH3)2

O

O

OH

Ph

O

O

5e

Ph

O

N

CH3O2C(CH2)3C

Ph

O PhCCH2OSi[CH(CH3)2]3

N

OH

O CH2Si(CH3)3

Sn(C4H9)3 6f

Ph

B

CH3O2C(CH2)3CH Sn(C4H9)3

90%

Ph O B H

BH3

OH PhCHCH2OSi[CH(CH3)2]3

281

99% e.e.

a. K. G. Hull, M. Visnick, W. Tautz, and A. Sheffron, Tetrahedron 53:12405 (1997). b. E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen, and V. K. Singh, J. Am. Chem. Soc., 109:7925 (1987). c. D. J. Mathre, A. S. Thompson, A. W. Douglas, K. Hoogsteen, J. D. Carroll, E. G. Corley, and E. J. J. Grabowski, J. Org. Chem. 58:2880 (1993). d. T. K. Jones, J. J. Mohan, L. C. Xavier, T. J. Blacklock, D. J. Mathre, P. Sohar, E. T. T. Jones, R. A. Reamer, F. E. Roberts, and E. J. J. Grabowski, J. Org. Chem. 56:763 (1991). e. E. J. Corey, A Guzman-Perez, and S. E. Lazerwith, J. Am. Chem. Soc. 119:11769 (1997). f. B. T. Cho and Y. S. Chun, J. Org. Chem. 63:5280 (1998).

Table 5.6. Catalysts for Enantioselective Reduction of Acetophenone

282 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Catalyst

Reductant

% e.e.

Con®g.

Reference

Ph Ph

N

BH3

93%

R

a

BH3

96%

R

b

BH3

92%

R

c

BH3

95%

R

d

BH3

72%

R

e

BH3

93–98



f

O

B

2 mol%

H Ph

Ph

O

N

B C2H5

Ph

Ph

O

H

N B CH3

H

N

B

O 10 mol%

H

N

NSO2Ar B 10 mol%

H

Ph Ph N

O B

10 mol% polymer a. b. c. d. e. f.

J. Martens, C. Dauelsburg, W. Behnen, and S. Wallbaum, Tetrahedron Asymmetry 3:347 (1992). E. J. Corey and J. O. Link, Tetrahedron Lett. 33:4141 (1992). G. J. Quallich and T. M. Woodall, Tetrahedron Lett. 34:4145 (1993). A. Sudo, M. Matsumoto, Y. Hashimoto, and K. Saigo, Tetrahedron Asymmetry 6:1853 (1995). O. Froelich, M. Bonin, J.-C. Quirion, and H.-P. Husson, Tetrahedron Asymmetry 4:2335 (1993). C. Franot, G. B. Stone, P. Engeli, C. Spondlin, and E. Waldvogel, Tetrahedron Asymmetry 6:2755 (1995).

Table 6.7. Reaction Conditions for Reductive Replacement of Halogen and Tosylate by Hydride Donors

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

Approximate conditions for complete reduction Hydride donor

Halides

a

Tosylates 

NaBH3 CN

1-Iodododecane, HMPA, 25 C, 4 h

1-Dodecyl tosylate, HMPA, 70 C, 8 h

NaBH4 b LiAlH4 c,d LiB…C2 H5 †3 Hc

1-Bromododecane, DMSO, 85 C, 1.5 h 1-Bromooctane, THF, 25 C, 1 h 1-Bromooctane, THF, 25 C, 3 h

1-Dodecyl tosylate, DMSO, 85 C, 2 h 1-Octyl tosylate, DME, 25 C, 6 h

a. R. O. Hutchins, D. Kandasamy, C. A. Maryanoff, D. Masilamani, and B. E. Maryanoff, J. Org. Chem. 42:82 (1977). b. R. O. Hutchins, D. Kandasamy, F. Dux III, C. A. Maryanoff, D. Rotstein, B. Goldsmith, W. Burgoyne, F. Cistone, J. Dalessandro, and J. Puglis, J. Org. Chem. 43:2259 (1978). c. S. Krishnamurthy and H. C. Brown, J. Org. Chem. 45:849 (1980). d. S. Krishnamurthy, J. Org. Chem. 45:25250 (1980).

by an SN 2 mechanism. R

X + e– . R X– R⋅ +

R

. X–

R⋅ + X–

X–

R

H + e–

One experimental test for the involvement of radical intermediates is to study 5-hexenyl systems and look for the characteristic cyclization to cyclopentane derivatives (see Section 12.2 of Part A). When 5-hexenyl bromide or iodide reacts with LiAlH4 , no cyclizataion products are observed. However, the more hindered 2,2-dimethyl-5-hexenyl iodide gives mainly cyclic product.107 CH2

CH(CH2)3CH2I + LiAlH4

CH2

CH(CH2)2CCH2I + LiAlH4

24°C 1h

CH2

CH(CH2)3CH3

CH3

94%

CH3 24°C 1h

CH2

CH(CH2)2CCH3

CH3

3%

CH3 +

CH3

H3C

CH3 81%

Some cyclization also occurs with the bromide but not with the chloride or the tosylate. The secondary iodide 6-iodo-1-heptene gives a mixure of cyclic and acyclic product in THF.108 CH3 CH2

CH(CH2)3CHCH3 I

LiAlH4 THF

CH2

283

CH3

CH(CH2)3CH2CH3 + 21% 72%, 3.7:1 cis:trans

107. E. C. Ashby, R. N. DePriest, A. B. Goel, B. Wenderoth, and T. N. Pham, J. Org. Chem. 49:3545 (1984). 108. E. C. Ashby, T. N. Pham, and A. Amrollah-Madjadabadi, J. Org. Chem. 56:1596 (1991).

284 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

The occurrence of a radical intermediate is also indicated in the reduction of 2-octyl iodide by LiAlD4 since, in contrast to the other halides, extensive racemization accompanies reduction. The presence of transition-metal ions has a catalytic effect on reduction of halides and tosylates by LiAlH4.109 Various ``copper hydride'' reducing agents are effective for removal of halide and tosylate groups.110 The primary synthetic value of these reductions is for the removal of a hydroxyl function after conversion to a halide or tosylate. Entry 6 in Scheme 5.5 is an example of the use of the reaction in synthesis. Epoxides are converted to alcohols by LiAlH4. The reaction occurs by nucleophilic attack, and hydride addition at the least hindered carbon of the epoxide is usually observed. H PhC

CH2 + LiAlH4 O

PhCHCH3 OH

Cyclohexene epoxides are preferentially reduced by an axial approach of the nucleophile.111 H

H LiAlH4

(CH3)3C

H

(CH3)3C

O

OH H

O (CH3)3C

H

LiAlH4

(CH3)3C H

Lithium triethylborohydride is a superior reagent for reduction of epoxides that are relatively unreactive or prone to rearrangement.112 Alkynes are reduced to E-alkenes by LiAlH4.113 This stereochemistry is complementary to that of partial hydrogenation, which gives Z-isomers. Alkyne reduction by LiAlH4 is greatly accelerated by a nearby hydroxyl group. Typically, propargylic alcohols react in ether or THF over a period of several hours,114 whereas forcing conditions are required for isolated triple bonds.115 (Compare entries 8 and 9 in Scheme 5.5.) This is presumably the result of coordination of the hydroxyl group at aluminum and formation of cyclic intermediate. The involvement of intramolecular Al H addition has been demonstrated by use of LiAlD4 as the reductant. When reduction by LiAlD4 is followed by quenching with normal water, propargylic alcohol gives 3-2 H-prop-2-enol. Quenching 109. E. C. Ashby and J. J. Lin, J. Org. Chem. 43:1263 (1978). 110. S. Masamune, G. S. Bates, and P. E. Georghiou, J. Am. Chem. Soc. 96:3686 (1974); E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem. 43:183 (1978). 111. B. Rickborn and J. Quartucci, J. Org. Chem. 29:3185 (1964); B. Rickborn and W. E. Lamke II, J. Org. Chem. 32:537 (1967); D. K. Murphy, R. L. Alumbaugh, and B. Rickborn, J. Am. Chem. Soc. 91:2649 (1969). 112. H. C. Brown, S. C. Kim, and S. Krishnamurthy, J. Org. Chem. 45:1 (1980); H. C. Brown, S. Narasimhan, and V. Somayaji, J. Org. Chem. 48:3091 (1983). 113. E. F. Magoon and L. H. Slaugh, Tetrahedron 23:4509 (1967). 114. N. A. Porter, C. B. Ziegler, Jr., F. F. Khouri, and D. H. Roberts, J. Org. Chem. 50:2252 (1985). 115. H. C. Huang, J. K. Rehmann, and G. R. Gray, J. Org. Chem. 47:4018 (1982).

Scheme 5.5. Reduction of Other Functional Groups by Hydride Donors

SECTION 5.2. GROUP III HYDRIDEDONOR REAGENTS

Halides NaBH4 DMSO

1a CH3(CH2)5CHCH3

CH3(CH2)6CH3

67%

CH3(CH2)8CH3

88–90%

Cl 2b

CH3(CH2)8CH2I

3c

NaBH3CN HMPA

Br LiAlH4

79%

THF, reflux

Sulfonates 4d

CH2OSO2C7H7

CH3

LiAlH4

33%

5e

H3C

CH2OSO2CH3 O

6f OSO2C7H7

H3C

CH3 OH

LiAlH4

LiCuHC4H9

75%

Epoxides 7g O

LiAlH4 89%

OH CH3

CH3 Acetylenes 8h CH3CH2C

9i

HO

CCH2CH3

LiAlH4 120–125°C, 4.5 h

OCH3 CHC

CCH3

CH3CH2

H C

C

H HO

90%

CH2CH3 OCH3 CH

LiAlH4 NaOCH3, 65°C, 45 min

285

H C

H

C

85%

CH3

a. R. O. Hutchins, D. Hoke, J. Keogh, and D. Koharski, Tetrahedron Lett. 1969:3495; H. M. Bell, C. W. Vanderslice, and A. Spehar, J. Org. Chem. 34:3923 (1969). b. R. O. Hutchins, C. A. Milewski, and B. E. Maryanoff, Org. Synth. 53:107 (1973). c. H. C. Brown and S. Krishnamurthy, J. Org. Chem. 34:3918 (1969). d. A. C. Cope and G. L. Woo, J. Am. Chem. Soc. 85:3601 (1963). e. A. Eschenmoser and A. Frey, Helv. Chim. Acta 35:1660 (1952). f. S. Masamune, G. S. Bates, and P. E. Geoghiou, J. Am. Chem. Soc. 96:3686 (1974). g. B. Rickborn and W. E. Lamke II, J. Org. Chem. 32:537 (1967). h. E. F. Magoon and L. H. Slaugh, Tetrahedron 23:4509 (1967). i. D. A. Evans and J. V. Nelson, J. Am. Chem. Soc. 102:774 (1980).

286 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

with D2 O gives 2-2 H-3-2 H-prop-2-enol indicating overall anti addition.116 HOCH2

D

D Al– O C



D3AlOCH2C

CH H

C

C

D

H

C

H

D C

D2O

H2O

D

H

HOCH2

H C

C

D

H

The ef®ciency and stereospeci®city of reduction are improved by using a 1 : 2 LiAlH4 ± NaOCH3 mixture as the reducing agent.117 The mechanistic basis of this effect has not been explored in detail.

5.3. Group IV Hydride Donors Both Si H and C H compounds can function as hydride donors under certain circumstances. The silicon±hydrogen bond is capable of transferring a hydride to carbocations. Alcohols that can be ionized in tri¯uoroacetic acid are reduced to hydrocarbons in the presence of a silane.

OH

H Ph3SiH CF3CO2H

92%

Ref. 118

H

Aromatic aldehydes and ketones are reduced to alkylaromatics.119 ArCR + H+

+

ArCR

O

R3SiH

OH ArCHR + R3SiH +

ArCHR

ArCHR + H2O +

OH ArCH2R

Aliphatic ketones can be reduced to hydrocarbons by triethylsilane and gaseous BF3 .120 The BF3 is a suf®ciently strong Lewis acid to promote formation of a carbocation from the 116. J. E. Baldwin and K. A. Black, J. Org. Chem. 48:2778 (1983). 117. E. J. Corey, J. A. Katzenellenbogen, and G. H. Posner, J. Am. Chem. Soc. 89:4245 (1967); B. B. Molloy and K. L. Hauser, J. Chem. Soc., Chem. Commun. 1968:1017. 118. F. A. Carey and H. S. Tremper, J. Org. Chem. 36:758 (1971). 119. C. T. West, S. J. Donnelly, D. A. Kooistra, and M. P. Doyle, J. Org. Chem. 38:2675 (1973); M. P. Doyle, D. J. DeBruyn, and D. A. Kooistra, J. Am. Chem. Soc. 94:3659 (1972); M. P. Doyle and C. T. West, J. Org. Chem. 40:3821 (1975). 120. J. L. Frey, M. Orfanopoulos, M. G. Adlington, W. R. Dittman, Jr., and S. B. Silverman, J. Org. Chem. 43:374 (1978).

287

intermediate alcohol.

SECTION 5.3. GROUP IV HYDRIDE DONORS



+O

BF3

RCR



OBF3 Et3SiH

R

C

R

R

+

C

H

R

Et3SiH

RCH2R

H

Aryl ketones have also been reduced with triethylsilane and TiCl4 . This method was used to prepare g-aryl amino acids.121 O ArCCH2CHNHCO2CH3 CO2H

1) TMSCl Et3N 2) (C2H5)3SiH, TiCl4

ArCH2CH2CHNHCO2CH3 CO2H

All of these reactions involve formation of oxonium and carbocation intermediates that can abstract hydride from the silane donor. There is also a group of reactions in which hydride is transferred from carbon. The carbon±hydrogen bond has little intrinsic tendency to act as a hydride donor so especially favorable circumstances are required to observe this reactivity. Frequently, these reactions proceed through a cyclic transition state in which a new C H bond is formed simultaneously with the C H cleavage. Hydride transfer is facilitated by high electron density at the carbon atom. Aluminum alkoxides catalyze transfer of hydride from an alcohol to a ketone. This is generally an equlibrium process, and the reaction can be driven to completion if the ketone is removed from the system by distillation, for example. This process is called the Meerwein±Pondorff±Verley reduction.122 3 R2C

O + Al[OCH(CH3)2]3

[R2CHO]3Al + 3 CH3CCH3 O

The reaction proceeds via a cyclic transition state involving coordination of both the alcohol and ketone oxygens to the aluminum. Hydride donation usually takes place from the less hindered face of the carbonyl group.123 Al O H3C H3C

O

C

C H

R

R

Certain lanthanide alkoxides, such as t-BuOSmI2 , have also been found to catalyze hydride exchange between alcohols and ketones.124 Isopropanol can serve as the reducing agent for aldehydes and ketones that are thermodynamically better hydride acceptors than 121. M. Yato, K. Homma, and A. Ishida, Heterocycles 49:233 (1998). 122. A. L. Wilds, Org. React. 2:178 (1944); C. F. de Graauw, J. A. Peters, H. van Bekkum and J. Huskens, Synthesis, 1007 (1994). 123. F. Nerdel, D. Frank, and G. Barth, Chem. Ber. 102:395 (1969). 124. J. L. Namy, J. Souppe, J. Collins, and H. B. Kagan, J. Org. Chem. 49:2045 (1984).

288 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

acetone. CH3CHCH3

O2N

CH

OH

O

O2N

t-BuOSmI2

CH2OH

94%

Like the Meerwein±Pondorff±Verley reduction, these reactions are believed to proceed under thermodynamic control, and the more stable stereoisomer is the main product.125 Another reduction process, catalysed by iridium chloride and characterized by very high axial : equatorial product ratios for cyclohexanones, apparently involves hydride transfer from isopropanol.126 IrCl4, HCl (CH3O)3P, H2O

(CH3)3C

(CH3)2CHOH

(CH3)3C

O

OH

Formic acid can also act as a donor of hydrogen. The driving force in this case is the formation of carbon dioxide. O + HCO2H

RNH2 + CH2

RN(CH3)2 + CO2

A useful application is the Clark±Eschweiler reductive alkylation of amines. Heating a primary or secondary amine with formaldehyde and formic acid results in complete methylation to the tertiary amine.127 The hydride acceptor is the iminium ion resulting from condensation of the amine with formaldehyde. +

R2N H O

CH2 H C O

5.4. Hydrogen-Atom Donors Reduction by hydrogen-atom donors involves free-radical intermediates. Tri-n-butyltin hydride is the most prominent example of this type of reducing agent. It is able to reductively replace halogen by hydrogen in organic compounds. Mechanistic studies have indicated a free-radical chain mechanism.128 The order of reactivity for the haldes is RI > RBr > RCl > RF, which re¯ects the relative ease of the halogen-atom abstraction.129 In⋅ + Bu3SnH Bu3Sn⋅ + R

In

H + Bu3Sn⋅

X

R⋅ + Bu3SnX

R⋅ + Bu3SnH

RH + Bu3Sn⋅

(In⋅ = initiator)

Tri-n-butyltin hydride shows substantial selectivity toward polyhalogenated compounds, permitting partial dehalogenation. The reason for the greater reactivity of 125. 126. 127. 128. 129.

D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, and T. J. Stout, J. Am. Chem. Soc. 112:7001 (1990). E. L. Eliel, T. W. Doyle, R. O. Hutchins, and E. C. Gilbert, Org. Synth. 50:13 (1970). M. L. Moore, Org. React. 5:301 (1949); S. H. Pine and B. L. Sanchez, J. Org. Chem. 36:829 (1971). L. W. Menapace and H. G. Kuivila, J. Am. Chem. Soc. 86:3047 (1964). H. G. Kuivila and L. W. Menapace, J. Org. Chem. 28:2165 (1963).

Scheme 5.6. Dehalogenations with Stannanes 1a

Bu3SnH

Br

2b

SECTION 5.4. HYDROGEN-ATOM DONORS

H

CF3

CF3 Br

3c

Ph3SnH

H

99%

O

O Bu3SnH 84%

Cl

H

Cl 4d

Cl Cl

F

Bu3SnH

F 5e

O

O

O

O (CH3)3SnCl NaBH4

CH2OCH3

I

CH2OCH3

O2CCH3 6f

O2CCH3

Br

D 1) Bu3SnD

Br

Br

2) KF, H2O

92%

D

Br

D D

a. H. G. Kuivila, L. W. Menapace, and C. R. Warner, J. Am. Chem. Soc. 84:3584 (1962). b. D. H. Lorenz, P. Shapiro, A. Stern, and E. I. Becker, J. Org. Chem. 28:2332 (1963). c. W. T. Brady and E. F. Hoff, Jr. J. Org. Chem. 35:3733 (1970). d. T. Ando, F. Namigata, H. Yamanaka, and W. Funasaka, J. Am. Chem. Soc. 89:5719 (1967). e. E. J. Corey and J. W. Suggs, J. Org. Chem. 40:2554 (1975). f. J. E. Leibner and J. Jacobson, J. Org. Chem. 44:449 (1979).

more highly halogented carbons toward reduction lies in the stabilizing effect that the remaining halogen has on the radical intermediate. This selectivity has been used, for example, to reduce dihalocyclopropanes to monohalocyclopropanes as in entry 4 of Scheme 5.6. A procedure which is catalytic in Bu3 SnH and uses NaBH4 as the stoichiometric reagent has been developed.130 This procedure has advantages in the isolation and puri®cation of product. Entry 5 in Scheme 5.6 is an example of this procedure. 130. E. J. Corey and J. W. Suggs, J. Org. Chem. 40:2554 (1975).

289

290 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Tri-n-butyltin hydride also serves as a hydrogen-atom donor in radical-mediated methods for reductive deoxygenation of alcohols.131 The alcohol is converted to a thiocarbonyl derivative. These thioesters undergo a radical reaction with tri-n-butyltin hydride. S R

S

OCX + Bu3Sn⋅

SnBu3

ROCX

R× + Bu3SnH

O R× + XCS

R

SnBu3

H + Bu3Sn⋅

This procedure gives good yields from secondary alcohols and, by appropriate adjustment of conditions, can also be adapted to primary alcohols.132 Scheme 5.7 illustrates some of the conditions which have been developed for the reductive deoxygenation of alcohols. Because of the expense, toxicity, and puri®cation problems associated with use of stoichiometric amounts of tin hydrides, there has been interest in ®nding other hydrogenatom donors. The trialkylboron±oxygen system for radical initiation has been used with tris(trimethylsily)silane or diphenylsilane as a hydrogen-donor system.133 S c-C12H23OCO

F

C2H5⋅ + R3SiH R3Si⋅ + R′OCOR′ S

c-C12H24

96%

C2H5⋅

(C2H5)3B + O2

⋅ R′OCOR′

Et3B, O2 (Ph)2SiH2

C2H6 + R3Si⋅ ⋅ R′OCOR′

SSiR3 R′⋅ + RO2CSSiR3

SSiR3 R′⋅ + R3SiH

R3Si⋅

The alcohol derivatives that have been successfully deoxygenated include thiocarbonates and xanthates.134 Peroxides can also be used as initiators.135 Dialkyl phosphites can also be used as hydrogen donors.136 (see Entry 4, Scheme 5.7)

5.5. Dissolving-Metal Reductions Another group of synthetically useful reductions employs a metal as the reducing agent. The organic substrate under these conditions accepts one or more electrons from the metal. The subsequent course of the reaction depends on the structure of the reactant and reaction conditions. Three broad classes of reactions can be recognized, and these will be discussed separately. These include reactions in which the overall change involves (a) net 131. D. H. R. Barton and S. W. McCombie, J. Chem. Soc., Perkin I Trans, 1 1975:1574; for reviews of this method, see W. Hartwig, Tetrahedron 39:2609 (1983); D. Crich and L. Quintero, Chem. Rev. 89:1413 (1989). 132. D. H. R. Barton, W. B. Motherwell, and A. Stange, Synthesis 1981:743. 133. D. H. R. Barton, D. O. Jang, and J. C. Jaszberenyi, Tetrahedron Lett. 31:4681 (1990). 134. J. N. Kirwan, B. P. Roberts, and C. R. Willis, Tetrahedron Lett. 31:5093 (1990). 135. D. H. Barton, D. O. Jang, and J. C. Jaszberenyi, Tetrahedron Lett. 32:7187 (1991). 136. D. H. R. Barton, D. O. Jang, and J. C. Jaszberenyi, Tetrahedron Lett. 33:2311 (1992).

Scheme 5.7. Deoxygenation of Alcohols via Thioesters and Related Derivatives 1a

OCH2Ph

H3C

OCH2Ph

H3C

S

H

H

H

60%

2) Bu3SnH

HOCH2 H OH H3C

O

H3C

O

HO

CH3

O

1) NaH, CS2 2) CH3I

O

CH3

H3C

O

H3C

O

H

O O

3) Bu3SnH

O

O

N

N

NH

N

CH3

S

N

1) Im C

NH

N

N

Im

60%

2) Bu3SnH

O

O

O

O

H3C

CH3

H3C

CH3

S

4d

CH2OCO

H3C

CH3

F O

O

O

H3C

(CH3O)PH

H3C

CH3

O

O

O

(PhCO2)2

O

O

H3C

O

O

CH3

PhCO2CH2

PhCO2CH2 S

O OCH3

HO

6f

O Im

OCH3

2) Bu3SnH

PhOCO S

O (TMS)3SiH

O

92%

O2CPh

PhCO2

O HO

a. b. c. d. e. f.

1) Im C

O2CPh

PhCO2

90%

CH3

O

CH3 5e

75%

CH3

O

HOCH2

CH3

O CH3

3c

SECTION 5.5. DISSOLVING-METAL REDUCTIONS

H

1) PhOCCl, DMAP

2b

291

azobis(isobutyronitrile)

HO

O

87%

OCOPh S

H. J. Liu and M. G. Kulkarni, Tetrahedron Lett. 26:4847 (1985). S. Iacono and J. R. Rasmussen, Org. Synth. 64:57 (1985). O. Miyashita, F. Kasahara, T. Kusaka, and R. Marumoto, J. Antibiot. 38:981 (1985). D. H. R. Barton, D. O. Jang, and J. C. Jaszberenyi, Tetrahedron Lett. 33:2311 (1992). J. R. Rasmussen, C. J. Slinger, R. J. Kordish, and D. D. Newman-Evans, J. Org. Chem. 46:4843 (1981). D. H. R. Barton, D. O. Jang, and J. C. Jaszberenyi, Tetrahedron Lett. 33:6629 (1992).

292 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

addition of hydrogen, (b) reductive removal of a functional group, and (c) formation of carbon±carbon bonds. 5.5.1. Addition of Hydrogen Although the method has been supplanted for synthetic purposes by the use of hydride donors, the reduction of ketones to alcohols by alkali metals in ammonia or alcohols provides some mechanistic insight into dissolving-metal reductions. The outcome of the reaction of ketones with metal reductants is determined by the fate of the initial ketyl intermediate formed by a single-electron transfer. The intermediate, depending on its structure and the reaction medium, may be protonated, disproportionate, or dimerize.137 In hydroxylic solvents such as liquid ammonia or in the presence of an alcohol, the protonation process dominates over dimerization. As will be discussed in Section 5.5.3, dimerization may become the dominant process under other conditions. O–

OH protonation S

RCH2

H

C⋅

R′

e– S

RCH2C

H

R′

H

RCH2

C

O– O–

O–

O R′

e–

RCH2 ketyl

C⋅

dimerization

R′

RCH2

C

C

CH2R

R′ R′ disproportionation

RCH2 protonation SH

O–

O–

CHR′ + RCH

CR′

OH RCH2

CHR′

a,b-Unsaturated carbonyl compounds are cleanly reduced to the enolate of the corresponding saturated ketone on reduction with lithium in ammonia.138 Usually, an alcohol is added to the reduction solution to serve as the proton source. O–

O R

C C

R

C H

R

e–

R R

C C⋅

C H

O–

R

e– S

H

R2CH

CH

C

R

As mentioned in Chapter 1, this is one of the best methods for generating a speci®c enolate of a ketone. The enolate generated by conjugate reduction can undergo the characteristic alkylation and addition reactions which were discussed in Chapters 1 and 2. When this is the objective of the reduction, it is important to use only one equivalent of the proton donor. Ammonia, being a weaker acid than an aliphatic ketone, does not protonate the enolate, and it remains available for reaction. If the saturated ketone is the desired product, the enolate is protonated either by use of excess proton donor during the reduction or on 137. V. Rautenstrauch and M. Geoffroy, J. Am. Chem. Soc. 99:6280 (1977); J. W. Huffman and W. W. McWhorter, J. Org. Chem. 44:594 (1979); J. W. Huffman, P. C. Desai, and J. E. LaPrade, J. Org. Chem. 48:1474 (1983). 138. D. Cain, Org. React. 23:1 (1976).

293

workup. O

O Li, NH3 1 equiv H2O

SECTION 5.5. DISSOLVING-METAL REDUCTIONS

O CH2CH

CH2 CHCH2Br

CH2

CH2CH

CH2 Ref. 139

+

CH3

CH3

CH3 2–2.5%

43–47%

H 1) LI, NH3

O

Ref. 140

47%

2) n-C4H9I

O H9C4

H

The stereochemistry of conjugate reduction is established by the proton transfer to the b carbon. In the well-studied case of D1;9 -2-octalones, the ring junction is usually trans.141 R

R LI, NH3 ROH –O

O

R = alkyl or H

H

The stereochemistry is controlled by a stereoelectronic preference for protonation perpendicular to the enolate system, and, given that this requirement is met, the stereochemistry will normally correspond to protonation of the most stable conformation of the dianion intermediate from its least hindered side. Dissolving-metal systems constitute the most general method for partial reduction of aromatic rings. The reaction is called the Birch reduction.142 The usual reducing medium is lithium or sodium in liquid ammonia. The reaction occurs by two successive electrontransfer=protonation steps. H R

Li

.–

R

H

S—H

H R

.

H

H

Li –

R

H

S—H

R H

H

The isolated double bonds in the dihydro product are much less easily reduced than the conjugated ring, so the reduction stops at the dihydro stage. Alkyl and alkoxy aromatics, phenols, and benzoate anions are the most useful reactants for Birch reduction. In aromatic ketones and nitro compounds, the substituents are reduced in preference to the aromatic ring. Substituents also govern the position of protonation, Alkyl and alkoxy aromatics 139. D. Caine, S. T. Chao, and H. A. Smith, Org. Synth. 56:52 (1977). 140. G. Stork, P. Rosen, and N. L. Goldman, J. Am. Chem. Soc. 83:2965 (1961). 141. G. Stork, P. Rosen, N. Goldman, R. V. Coombs, and J. Tsuji, J. Am. Chem. Soc. 87:275 (1965); M. J. T. Robinson, Tetrahedron 21:2475 (1965). 142. A. J. Birch and G. Subba Rao, Adv. Org. Chem. 8:1 (1972); R. G. Harvey, Synthesis 1980:161; J. M. Hook and L. N. Mander, Nat. Prod. Rep. 3:35 (1986); P. W. Rabideau, Tetrahedron 45:1599 (1989); A. J. Birch, Pure Appl. Chem. 68:553 (1996).

294

normally give the 2,5-dihydro derivative. Benzoate anions give 1,4-dihydro derivatives.

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

OCH3

OCH3 Li, NH3 C2H5OH

CO2–

CO2– Li, NH3 C2H5OH

The structure of the products is determined by the site of protonation of the radicalanion intermediate formed after the ®rst electron-transfer step. In general, electronreleasing substituents favor protonation at the ortho position, whereas electron-attracting groups favor protonation at the para position.143 Addition of a second electron gives a pentadienyl anion, which is protonated at the center carbon. As a result, 2,5-dihydro products are formed with alkyl or alkoxy substituents, and 1,4-products are formed from aromatics with electron-attracting substituents. The preference for protonation of the central carbon of the pentadienyl anion is believed to be the result of the greater 1,2 and 4,5 bond order and a higher concentration of negative charge at the 3-carbon.144 The reduction of methoxybenzenes is of importance in the synthesis of cyclohexenones via hydrolysis of the intermediate enol ethers: OCH3

OCH3

O

Li, NH3

H+

ROH

H2O

The anionic intermediates formed in Birch reductions can be used in tandem reactions. O

CH2OCH3

O H5C2

C

CH2OCH3

C

1) K, NH3, t-BuOH, 1 equiv

97%

2) LiBr, C2H5I

Si(CH3)3

Ref. 145

Si(CH3)3

1) Li, NH3 71%

CO2H 2)

Br

CO2H

Ref. 146

Scheme 5.8 lists some examples of the use of the Birch reduction. 143. A. J. Birch, A. L. Hinde, and L. Radom, J. Am. Chem. Soc. 102:2370 (1980); H. E. Zimmerman and P. A. Wang, J. Am. Chem. Soc. 112:1280 (1990). 144. P. W. Rabideau and D. L. Huser, J. Org. Chem. 48:4266 (1983); H. E. Zimmerman and P. A. Wang, J. Am. Chem. Soc. 115:2205 (1993). 145. P. A. Baguley and J. C. Walton, J. Chem. Soc., Perkin Trans. 1 1998:2073. 146. A. G. Schultz and L. Pettus, J. Org. Chem. 62:6855 (1997).

Scheme 5.8. Birch Reduction of Aromatic Rings 1a

OCH3

OCH3 Li, NH3

2b

295 SECTION 5.5. DISSOLVING-METAL REDUCTIONS

63%

C(CH3)3

C(CH3)3

C(CH3)3

C(CH3)3 Li

56%

C2H5NH2

C(CH3)3

C(CH3)3

3c

O

OCH3

1) Li, NH3 2)

H+,

80%

H2O

H3C

H3C

4d

CO2H

CO2H

Na, NH3

90%

C2H5OH

5e

OH

OH Li, NH3

97–99%

C2H5OH

OC2H5

6f

OC2H5

Na C2H5OH

a. D. A. Bolton, J. Org. Chem. 35:715 (1970). b. H. Kwart and R. A. Conley, J. Org. Chem. 38:2011 (1973). c. E. A. Braude, A. A. Webb, and M. U. S. Sultanbawa, J. Chem. Soc. 1958:3328; W. C. Agosta and W. L. Schreiber, J. Am. Chem. Soc. 93:3947 (1971). d. M. E. Kuehne and B. F. Lambert, Org. Synth. V:400 (1973). e. C. D. Gutsche and H. H. Peter, Org. Synth. IV:887 (1963). f. M. D. Soffer, M. P. Bellis, H. E. Gellerson, and R. A. Stewart, Org. Synth. IV:903 (1963).

Reduction of alkynes with sodium in ammonia,147 lithium in low-molecular-weight amines,148 or sodium in hexamethylphosphoric triamide containing t-butanol as a proton source149 leads to the corresponding E-alkene. The reaction is assumed to involve successive electron-transfer and proton-transfer steps. e–

R ..

C

. C

S

R

H

R C H

C

e–

.

CR

R

..

RC

R C H

C R

S

H

R

H C

H

C R

147. K. N. Campbell and T. L. Eby, J. Am. Chem. Soc. 63:216, 2683 (1941); A. L. Henne and K. W. Greenlee, J. Am. Chem. Soc. 65:2020 (1943). 148. R. A. Benkeser, G. Schroll, and D. M. Sauve, J. Am. Chem. Soc. 77:3378 (1955). 149. H. O. House and E. F. Kinloch, J. Org. Chem. 39:747 (1974).

296

5.5.2. Reductive Removal of Functional Groups

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

The reductive removal of halogen can be accomplished with lithium or sodium. Tetrahydrofuran containing t-butanol is a useful reaction medium. Good results have also been achieved with polyhalogenated compounds by using sodium in ethanol. Cl Cl

O2CCH3

Cl Cl Cl

OH Na, C2H5OH

70%

Ref. 150

Cl

An important synthetic application of this reaction is in dehalogenation of dichloro- and dibromocyclopropanes. The dihalocyclopropanes are accessible via carbene addition reactions (see Section 10.2.3). Reductive dehalogenation can also be used to introduce deuterium at a speci®c site. Some examples of these types of reactions are given in Scheme 5.9. The mechanism of the reaction presumably involves electron transfer to form a radical anion, which then fragments with loss of a halide ion. The resulting radical is reduced to a carbanion by a second electron transfer and subsequently protonated. R

X

e–

R

⋅ X–

–X–

R⋅

e–



R:

S—H

R

H

Phosphate groups can also be removed by dissolving-metal reduction. Reductive removal of vinyl phosphate groups is one of the better methods for conversion of a carbonyl compound to an alkene.151 The required vinyl phosphate esters are obtained by phosphorylation of the enolate with diethyl phosphorochloridate or N,N ,N 0 ,N 0 -tetramethyldiamidophosphorochloridate.152 O

OPO(X)2

RCH2CR′

LiNR2 (X)2POCl

RCH

CR′

Li, RNH2 t-BuOH

RCH

CHR′

X = OEt or NMe2

Reductive removal of oxygen from aromatic rings can also be achieved by reductive cleavage of aryl diethyl phosphate esters. O CH3

OP(OC2H5)2 OCH3

K, NH3

CH3

77%

Ref. 153

OCH3

There are also examples where phosphate esters of saturated alcohols are reductively deoxygenated.154 Mechanistic studies of the cleavage of aryl dialkyl phosphates have 150. 151. 152. 153. 154.

B. V. Lap and M. N. Paddon-Row, J. Org. Chem. 44:4979 (1979). R. E. Ireland and G. P®ster, Tetrahedron Lett. 1969:2145. R. E. Ireland, D. C. Muchmore, and U. Hengartner, J. Am. Chem. Soc. 94:5098 (1972). R. A. Rossi and J. F. Bunnett, J. Org. Chem. 38:2314 (1973). R. R. Muccino and C. Djerassi, J. Am. Chem. Soc. 96:556 (1974).

Scheme 5.9. Reductive Dehalogenation and Deoxygenation

297

A. Dehalogenation 1a

Mg

Cl 2b

H

i-PrOH

OCH3

CH3O

SECTION 5.5. DISSOLVING-METAL REDUCTIONS

OCH3

CH3O

Cl

Cl

Na, t-BuOH THF

Cl

40%

Cl

3c

Cl Cl

Cl

Cl

Na, t-BuOH THF

Cl

69%

Cl

4d

Cl C2H5MgBr

Ph

Cl

Ti(O-i-Pr)4

Cl

10%

Ph

B. Deoxygenation O

5e

OP(OC2H5)2 (CH3)2C

H Li C2H5NH2

CH3

(CH3)2C CH3

CH3

CH3

(CH3O)2CH

(CH3O)2CH O

6f (CH3)2CH

OH

ClP(OC2H5)2

Ti(0)

(CH3)2CH

92%

7g O OP(OC2H5)2 a. b. c. d.

Li, NH3 85%

D. Bryce-Smith and B. J. Wake®eld, Org. Synth. 47:103 (1967). P. G. Gassman and J. L. Marshall, Org. Synth. 48:68 (1968). B. V. Lap and M. N. Paddon-Row, J. Org. Chem. 44:4979 (1979). J. R. Al Dulayymi, M. S. Baird, I. G. Bolesov, V. Tversovsky, and M. Rubin, Tetrahedron Lett. 37:8933 (1996). e. S. C. Welch and T. A. Valdes, J. Org. Chem. 42;2108 (1977). f. S. S. Welch and M. E. Walter, J. Org. Chem. 43:4797 (1978). g. M. R. Detty and L. A. Paquette, J. Am. Chem. Soc. 99:821 (1977).

298 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

indicated that the crucial C O cleavage occurs after transfer of two electrons.155 O ArOP(OC2H5)2

2e–

[ArOPO(OEt)2]2–

Ar– + (EtO)2PO2–

For preparative purposes, titanium metal can be used in place of sodium or lithium in liquid ammonia for both the vinyl phosphate156 and aryl phosphate157 cleavages. The titanium metal is generated in situ from TiCl3 by reduction with potassium metal in THF. Both metallic zinc and aluminum amalgam are milder reducing agents than the alkali metals. These reductants selectively remove oxygen and sulfur functional groups a to carbonyl groups. The mechanistic picture which seems most generally applicable is a net two-electron reduction with expulsion of the oxygen or sulfur substituent as an anion. The reaction seems to be a concerted process because the isolated functional groups are not reduced under these conditions. –O

O

Zn: R

C

CHR

R

O

C

CHR

S—H

RCCH2R

OAc

Another useful reagent for reduction of a-acetoxyketones and similar compounds is samarium diiodide.158 SmI2 is a strong one-electron reducing agent, and it is believed that the reductive elimination occurs after a net two-electron reduction of the carbonyl group. O–

O SmI2

RCCHR′ O2CR′′

OH

RCCHR′ ⋅ O2CR′′

H+

OH

OH

RCCHR′ ⋅ O2CR′′

SmI2

RC

RCCHR′ – ⋅⋅ O2CR′′

CHR′

These conditions were used, for example, in the preparation of the anticancer compound 10-deacetoxytaxol. CH3CO2 O

O OH

HO

OH SmI2

HO Ref. 159

THF

HO Ph

O AcO O

HO O

Ph

O AcO

O

O

The reaction is also useful for deacetoxylaton or dehydroxylation of a-oxygenated lactones derived from carbohydrates.160 (See entires 9 and 10 in Scheme 5.10.) Some other examples of this type of reaction are given in Scheme 5.10. Vinylogous oxygen 155. 156. 157. 158. 159. 160.

S. J. Shafer, W. D. Closson, J. M. F. vanDijk, O. Piepers, and H. M. Buck, J. Am. Chem. Soc. 99:5118 (1977). S. C. Welch and M. E. Walters, J. Org. Chem. 43:2715 (1978). S. C. Welch and M. E. Walters, J. Org. Chem. 43:4797 (1978). G. A. Molander and G. Hahn, J. Org. Chem. 51:1135 (1986). R. A. Holton, C. Somoza, and K.-B. Chai, Tetrahedron Lett. 35:1665 (1994). S. Hanessian, C. Girard, and J. L. Chiara, Tetrahedron Lett. 33:573 (1992).

substituents are also subject to reductive elimination by zinc or aluminum amalgam (see entry 8 in Scheme 5.10). 5.5.3. Reductive Carbon±Carbon Bond Formation Because reductions by metals often occur as one-electron processes, radicals are involved as intermediates. When the reaction conditions are adjusted so that coupling competes favorably with other processes, the formation of a carbon±carbon bond can occur. The reductive coupling of acetone to form 2,3-dimethyl-2,3-butanediol (pinacol) is an example of such a process. (CH3)2CO

Mg–Hg

(CH3)2C

Ref. 161

C(CH3)2

HO

OH

Reduced forms of titanium are currently the most versatile and dependable reagents for reductive coupling of carbonyl compounds. Depending on the reagent used, either diols or alkenes can be formed.162 One reagent for effecting diol formation is a combination of TiCl4 and magnesium amalgam.163 The active reductant is presumably titanium metal formed by reduction of TiCl4 . OH O

Mg–Hg

95%

TiCl4

HO O

H3C

O

CH3CCH2CH2CCH3

OH

Mg–Hg

81%

TiCl4

H3C

OH

Good yields of pinacols from aromatic aldehydes and ketones are obtained by adding catechol to the TiCl3 ±Mg reagent prior to the coupling.164 O PhCCH3

OH OH TiCl3, Mg THF, catechol

PhC

CPh

95%

CH3 CH3

Pinacols are also obtained using TiCl3 in conjunction with Zn±Cu as the reductant.165 This reagent is capable of forming normal, medium, and large rings with comparable ef®ciency. The macrocyclization has proven useful in the formation of a number of natural products.166 (See entry 3 in Scheme 5.11.) 161. 162. 163. 164. 165. 166.

R. Adams and E. W. Adams, Org. Synth. I:448 (1932). J. E. McMurry, Chem. Rev. 89:1513 (1989). E. J. Corey, R. L. Danheiser, and S. Chandrashekaran, J. Org. Chem. 41:260 (1976). N. Balu, S. K. Nayak, and A. Banerji, J. Am. Chem. Soc. 118:5932 (1996). J. E. McMurry and J. G. Rico, Tetrahedron Lett. 30:1169 (1989). J. E. McMurry, J. G. Rico, and Y. Shih, Tetrahedron Lett. 30:1173 (1989); J. E. McMurry and R. G. Dushin, J. Am. Chem. Soc. 112:6942 (1990).

299 SECTION 5.5. DISSOLVING-METAL REDUCTIONS

Scheme 5.10. Reductive Removal of Functional Groups from a-Substituted Carbonyl Compounds

300 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

1a

CH3

CH3 Zn (CH3CO)2O

63%

O

O O2CCH3

2b

CH3

O

CH3

O Ca NH3

80%

CH3CO2 3c

O

O Zn, HCl CH3CO2H

75%

OH H3C OSO2CH3 O

4d

CH3 O Zn NH4Cl

CH3 5e

CH3 O

H3C O

O H3C

O

H3C O H3C

Al–Hg

CH3

O

O

6f

CH3 O

O CH3

CH3

O

CH3

CH3

Ph

CH3

Ph

(CH3)3CSi

O

O

(CH3)3CSi

Ph

CH3 O

O

Ph

7g

O

75%

O Al–Hg

CH3O

8h

H11C5

CCH2SO2CH3

CH3O

H11C5

H

CCH3

98%

H

Zn

H O

N

N H H O

CO2CH3

CO2H

CO2CH3

Scheme 5.10. (continued ) 9i

Ph

301 SECTION 5.5. DISSOLVING-METAL REDUCTIONS

H

O

H

SmI2

O

90%

O CH3 CH3 10j

O

O

O

O

SmI2

O2CCH3

O

O

O

O Ph

Ph a. b. c. d. e. f. g. h. i. j.

R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, and W. M. McLamore, J. Am. Chem. Soc. 74:4223 (1952). J. A. Marshall and H. Roebke, J. Org. Chem. 34:4188 (1969). A. C. Cope, J. W. Barthel, and R. D. Smith, Org. Synth. IV:218 (1963). T. Ibuka, K. Hayashi, H. Minakata, and Y. Inubushi, Tetrahedron Lett. 1979:159. E. J. Corey, E. J. Trybulski, L. S. Melvin, Jr., K. C. Nicolaou, J. A. Secrist, R. Lett, P. W. Sheldrake, J. R. Falck, D. J. Brunelle, M. F. Haslanger, S. Kim, and S. Yoo, J. Am. Chem. Soc. 100:4618 (1978). P. A. Grieco, E. Williams, H. Tanaka, and S. Gilman, J. Org. Chem. 45:3537 (1980). E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc. 86:1639 (1964). L. E. Overman and C. Fukaya, J. Am. Chem. Soc. 102:1454 (1980). J. Castro, H. Sorensen, A. Riera, C. Morin, C. Morin, A. Moyano, M. A. Percias, and A. E. Green, J. Am. Chem. Soc. 112:9338 (1990). S. Hanessian, C. Girard, and J. L. Chiara, Tetrahedron Lett. 33:573 (1992).

Titanium metal generated by stronger reducing agents, such as LiAlH4 , or lithium or potassium metal, results in complete removal of oxygen with formation of an alkene.167 A particularly active form of Ti is obtained by reducing TiCl3 with lithium metal and then treating the reagent with 25 mol % of I2 .168. This reagent is especially reliable when prepared form TiCl3 puri®ed as a DME complex.170 A version of titanium-mediated reductive coupling in which TiCl3 Zn Cu serves as the reductant is ef®cient in closing large rings.

O

CH(CH2)12CH

O

TiCl2 Zn–Cu

71%

Ref. 171

Alkenes as large as 36-membered macrocycles have been prepared using the TiCl3 ±Zn±Cu combination.169 Alkene formation can also be achieved using potassium=graphite …C8 K† or sodium naphthalenide for reduction.172 The reductant prepared in this way is more ef®cient at 167. J. E. McMurry and M. P. Fleming; J. Org. Chem. 41:896 (1976); J. E. McMurry and L. R. Krepski, J. Org. Chem. 41:3929 (1976); J. E. McMurry, M. P. Fleming, K. L. Kees, and L. R. Krepski, J. Org. Chem. 43:3255 (1978); J. E. McMurry, Acc. Chem. Res. 16:405 (1983). 168. S. Talukdar, S. K. Nayak, and A. Banerji, J. Org. Chem. 63:4925 (1998). 169. T. Eguchi, T. Terachi, and K. Kakinuma, Tetrahedron Lett. 34:2175 (1993). 170. J. E. McMurry, T. Lectka, and J. G. Rico, J. Org. Chem. 54:3748 (1989). 171. J. E. McMurry, J. R. Matz, K. L. Kees, and P. A. Bock, Tetrahedron Lett. 23:1777 (1982). 172. D. L. J. Clive, C. Zhang, K. S. K. Murthy, W. D. Hayward, and S. Daigneault, J. Org. Chem. 56:6447 (1991).

Scheme 5.11. Reductive Carbon±Carbon Bond Formation

302 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

A. Pinacol formation 1a

H

H 1) Mg–Al/(CH3)2SiCl2

75%

2) –OH

O

CH2CH

HO

O

HO 2b

HO

Mg–Hg

O

93%

TiCl4

OH 3c OH O O

OH TiCl3

CHCH2

58%

Zn–Cu

O O

O

O

B. Alkene formation 4d O

5d

TiCl3 K

86%

Ph

Ph O

TiCl3

80%

Zn–Cu

(CH2)3CH

O

C. Acyloin formation O 6f

CH3O2C(CH2)8CO2CH3

1) Na, xylene 70%

2) CH3CO2H

OH O 7g

C2H5O2CH2CH2CO2C2H5

1) Na, (CH3)3SiCl 85%

2) CH3OH

OH OH 8h

CH3(CH2)6CO2C2H5

Na/NaCl benzene

CH3(CH2)6CHC(CH2)6CH3

78%

O a. b. c. d. e. f. g. h.

E. J. Corey and R. L. Carney, J. Am. Chem. Soc. 93:7318 (1971). E. J. Corey, R. L. Danheiser, and S. Chandrasekaran, J. Org. Chem. 41:260 (1976). J. E. McMurry and R. G. Dushin, J. Am. Chem. Soc. 112:6942 (1990). J. E. McMurry, M. P. Fleming, K. L. Kees, and L. R. Krepski, J. Org. Chem. 43:3255 (1978). C. B. Jackson and G. Pattenden, Tetrahedron Lett. 26:3393 (1985). N. L. Allinger, Org. Synth. IV:840 (1963). J. J. Bloom®eld and J. M. Nelke, Org. Synth. 57:1 (1977). M. Makosza and K. Grela, Synlett 1997:267.

303

coupling reactants with several oxygen substituents. OC(CH3)3 (C2H5)3SiO

OC(CH3)3 OSi(Ph2)C(CH3)3

H

CH3

(C2H5)3SiO

OSi(Ph2)C(CH3)3 H

CH3

TiCl3 C8K

O

CH

O

Both unsymmetrical diols and alkenes can be prepared by applying these methods to mixtures of two different carbonyl compounds. An excess of one component can be used to achieve a high conversion of the more valuable reactant. A mixed reductive deoxygenation using TiCl4 =Zn has been used to prepare 4-hydroxytamoxifen, the active antiestrogenic metabolite of tamoxifen. O

O HO

C

C2H5 TiCl4 Zn

O(CH2)2N(CH3)2 +

Ref. 173 HO C2H5

(CH3)2N(CH2)2O

26%

The mechanism of the titanium-mediated reductive couplings is presumably similar to that of reduction by other metals, but titanium is uniquely effective in reductive coupling of carbonyl compounds. The strength of Ti O bonds is probably the basis for this ef®ciency. Titanium-mediated reductive couplings are normally heterogeneous, and it is likely that the reaction takes place at the metal surface.174 The partially reduced intermediates are probably bound to the metal surface, and this may account for the effectiveness of the reaction in forming medium and large rings. R

C

R

O 0

Ti

Ti0

R

C

R

R

⋅ R C

O

O–

Ti0

1+

Ti

R

⋅ R C O–

Ti0

Ti1+

R

R

R

C

C

–O

O–

R R

Ti1+ Ti1+ Ti0

R C

R

C R

O

O

Ti2+ Ti2+ Ti0

Samarium diiodide is another powerful one-electron reducing agent that can effect carbon±carbon bond formation under appropriate conditions.175 Aromatic aldehydes and 173. S. Gauthier, J. Mailhot, and F. Labrie, J. Org. Chem. 61:3890 (1996). 174. R. Dams, M. Malinowski, I. Westdrop, and H. Y. Geise, J. Org. Chem. 47:248 (1982). 175. G. A. Molander, Org. React. 46:211 (1994); J. L. Namy, J. Souppe, and H. B. Kagan, Tetrahedron Lett. 24:765 (1983); A. Lebrun, J.-L. Namy, and H. B. Kagan, Tetrahedron Lett. 34:2311 (1993); H. Akane, T. Hatano, H. Kusui, Y. Nishiyama, and Y. Ishii, J. Org. Chem. 59:7902 (1994).

SECTION 5.5. DISSOLVING-METAL REDUCTIONS

304

aliphatic aldehydes and ketones undergo pinacol-type coupling, with SmI2 or SmBr2.

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

R′ R′ SmI2

RCR′

RC

CR

OH OH

O SmI2

ArCH O

Ar CH OH

CHAr OH

d-Ketoaldehydes and d-diketones are reduced to cis-cyclopentanediols.176 e-Diketo compounds can be cyclized to cyclohexanediols, again with a preference for cisdiols.177 These reactions are believed to occur through successive one-electron transfer, radical coupling, and a second electron transfer with Sm2‡ serving as a template and Lewis acid. Sm2+ O

O–

O

R

R

R

Sm3+ O–

O



Sm3+ O⋅

O– e–

Sm3+ O–

R

Many of the compounds used have additional functional groups, including ester, amide, ether, and acetal. These groups may be involved in coordination to samarium and thereby in¯uence the stereoselectivity of the reaction. The ketyl intermediates in SmI2 reductions can also be trapped by carbon±carbon double bonds, leading to cyclization of d,e-enones to cyclopentanols. O CH2

HO

CCH3

CH(CH2)3CCO2C2H5

SmI2

H3C

R

CH3 CO2C2H5

Ref. 178

R

O

OH CH2CO2CH3 (CH2)2CH

CHCO2CH3

SmI2 87%

Ref. 179

H

SmI2 has also been used to form cyclooctanols by cyclization of 7,8-enones.180 These alkene addition reactions all presumably proceed by addition of the ketyl radical to the 176. G. A. Molander and C. Kemp, J. Am. Chem. Soc. 111:8236 (1989); J. Uenishi, S. Masuda, and S. Wakabashi, Tetrahedron Lett. 32:5097 (1991). 177. J. L. Chiara, W. Cabri, and S. Hanessian, Tetrahedron Lett. 32:1125 (1991); J. P. Guidok, T. Le Gall, and C. Mioskowski, Tetrahedron Lett. 35:6671 (1994). 178. G. Molander and C. Kenny, J. Am. Chem. Soc. 111:8236 (1989). 179. E. J. Enholm and A. Trivellas, Tetrahedron Lett. 30:1063 (1989). 180. G. A. Molander and J. A. McKie, J. Org. Chem. 59:3186 (1994).

305

double bond, followed by a second electron transfer.

SECTION 5.5. DISSOLVING-METAL REDUCTIONS

CH2⋅ O–

O RC(CH2)nCH CH2

O–

RC(CH 2)nCH CH2 ×



O

⋅ or

R

R

(CH2)n

(CH2)n–1

CH2Sm O–

O– Sm

R

R

(CH2)n

(CH2)n–1

The initial products of such additions under aprotic conditions are organosamarium reagents, and further (tandem) transformations are possible, including addition to ketones, anhydrides, and carbon dioxide. HO

CH3

O CH3C(CH2)3CH

CH2

CH2

1) SmI2

OH

Ref. 181

80%

2) cyclohexanone

Another reagent which has found use in pinacolic coupling is prepared from VCl3 and zinc dust.182 This reagent is selective for aldehydes that can form chelated intermediates, such as b-formyl amides, a-amido aldehydes, a-phosphinoyl aldehydes,183 and g-keto aldehydes.184 It can be used for both homodimerization and heterodimerization. In the latter case, the more reactive aldehyde is added to an excess of the second aldehyde. Under these conditions, the ketal formed from the chelated aldehyde reacts with the second aldehyde. R′ R

CH X

O V2+

⋅ CH

R

O–

X V3+

R R′CH

CH

O

O–

X V3+

R′ O⋅

R

O–

CH

V2+

O–

X V3+

OH R

R′ X

OH

Another important reductive coupling is the conversion of esters to a-hydroxyketones (acyloins).185 This reaction is usually carried out with sodium metal in an inert solvent. 181. 182. 183. 184. 185.

G. A. Molander and J. A. McKie, J. Org. Chem. 57:3132 (1992). J. H. Freudenberg, A. W. Konradi, and S. F. Pedersen, J. Am. Chem. Soc. 111:8014 (1989). J. Park and S. F. Pedersen, J. Org. Chem. 55:5924 (1990). A. S. Raw and S. F. Pederson, J. Org. Chem. 56:830 (1991). J. J. Bloom®eld, D. C. Owsley, and J. M. Nelke, Org. React. 23:259 (1976).

306 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Good results have also been reported for sodium metal dispersed on solid supports.186 Diesters undergo intramolecular reactions, and this is also an important method for preparation of medium and large carbocyclic rings. O 1) Na

CH3O2C(CH2)8CO2CH3

Ref. 187

2) CH3CO2H

OH

There has been considerable discussion of the mechanism of the acyloin condensation. A simple formulation of the mechanism envisages coupling of radicals generated by one-electron transfer. O–

O RCOR′ + Na⋅

O RC

RCOR′ ⋅

–O

O–

O

RC

CR

RC

R′O

OR′

–O

O CR + 2 Na⋅

O–

RC

CR

O CR

O H+

RCCHR OH

An alternative mechanism bypasses the postulated a-diketone intermediate since its involvement is doubtful.188 O– RCO2R′ + Na×

RCOR′ ⋅

OR′ RCO2R¢

RC⋅

OR′ O

CR

OR′ Na×

RC –

OR′ O

O–

O–

OR′ RC O

OR′ CR O–

CR

Na

RC

⋅ CR

–O

O–

Na⋅

OR′ O– RC

CR –

–O

O–

RC

CR

–O

Regardless of the details of the mechanism, the product prior to neutralization is the dianion of the ®nal a-hydroxy ketone, namely, an enediolate. It has been found that the overall yields are greatly improved if trimethylsilyl chloride is present during the reduction to trap these dianions as trimethylsilyl ethers.189 These derivatives are much more stable under the reaction conditions than the enediolates. Hydrolysis during workup gives the acyloin product. This modi®ed version of the reaction has been applied to cyclizations leading to small, medium, and large rings, as well as to intermolecular couplings. A few examples of acyloin formation from esters are given in Scheme 5.11. 186. M. Makosza and K. Grela, Synlett. 1997:267; M. Makosza, P. Nieczypor, and K. Grela, Tetrahedron 54:10827 (1998). 187. N. Allinger, Org. Synth. IV:840 (1963). 188. J. J. Bloom®eld, D. C. Owsley, C. Ainsworth, and R. E. Robertson, J. Org. Chem. 40:393 (1975). 189. K. Ruhlmann, Synthesis 1971:236.

307

5.6. Reductive Deoxygenation of Carbonyl Groups Several methods are available for reductive removal of carbonyl groups form organic molecules. Complete reduction to methylene groups or conversion to alkenes can be achieved. Some examples of both types of reactions are given in Scheme 5.12. Zinc and hydrochloric acid is a classical reagent combination for conversion of carbonyl groups to methylene groups. The reaction is known as the Clemmensen reduction.190 The corresponding alcohols are not reduced under the conditions of the reaction, so they are evidently not intermediates. The Clemmensen reaction works best for aryl ketones and is less reliable with unconjugated ketones. The mechanism is not known in detail, but it most likely involves formation of carbon±zinc bonds at the metal surface.191 The reaction is commonly carried out in hot concentrated hydrochloric acid with ethanol as a co-solvent. These conditions preclude the presence of acid-sensitive or hydrolyzable functional groups. A modi®cation in which the reaction is run in ether saturated with dry hydrogen chloride gave good results in the reduction of steroidal ketones.192 The Wolf±Kishner reaction193 is the reduction of carbonyl groups to methylene groups by base-catalyzed decomposition of the hydrazone of the carbonyl compound. Alkyldiimides are believed to be formed and then collapse with loss of nitrogen.

R2C

N



NH2 + OH

R2C

N



NH

R2C N H

N

H

–N2

R2CH2

The reduction of tosylhydrazones by LiAlH4 or NaBH4 also converts carbonyl groups to methylene groups.194 It is believed that a diimide is involved, as in the Wolff±Kishner reaction.

R2C

NNHSO2Ar

NaBH4

H H R2CHN N

SO2Ar ⋅

R2CHN

NH

R2CH2

Excellent yields can also be obtained by using NaBH3 CN as the reducing agent.195 The NaBH3CN can be added to a mixture of the carbonyl cmpound and p-toluensulfonylhydrazide. Hydrazone formation is faster than reduction of the carbonyl group by NaBH3CN, and the tosylhydrazone is reduced as it is formed. Another reagent which can reduce tosylhydrazones to give methylene groups is CuBH4 …PPh3 †2 .196 Reduction of tosylhydrazones of a,b-unsaturated ketones by NaBH3 CN gives alkenes with double bond located between the former carbonyl carbon and the a carbon.197 This reaction is believed to proceed by an initial conjugate reduction, followed by decomposi190. 191. 192. 193. 194. 195. 196. 197.

E. Vedejs, Org. React. 22:401 (1975). M. L. Di Vona and V. Rosnati, J. Org. Chem. 56:4269 (1991). M. Toda, M. Hayashi, Y. Hirata, and S. Yamamura, Bull. Chem. Soc. Jpn. 45:264 (1972). D. Todd, Org. React. 4:378 (1948); Huang-Minlon, J. Am. Chem. Soc. 68:2487 (1946). L. Caglioti, Tetrahedron 22:487 (1966). R. O. Hutchins, C. A. Milewski, and B. E. Maryanoff, J. Am. Chem. Soc. 95:3662 (1973). B. Milenkov and M. Hesse, Helv. Chim. Acta 69:1323 (1986). R. O. Hutchins, M. Kacher, and L. Rua, J. Org. Chem. 40:923 (1975).

SECTION 5.6. REDUCTIVE DEOXYGENATION OF CARBONYL GROUPS

Scheme 5.12. Carbonyl-to=Methylene Reductions

308 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

A. Clemmensen 1a

OH

OH

OCH3

OCH3 Zn (Hg) HCl

CH 2b

60–67%

O

CH3

OH

OH CO(CH2)5CH3

CH2(CH2)5CH3

Zn (Hg) HCl

81–86%

B. Wolff–Kishner 3c 4d

HO2C(CH2)4CO(CH2)4CO2H Ph

C

Ph

KOC(CH3)3

NH2NH2

PhCH2Ph

DMSO

HO2C(CH2)9CO2H

KOH

87–93%

90%

NNH2 C. Tosylhydrazone reduction 5e

CH

NNHSO2C7H7

CH3 LiAlH4

6f (CH3)3C

O

7g

C7H7SO2NHNH2 NaBH3CN

(CH3)3C

O

CO2C2H5

70%

BH

77%

CO2C2H5

O

67%

TsNHN D. Thioketal desulfurization 8h

S S H5C2O2C

CO2C2H5

Raney Ni

H5C2O2C

CO2C2H5

S S 9i

H3C

O

CH3 1) HSCH2CH2SH, BF3 2) Raney Ni

(CH3)2CH a. b. c. d. e. f. g. h. i.

CH3

58%

(CH3)2CH

CH3

R. Schwarz and H. Hering, Org. Synth. IV:203 (1963). R. R. Read and J. Wood Jr., Org. Synth. III:444 (1955). L. J. Durham, D. J. McLeod, and J. Cason, Org. Synth. IV:510 (1963). D. J. Cram, M. R. V. Sahyun, and G. R. Knox, J. Am. Chem. Soc. 84:1734 (1962). L. Caglioti and M. Magi, Tetrahedron 19:1127 (1963). R. O. Hutchins, B. E. Maryanoff, and C. A. Milewski, J. Am. Chem. Soc. 93:1793 (1971). M. N. Greco and B. E. Maryanoff, Tetrahedron Lett. 33:5009 (1992). J. D. Roberts and W. T. Moreland Jr., J. Am. Chem. Soc. 75:2167 (1953). P. N. Rao, J. Org. Chem. 36:2426 (1971).

309

tion of the resulting vinylhydrazine to a vinyldiimide. NNHSO2Ar RCH

NHNHSO2Ar NaBH3CN

CHCR′

RCH2CH

N

CR′

RCH2CH

SECTION 5.6. REDUCTIVE DEOXYGENATION OF CARBONYL GROUPS

NH

CR′

–N2

RCH2CH

CHR′

Catecholborane or sodium borohydride in acetic acid can also be used as reducing reagents in this reaction.198 Ketones can also be reduced to alkenes via enol tri¯ates. The use of Pd…OAc†2 , triphenylphosphine as the catalyst, and tertiary amines as the hydrogen donors is effective.199 H3C

H3C

N CO2CH3

N

Pd(O2CCH3)2, PPh3

CO2CH3

(C2H5)3N, HCO2H

Ref. 200

O3SCF3

Carbonyl groups can be converted to methylene groups by desulfurization of thioketals. The cyclic thioketal from ethanedithiol is commonly used. Reaction with excess Raney nickel causes hydrogenolysis of both C S bonds. H3C H3C H3C

H3C BF3 HSCH2CH2SH

O

H3C

H3C H3C

S S

Ni

Ref. 201

H3C H3C

81%

Other reactive forms of nickel including nickel boride202 and nickel alkoxide complexes203 can also be used for desulfurization. Tri-n-butyltin hydride is an alternative reagent for desulfurization.204 The conversion of ketone p-toluenesulfonylhydrazones to alkenes takes place on treatment with strong bases such as an alkyllithium or lithium dialkylamide.205 This is known as the Shapiro reaction.206 The reaction proceeds through the anion of a vinyldiimide, which decomposes to a vinyllithium reagent. Contact of this intermediate 198. G. W. Kabalka, D. T. C. Yang, and J. D. Baker, Jr., J. Org. Chem. 41:574 (1976); R. O. Hutchins and N. R. Natale, J. Org. Chem. 43:2299 (1978). 199. W. J. Scott and J. K. Stille, J. Am. Chem. Soc. 108:3033 (1986); L. A. Paquette, P. G. Meiser, D. Friedrich, and D. R. Sauer, J. Am. Chem. Soc. 115:49 (1993). 200. K. I. Keverline, P. Abraham, A. H. Lewin, and F. I. Carroll, Tetrahedron Lett. 36:3099 (1995). 201. F. Sondheimer and S. Wolfe, Can. J. Chem. 37:1870 (1959). 202. W. E. Truce and F. M. Perry, J. Org. Chem. 30:1316 (1965). 203. S. Becker, Y. Fort, and P. Caubere, J. Org. Chem. 55:6194 (1990). 204. C. G. Guiterrez, R. A. Stringham, T. Nitasaka, and K. G. Glasscock, J. Org. Chem. 45:3393 (1980). 205. R. H. Shapiro and M. J. Health, J. Am. Chem. Soc. 89:5734 (1967). 206. R. H. Shapiro, Org. React. 23:405 (1976); R. M. Adington and A. G. M. Barrett, Acc. Chem. Res. 16:53 (1983); A. R. Chamberlin and S. H. Bloom, Org. React. 39:1 (1990).

310 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

with a proton source gives the alkene. Li+ NNSO2Ar

NNHSO2Ar 2 RLi

RCCH2R′

N –LiSO2Ar

RCCHR′

RC

N– Li+ CHR′

Li –N2

RC

CHR′

Li

The Shapiro reaction has been particularly useful for cyclic ketones, but the scope of the reaction also includes acyclic systems. In the case of unsymmetrical acyclic ketones, questions of both regiochemistry and stereochemistry arise. 1-Octene is the exclusive product from 2-octanone.207 H C7H7SO2NN CH3C(CH2)5CH3

2 LiNR2

CH2

CH(CH2)5CH3

This regiospeci®city has been shown to depend on the stereochemistry of the CˆN bond in the starting hydrazone. There is evidently a strong preference for abstracting the proton syn to the arenesulfonyl group, probably because this permits chelation with the lithium ion. ArSO2N–

ArSO2N– N

N

Li

CH3CCH2R

CH2CCH2R

H+

CH2

CHCH2R

The Shapiro reaction converts the p-toluenesulfonylhydrazones of a,b-unsaturated ketones to dienes (see entries 3±5 in Scheme 5.13).208

5.7. Reductive Elimination and Fragmentation The placement of a potential leaving group b to the site of carbanionic character usually leads to b elimination.

2e–

X

Y

X– +

+ Y–

Similarly, carbanionic character d to a leaving group can lead to b,g-fragmentation.

2e–

X

Y

X– +

+

+ Y–

In some useful synthetic procedures, the carbanionic character results from a reductive process. A classical example of the b-elimination reaction is the reductive debromination of vicinal dibromides. Zinc metal is the traditional reducing agent.209 A multitude of other 207. K. J. Kolonko and R. H. Shapiro, J. Org. Chem. 43:1404 (1978). 208. W. G. Dauben, G. T. Rivers, and W. T. Zimmerman, J. Am. Chem. Soc. 99:3414 (1977). 209. J. C. Sauer, Org. Synth. IV:268 (1965).

Scheme 5.13. Conversion of Ketones to Alkenes via Sulfonylhydrazones 1a

H3C

CH3

H3C

CH3

CH3Li

CH3

98–99%

CH3

NNHSO2C7H7

2b

H

H

NNHSO2C7H7 CH3Li

O

O H

O 3c

CH3

CH3

H

O

O 1) C7H7SO2NHNH2 2) CH3Li

H3C

CH3

CH3

100%

H3C

CH3

CH3

4d + NNHSO2C7H7 H3C

CH3Li

CH3

H3C

CH3

H3C

80%

5e

PhCH2O

9%

PhCH2O

CH3

CH3

1) C7H7SO2NHNH2

98%

2) LiN(i-Pr)2

H

O

H

CH3

CH2

CH3



6f

Li+ N

H NNSO2C7H7 35–55%

a. R. H. Shapiro and J. H. Duncan, Org. Synth. 51:66 (1971). b. W. L. Scott and D. A. Evans, J. Am. Chem. Soc. 94:4779 (1972). c. W. G. Dauben, M. E. Lorber, N. D. Vietmeyer, R. H. Shapiro, J. H. Duncan, and K. Tomer, J. Am. Chem. Soc. 90:4762 (1968). d. W. G. Dauben, G. T. Rivers and W. T. Zimmerman, J. Am. Chem. Soc. 99:3414 (1977). e. P. A. Grieco, T. Oguri, C.-L. J. Wang, and E. Williams, J. Org. Chem. 42:4113 (1977). f. L. R. Smith, G. R. Gream, and J. Meinwald, J. Org. Chem. 42:927 (1977).

311 SECTION 5.7. REDUCTIVE ELIMINATION AND FRAGMENTATION

Table 5.8. Reagents for Reductive Dehalogenation

312

Reagent

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

Anti stereoselectivity

Reference

Yes ? ? No Yes No

a b c d e f

Zn, cat. TiCl4 Zn, H2 NCSNH2 SnCl2 , DIBAlH Sm, CH3 OH Fe, graphite C2 H5 MgBr, cat. Ni…dppe†Cl2 a. b. c. d.

F. Sato, T. Akiyama, K. Iida, and M. Sato, Synthesis 1982:1025. R. N. Majumdar and H. J. Harwood, Synth. Commun. 11:901 (1981). T. Oriyama and T. Mukaiyama, Chem. Lett. 1984:2069. R. Yanada, N. Negoro, K. Yanada, and T. Fujita, Tetrahedron Lett. 37:9313 (1996). e. D. Savoia, E. Tagliavini, C. Trombini, and A. Umani-Ronchi, J. Org. Chem. 47:876 (1982). f. C. Malanga, L. A. Aronica, and L. Lardicci, Tetrahedron Lett. 36:9189 (1995).

reducing agents have been found to give this and similar reductive eliminations. Some examples are given in Table 5.8. Some of the reagents exhibit anti stereospeci®city while others do not. A stringent test for anti stereoselectivity is the extent of Z-alkene formation from a syn precursor. X

X R′

R

R′

R

Y

R

R′

Y

Anti stereospeci®city is associated with a concerted reductive elimination, whereas singleelectron transfer±fragmentation leads to loss of stereospeci®city. E–

X R′

R Y



e–

R′

R Y



R′

R Y

R′

e–

R

Because vicinal dibromides are usually made by bromination of alkenes, their utility for synthesis is limited, except for temporary masking of a double bond. Much more frequently, it is desirable to convert a diol to an alkene. Several useful procedures have been developed. The reductive deoxygenation of diols via thiocarbonates was developed by Corey and co-workers.210 Triethyl phosphite is useful for many cases, but the more reactive reductant 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine can be used when milder conditions are required.211 The reaction presumably occurs by initial P S bonding

210. E. J. Corey and R. A. E. Winter, J. Am. Chem. Soc. 85:2677 (1963); E. J. Cory, F. A. Cary, and R. A. E. Winter, J. Am. Chem. Soc. 87:934 (1965). 211. E. J. Corey and P. B. Hopkins, Tetrahedral Lett. 23:1979 (1982).

followed by a concerted elimination of carbon dioxide and the thiophosphoryl compound. R

R

O



PR3

S O

R

O P+R3

S

RCH

CHR + CO2 + S

PR3

O

R

Diols can also be deoxygenated via bis-sulfonate esters using sodium naphthalenide.212 Cyclic sulfate esters are also cleanly reduced by lithium naphthalenide.213 O CH3(CH2)5

SO2

Li powder

O

naphthalene

CH3(CH2)5CH

CH2

This reaction, using sodium naphthalenide, has been used to prepare unsaturated nucleosides. NH2

NH2

N HOCH2

O

O

N N

N

HOCH2

sodium naphthalenide

N

O

N

N

59%

Ref. 214

N

O SO2

It is not entirely clear whether these reactions involve a redox reaction at sulfur or proceed via organometallic intermediates.

Y 2e–

Y

O

O

O– –

S

Y– +

R

+ –O3SR

O

O S

R

O Y

M

Y– +

+ M+

Iodination reagents combined with aryl phosphines and imidazole can also effect reductive conversion of diols to alkenes. One such combination is 2,4,5-triiodoimidazole, imidazole, and triphenylphosphine.215 These reagent combinations are believed to give oxyphosphonium intermediates which then serve as leaving groups, forming triphenylphosphine oxide as in the Mitsunobu reaction (see Section 3.2.4). The iodide serves as both a 212. J. C. Carnahan, Jr., and W. D. Closson, Tetrahedron Lett. 1972:3447; R. J. Sundberg and R. J. Cherney, J. Org. Chem. 55:6028 (1990). 213. D. Guijarro, B. Mancheno, and M. Yus, Tetrahedron Lett. 33:5597 (1992). 214. M. J. Robbins, E. Lewandowska, and S. F. Wnuk, J. Org. Chem. 63:7375 (1998). 215. P. J. Garegg and B. Samuelsson, Synthesis 1979:813; Y. Watanabe, M. Mitani, and S. Ozaki, Chem. Lett. 1987:123.

313 SECTION 5.7. REDUCTIVE ELIMINATION AND FRAGMENTATION

314

nucleophile and a reductant.

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

OP+Ph3

OH RCH

CHR

RCH

CHR

I or

RCH

Ph3P+O

OH

I–

CHR

RCH

CHR

Ph3P+O

In a related procedure, chlorodiphenylphosphine, imidazole, iodine, and zinc cause reductive elimination of diols.216 b-Iodophosphinate esters can be shown to be intermediates in some cases. HO HO

I OCH2Ph O O

Ph2PCl, I2

OCH2Ph O

Ph2PO2

imidazole

CH2

CH

Zn

OCH2Ph O O

O O

O

O

Another alternative to conversion of diols to alkenes is the use of the Barton radical fragmentation conditions (see Section 5.4) with a silane hydrogen-atom donor.217 RCH CH3SCO

CHR OCSCH3

S

Et3SiH (PhCO2)2

RCH

CHR

S

The reductive elimination of b-hydroxysulfones is the ®nal step in the Julia±Lythgoe ole®n synthesis.218 The b-hydroxysulfones are normally obtained by an aldol addition. SO2R′′ RCH O + R′CH2SO2R′′

base

RCH

CHR′

2e–

RCH

CHR′′

HO

Several reducing agents have been used for the elimation, including sodium amalgam219 and samarium diiodide.220 The elimination can also be done by converting the hydroxy group to a xanthate or thiocarbonate and using radical fragmentation.221 Reductive elimination from 2-ene-1,4-diol derivatives has been used to generate 1,3dienes. Low-valent titanium generated from TiCl3 =LiAlH4 can be used directly with the 216. Z. Liu, B. Classon, and B. Samuelsson, J. Org. Chem. 55:4273 (1990). 217. D. H. R. Barton, D. O. Jang, and J. C. Jaszberenyi, Tetrahedron Lett. 32:2569 (1991); D. H. R. Barton, D. O. Jang and J. C. Jaszberenyi, Tetrahedron Lett. 32:7187 (1991). 218. P. Kocienski, Phosphorus Sulfur 24:97 (1985). 219. P. J. Kocienski, B. Lythgoe, and I. Waterhouse, J. Chem. Soc., Perkin Trans. 1 1980:1045; A. Armstrong, S. V. Ley, A. Madin, and S. Mukherjee, Synlett 1990:328; M. Kageyama, T. Tamura, M. H. Nantz, J. C. Roberts, P. Somfai, D. C. Whritenour, and S. Masamune, J. Am. Chem. Soc. 112:7407 (1990). 220. A. S. Kende and J. S. Mendoza, Tetrahedron Lett. 31:7105 (1990); I. E. Marko, F. Murphy, and S. Dolan, Tetrahedron Lett. 37:2089 (1996); G. E. Keck, K. A. Savin, and M. A. Weglarz, J. Org. Chem. 60:3194 (1995). 221. D. H. R. Barton, J. C. Jaszberenyi, and C. Tachdjian, Tetrahedron Lett. 32:2703 (1991).

diols. This reaction has been used successfully to create extended polyene conjugation.222

SECTION GENERAL REFERENCES

OH HO OTBDMS

OTBDMS

Benzoate esters of 2-ene-1,4-diols undergo reductive elimination with sodium amalgam.223 OSi(i-Pr)3

OSi(i-Pr)3

OTBDMS

(CH2)4OTBDMS C5H11

C5H11 PhCO2

(CH2)4OTBDMS

O2CPh OTBDMS

The b,g fragmentation is known as Grob fragmentation. Its synthetic application is usually in the construction of medium-sized rings by fragmentation of fused ring systems. O O

S O

O O

315

O Br

Na naphthalenide

Ref. 224

–78° to –40°C

OTBDMS

OTBDMS

General References R. L. Augustine, ed., Reduction Techniques and Applications in Organic Synthesis, Marcel Dekker, New York, 1968. M. Hudlicky, Reductions in Organic Chemistry, Halstead Press, New York, 1984.

Catalytic Reduction M. Freifelder, Catalytic Hydrogenation in Organic Synthesis, Procedures and Commentary, John Wiley & Sons, New York, 1978. B. R. James, Homogeneous Hydrogenation, John Wiley & Sons, New York, 1973. P. N. Rylander, Hydrogenation Methods, Academic Press, Orlando, Florida, 1985. P. N. Rylander, Hydrogenation in Organic Synthesis, Academic Press, New York, 1979. 222. G. Solladie, A. Givardin, and G. Lang, J. Org. Chem. 54:2620 (1989); G. Solladie and V. Berl, Tetrahedron Lett. 33:3477 (1992). 223. G. Solladie, A. Urbana, and G. B. Stone, Tetrahedron Lett. 34:6489 (1993). 224. W. B. Wang and E. J. Roskamp, Tetrahedral Lett. 33:7631 (1992).

316

Metal Hydrides

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

A. Hajos, Complex Hydrides and Related Reducing Agents in Organic Synthesis, Elsevier, New York, 1979. J. Malek, Org. React. 34:1 (1985); 36:249 (1988). J. Sayden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, VCH Publishers, New York, 1991.

Dissolving-Metal Reductions A. A. Akhrem, I. G. Rshetova, and Y. A. Titov, Birch Reduction of Aromatic Compounds, IFGI=Plenum, New York, 1972.

Problems (References for these problems will be found on page 929.) 1. Give the product(s) to be expected from the following reactions. Be sure to specify all facets of stereochemistry. (a) (CH3)2CHCH CHCH CHCO2CH3 (b) H3C

(i-Bu)2AlH

O LiHBt(Et)3 THF

(c)

(d)

H3C

NNHSO2Ar

O

CCH3

O

CH3 H

O O

(e)

BH

O

CH3 O

H O O Et3SiH CF3CO2H

OCH3

(i-Bu)2AlH

317

(f) LiAlH4

CH3

PROBLEMS

O

(g)

NaBH4

CHCH3

DMSO

Br

(h) H3C

H

CH3

CH3 CH2

C

C

H

CH3

C CHC

C

OH

CH2OH

C

H2, PdCO3 Pd(OAc)2, quinoline

CH3

(i) CH3 OCH2OCH3 CH3 CH3

S

(j)

O

CH CH

TsNHNH2 Et3N 180°C

O TiCl Zn–Cu

2. Indicate the stereochemistry of the major alcohol that would be formed by sodium borohydride reduction of each of the cyclohexanone derivatives shown: O

O

CH3

CH2CH3

(a)

CH3

(c)

C(CH3)3 O

O CH(CH3)2

(b)

CH(CH3)2

(d) H3C

H3C

H3C

3. Indicate reaction conditions that would accomplish each of the following transformations in one step. (a)

O

O

O

O

I

CH3CO2

CH2OCH3

CH3CO2

CH2OCH3

318

(b)

O

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

(c)

OH

O

O

O

O

O

N(CH3)2

(d)

O

OH H

H

H

H

(e)

C

N

CH

CH3O

O

CH3O

(f) CH3

O

CH3

O

O OH

CH3

O

CH3

O

O

O

O CH3

O

(g)

H3C

CH3 O

CH3 CH2CN

H3C

H3C

O

(h)

H

HO HO

CH3

O CH3

(i)

H

(j)

H

CH3

CH3

OCH2Ph

C2H5O

CH2CN

H3C

H

HO

CH3

OH CH3

CH3

CH3

CH3

CH2OPO[N(CH3)2]2 OC2H5

C2H5O

CH3 OC2H5

O O2N

CN(CH3)2

O2N

CH2N(CH3)2

(k)

319

O

PROBLEMS

H3C

H3C

CH3

CH3

CH3

CH3

(l)

O

(m)

O CO2CH3

(n)

O

CO2CH3 CH3

O C H3C

O

CH3

CCH3 CH3

CH3 HO

(o) O

O

H3C

(CH2)3C

C(CH2)3OTHP

O

O H

H3C

(CH2)3

(CH2)3OTHP C

C H

4. Predict the stereochemistry of the products from the following reactions and justify your prediction. (a)

O O CH3 O

O

(b)

H

CH3 C

O C

Ph

Ph

(c) H

KBH4 H2O

CH3 LiAlH4 Et2O

O LiBH(Et)3

H

(d) (CH3)2CH Pt, H2 ethanol

HO

CH3

(e)

H3C

O

O H2 (PPh3)3RhCl

H3C

CH3 O2CCH3

320

(f)

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

C(CH3)3 H2 Rh/Al2O3

H3C

CH3 OH

(g)

H2C O HO

H2, Pd

OCH3 HNCCH3 O

(h)

O

CH3

O

H2/Pd–C

O CH3

(i)

OCH2OCH3 PhCH2O

Zn(BH4)2

CH3OCH2O

(j)

O

OMe

CH3 P ]1+

[NBD Rh P

OH

(k) CH3(CH2)4C

CCH2OH

(l)

CH3 OH

LiAlH4 ether

Ir(COD)py]1+

[R3P

CH3

(m)

O PhCHCCH2CH3

L-Selectride

CH3

(n) H N [(C6H11)3P

N H CH3CO2

(o)

O

OCH3 OCH3

CH3O

Ir(COD)py]PF6

H2, CH2Cl2

TBDMSO

O

O2N

NOCH3 CH3 OCH3

O

CH3

CH3

CH3

CH3

ZnBH4

(p)

321

O

CH3

[(C6H11)3P

PROBLEMS

Ir(COD)py]PF6

H2, CH2Cl2

CH2Ph

(q)

CH2OCH3

O L-Selectride

PhCHCCH2CH3 CH3

5. Suggest a convenient method for carrying out the following syntheses. The compound on the left is to be synthesized from the one on the right (retrosynthetic notation). No more than three steps should be necessary. (a) C

(b)

CO2CH3

O

CO2CH3 O

(c) H3C

O H3C

(d)

H3C

O

O O

O

H CH2OH

CH3

H OH H

HO H3C

O

C

C

HO

C H H

HOCH2 HO

CH2OH

C

OH

OH OH

HO O

(e)

CH3

CH3

(f)

CH3

OCH3

HOCH2

HO2C

OCH3

(g)

O

OCH3

OCH3

CH3

CH3 O

O

CH3

O CH3

(h) meso-(CH3)2CHCHCHCH(CH3)2 HO OH

(CH3)2CHCO2CH3

322

(i) CH3O

CH2CH(CH2OH)2

CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

CH3O

CH2Cl

OCH3

OCH3 O

(j)

C6H5CHCH2CHCH3 S

C6H5CH

CHCCH3

OH

C6H5

6. Offer an explanation to account for the observed differences in rate which are described. (a) LiAlH4 reduces the ketone camphor about 30 times faster than does NaAlH4 . (b) The rate of reduction of camphor by LiAlH4 is decreased by a factor of about 4 when a crown ether is added to the reaction mixture. (c) For reduction of cyclohexanones by lithium tri-t-butyoxyaluminum hydride, the addition of one methyl group at C-3 has little effect on the rate, but a second group has a large effect. The addition of a third methyl group at C-5 has no effect. The effect of a fourth group is also rather small. Rate Cyclohexanone 3-Methylcyclohexanone 3,3-Dimethylcyclohexanone 3,3,5-Trimethylcyclohexanone 3,3,5,5-Tetramethylcyclohexanone

439 280 17.5 17.4 8.9

7. Suggest reaction conditions appropriate for stereoselectively converting the octalone shown to each of the diastereomeric decalones.

CH3

O

H

CH3

O CH3

CH3

O CH3

H

CH3

8. The fruit of a shrub which grows in Sierra Leone is very toxic and has been used as a rat poison. The toxic principle has been identi®ed as Z-18-¯uoro-9-octadecenoic acid. Suggest a synthesis for this material from 8-¯uorooctanol, 1-chloro-7-iodo-heptane, acetylene, and any other necessary organic or inorganic reagents.

9. Each of the following molecules contains more than one potentially reducible group. Indicate a reducing agent which would be suitable for effecting the desired selective

323

reduction. Explain the basis for the expected selectivity. (a)

CO2CH3

H O

PROBLEMS

CO2CH3

H O

O

O

H

H

CH2

CH3

CH3

CH3

(b)

O

OH

H

O

H

O O

O

O

O H

CH3O

H

O

CH3O

OCH3

OCH3

OCH3

(c) HO2C

O

OCH3 HOCH2 O

CH2CO2C2H5

O

O

H3C

O

CH2CO2C2H5

O

CH3

O

H3C

CH3 H

(d) CH3CH2C CCH2C CCH2OH

CH3CH2C

CCH2C

CCH2OH H

(e)

O

CH2CHCH2CO2CH3

CH3

OTMS

CH3CH2CHCO2 H

CH3

CH3

O

CH3CH2CHCO2

CH2CH2CCH2CHCH2CO2CH3 H

O

(f)

O

CH3(CH2)3C(CH2)4CCl

(g) H3C

H

HOH2C

H

OH

H

O CH3(CH2)3C(CH2)4CH

O

OCH2Ph

H

H3C

H3C

OH

H

OCH2Ph

CH3

OTMS

324 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

(h) CH3(CH2)2C(CH2)4CCl (i)

O

O

CH3O

O

Ph

CH3(CH2)2C(CH2)4CH O

O

NOCH3 CH3

CH3

(j)

CH3 O

CH3

O

O

H

O

CH3 O H

HC CH3

CH3 O

CH3

O

HO

OSiR3

OSiR3

10. Explain the basis of the observed stereoselectivity for the following reductions. (a) H

O CH3

(b)

H

OH

B–

CH3

H

Br Br

H

Bu3SnH

H

H

(c)

H3C

Br

OCH3

H3C Li, NH3

OCH3

EtOH

O

O

H

11. A valuable application of sodium cyanoborohydride is in the synthesis of amines by reductive amination. What combination of carbonyl and amine components would you choose to prepare the following amines by this route? Explain your choices.

(a)

N(CH3)2

(b)

(c) N H NH2

12. The reduction of o-bromophenyl allyl ether by LiAlH4 has been studied in several solvents. In ether, two products are formed. The ratio A : B increases with increasing LiAlH4 concentration. When LiAlD4 is used as the reductant about half of the product B is a monodeuterated derivative. Provide a mechanistic rationale for these results.

What is the most likely location of the deuterium atom in the deuterated product? Why is the product not completely deuterated.

OCH2CH

CH2

OCH2CH

CH2

LiAlH4

Br

O +

A

B

CH3

13. A simple synthesis of 2-substituted cyclohexenones has been developed. Although the yields are only 25±30%, it is carried out as a ``one-pot'' process using the sequence of reactions shown below. Explain the mechanistic basis of this synthesis and identify the intermediate present after each stage of the reaction.

OCH3

O CO2H

Li, THF NH3

R—X room temp.

R

H2O, H+ reflux 30 min

R—X = primary bromide or iodide

14. Birch reduction of 3,4,5-trimethoxybenzoic acid gives in 94% yield a dihydrobenzoic acid which bears only two methoxy substituents. Suggest a plausible structure for this product based on the mechanism of the Birch reduction.

15. The cyclohexenone C has been prepared in a one-pot process beginning with 4methylpent-3-en-2-one. The reagents which are added in succession are 4-methoxyphenyllithium, Li, and NH3, followed by acidic workup. Show the intermediate steps that are involved in this process.

O C

16. Ketones can be converted to nitriles by the following sequence of reagents. Indicate the intermediate stages of the reaction.

R2C

O

(1)

LiCN (C2H5O)2PCN

(2)

SmI2

R2CHCN

325 PROBLEMS

326 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

17. Provide a mechanistic rationale for the outcome, including stereoselectivity, of the following reactions.

OH

O R-alpine-hybride

Ph

X

Ph

Ph

X OH

OH

Ph anti

X

anti:syn

CH2 S NCH2Ph

1.2:1 1.3:1 12:1

OH

R-alpine-hybride = lithium B-isopinocampheyl-9 borabicyclo[3.3.1]nonyl hydride

+

Ph

X OH

Ph syn

18. In a multistep synthetic sequence, it was necessary to remove selectively one of two secondary hydroxyl groups.

OH H

H O

O

O HO

CH3

O HO

CH3

Consider several (at least three) methods by which this transformation might be accomplished. Discuss the relative merits of the various possibilities and recommend one as the most likely to succeed or be most convenient. Explain your choice. 19. In the synthesis of ¯uorinated analogs of an acetylcholinesterase inhibitor, huperzine A, it was necessary to accomplish reductive elimination of the diol D to E. Of the methods for diol reduction, which seem most compatible with the other functional groups in the molecule?

O

O N

HO

HO

N

OCH3

OCH3

CF3 CH2OCH2OCH3 CF3 D

CH2OCH2OCH3 E

20. Wolff±Kishner reduction of ketones that bear other functional groups sometimes give products other than the corresponding methylene compound. Some examples are

327

given. Indicate a mechanism for each of the reactions.

PROBLEMS

O

(a)

(CH3)3CCCH2OPh

(b)

(CH3)3CCH

CH2

O

O

H3C CH3

(c) H3C

OH

CH3

CH3 CH

CH3

H3C

CH3 H3C

O

CH3 CH2

CH3

CH3

(d) PhCH CHCH O

Ph

N H H

N

21. Suggest reagents and reaction conditions that would be suitable for each of the following selective or partial reductions. (a) HO2C(CH2)4CO2C2H5 (b)

HOCH2(CH2)4CO2C2H5

CH3

CH3

CH(CH3)2 CH2CN(CH3)2

CH2CH

CH(CH3)2 O

O

(c)

O CH3C(CH2)2CO2C8H17

(d)

CH3(CH2)3CO2C8H17

O CH3CNH

CO2CH3

(e)

CH3CH2NH

CO2CH3

O O2N

C

O2N

(f) O

OH CH3

CH3

(g) O O

O

O O

O

CH2

328 CHAPTER 5 REDUCTION OF CARBONYL AND OTHER FUNCTIONAL GROUPS

22. In the reduction of the ketone F, product G is favored with increasing stereoselectivity in the order NaBH4 < LiAlH2 …OCH2 CH2 OCH3 †2 < Zn…BH4 †2. With L-Selectride, stereoisomer H is favored. Account for the dependence of the stereoselectivity on the various reducing agents.

RO

RO

Ar

MOMO

OMOM

OMOM

OMOM

Ar

MOMO

O F

Ar = 4-methoxyphenyl R = benzyl MOM = methoxymethyl

OH

RO

Ar

MOMO

G

OH H

23. The following reducing agents effect enantioselective reduction of ketones. Propose a mechanism and transition-state structure which would be in accord with the observed enantioselectivity. (a)

O

CH3

CCO2CH3

B +

(b)

R-α-hydroxyester in 90% e.e.

Ph

O

Ph

H

CCH2CH3

O + BH3 +

R-alcohol in 97% e.e.

N B Me

(0.6 equiv)

(c)

O

(0.1 equiv)

CH3 BCl

CCH3 +

S-alcohol in 97% e.e.

Br

2

24. Devise a sequence of reactions which would accomplish the following synthesis: O

O from MeO

MeO

25. A group of topologically unique molecules known as ``betweenanenes'' have been synthesized. Successful synthesis of such molecules depends on effective means of closing large rings. Suggest an overall strategic approach (details are not required) to synthesize such molecules. Suggest reaction types which might be considered for formation of the large rings.

26. Give the products expected from the following reactions of Sm(II) reagents. (a) O

PROBLEMS

OCH2Ph

PhCH2O

SmI2

CH

CH

PhCH2O

O

OCH2Ph

(b)

(CH2)3CH

CHCO2CH3 SmI2

O

CH3

(c) CH3

H

O

SmI2

OH

HMPA

CH2CCH3

O

O

(d)

TBDMSO

CO2CH3 SmI2

O

CH3 CH3

CO2CH3 CH3

O

(e) CH O

OTBDMS CO2CH3 1) SmI2 2)

O

CH O

O

CH3

CH3

(f)

CO2Ph (CH3)3SiC

CCH2CH2N

329

CH

SmI2

CH2OTBDMS

6

Cycloadditions, Unimolecular Rearrangements, and Thermal Eliminations Introduction Most of the reactions described in the preceding chapters involve polar or polarizable reactants and proceed through polar intermediates or transition states. One reactant can be identi®ed as nucleophilic, and the other as electrophilic. Carbanion alkylations, nucleophilic additions to carbonyl groups, and electrophilic additions to alkenes are examples of such reactions. The reactions to be examined in this chapter, on the other hand, occur by a reorganization of valence electrons through activated complexes that are not much more polar than the reactants. These reactions usually proceed through cyclic transition states, and little separation of charge occurs during these processes. The energy necessary to attain the transition state is usually provided by thermal or photochemical excitation of the reactant(s), and frequently no other reagents are involved. Many of the transformations fall into the category of concerted pericyclic reactions, and the transition states are stabilized by favorable orbital interactions, as discussed in Chapter 11 of Part A. We will also discuss some reactions which effect closely related transformations but which, on mechanistic scrutiny, are found to proceed through discrete intermediates.

6.1. Cycloaddition Reactions Cycloaddition reactions result in the formation of a new ring from two reacting molecules. A concerted mechanism requires that a single transition state, and therefore no intermediate, lie on the reaction path between reactants and adduct. Two important

331

332 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

examples of cycloadditions that usually occur by concerted mechanisms are the Diels± Alder reaction, X

X

X

and 1,3-dipolar cycloaddition: C +

X

C δ+B

B A–

X

δ−

A

C

X

:B A

A ®rm understanding of concerted cycloaddition reactions developed as a result of the formulation of the mechanisms within the framework of molecular orbital (MO) theory. Consideration of the molecular orbitals of reactants and products revealed that, in many cases, a smooth transformation of the orbitals of the reactants to those of products is possible. In other cases, reactions that might appear feasible if no consideration is given to the symmetry and spatial orientation of the orbitals are found to require high-energy transition states when the orbitals are considered in detail. (Review Section 11.3 of Part A for a discussion of the orbital symmetry analysis of cycloaddition reactions.) The relationships between reactant and transition-state orbitals permit description of potential cycloaddition reactions as ``allowed'' or ``forbidden'' and permit conclusions as to whether speci®c reactions are likely to be energetically feasible. In this chapter, the synthetic applications of cycloaddition reactions will be emphasized. The same orbital symmetry relationships that are informative as to the feasibility of a reaction are often predictive of the regiochemistry and stereochemistry. This predictability is an important feature for synthetic purposes. Another attractive feature of cycloaddition reactions is the fact that two new bonds are formed in a single reaction. This can enhance the ef®ciency of a synthetic process. 6.1.1. The Diels±Alder Reaction: General Features The cycloaddition of alkenes and dienes is a very useful method for forming substituted cyclohexenes. This reaction is known as the Diels±Alder reaction.1 The concerted nature of the mechanism was generally accepted and the stereospeci®city of the reaction was ®rmly established before the importance of orbtial symmetry was recognized. In the terminology of orbital symmetry classi®cation, the Diels±Alder reaction is a [4ps ‡ 2ps ] cycloaddition, an allowed process. The transition state for a concerted reaction requires that the diene adopt the s-cis conformation. The diene and substituted alkene (which is called the dienophile) approach each other in approximately parallel planes. The symmetry properties of the p orbitals permit stabilizing interations between C-1 and C-4 of the diene and the dienophile. Usually, the strongest interaction is between the highest occupied molecular orbital (HOMO) of the diene and the lowest unoccupied molecular orbital (LUMO) of the dienophile. The interaction between the frontier orbitals is depicted in Fig. 6.1. 1. L. W. Butz and A. W. Rytina, Org. React. 5:136 (1949); M. C. Kloetzel, Org. React. 4:1 (1948); A. Wasserman, Diels±Alder Reactions, Elsevier, New York, 1965; R. Huisgen, R. Grashey, and J. Sauer, in Chemistry of Alkenes, S. Patai, ed., John Wiley & Sons, New York, 1964, pp. 878±928.

333

LUMO of dienophile

SECTION 6.1. CYCLOADDITION REACTIONS

HOMO of diene

Fig. 6.1. Cycloaddition of an alkene and a diene, showing interaction of LUMO of alkene with HOMO of diene.

There is a strong electronic substituent effect on the Diels±Alder addition. The alkenes that are most reactive toward simple dienes are those with electron-attracting groups. Thus, among the most reactive dienophiles are quinones, maleic anhydride, and nitroalkenes. a,b-Unsaturated aldehydes, esters, ketones, and nitriles are also effective dienophiles. It is signi®cant that if an electron-poor diene is utilized, the preference is reversed and electron-rich alkenes, such as vinyl ethers, are the best dienophiles. Such reactions are called inverse electron demand Diels±Alder reactions. These relationships are readily understood in terms of frontier orbital theory. Electron-rich dienes have highenergy HOMOs and interact strongly with the LUMOs of electron-poor dienophiles. When the substituent pattern is reversed and the diene is electron-poor, the strongest interaction is between the dienophile HOMO and the diene LUMO. A question of regioselectivity arises when both the diene and the alkene are unsymmetrically substituted. Generally, there is a preference for the ``ortho'' and ``para'' orientations, respectively, as in the examples shown.2 N(CH2CH3)2

N(CH2CH3)2 CO2CH2CH3 +

CO2CH2CH3 20°C

“ortho”-like only product (94%)

CH3CH2O

CH3CH2O

160°C

+ CO2CH3

CO2CH3 “para”-like only product (50%)

This preference can also be understood in terms of frontier orbital theory.3 When the dienophile bears an electron-withdrawing substituent and the diene an electron-releasing one, the strongest interaction is between the HOMO of the diene and the LUMO of the dienophile. The reactants are oriented so that the carbons having the highest coef®cients of the two frontier orbitals begin the bonding process. This is illustrated in Fig. 6.2 and leads to the observed regiochemical preference. 2. J. Sauer, Angew. Chem. Int. Ed. Engl. 6:16 (1967). 3. K. N. Houk, Acc. Chem. Res. 8:361 (1975); I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley-Interscience, New York, 1976; O. Eisenstein, J. M. LeFour, N. T. Anh, and R. F. Hudson, Tetrahedron 33:523 (1977).

334 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

(a) Coef®cient of C-2 is higher than coef®cient of C-1 in LUMO of dienophile bearing an electronwithdrawing substituent. 1 2

EWG is a p acceptor such as

C(O)R,

1

2

EWG NO2,

EWG

CN

(b) Coef®cient of C-4 is higher than coef®cient of C-1 in HOMO of diene bearing an electron-releasing substituent at C-1. 3 4

ERG is p donor such as

3

2

ERG

1

OR,

SR,

2

4

ERG

1

OSiMe3

(c) Coef®cient of C-1 is higher than coef®cient of C-4 in HOMO of diene bearing an electron-releasing substituent at C-2.

ERG 3

ERG

2

3

2

4

4

1

1

(d) Regioselectivity of Diels±Alder addition corresponds to that given by matching carbon atoms having the largest coef®cients in the frontier orbitals.

“ortho”-like orientation: ERG

ERG

ERG EWG

EWG

EWG

+

+

favored

“para”-like orientation: ERG

ERG +

ERG +

EWG

EWG

EWG favored

Fig. 6.2. HOMO±LUMO interactions rationalize regioselectivity of Diels±Alder cycloaddition reactions.

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations are called endo and exo, as illustrated in Fig. 6.3. In the endo transition state, the reference substituent on the dienophile is oriented toward the p orbitals of the diene. In the exo transition state, the substituent is oriented away from the p system. For many substituted butadiene derivatives, the two transition states lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an electron-attracting substituent such as a carbonyl group is present on the dienophile. The empirical statement which describes this preference is called the Alder rule. Frequently, a mixture of both stereoisomers is formed, and sometimes the exo product predominates, but the Alder rule is a useful initial guide to prediction of the stereochemistry of a Diels±Alder reaction. The endo product is often the more sterically congested. The preference for the endo transition state

(a)

H H

Y

H H

X

X

H3C

CH3

Y

CH3

CH3

H3C

(b)

X

X

CH3

335

Y

Y

H

Y

H

Y

H

X

X

H

CH3

CH3

CH3

H3C

H3C

CH3

Fig. 6.3. Endo (a) and exo (b) addition in a Diels±Alder reaction.

is the result of interaction between the dienophile substituent and the p electrons of the diene. Dipolar attractions and van der Waals attractions may also be involved.4 Diels±Alder cycloadditions are sensitive to steric effects of two major types. Bulky substituents on the dienophile or on the termini of the diene can hinder approach of the two components to each other and decrease the rate of reaction. This effect can be seen in the relative reactivity of 1-substituted butadienes toward maleic anhydride.5 R R

krel (25°C)

H CH3 C(CH3)3

1 4.2 < 0.05

Substitution of hydrogen by a methyl group results in a slight rate increase, as a result of the electron-releasing effect of the methyl group. A t-butyl substituent produces a large rate decrease, because the steric effect is dominant. The other type of steric effect has to do with interactions between diene substituents. Adoption of the s-cis conformation of the diene in the transition state brings the cisoriented 1- and 4-substituents on the diene close together. trans-1,3-Pentadiene is 103 times more reactive than 4-methyl-1,3-pentadiene toward the very reactive dienophile tetracyanoethylene. This is because of the unfavorable interaction between the additional methyl substituent and the C-1 hydrogen in the s-cis conformation.6

H

CH3 H

R

R

krel

H CH3

1 10–3

4. Y. Kobuke, T. Sugimoto, J. Furukawa, and T. Fueno, J. Am. Chem. Soc. 94:3633 (1972); K. L. Williamson and Y.-F. L. Hsu, J. Am. Chem. Soc. 92:7385 (1970). 5. D. Craig, J. J. Shipman, and R. B. Fowler, J. Am. Chem. Soc. 83:2885 (1961). 6. C. A. Stewart, Jr., J. Org. Chem. 28:3320 (1963).

SECTION 6.1. CYCLOADDITION REACTIONS

336 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Relatively small substituents at C-2 and C-3 of the diene exert little steric in¯uence on the rate of Diels±Alder addition. 2,3-Dimethylbutadiene reacts with maleic anhydride about 10 times faster than butadiene, and this is because of the electronic effect of the methyl groups. 2-t-Butyl-1,3-butadiene is 27 times more reactive than butadiene. This is because the t-butyl substituent favors the s-cis conformation, because of the steric repulsions in the s-trans conformation.

CH3 H

H3C H3C

C

H

H

H

H

H3C H3C

C

H

H3C

H

H

H

H

The presence of a t-butyl substituent on both C-2 and C-3, however, prevents attainment of the s-cis conformation, and Diels±Alder reactions of 2,3-di(t-butyl)-1,3-butadiene have not been observed.7 Lewis acids such as zinc chloride, boron tri¯uoride, aluminum chloride, and diethylaluminum chloride catalyze Diels±Alder reactions.8 The catalytic effect is the result of coordination of the Lewis acid with the dienophile. The complexed dienophile is more electrophilic and more reactive toward electron-rich dienes. The mechanism of the cycloaddition is still believed to be concerted, and high stereoselectivity is observed.9 Lewis acid catalysts also usually increase the regioselectivity of the reaction.

H3C

H3C

H3C +

+ CO2CH3

Uncatalyzed reaction: 120°C, 6 h Aluminum chloride catalyzed: 20°C, 3 h

CO2CH3 Ref. 10

CO2CH3 “para”-like “meta”-like Product ratio 70% 30% 95% 5%

The stereoselectivity of any particular reaction depends on the details of the structure of the transition state. The structures of several enone±Lewis acid complexes have been determined by X-ray crystallography.11 The site of complexation is the carbonyl oxygen, which maintains a trigonal geometry, but with somewhat expanded angles (130±140 ). The Lewis acid is normally anti to the larger carbonyl substituent. Boron tri¯uoride 7. H. J. Backer, Rec. Trav. Chim. Pays-Bas 58:643 (1939). 8. P. Yates and P. Eaton, J. Am. Chem. Soc. 82:4436 (1960); T. Inukai and M. Kasai, J. Org. Chem. 30:3567 (1965); T. Inukai and T. Kojima, J. Org. Chem. 32:869, 872 (1967); F. Fringuelli, F. Pizzo, A. Taticchi, and E. Wenkert, J. Org. Chem. 48:2802 (1983); F. K. Brown, K. N. Houk, D. J. Burnell, and Z. Valenta, J. Org. Chem. 52:3050 (1987). 9. K. N. Houk, J. Am. Chem. Soc. 95:4094 (1973). 10. T. Inukai and T. Kojima, J. Org. Chem. 31:1121 (1966). 11. S. Shambayati, W. E. Crowe, and S. L. Schreiber, Angew. Chem. Int. Ed. Engl. 29:256 (1990).

complexes are tetrahedral, but Sn(IV) and Ti(IV) complexes can be trigonal bipyramidal or octahedral. The structure of the 2-methylpropenal±BF3 complex is illustrative.12

Chelation can favor a particular structure. For example, O-acryloyl lactates adopt a chelated structure with TiCl4.13

Cl1

O3 O4

C4

Ti C12 O1 O2

C1 C2

C3

Theoretical calculations (6-31G*) have been used to compare the energies of four possible transition states for Diels±Alder reaction of the BF3 complex of methyl acrylate with 1,3butadiene. The results are summarized in Fig. 6.4. The endo transition state with the s-trans conformation of the dienophile is preferred to the others by about 2 kcal=mol.14 Some Diels±Alder reactions are also catalyzed by high concentrations of LiClO4 in ether.15 This catalysis may be a re¯ection of Lewis acid complexation of Li‡ with the dienophile.16 Other cations can catalyze Diels±Alder reactions of certain dienophiles. For 12. Structure reprinted from E. J. Corey, T.-P. Loh, S. Sarshar, and M. Azimioara, Tetrahedron Lett. 33:6945, Copyright 1992, with permission from Elsevier Science. 13. Structure reprinted from T. Poll, J. O. Metter, and G. Helmchen, Angew. Chem. Int. Ed. Engl. 24:112 (1985), with permission. 14. (a) J. I. Garcia, J. A. Mayoral, and L. Salvatella, J. Am. Chem. Soc. 118:11680 (1996); (b) J. I. Garcia, J. A. Mayoral, and L. Salvatella, Tetrahedron 53:6057 (1997). 15. P. A. Grieco, J. J. Nunes, and M. D. Gaul, J. Am. Chem. Soc. 112:4595 (1990). 16. M. A. Forman and W. P. Dailey, J. Am. Chem. Soc. 113:2761 (1991).

337 SECTION 6.1. CYCLOADDITION REACTIONS

338 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Fig. 6.4. Transition structures of the reaction between 1,3-butadiene and methyl acrylate, calculated at the ab initio RHF=6-31G* level. Total energies are in hartrees and relative energies in kcal=mol. (Reprinted from Ref. 14b, Copyright 1997, with permission from Elsevier Science.)

example, Cu2‡ strongly catalyzes addition reactions of 2-pyridyl styryl ketones, presumably through a chelate with the carbonyl oxygen and pyridine nitrogen.17 NO2

O O2N

N

+

Rate (M –1 s–1)

Relative rate

Solvent

1.3 × 10–5 3.8 × 10–5 4.0 × 10–3 3.25

1 2.9 310 250,000

Acetonitrile Ethanol Water Water + 0.01 M Cu(NO3)2

17. S. Otto and J. B. F. N. Engberts, Tetrahedron Lett. 36:2645 (1995).

O N

Lanthanide salts have also been found to catalyze Diels±Alder reactions. For example, with 10 mol % Sc(O3SCF3)3 added, isoprene and methyl vinyl ketone react to give the expected adduct in 91% yield after 13 h at 0 C.18 O CH3CCH

CH3

CH3 CH2 + CH2

CCH

CH2

10 mol % Sc(O3SCF3)3

O CH3C

Among the unique features of Sc(O3SCF3)3 is its ability to function as a catalyst in hydroxylic solvents. Other dienophiles, including N -acryloyloxazolinones (see page 349), also are subject to catalysis by Sc(O3SCF3)3. The solvent also has an important effect on the rate of Diels±Alder reactions. The traditional solvents have been nonpolar organic solvents such as aromatic hydrocarbons. However, water and other highly polar solvents, such as ethylene glycol and formamide, have been found to accelerate a number of Diels±Alder reactions.19 The accelerating effect of water is attributed to ``enforced hydrophobic interactions.'' That is, the strong hydrogenbonding network in water tends to exclude nonpolar solutes and force them together, resulting in higher effective concentrations and also relative stabilization of the developing transition state.20 More speci®c hydrogen bonding with the transition state also contributes to the rate acceleration.21 6.1.2. The Diels±Alder Reaction: Dienophiles Examples of some compounds which exhibit a high level of reactivity as dienophiles are collected in Table 6.1. Scheme 6.1 presents some typical Diels±Alder reactions. Each of the reactive dienophiles has at least one strongly electron-attracting substituent on the double or triple carbon±carbon bond. Ethylene, acetylene, and their alkyl derivatives are poor dienophiles and react only under extreme conditions. Diels±Alder reactions have long played an important role in synthetic organic chemistry. The reaction of a substituted benzoquinone and 1,3-butadiene, for example, was the ®rst step in one of the early syntheses of steroids. The angular methyl group is introduced from the quinone, and the other functional groups were used for further structural elaboration. O

O CH3 + CH3O

86%

100°C

CH3O O

CH3

benzene

O

Ref. 22

H

18. S. Kobayashi, I. Hachiya, M. Araki, and H. Ishitami, Tetrahedron Lett. 34:3755 (1993); S. Kobayahsi, Eur. J. Org. Chem. 1999:15. 19. D. Rideout and R. Breslow, J. Am. Chem. Soc. 102:7816 (1980); R. Breslow and T. Guo, J. Am. Chem. Soc. 110:5613 (1988); T. Dunams, W. Hoekstra, M. Pentaleri, and D. Liotta, Tetrahedron Lett. 29:3745 (1988). 20. R. Breslow and C. J. Rizzo, J. Am. Chem. Soc. 113:4340 (1991). 21. W. Blokzijl, M. J. Blandamer, and J. B. F. N. Engberts, J. Am. Chem. Soc. 113:4241 (1991); W. Blokzijl and J. B. F. N. Engberts, J. Am. Chem. Soc. 114:5440 (1992); S. Otto, W. Blokzijl, and J. B. F. N. Engberts, J. Org. Chem. 59:5372 (1994); A. Meijer, S. Otto, and J. B. F. N. Engberts, J. Org. Chem. 63:8989 (1998). 22. R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler, and W. M. McLamore, J. Am. Chem. Soc. 74:4223 (1952).

339 SECTION 6.1. CYCLOADDITION REACTIONS

Table 6.1. Representative Dienophiles

340 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

A. Substituted alkenes 1a Maleic anhydride

2b Benzoquinone

O

3c Vinyl ketones, acrolein, acrylate esters, acrylonitrile, nitroalkenes, etc. RCH CH X

O

O

X = CR, COR, C O

O

O

O

4d Methyl vinyl sulfone

O H2C

N, NO2

5e Tetracyanoethylene

(NC)2C

6f Diethyl vinylphosphonate

O

C(CN)2

CHSCH3

H2C

CHP(OC2H5)2

O B. Substituted alkynes 7f Esters of acetylenedicarboxylic acid H3CO2CC CCO2CH3

8g Hexa¯uoro-2-butyne

F3CC

CCF3

9h Dibenzoylacetylene

O

O

PhCC

CCPh

10i Dicyanoacetylene N

CC

CC

N

C. Heteroatomic dienophiles 11i Esters of azodicarboxylic acid

H3CO2CN

12k 4-Phenyl-1,2,4-triazoline3,5-dione

NCO2CH3

CH2

O N N

N

13l Iminocarbamates

NCO2C2H5

Ph

O a. b. c. d. e. f. g. h. i. j. k. l.

M. C. Kloetzel, Org. React. 4:1 (1948). L. W. Butz and A. W. Rytina, Org. React. 5:136 (1949). H. L. Holmes, Org. React. 4:60 (1948). J. C. Philips and M. Oku, J. Org. Chem. 37:4479 (1972). W. J. Middleton, R. E. Heckert, E. L. Little, and C. G. Krespan, J. Am. Chem. Soc. 80:2783 (1958); E. Ciganek, W. J. Linn, and O. W. Webster, The Chemistry of the Cyano Group, Z. Rappoport, ed., John Wiley & Sons, New York, 1970, pp. 423±638. W. M. Daniewski and C. E. Grif®n, J. Org. Chem. 31:3236 (1966). R. E. Putnam, R. J. Harder, and J. E. Castle, J. Am. Chem. Soc. 83:391 (1961); C. G. Krespan, B. C. McKusick, and T. L. Cairns, J. Am. Chem. Soc. 83:3428 (1961). J. D. White, M. E. Mann, H. D. Kirshenbaum, and A. Mitra, J. Org. Chem. 36:1048 (1971). C. D. Weis, J. Org. Chem. 28:74 (1963). B. T. Gillis and P. E. Beck, J. Org. Chem. 28:3177 (1963). B. T. Gillis and J. D. Hagarty, J. Org. Chem. 32:330 (1967). M. P. Cava, C. K. Wilkins, Jr., D. R. Dalton, and K. Bessho, J. Org. Chem. 30:3772 (1965); G. Krow, R. Rodebaugh, R. Carmosin, W. Figures, H. Pannella, G. De Vicaris, and M. Grippi, J. Am. Chem. Soc. 95:5273 (1973).

The synthetic utility of the Diels±Alder reaction can be signi®cantly expanded by the use of dienophiles that contain masked functionality and are the synthetic equivalents of unreactive or inaccessible species (see Section 13.2 for a more complete discussion of the concept of synthetic equivalents). For example, a-chloroacrylonitrile shows satisfactory reactivity as a dienophile. The a-chloronitrile functionality in the adduct can be hydrolyzed to a carbonyl group. Thus, a-chloroacrylonitrile can function as the equivalent of ketene,

Scheme 6.1. Diels±Alder Reactions of Some Representative Dienophiles 1a Maleic anhydride O H3C

O

CH2 +

CHCH

H

SECTION 6.1. CYCLOADDITION REACTIONS

O

benzene 100°C

O H

O

90%

O

2b Benzoquinone O O

H benzene 40°C

+

97%

H O 3c

O

Methyl vinyl ketone O 140°C

H3C

CHCH

CH2 + H2C

CHCCH3

90%

CCH3 O 4d

Methyl acrylate OAc

OAc CH3O2C

75%

OAc 5e

CO2CH3

85–90°C

+

OAc

Acrolein CH3O H3C

CCH

CH CH2 + H2C

CHCH

O

O

75%

CH3O 6f

Tetracyanoethylene H3C N

O H3C

a. b. c. d.

NC NC

C2H5

CH3

+ (NC)2C

C(CN)2 H3C

341

CN CN CN NC2H5 O CH3

L. F. Fieser and F. C. Novello, J. Am. Chem. Soc. 64:802 (1942). A. Wassermann, J. Chem. Soc. 1935:1511. W. K. Johnson, J. Org. Chem. 24:864 (1959). R. McCrindle, K. H. Overton, and R. A. Raphael, J. Chem. Soc. 1960:1560; R. K. Hill and G. R. Newkome, Tetrahedron Lett. 1968:1851. e. J. I. DeGraw, L. Goodman, and B. R. Baker, J. Org. Chem. 26:1156 (1961). f. L. A. Paquette, J. Org. Chem. 29:3447 (1964).

342 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

CH2ˆCˆO.23 Ketene is not a suitable dienophile because it has a tendency to react with dienes by [2 ‡ 2] cycloaddition, rather than in the desired [4 ‡ 2] fashion. CH3OCH2

CH3OCH2

CH3OCH2

Cl + H2C

H2O

C C

Ref. 24

Cl

N C

N

O 50–55%

Nitroalkenes are good dienophiles, and the variety of transformations that are available for nitro groups make them versatile intermediates.25 Nitro groups can be converted to carbonyl groups by reductive hydrolysis, so nitroethylene can be used as a ketene equivalent.26 CH3OCH2

CH3OCH2 + H2C

CHNO2

CH3OCH2

ether

1) NaOCH3

25°C

2) TiCl3, NH4OAc

Ref. 27 O

NO2 56%

Vinyl sulfones are reactive as dienophiles. The sulfonyl group can be removed reductively with sodium amalgam (see Section 5.5.2). In this two-step reaction sequence, the vinyl sulfone functions as an ethylene equivalent. The sulfonyl group also permits alkylation of the Diels±Alder adduct, via the carbanion. This three-step sequence allows the vinyl sulfone to serve as the synthetic equivalent of a terminal alkene.28 H3C

CH2

H3C + PhSO2CH

H3C

CH2

CH2

SO2Ph

135°C

H3C Na–Hg

H3C

H3C 94%

76%

1) PhCH2Br, base 2) Na–Hg

H3C H3C

CH2Ph

85%

Phenyl vinyl sulfoxide is a useful acetylene equivalent. Its Diels±Alder adducts can 23. 24. 25. 26.

V. K. Aggarwal, A. Ali, and M. P. Coogan, Tetrahedron 55:293 (1999). E. J. Corey, N. M. Weinshenker, T. K. Schaaf, and W. Huber, J. Am. Chem. Soc. 91:5675 (1969). D. Ranganathan, C. B. Rao, S. Ranganathan, A. K. Mehrotra, and R. Iyengar, J. Org. Chem. 45:1185 (1980). For a review of ketene equivalents, see S. Ranganathan, D. Ranganathan, and A. K. Mehrotra, Synthesis 1977:289. 27. S. Ranganathan, D. Ranganathan, and A. K. Mehrotra, J. Am. Chem. Soc. 96:5261 (1974). 28. R. V. C. Carr and L. A. Paquette, J. Am. Chem. Soc. 102:853 (1980); R. V. C. Carr, R. V. Williams, and L. A. Paquette, J. Org. Chem. 48:4976 (1983); W. A. Kinney, G. O. Crouse, and L. A. Paquette, J. Org. Chem. 48:4986 (1983).

343

undergo elimination of benzenesulfenic acid.

Cl

Cl

Cl

Cl

Cl

Cl

O

Cl

Cl

CH2

+ PhSCH

Cl Cl

Cl

100°C

Cl

100°C

Cl

Cl

Ref. 29 Cl

Cl S

SECTION 6.1. CYCLOADDITION REACTIONS

Cl

Cl

O

83%

Ph

Cis- and trans(bisbenzenesulfonyl)ethene are also acetylene equivalents. The two sulfonyl groups undergo reductive elimination on reaction with sodium amalgam.

PhSO2 +

SO2Ph C

H

Na–Hg

C

SO2Ph

H

69%

MeOH

Ref. 30

SO2Ph

Vinylphosphonium salts are reactive as dienophiles as a result of the electronwithdrawing capacity of the phosphonium substituent. The Diels±Alder adducts can be deprotonated to give ylides which undergo the Wittig reaction to introduce an exocyclic double bond. This sequence of reactions corresponds to a Diels±Alder reaction employing allene as the dienophile.31

+ H2C

+

+

PPh3

CHPPh3

1) LiNR2 2) CH2 O

96%

CH2 50%

The use of 2-vinyldioxolane, the ethylene glycol acetal of acrolein, as a dienophile illustrates application of the masked functionality concept in a different way. The acetal itself would not be expected to be a reactive dienophile, but in the presence of a catalytic amount of acid, the acetal is in equilibrium with the highly reactive oxonium ion. O CH2

+ H+

CH

CH2

CH

CH

+

O

CH2CH2OH

O

Diels±Alder addition occurs through this cationic intermediate at room temperature.32 29. 30. 31. 32.

L. A. Paquette, R. E. Moerck, B. Harirchian, and P. D. Magnus, J. Am. Chem. Soc. 100:1597 (1978). O. DeLucchi, V. Lucchini, L. Pasquato, and G. Modena, J. Org. Chem. 49:596 (1984). R. Bonjouklian and R. A. Ruden, J. Org. Chem. 42:4095 (1977). P. G. Gassman, D. A. Singleton, J. J. Wilwerding, and S. P. Chavan, J. Am. Chem. Soc. 109:2182 (1987).

344

Similar reactions occur with substituted alkenyldioxolanes.

CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

O

R1 CH

+

R2

CF3SO3H

CHR2

2 mol % –78 → –10°C

O

R1 O

O

Alkenyl- and alkynylboranes also function as dienophiles. The electron-de®cient boron is responsible for the electronic effect. CH2

CH

+

BR2

CH2

CH



BR2

Alkenylboranes are less sensitive to substituents on the diene than are carbonyl-activated dienophiles.33 Relatively hindered dialkylboranes, such as B-vinyl-9-BBN, show steric effects which lead to a preference for the ``meta'' regioisomer and reduced endo : exo ratios.34 BR2

+ CH2

CHBR2

H

b-Trimethylsilylvinyl-9-BBN shows a preference for the ``meta'' adduct with both isoprene and 2-(t-butyldimethylsilyloxy)butadiene.35 CH3

Si(CH3)3 + (CH3)3SiCH

CHBR2 CH3

BR2

The characterisitics of the vinylboranes as dienophiles can be rationalized in terms of a strong interaction of the diene with the empty p orbital at boron. Molecular orbital calculations show a strong interaction between B and C-1 in the transition state, and the transition state shows little charge separation, accounting for the relative insensitivity to substituent effects. As for regiochemistry, the ``para-like'' selectivity would also be expected to be reduced because the LUMO of the dienophile is nearly equally distributed between B and C-2.36

BR2 33. 34. 35. 36.

Y. Singleton, J. P. Martinez, and J. V. Watson, Tetrahedron Lett. 33:1017 (1992). D. A. Singleton and J. P. Martinez, J. Am. Chem. Soc. 112:7423 (1990). D. A. Singleton and S.-W. Leung, J. Org. Chem. 57:4796 (1992). D. A. Singleton, J. Am. Chem. Soc. 114:6563 (1992).

345

6.1.3. The Diels±Alder Reaction: Dienes Simple dienes react readily with good dienophiles in Diels±Alder reactions. Functionalized dienes are also important in organic synthesis. One example which illustrates the versatility of such reagents is 1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky's diene).37 Its Diels±Alder adducts are trimethylsilyl enol ethers which can be readily hydrolyzed to ketones. The b-methoxy group is often eliminated during hydrolysis. OCH3

OCH3 + H2C

CHO

benzene, ∆

CCHO

CH3

CH3

Me3SiO

CHO H2O+

CH3 O

Me3SiO

72%

Related transformations of the adduct with dimethyl acetylenedicarboxylate lead to dimethyl 4-hydroxyphthalate. OCH3

OCH3 O

O

+ CH3OCC

CO2CH3

benzene

CCOCH3

CO2CH3

H2O+



Me3SiO

Me3SiO

CO2CH3

HO

CO2CH3

The corresponding enamine shows a similar reactivity pattern.38 (CH3)2N

N(CH3)2 CH3

CH

O

CH3 CH

CH3 CH

O

O

+ TBDMSO

TBDMSO

O

Unstable dienes can also be generated in situ in the presence of a dienophile. Among the most useful examples of this type of diene are the quinodimethanes. These compounds are exceedingly reactive as dienes because the cycloaddition reestablishes a benzenoid ring and results in aromatic stabilization.39 CH2

X

X

+ CH2 quinodimethane

37. S. Danishefsky and T. Kitahara, J. Am. Chem. Soc. 96:7807 (1974). 38. S. A. Kozmin and V. H. Rawal, J. Org. Chem. 62:5252 (1997). 39. W. Oppolzer, Angew. Chem. Int. Ed. Engl. 16:10 (1977); T. Kametani and K. Fukumoto, Heterocycles 3:29 (1975); J. J. McCullogh, Acc. Chem. Res. 13:270 (1980); W. Oppolzer, Synthesis 1978:73; J. L. Charlton and M. M. Alauddin, Tetrahedron 43:2873 (1987); H. N. C. Wong, K.-L. Lau and K. F. Tam, Top. Curr. Chem. 133:85 (1986); P. Y. Michellys, H. Pellissier, and M. Santelli, Org. Prep. Proced. Int. 28:545 (1996).

SECTION 6.1. CYCLOADDITION REACTIONS

346 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

There are several general routes to quinodimethanes. One is pyrolysis of benzocyclobutenes.40 CH2 heat

CH2

Eliminations from a,a0 -ortho-disubstituted benzenes with various potential leaving groups can be carried out. Benzylic silyl substituents can serve as the carbanion precursors. CH3

CH3

CHSi(CH3)3

CO2CH3 F–, 50°C CH3O2C

+

CHN(CH3)3

Ref. 41

100% H

C

CO2CH3

C CO2CH3

H

CH3

CH3

Several procedures have been developed for obtaining quinodimethane intermediates from ortho-substituted benzylstannanes. The reactions occur by generating an electrophilic center at the adjacent benzylic position, which triggers a 1,4-elimination. R

R

E+ X

XE

SnR3 X = CHOH,

O,

R

+

XE

SnR3 CH2

Speci®c examples include treatment of o-stannyl benzyl alcohols with TFA,42 reactions of ketones and aldehydes with Lewis acids,43 and selenation of styrenes.44 OH CH

O

CH3O2C

CO2CH3

+ H

CH2Sn(C4H9)3

CO2CH3 MgBr2

69%

H

CO2CH3 O N

CH

CH2

SePh

CH2SePh CO2CH3

+ CH2

CHCO2CH3

O

59%

CH2Sn(C4H9)3 40. M. P. Cava and M. J. Mitchell, Cyclobutadiene and Related Compounds, Academic Press, New York, 1967, Chapter 6; I. L. Klundt, Chem. Rev. 70:471 (1970); R. P. Thummel, Acc. Chem. Res. 13:70 (1980). 41. Y. Ito, M. Nakatsuka, and T. Saegusa, J. Am. Chem. Soc. 104:7609 (1982). 42. H. Sano, H. Ohtsuka, and T. Migita, J. Am. Chem. Soc. 110:2014 (1988). 43. S. H. Woo, Tetrahedron Lett. 35:3975 (1994). 44. S. H. Woo, Tetrahedron Lett. 34:7587 (1993).

o-(Dibromomethyl)benzenes can be converted to quinodimethanes with reductants such as zinc, nickel, chromous ion, and tri-n-butylstannide.45 CH3

CH3

O

O

CH2Br + CH2

CCH3

CHCCH3

Zn–Ag

74%

CH2Br CH3

CH3

Quinodimethanes have been especially useful in intramolecular Diels±Alder reactions, as will be illustrated in Section 6.1.5. Another group of dienes with extraordinarily high reactivity are derivatives of benzo[c]furan (isobenzofuran).46 Ph

Ph 100°C

O + Ph

O

Ref. 47

69%

Ph

Here again, the high reactivity can be traced to the gain in aromatic stabilization of the adduct. Polycyclic aromatic hydrocarbons are moderately reactive as the diene component of Diels±Alder reactions. Anthracene forms adducts with a number of reactive dienophiles. The addition occurs at the center ring. There is no net loss of resonance stabilization, because the anthracene ring (resonance energy ˆ 1.60 eV) is replaced by two benzenoid rings (total resonance energy ˆ 2  0:87 ˆ 1:74 eV).48 O

O

O

PhCCH CHCPh

PhC H

H CPh O

56%

Ref. 49

The naphthalene ring is much less reactive. Polymethylnaphthalenes are more reactive than the parent molecule, and 1,2,3,4-tetramethylnaphthalene gives an adduct with maleic anhydride in 82% yield. Reaction occurs exclusively in the substituted ring.50 This is because the steric repulsions between the methyl groups, which are relieved in the nonplanar adduct, exert an accelerating effect. 45. G. M. Rubottom and J. E. Wey, Synth. Commun. 14:507 (1984); S. Inaba, R. M. Wehmeyer, M. W. Forkner, and R. D. Rieke, J. Org. Chem. 53:339 (1988); D. Stephan, A. Gorgues, and A. LeCoq, Tetrahedron Lett. 25:5649 (1984); H. Sato, N. Isono, K. Okamura, T. Date, and M. Mori, Tetrahedron Lett. 35:2035 (1994). 46. M. J. Haddadin, Heterocycles 9:865 (1978); W. Friedrichsen, Adv. Heterocycl. Chem. 26:135 (1980). 47. G. Wittig and T. F. Burger, Justus Liebigs Ann. Chem. 632:85 (1960). 48. M. J. S. Dewar and D. de Llano, J. Am. Chem. Soc. 91:789 (1969). 49. D. M. McKinnon and J. Y. Wong, Can. J. Chem. 49:3178 (1971). 50. A. Oku, Y. Ohnishi, and F. Mashio, J. Org. Chem. 37:4264 (1972).

347 SECTION 6.1. CYCLOADDITION REACTIONS

348 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Diels±Alder addition of simple benzene derivatives is dif®cult and occurs only with very reactive dienophiles. Formation of an adduct between benzene and dicyanoacetylene in the presence of AlCl3 has been reported, for example.51

+ N

CC

CC

N

AlCl3

C C

N

N

Pyrones are a useful type of diene. Although they are not particularly reactive dienes, the adducts have the potential for elimination of carbon dioxide, resulting in the formation of an aromatic ring. CH3

CO2Et EtO2C

CH3

CH3

–CO2

O O C

+ (MeO)2C CH2 O

CH3

OMe

–MeOH

OMe CH3

O EtO2C

Ref. 52 OMe

CH3 O

OCH3

O + CH2

C(OCH3)2

110°C

Ref. 53

84%

Vinyl ethers are frequently used as dienophiles with pyrones. These reactions can be catalyzed by Lewis acids such as bis(alkoxy)titanium dichlorides54 and lanthanide salts.55 O CO2CH3

O + CH2

O

CHOC4H9

Yb(hfc)3 94%

OC4H9

O

O CO2CH3

Yb(O3SCF3)3

+ CH2 O

O

CHO

c-C6H11

R-BINOL, i-C3H7N(C2H5)2

O >95%

O-c-C6H11

Another use of special dienes, the polyaza benzene heterocyclics, such as triazines and tetrazines, will be discussed in Section 6.8.2. 51. 52. 53. 54.

E. Ciganek, Tetrahedron Lett. 1967:3321. M. E. Jung and J. A. Hagenah, J. Org. Chem. 52:1889 (1987). D. L. Boger and M. D. Mullican, Org. Synth. 65:98 (1987). G. H. Posner, J.-C. Carry, J. K. Lee, D. S. Bull, and H. Dai, Tetrahedron Lett. 35:1321 (1994); G. H. Posner, H. Dai, D. S. Bull, J.-K. Lee, F. Eydoux, Y. Ishihara, W. Welsh, N. Pryor, and S. Petr, Jr., J. Org. Chem. 61:671 (1996). 55. G. H. Posner, J.-C. Carry, T. E. N. Anjeh, and A. N. French, J. Org. Chem. 57:7012 (1992).

349

6.1.4. Asymmetric Diels±Alder Reactions The highly ordered cyclic transition state of the Diels±Alder reaction permits design of reaction parameters which lead to a preference between the transition states leading to diastereomeric or enantiomeric adducts. (See Part A, Section 2.3, to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.56 The cycloaddition proceeds to give two diastereomeric products which can be separated and puri®ed. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best enantioselectivity is often observed in catalyzed reactions. Chiral esters and amides of acrylic acid are particularly useful because the chiral auxiliary can be easily recovered upon hydrolysis of the adduct to give the enantiomerically pure carboxylic acid. CH3 EtO2C

H

O

O CCH



TiCl4

CH2 +

OH H2O

CH3 EtO2C

C

OC

H

O

Ref. 57 CO2H

Prediction and analysis of diastereoselectivity is based on steric, stereoelectronic, and complexing interactions in the transition state.58 Methyl shields top face of the dienophile.

O

Cl Cl Ti

O

Cl Cl

EtO CH3 H

C O

EtO CH3 C C H O

O O

H

a,b-Unsaturated derivatives of chiral oxazolinones have proven to be especially useful for enantioselective Diels±Alder additions. Reaction occurs at low temperatures in the presence of such Lewis acids as SnCl4, TiCl4 and (C2H5)2AlCl.59

R

R1

O

O N

O +

R1

N

(C2H5)2AlCl

R2

O

O

R2

PhCH2 R

R1

R2

Yield

dr

H H CH3 CH3

H CH3 H CH3

CH3 H CH3 H

85% 84% 83% 77%

95:5 >100:1 94:6 95:5

O

R PhCH2

56. W. Oppolzer, Angew. Chem. Int. Ed. Engl. 23:876 (1984); M. J. Tascher, in Organic Synthesis, Theory and Applications, Vol. 1, T. Hudlicky, ed., JAI Press, Greenwich, Connecticut, 1989, pp. 1±101; H. B. Kagan and O. Riant, Chem. Rev. 92:1007 (1992); K. Narasaka, Synthesis 1991:1. 57. T. Poll, G. Helmchen, and B. Bauer, Tetrahedron Lett. 25:2191 (1984). 58. For example, see T. Poll, A. Sobczak, H. Hartmann, and G. Helmchen, Tetrahedron Lett. 26:3095 (1985). 59. D. A. Evans, K. T. Chapman, and J. Bisaha, J. Am. Chem. Soc. 110:1238 (1988).

SECTION 6.1. CYCLOADDITION REACTIONS

350 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Scheme 6.2 gives some other examples of use of chiral auxiliaries in Diels±Alder reactions.60 The alkenyl oxonium ion dienophiles generated from dioxolanes have been made enantioselective by use of chiral diols. For example, dioxolanes derived from syn-1,2diphenylethane-1,2-diol react with dienes such as cyclopentadiene and isoprene, but the stereoselectivity is very modest in most cases. Ph

Ph O

Ph

O

OC2H5 CH

CH3

O

(CH3)3SiO3SCF3

+

CCH

CH2

O

Ph

CH2

CH2

Ph

OH O CH3

O

Ph

Ref. 61 82% yield, 55:45 dr

Acetals derived from anti-pentane-2,4-diol react with dienes under the in¯uence of TiCl4=Ti(i-OPr)4 to give adducts with stereoselectivity ranging from 3 : 1 to 15 : 1. H3C O O

CH2 R

H3C

CH3 CH2

CCH

O H

CH2

CH3

TiCl4 or (CH3)3SiO3SCF3

O

Ref. 62

R

H3C

H3C

Enantioselectivity can also be achieved with chiral catalysts. For example, additions of N -acryloyloxazolinones can be made enantioselective using Sc(O3SCF3)3 in the presence of a BINOL ligand.63 Optimized conditions involved use of 5±20 mol % of the catalyst along with a hindered amine such as cis-1,2,6-trimethylpiperidine. A hexacoordinate transition state in which the amine is hydrogen-bonded to the BINOL has been proposed.

O H

O Sc H

O

O N

N

O OTf

TfO N

R diene

60. 61. 62. 63.

For additional examples see W. Oppolzer, Tetrahedron 43:1969, 4057 (1987). A. Haudrechy, W. Picoul, and Y. Langlois, Tetrahedron Asymmetry 8:139 (1997). T. Sammakia and M. A. Berliner, J. Org. Chem. 59:6890 (1994). S. Kobayashi, M. Araki, and I. Hachiya, J. Org. Chem. 59:3758 (1994).

Scheme 6.2. Diels±Alder Reactions with Chiral Auxiliaries Entry Dienophile

Diene

1a

Catalyst

351 Yield (%)

dr

O O

TiCl2(i-OPr)2, –20°C

90

>99:1

(C2H5)2AlCl, –78°C

88

99:1

SnCl4, –78°C

93

96:4

(C2H5)2AlCl, –40°C

94

98:2

ZnCl4, –78°C

86

>99:1

(C2H5)2AlCl, –40°C

62

97:3

TiCl4, –55 to –20°C

79

96:2

O

2b O N SO2 3c O O

O OCH3

O O 4

d

SO2 N O CH3 5e Ph O N

Ph

O

6f O CH3OCH2OCH2

N O CH2OCH2Ph

7g

O O

O O

a. W. Oppolzer, C. Chapuis, D. Dupuis, and M. Guo, Helv. Chim. Acta 68:2100 (1985). b. W. Oppolzer, C. Chapuis, and G. Bernardinelli, Helv. Chim. Acta 67:1397 (1984); M. Vanderwalle, J. Van der Eycken, W. Oppolzer, and C. Vullioud, Tetrahedron 42:4035 (1986). c. R. Nougier, J.-L. Gras, B. Giraud, and A. Virgili, Tetrahedron Lett. 32:5529 (1991). d. W. Oppolzer, B. M. Seletsky, and G. Bernardinelli, Tetrahedron Lett. 35:3509 (1994). e. M. P. Sibi, P. K. Deshpande, and J. Ji, Tetrahedron Lett. 36:8965 (1995). f. N. Ikota, Chem. Pharm. Bull. 37:2219 (1989). g. K. Miyaji, Y. Ohara, Y. Takahashi, T. Tsuruda, and K. Arai, Tetrahedron Lett. 32:4557 (1991).

SECTION 6.1. CYCLOADDITION REACTIONS

352 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

The chiral oxazaborolidines introduced in Section 2.1.3.5 as enantioselective aldol addition catalysts have also been found to be useful in Diels±Alder reactions. The tryptophan-derived catalyst A, for example, can achieve 99% enantioselectivity in the Diels±Alder reaction between 5-benzyloxymethyl-1,3-cyclopentadiene and 2-bromopropenal. The adduct is an important intermediate in the synthesis of prostaglandins.64 O

PhCH2OCH2

PhCH2OCH2

CH2Ph

CH + CH2

CCH

O

O

1) NH2OH 2) TsCl pyridine 3) NaOH

5 mol % A

Br

Br

O

H ⋅ N

Br

O

O

A

O

S

H H O

B

N

H

H

O

R

Me

Enantioselective Diels±Alder reactions of acrolein are also catalyzed by 3-(2hydroxy-3-phenyl) derivatives of BINOL in the presence of an aromatic boronic acid. The optimum boronic acid is 3,5-di(tri¯uoromethyl)benzeneboronic acid, with which >95% e.e. can be achieved. The transition state is believed to involve Lewis acid complexation of the boronic acid at the carbonyl oxygen and hydrogen bonding with the hydroxyl substituent. In this transition state, p,p-interactions between the dienophile and the hydroxybiphenyl substitutent can also help to align the dienophile.65 CF3

CF3 O

Dienophile CH2 CH2

CHCH O CCH O

Br E-CH3CH

CHCH

E-PhCH CHCH

O O

Diene

B O O O H

H Ph R3

R4

Yield (%)

exo:endo

e.e. (%)

84 99

3:97 90:10

95 >99

94

10:90

95

94

26:74

80

64. E. J. Corey and T. P. Loh, J. Am. Chem. Soc. 113:8966 (1991). 65. K. Ishihara, H. Kurihara, M. Matsumoto, and H. Yamamoto, J. Am. Chem. Soc. 120:6920 (1998).

353

Another useful group of catalysts are Cu2‡ chelates of bis-oxazolines.

SECTION 6.1. CYCLOADDITION REACTIONS

O OTBDMS

O O

O + CH2

CHC

O N

–78°C

O CH3

N

O

1) LiSC2H5 2) CsCO3, CH3OH 3) LiHMDS 4) TBDMSOTf, 2,6-dimethylpyridine

Ref. 66 CO2CH3

CH3

O

O N

Cu

N t-Bu

t-Bu

Several other examples of catalytic enantioselective Diels±Alder reactions are given in Scheme 6.3. 6.1.5. Intramolecular Diels±Alder Reactions Intramolecular Diels±Alder reactions have proven very useful in the synthesis of polycylic compounds.67 Some examples are given in Scheme 6.4. In entry 1 of Scheme 6.4, the dienophilic portion bears a carbonyl substituent, and cycloaddition occurs easily. Two stereoisomeric products are formed in a 90:10 ratio, but both have the cis ring fusion. This is the stereochemistry expected for an endo transition state. O

O

H

H

H

H

O

H

H

In entry 2, a similar triene that lacks the activating carbonyl group undergoes reaction, but a much higher temperature is required. In this case, the ring junction is trans. This corresponds to an exo transition state and presumably re¯ects the absence of an important secondary orbital interaction between the diene and dienophile. H H

H H

H

H

H H

H

In entry 3, the dienophilic double bond bears an electron-withdrawing group, but a higher temperature than for entry 1 is required because the connecting chain contains one 66. D. A. Evans and D. M. Barnes, Tetrahedron Lett. 38:57 (1997). 67. W. Oppolzer, Angew. Chem. Int. Ed. Engl. 16:10 (1977); G. Brieger and J. N. Bennett, Chem. Rev. 80:63 (1980); E. Ciganek, Org. React. 32:1 (1984); D. F. Taber, Intramolecular Diels±Alder and Alder Ene Reactions, Springer-Verlag, Berlin, 1984.

Scheme 6.3. Catalytic Enantioselective Diels±Alder Reactions

354 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Entry Dienophile

1a

O

Diene

Catalyst

O O

O

O

N

N

O

94

79

91

88

84

79

91

92

93

94

80

O

N

O S

79

O N

N Cu

t-Bu 3c

95

Ph

O S

82 N Mg

Ph 2b

Yield (%) e.e.

t-Bu

O N ArCH

N

N

CHAr

Cu Ar = 2,6-dichlorophenyl

4d

O O

O

H

O

O

N

N

5e

O O

O O

N

Ph H

O O

H

Ph O TiCl2

O

6f

N Cu

H

H

O O

N

O

H Ph

Ph

Ar H

Ar O TiCl2

O

O

H Ar

Ar

Ar = 2,6-dimethylphenyl

O

7g CH3O

H CH3

Ph

O

H3C

O

O Ti(IV) H

O

O

Scheme 6.3. (continued ) 8h

O H3C

CF3SO2N

O

9i CH2

SECTION 6.1. CYCLOADDITION REACTIONS

Ar

Ar

OCH3

N

355

Al

98

NSO2CF3

93

CH3 Ar = 3,5-dimethylphenyl

CCH

Ar

O

>99.5

Br O

TsN B Bu

Ar = 3-indolyl

a. b. c. d. e. f. g. h. i.

E. J. Corey and K. Ishihara, Tetrahedron Lett. 33:6807 (1992). D. A. Evans, S. J. Miller, and T. Lectka, J. Am. Chem. Soc. 115:6460 (1993). D. A. Evans, T. Lectka, and S. J. Miller, Tetrahedron Lett. 34:7027 (1993). A. K. Ghosh, H. Cho, and J. Cappiello, Tetrahedron Asymmetry 9:3687 (1998). K. Narasaka, N. Iwasawa, M. Inoue, T. Yamada, M. Nakashima, and J. Sugimori, J. Am. Chem. Soc. 111:5340 (1989). E. J. Corey and Y. Matsumura, Tetrahedron Lett. 32:6289 (1991). T. A. Engler, M. A. Letavic, K. O. Lynch, Jr., and F. Takusagawa, J. Org. Chem. 59:1179 (1994). E. J. Corey, S. Sarshar, and D.-H. Lee, J. Am. Chem. Soc. 116:12089 (1994). E. J. Corey, T.-P. Loh, T. D. Roper, M. D. Azimioara, and M. C. Noe, J. Am. Chem. Soc. 114:8290 (1992).

less methylene group and this leads to a more strained transition state. A mixture of stereoisomers is formed, re¯ecting a con¯ict between the Alder rule, which favors endo addition, and conformational factors that favor the exo transition state. The stereoselectivity of a number of intramolecular Diels±Alder reactions has been analyzed, and conformational factors in the transition state seem to play the dominant role in determining product structure.68 Lewis acid catalysis usually substantially improves the stereoselectivity of intramolecular Diels±Alder reactions, just as it does in intermolecular cases. For example, the thermal cyclization of 1 at 160 C gives a 50 : 50 mixture of two stereoisomers, but the use of Et2AlCl as a catalyst permits the reaction to proceed at room temperature, and endo addition is favored by 8 : 1.69 MeO2C

H

MeO2C

H

CO2CH3 1

thermal (160°C) Et2AlCl (23ºC)

H

H

endo T.S.

exo T.S.

50% 88%

50% 12%

68. W. R. Roush, A. I. Ko, and H. R. Gillis, J. Org. Chem. 45:4264 (1980); R. K. Boeckman, Jr. and S. K. Ko, J. Am. Chem. Soc. 102:7146 (1980); W. R. Roush and S. E. Hall, J. Am. Chem. Soc. 103:5200 (1981); K. A. Parker and T. Iqbal, J. Org. Chem. 52:4369 (1987). 69. W. R. Roush and H. R. Gillis, J. Org. Chem. 47:4825 (1982).

Scheme 6.4. Intramolecular Diels±Alder Reactions

356 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

1a

O

O

H 0°C

87%

H3C

H3C

H

CH(CH3)2

CH(CH3)2

H

2b 160°C

95%

CH3 3c

H3C

H

CH3O2C

CH3O2C

(CH3)2CH

(CH3)2CH

H

150°C

60%

H

OH

OH

mixture of stereoisomers

4d

H

H3C

H3C

H

230°C 16 h

N

60%

CH2CH2CH3

H

CH(CH3)2

O

N

CH(CH3)2

O

5e

H O

Et2AlCl

CH OSiR3

6f

62%

O

CH

H

OSiR3 OCH3

H3C

OCH3

H3C

195°C 4.5 h

HO

7

CH2CH2CH3

g

H H

H

HO H3C

H

OH

H3C

OH

200°C

CH3O

91%

H

7.5 h

H

H

H

CH3O a. b. c. d. e. f. g.

D. F. Taber and B. P. Gunn, J. Am. Chem. Soc. 101:3992 (1979). S. R. Wilson and D. T. Mao, J. Am. Chem. Soc. 100:6289 (1978). W. R. Roush, J. Am. Chem. Soc. 102:1390 (1980). W. Oppolzer and E. Flaskamp, Helv. Chim. Acta 60:204 (1977). J. A. Marshall, J. E. Audia, and J. Grote, J. Org. Chem. 49:5277 (1984). T. Kametani, K. Suzuki, and H. Nemoto, J. Org. Chem. 45:2204 (1980); J. Am. Chem. Soc. 103:2890 (1981). P. A. Grieco, T. Takigawa, and W. J. Schillinger, J. Org. Chem. 45:2247 (1980).

It has also been noted in certain systems that the stereoselectivity is a function of the activating substituent on the double bond, both for thermal and Lewis acid-catalyzed reactions.70 The general trend in these systems is consistent with frontier orbital interactions and conformational effects being the main factors in determining stereoselectivity. Because the conformational interactions depend on the substituent pattern in each speci®c case, no general rules regarding stereoselectivity can be put forward. Molecular modeling can frequently identify the controlling structural features.71 As in intermolecular reactions, enantioselectivity can be enforced in intramolecular Diels±Alder additions by use of chiral structures. For example, the dioxolane rings in 2 and 3 result in transition-state structures that lead to enantioselective reactions.72

O

O

O

O H

O

H

O

H

O O

O

H

2 O

O

O

O

O 3

H

O

O

CH3OCH2O O H

OCH2OCH3

H

O

CH3OCH2O

H

Chiral catalysts (see Section 6.1.4) can also achieve enantioselectivity in intramolecular Diels±Alder reactions.

O

O

TBDMSO

N

O

t-Bu

N

Cu

N

O

i-Bu

O O

O TBDMSO

O N H Ref. 73

H 96% e.e.

70. J. A. Marshall, J. E. Audia, and J. Grote, J. Org. Chem. 49:5277 (1984); W. R. Roush, A. P. Essenfeld, and J. S. Warmus, Tetrahedron Lett. 28:2447 (1987); T.-C. Wu and K. N. Houk, Tetrahedron Lett. 26:2293 (1985). 71. K. J. Shea, L. D. Burke, and W. P. England, J. Am. Chem. Soc. 110:860 (1988); L. Raimondi, F. K. Brown, J. Gonzalez, and K. N. Houk, J. Am. Chem. Soc. 114:4796 (1992); D. P. Dolata and L. M. Harwood, J. Am. Chem. Soc. 114:10738 (1992); F. K. Brown, U. C. Singh, P. A. Kollman, L. Raimondi, K. N. Houk, and C. W. Bock, J. Org. Chem. 57:4862 (1992); J. D. Winkler, H. S. Kim, S. Kim, K. Ando, and K. N. Houk, J. Org. Chem. 62:2957 (1997). 72. T. Wong, P. D. Wilson, S. Woo, and A. G. Fallis, Tetrahedron Lett. 38:7045 (1997). 73. D. A. Evans and J. S. Johnson, J. Org. Chem. 62:786 (1997).

357 SECTION 6.1. CYCLOADDITION REACTIONS

358 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

The favorable kinetics of intramolecular Diels±Alder additions can be exploited by temporary links (tethers) between the diene and dienophile components.74 After the addition reaction, the tether can be broken. Siloxy derivatives have been used in this way, because silicon±oxygen bonds can be broken by solvolysis or by ¯uoride ion.75 CH2OH CH3 OSi

CH3

O

75%

TBAF 60°C

Si(CH3)2

CO2CH3

160°C

CH3

CO2CH3

CO2CH3 CH3

Ref. 75a

CH2OH

TBAF, H2O2

OH

CO2CH3 CH3 Ph O

Si

H O

CO2CH3

O

117°C, 112 h, toluene

SiPh2

Ph

HF CH3CN

O H CH3 CO2CH3

H3C

80%

H CH2OH H3C

OH H CO2CH3

Ref. 75d

CH3

Acetals have also been used as removable tethers. O O CH3O2C

O

O 165°C

+ O

H3C CO2CH3

2.7:1

Ref. 76 O

H3C CO2CH3

The activating capacity of boronate groups can be combined with the ability for facile transesteri®cation at boron in such a way as to permit intramolecular reactions between 74. L. Fensterbank, M. Malacria, and S. McN. Sieburth, Synthesis 1997:813; M. Bols and T. Skrydstrup, Chem. Rev. 95:1253 (1995). 75. (a) G. Stork, T. Y. Chan, and G. A. Breault, J. Am. Chem. Soc. 114:7578 (1992); (b) S. McN. Sieburth, and L. Fensterbank, J. Org. Chem. 57:5279 (1992); (c) J. W. Gillard, R. Fortin, E. L. Grimm, M. Maillard, M. Tjepkema, M. A. Bernstein, and R. Glaser, Tetrahedron Lett. 32:1145 (1991); (d) D. Craig and J. C. Reader, Tetrahedron Lett. 33:4073 (1992). 76. P. J. Ainsworth, D. Craig, A. J. P. White, and D. J. Williams, Tetrahedron 52:8937 (1996).

359

vinylboronates and 2,4-dienols.

SECTION 6.2. DIPOLAR CYCLOADDITION REACTIONS

OR B R

R B(OR)2 +

O

OH

OR

OR R

B

R O

H3C

+

B

O Ref. 77

H3C (CH3)3N+O–

R H3C

R

OH

CH2OH

+ HC 3

OH

CH2OH

6.2. Dipolar Cycloaddition Reactions In Chapter 11 of Part A, the mechanistic classi®cation of 1,3-dipolar cycloadditions as a type of concerted cycloadditions was developed. Dipolar cycloaddition reactions are useful both for the synthesis of heterocyclic compounds and for carbon±carbon bond formation. Table 6.2 lists some of the types of molecules that are capable of dipolar cycloaddition. These molecules, which are called 1,3-dipoles, have p-electron systems that are isoelectronic with allyl anion, consisting of two ®lled and one empty orbital. Each molecule has at least one charge-separated resonance structure with opposite charges in a 1,3-relationship. It is this structural feature that leads to the name 1,3-dipolar cycloadditions for this class of reactions.78 The other reactant in a dipolar cycloaddition, usually an alkene or alkyne, is referred to as the dipolarophile. Other multiply bonded functional groups such as imine, azo, and nitroso groups can also act as dipolarophiles. The transition states for 1,3-dipolar cycloadditions involve four p electrons from the 1,3-dipole and two from the dipolarophile. As in the Diels±Alder reaction, the reactants approach one another in parallel planes.

Mechanistic studies have shown that the transition state for 1,3-dipolar cycloaddition is not very polar. The rate of reaction is not strongly sensitive to solvent polarity. In most 77. R. A. Batey, A. N. Thadani, and A. J. Lough, J. Am. Chem. Soc. 121:450 (1999). 78. For comprehensive reviews of 1,3-dipolar cycloaddition reactions, see G. Bianchi, C. DeMicheli, and R. Gandol®, in The Chemistry of Double Bonded Functional Groups, Part I, Supplement A, S. Patai, ed., John Wiley & Sons, New York, 1977, pp. 369±532; A. Padwa, ed., 1,3-Dipolar Cycloaddition Chemistry, John Wiley & Sons, New York, 1984. For a review of intramolecular 1,3-dipolar cycloaddition reactions, see A. Padwa, Angew. Chem. Int. Ed. Engl. 15:123 (1976).

Table 6.2. 1,3-Dipolar Compounds

360 .. N

..

+

N

+

RC



RC

N

CR .. 2

Diazoalkane

. . .–. N NR ..

N

+

.–. NR ..

Azide

RC RC



+

N +

N +

N



Nitrile ylide

CR .. 2 .–. NR .. .–. O ..

Nitrile imine Nitrile oxide

..

RC

+



R2C

N R

.–. O ..

R2C

.–. + N O R ..

.. – O ..

R2C

O ..

Azomethine ylide

CR .. 2

Nitrone

..

CR .. 2

..

.. – O ..

+

Carbonyl oxide

..

..

.N. .. + R2C N R .. + R2C N R .. + R2C .O.

CR .. 2 .–. NR .. .–. O ..

..

RC

N



.N.

+



N

.N.

+

+

CR .. 2

..

..

N

..

+

CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

cases, the reaction is a concerted [2ps ‡ 4ps ] cycloaddition.79 The destruction of charge separation that is implied is more apparent than real, because most 1,3-dipolar compounds are not highly polar. The polarity implied by any single structure is balanced by other contributing structures. .. N

R

δ+

.. N

δ–

N

.. N

R

C

N

..

..

N

C–

..

+

R

R

R C R

Two questions are of immediate interest for predicting the structure of 1,3-dipolar cycloaddition products: (1) What is the regioselectivity? and (2) what is the stereoselectivity? Many speci®c examples demonstrate that 1,3-dipolar cycloaddition is a stereospeci®c syn addition with respect to the dipolarophile. This is what would be expected for a concerted process. N

Ph

N

H

Ph

cis-stilbene

H Ph

Ph

+

PhC

N

trans-stilbene



NPh

N

Ph

N

H

diphenylnitrilimine

Ph



O2N

N

+

N

Ref. 80

H

Ph

Z-CH3CH CHOC3H7

Ph

E-CH3CH CHOC3H7

N

p-nitrophenyl azide

Ref. 81 N O2N

N H H3C

N N H OC3H7

O2N

N H3C

H

N H OC3H7

79. P. K. Kadaba, Tetrahedron 25:3053 (1969); R. Huisgen, G. Szeimes, and L. Mobius, Chem. Ber. 100:2494 (1967); P. Scheiner, J. H. Schomaker, S. Deming, W. J. Libbey, and G. P. Nowack, J. Am. Chem. Soc. 87:306 (1965). 80. R. Huisgen, M. Seidel, G. Wallibillich, and H. Knupfer, Tetrahedron 17:3 (1962). 81. R. Huisgen and G. Szeimies, Chem. Ber. 98:1153 (1965).

With some 1,3-dipoles, two possible stereoisomers can be formed by syn addition. These result from two differing orientations of the reacting molecules, which are analogous to the endo and exo transition states in Diels±Alder reactions. Diazoalkanes, for example, can add to unsymmetrical dipolarophiles to give two diastereomers. –

PhCH N

H

CH3

H

+

Ph

N + CH3O2C

CO2CH3

phenyldiazomethane

H CH3O2C

Ph

N N

+

CH3 CO2CH3

N

H

N

H CH3O2C

Ref. 82

CH3 CO2CH3

Each 1,3-dipole exhibits a characteristic regioselectivity toward different types of dipolarophiles. The dipolarophiles can be grouped, as were dienophiles, depending upon whether they have electron-donating or electron-withdrawing substituents. The regioselectivity can be interpreted in terms of frontier orbital interactions. Depending on the relative orbital energies in the 1,3-dipole and dipolarophile, the strongest interaction may be between the HOMO of the dipole and the LUMO of the dipolarophile or vice versa. Usually, for dipolarophiles with electron-withdrawing groups, the dipole-HOMO=dipolarophile-LUMO interaction is dominant. The reverse is true for dipolarophiles with donor substituents. In some circumstances, the magnitudes of the two interactions may be comparable.83 The prediction of regiochemistry requires estimation or calculation of the energies of the orbitals that are involved, which permits identi®cation of the frontier orbitals. The energies and orbital coef®cients for the most common dipoles and dipolarophiles have been summarized.83 Figure 11.14 in Part A gives the orbital coef®cients of some representative 1,3-dipoles. Regioselectivity is determined by the preference for the orientation that results in bond formation between the atoms having the largest coef®cients in the two frontier orbitals. This analysis is illustrated in Fig. 6.5. CH3C

+

N

O–

+

CH3CH

CH2

LUMO(+2) LUMO(–0.5)

+

CH3CH N

O–

+

CH2

CH3 LUMO(–0.5)

CHCO2CH3 LUMO(0)

dominant dominant

HOMO(–9)

HOMO(–9.7)

HOMO(–11)

HOMO(–10.9) α<β

0.56 0.21 0.80 + N O–

CH3C

CH3CH

LUMO

CH2

HOMO

0.65

β>α

0.15 0.74 + O–

CH2

CH3CH N HOMO

CH3

LUMO CO2CH3

CH3 predicted

O N

CH3

CHCO2CH3

predicted

O N

CH3

CH3 Fig. 6.5. Prediction of regioselectivity of 1,3-dipolar cycloaddition. The energies of the HOMO and LUMO of each reactant (in units of electron volts) are indicated in parentheses. 82. R. Huisgen and P. Eberhard, Tetrahedron Lett. 1971:4343. 83. K. N. Houk, J. Sims, B. E. Duke, Jr., R. W. Strozier, and J. K. George, J. Am. Chem. Soc. 95:7287 (1973); I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John Wiley & Sons, New York, 1977; K. N. Houk, in Pericyclic Reactions, Vol. II, A. P. Marchand and R. E. Lehr, eds., Academic Press, New York, 1977, pp. 181±271.

361 SECTION 6.2. DIPOLAR CYCLOADDITION REACTIONS

362 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Table 6.3. Relative Reactivity of Substituted Alkenes toward Some 1,3-Dipolesa,b Substituted alkene

Ph2CN2

PhN3

Dimethyl fumarate Dimethyl maleate Norbornene Ethyl acrylate Butyl vinyl ether Styrene Ethyl crotonate Cyclopentene Terminal alkene Cyclohexene

100 27.8 1.15 28.8 Ð 0.57 1.0 Ð Ð Ð

31 1.25 700 36.5 1.5 1.5 1.0 6.9 0.8d Ð

+

PhN

N



PhC

NPh

+

N



PhC

O

H 283 7.9 3.1 48 Ð 1.6 1.0 0.13 0.15d 0.011

94 1.61 97 66 15 9.3 1.0 1.04 2.6e 0.055

+

N

CH3

O–

18.3 6.25 0.13 11.1c Ð 0.32 1.0 0.022 0.072d Ð

a. Data are selected from those compiled by R. Huisgen, R. Grashey, and J. Sauer, in Chemistry of Alkenes, S. Patai, ed., John Wiley & Sons, New York, 1964, pp. 806±977. b. Conditions such as solvent and temperature vary for each 1,3-dipole, so comparison from dipole to dipole is not possible. Following Huisgen, Grashey, and Sauer,a ethyl crotonate is assigned reactivity ˆ 1.0 for each 1,3-dipole. c. Methyl ester d. Heptene d. Hexene

In addition to the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity. Norbornene, for example, is consistently more reactive than cyclohexene in 1,3-dipolar cycloadditions. Conjugated functional groups also usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enamines, enol ethers, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with a few 1,3-dipoles are given in Table 6.3. Scheme 6.5 gives some examples of 1,3-dipolar cycloaddition reactions. Dipolar cycloadditions are an important means of synthesis of a wide variety of heterocyclic molecules, some of which are useful intermediates in multistage synthesis. Pyrazolines, which are formed from alkenes and diazo compounds, for example, can be pyrolyzed or photolyzed to give cyclopropanes.

Ph PhCH

CH(OMe)2

Ph

CH(OMe)2



CH2 + N2CHCH(OMe)2

Ref. 84

N N

TBDPSO

TBDPSO

O O

TBDPSO

O

CH2N2

O

N



O O

Ref. 85

N

84. P. Carrie, Heterocycles 14:1529 (1980). 85. M. Martin-Vila, N. Hana®, J. M. Jiminez, A. Alvarez-Larena, J. F. Piniella, V. Branchadell, A. Oliva, and R. M. Ortuno, J. Org. Chem. 63:3581 (1998).

Scheme 6.5. Typical 1,3-Dipolar Cycloaddition Reactions

363

A. Intermolecular cycloaddition

SECTION 6.2. DIPOLAR CYCLOADDITION REACTIONS

1a N O2N

+

N

N



N

N +

N

92%

NO2 2b N

+

N

N

Ph



N + H3CO2CC

N

CCO2CH3

N CO2CH3

H3CO2C 3c

O

O CH2N2 + H2C

87%

CH

80%

O

O

N N

4d

CH3

+

PhCH NCH3 + H2C

CHC

H

N

N O

O–

91%

Ph C

5e

O

N O

O R

R

R C5H11C

PhNCO

CH 60%

Et3N

CH2NO2

C

+

N

O– N

C5H11

O

R = –(CH2)6CO2(CH2)3CH3

B. Intramolecular cycloaddition PhSO2(CH2)3 6f

CH3CH2CH2CHCH2CH2

H

CH3 + PhSO2(CH2)3CH O

NHOH

H

CH3

H

O N CH2CH2CH3 74%

CH3 CH3

7g (CH3)2C

CHCH2CH2CHCH2CH

O

CH3

CH3NHOH⋅HCl NaOCH3 toluene, ∆

O

64–67%

N

CH3

CH3 8h

O– N +

O CH2CH

CH2

toluene ∆

N

1) H2, Pd/C 2) CH2O, HCO2H

CH3N

OH

(continued)

Scheme 6.5. Typical 1,3-Dipolar Cycloaddition Reactions

364 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

9i

PhCH2N

O

O

PhCH2NH HO

PhCH2NHOH

Zn

acetonitrile

HOAc, H2O

S

CHCH2S

S

66%

10j

96%

CH2CH2CH3 +

CH3CO2(CH2)3CH NCH(CH2)2CH

heat

CH2

CH3CH2CH2

N O

O– CH3CO2 CH3 OC(CH3)3

11k

NaOCl

CH3O2C CH3

CH3 OC(CH3)3

(CH2)2CH

CH3O2C

96%

CH3

NOH

N a. b. c. d. e. f. g. h. i. j. k.

O

P. Scheiner, J. H. Schomaker, S. Deming, W. J. Libbey, and G. P. Nowack, J. Am. Chem. Soc. 87:306 (1965). R. Huisgen, R. Knorr, L. Mobius, and G. Szeimies, Chem. Ber. 98:4014 (1965). J. M. Stewart, C. Carlisle, K. Kem, and G. Lee, J. Org. Chem. 35:2040 (1970). R. Huisgen, H. Hauck, R. Grashey, and H. Seidl, Chem. Ber. 101:2568 (1968). A. Barco, S. Benetti, G. P. Pollini, P. G. Baraldi, M. Guarneri, D. Simoni, and C. Gandol®, J. Org. Chem. 46:4518 (1981). N. A. LeBel and N. Balasubramanian, J. Am. Chem. Soc. 111:3363 (1989). N. A. LeBel and D. Hwang, Org. Synth. 58:106 (1978). J. J. Tufariello, G. B. Mullen, J. J. Tegeler, E. J. Trybulski, S. C. Wong, and S. A. Ali, J. Am. Chem. Soc. 101:2435 (1979). P. N. Confalone, G. Pizzolato, D. I. Confalone, and M. R. Uskokovic, J. Am. Chem. Soc. 102:1954 (1980). A. L. Smith, S. F. Williams, A. B. Holmes, L. R. Hughes, Z. Lidert, and C. Swithenbank, J. Am. Chem. Soc. 110:8696 (1988). M. Ihara, Y. Tokunaga, N. Taniguchi, K. Fukumoto, and C. Kabuto, J. Org. Chem. 56:5281 (1991).

Intramolecular 1,3-dipolar cycloadditions have proven to be especially useful in synthesis. The addition of nitrones to alkenes serves both to form a carbon±carbon bond and to introduce oxygen and nitrogen functionality.86 Entry 7 in Scheme 6.5 is an example. The nitrone B is generated by condensation of the aldehyde group with N -methylhydroxylamine and then goes on to product by intramolecular cycloaddition. CH3 H3C –O

+

N

CH3

CH3 B

The products of nitrone±alkene cycloadditions are isoxazolines, and the oxygen±nitrogen bond can be cleaved by reduction, leaving both an amino and a hydroxy function in place. 86. For reviews of nitrone cycloadditions, see D. St. C. Black, R. F. Crozier, and V. C. Davis, Synthesis 1975:205; J. J. Tufariello, Acc. Chem. Res. 12:396 (1979); P. N. Confalone and E. M. Huie, Org. React. 36:1 (1988).

A number of clever syntheses have employed this strategy. Entry 8 in Scheme 6.5 shows the ®nal steps in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxyl group is ensured by the structure of the isoxazoline from which it is formed by reduction. Entry 9 portrays the early stages of a synthesis of the biologically important molecule biotin. Nitrile oxides, which are formed by dehydration of nitroalkanes or by oxidation of oximes with hypochlorite,87 are also useful 1,3-dipoles. They are highly reactive and must be generated in situ.88 They react with both alkenes and alkynes. Entry 5 in Scheme 6.5 is an example in which the cycloaddition product (an isoxazole) was eventually converted to a prostaglandin derivative. As with the Diels±Alder reaction, it is possible to achieve enantioselective cycloaddition in the presence of chiral catalysts.89 The Ti(IV) catalyst C with chiral diol ligands leads to moderate to high enantioselectivity in nitrone±alkene cycloadditions.90

Ph

Ph

O Ph

+

–O

O

O

O

Ti(OTs)2

O

Ph

H + CH3

N

O

N

O

C

Ph

Ph Ph

O

CH3

N

Ph

O

CH3

N

+ N

Ph

O

N

Ph

O O exo

O

O O endo

5:95

93% e.e.

Other effective catalysts include Yb(O3SCF3)391 with BINOL, Mg2‡ -bis-oxazolines,92 and oxaborolidines.93 Intramolecular nitrone cycloadditions can be facilitated by Lewis acids such as ZnCl2.94 The catalysis can be understood as resulting from a lowering of the LUMO energy of the 1,3-dipole, reasoning which is analogous to that employed to account for the Lewis acid catalysis of Diels±Alder reactions. The more organized transistion state, incorporating the metal ion and associated ligands, then enforces a 87. 88. 89. 90. 91. 92. 93. 94.

G. A. Lee, Synthesis 1982:508. K. Torssell, Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis, VCH Publishers, New York, 1988. K. V. Gothelf and K. A. Jorgensen, Chem. Rev. 98:863 (1998); M. Frederickson, Tetrahedron 53:403 (1997). K. V. Gothelf and K. A. Jorgensen, Acta Chem. Scand. 50:652 (1996); K. B. Jensen, K. V. Gothelf, R. G. Hazell, and K. A. Jorgensen, J. Org. Chem. 62:2471 (1997); K. B. Jensen, K. V. Gothelf, and K. A. Jorgensen, Helv. Chim. Acta 80:2039 (1997). M. Kawamura and S. Kobayashi, Tetrahedron Lett. 40:3213 (1999). G. Desimoni, G. Faita, A. Mortoni, and P. Righetti, Tetrahedron Lett. 40:2001 (1999); K. V. Gothelf, R. G. Hazell, and K. A. Jorgensen, J. Org. Chem. 63:5483 (1998). J. P. G. Seerden, M. M. M.Boeren, and H. W. Scheeren, Tetrahedron 53:11843 (1997). J. Marcus, J. Brussee, and A. van der Gen, Eur. J. Org. Chem. 1998:2513.

365 SECTION 6.2. DIPOLAR CYCLOADDITION REACTIONS

366

preferred orientation of the reagents.

CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

alkene

LUMO

dipole dipole–Lewis acid

HOMO

The change in frontier orbitals by coordination of a Lewis acid to the dipole

An interesting variation of the 1,3-dipolar cycloaddition involves generation of 1,3dipoles from three-membered rings. As an example, aziridines 4 and 6 give adducts derived from apparent formation of 1,3-dipoles 5 and 7, respectively.95

Ar H

N

CH3O2C

H

CH3O2C

CHX

CO2CH3

CO2CH3

X Ar

Ar CO2CH3 H

6

CH2

5

Ar N

H

N



H

CO2CH3

CH3O2C

N+

CH3O2C

4

H

Ar

Ar

CH3O2C

N+

CH3O2C



H

H 7

CO2CH3

CH2

CHX

N CO2CH3 X

The evidence for the involvement of 1,3-dipoles as discrete intermediates includes the observation that the reaction rates are independent of dipolarophile concentration. This fact indicates that the ring opening is the rate-determining step in the reaction. Ring opening is most facile for aziridines that have an electron-attracting substituent to stabilize the carbanion center in the dipole. Cyclopropanones are also reactive toward certain types of cycloadditions. Theoretical modeling indicates that a dipolar species resulting from reversible cleavage of the cyclopropanone ring is the reactive species.96 cis-Disubstituted cyclopropanes with bulky substituents exhibit NMR features that indicate a barrier of 10±13 kcal=mol for 95. R. Huisgen and H. Mader, J. Am. Chem. Soc. 93:1777 (1971). 96. D. Lim, D. A. Hrovat, W. T. Borden, and W. L. Jorgenson, J. Am. Chem. Soc. 116:3494 (1994); B. A. Hess, Jr., U. Eckart, and J. Fabian, J. Am. Chem. Soc. 120:12310 (1998).

the ring-opening process.97

367 O

SECTION 6.3. [2 + 2] CYCLOADDITIONS AND OTHER REACTIONS LEADING TO CYCLOBUTANES



O R

R +

R

R

∆G‡ = 10–13 kcal/mol for R = (CH3)2CCH2CH3, (CH3)2CCH(CH3)2, (CH3)2CC(CH3)3

The ring-opened intermediates, which are known as oxyallyl cations, can also be generated by a number of other reaction processes.98 O–

O

O

(C2H5)3N H2O

O CH3

O

CH3

+

+

O

Cl

Ref. 99

O

CH3

CH3 30:70 76% total yield

O

OSi(CH3)3 + O

(CH3)3SiO3SCF3

H2C

CH(OCH3)2

5 mol %

OCH3

67%

Ref. 100

O

6.3. [2 + 2] Cycloadditions and Other Reactions Leading to Cyclobutanes [2 ‡ 2] Cycloadditions of ketenes and alkenes have been shown to have synthetic utility for the preparation of cyclobutanones.101 The stereoselectivity of ketene±alkene cycloaddition can be analyzed in terms of the Woodward±Hoffmann rules.102 To be an allowed process, the [2p ‡ 2p] cycloaddition must be suprafacial in one component and antarafacial in the other. An alternative description of the transition state is a [2ps ‡ …2ps ‡ 2ps †] addition.103 Figure 6.6 illustrates these transition states. The ketene, utilizing its low-lying LUMO, is the antarafacial component and interacts with the HOMO of the alkene. The stereoselectivity of ketene cycloadditions can be rationalized in terms of steric effects in this transition state. Minimization of interaction between the substituents R and R0 leads to a cyclobutanone in which these substituents are cis. This is the 97. T. S. Sorensen and F. Sun, J. Chem. Soc., Perkin Trans. 2 1998:1053. 98. N. J. Turro, S. S. Edelson, J. R. Williams, T. R. Darling, and W. B. Hammond, J. Am. Chem. Soc. 91:2283 (1969); S. S. Edelson and N. J. Turro, J. Am. Chem. Soc. 92:2770 (1970); N. J. Turro, Acc. Chem. Res. 2:25 (1969); J. Mann, Tetrahedron 42:4611 (1986). 99. A. Lubineau and G. Bouchain, Tetrahedron Lett. 38:8031 (1997). 100. D. H. Murray and K. F. Albizati, Tetrahedron Lett. 31:4109 (1990). 101. For reviews, see W. T. Brady in The Chemistry of Ketenes, Allenes, and Related Compounds, S. Patai, ed., John Wiley & Sons, New York, 1980, Chapter 8; W. T. Brady, Tetrahedron 37:2949 (1981). 102. R. B. Woodward and R. Hoffmann, Angew. Chem. Int. Ed. Engl. 8:781 (1969). 103. E. Valenti, M. A. Pericas, and A. Moyano, J. Org. Chem. 55:3582 (1990).

368

stereochemistry usually observed in these reactions.

CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

H

H C

C

O

O +

Ref. 104

C2H5 H

H C2H5

Ketenes are especially reactive in [2 ‡ 2] cycloadditions, and an important reason is that they offer a low degree of steric interactions in the transition state. Another reason is the electrophilic character of the ketene LUMO. The best yields are obtained in reactions in which the ketene has an electronegative substituent, such as halogen. Simple ketenes are not very stable and usually must be generated in situ. The most common method for generating ketenes for synthesis is by dehydrohalogenation of acyl chorides. This is usually done with an amine such as triethylamine.105 Other activated carboxylic acid derivatives, such as acyloxypyridinium ions, have also been used as ketene precursors106 H

H

R

R′

HOMO of alkene

O

LUMO of ketene (a)

R

H

H

O

R′

O

R′ H

R′

R H

O

R (b)

R O

H

R

O

H R

H R

H (c)

Fig. 6.6. HOMO±LUMO interactions in the [2 ‡ 2] cycloaddition of an alkene and a ketene. (a) Frontier orbitals of alkene and ketene. (b) [2ps ‡ 2pa ] Transition state required for suprafacial addition to alkene and antarafacial addition to ketene, leading to R and R0 in cis orientation in cyclobutanone products. (c) [2ps ‡ …2ps ‡ 2ps †] alternative transition state. 104. M. Rey, S. M. Roberts, A. S. Dreiding, A. Roussel, H. Vanlierde, S. Toppert, and L. Ghosez, Helv. Chim. Acta 65:703 (1982). 105. K. Shishido, T. Azuma, and M. Shibuya, Tetrahedron Lett. 31:219 (1990). 106. R. L. Funk, P. M. Novak, and M. M. Abelman, Tetrahedron Lett. 29:1493 (1988).

Scheme 6.6. [2 ‡ 2] Cycloadditions of Ketenes

369

CH3

1a + (CH3)2C

C

CH3

O

SECTION 6.3. [2 + 2] CYCLOADDITIONS AND OTHER REACTIONS LEADING TO CYCLOBUTANES

77%

O 2b

O CH2 + CH3CHCCl

Et3N

O

Cl

CH3 Cl H

H 3c

O

O

Et3N

+ CH3CHCCl

O +

0–5°C

Cl

Cl

H

CH3 H

CH3 63%

4d

R3SiO

R3SiO

CH3

O + Cl2CHCCl

H 5e

CH2

14%

CH3

O Cl

H

Cl

CH3

CH3 N

Cl 35–47%

(C2H5)3N

O

CO2H a. b. c. d. e.

Cl

Et3N

CH3

CH(CH2)2

60%

A. P. Krapcho and J. H. Lesser, J. Org. Chem. 31:2030 (1966). W. T. Brady and A. D. Patel, J. Org. Chem. 38:4106 (1973). W. T. Brady and R. Roe, J. Am. Chem. Soc. 93:1662 (1971). P. A. Grieco, T. Oguri, and S. Gilman, J. Am. Chem. Soc. 102:5886 (1980). R. L. Funk, P. M. Novak, and M. M. Abraham, Tetrahedron Lett. 29:1493 (1988).

(see entry 5 in Scheme 6.6). Ketene itself and certain alkyl derivatives can be generated by pyrolysis of carboxylic anhydrides.107 Scheme 6.6 gives some speci®c examples of ketene±alkene cycloadditions. Intramolecular ketene cycloadditions are possible if the ketene and alkene functionalities can achieve an appropriate orientation.108

EtNH(i-Pr)

CH2COCl

43%

105°C

Ref. 109

O

107. G. J. Fisher, A. F. MacLean, and A. W. Schnizer, J. Org. Chem. 18:1055 (1953). 108. B. B. Snider, R. A. H. F. Hui, and Y. S. Kulkarni, J. Am. Chem. Soc. 107:2194 (1985); B. B. Snider and R. A. H. F. Hui, J. Org. Chem. 50:5167 (1985); W. T. Brady and Y. F. Giang, J. Org. Chem. 50:5177 (1985). 109. E. J. Corey and M. C. Desai, Tetrahedron Lett. 26:3535 (1985).

370 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Cyclobutanes can also be formed by nonconcerted processes involving zwitterionic intermediates. The combination of an electron-rich alkene (enamine, enol ether) and a very electrophilic one (nitro- or polycyanoalkene) is required for such processes. ERG C

ERG

C EWG

C

C

C

C

ERG

C

C

EWG

+ –

EWG ERG = electron releasing group (–OR, –NR2) EWG = electron withdrawing group (–NO2, –C≡N)

Two examples of this reaction type are:

CH3CH2CH

CHN

+ PhCH

CHNO2

N

CH3CH2

100%

Ph

NO2

Ref. 110

CN H3C

CHOCH3 + (NC)2C

CN

C(CN)2

90%

CN CH3O

Ref. 111

CN

The stereochemistry of these reactions depends on the lifetime of the dipolar intermediate, which, in turn, is in¯uenced by the polarity of the solvent. In the reactions of enol ethers with tetracyanoethylene, the stereochemistry of the enol ether portion is retained in nonpolar solvents. In polar solvents, cycloaddition is nonstereospeci®c, as a result of a longer lifetime for the zwitterionic intermediate.112

6.4. Photochemical Cycloaddition Reactions Photochemical cycloadditions provide a method that is often complementary to thermal cycloadditions with regard to the types of compounds that can be prepared. The theoretical basis for this complementary relationship between thermal and photochemical modes of reaction lies in orbital symmetry relationships, as discussed in Chapter 13 of Part A. The reaction types permitted by photochemical excitation that are particularly useful for synthesis are [2 ‡ 2] additions between two carbon±carbon double bonds and [2 ‡ 2] additions of alkenes and carbonyl groups to form oxetanes. Photochemical cycloadditions are often not concerted processes because in many cases the reactive excited state is a triplet. The initial adduct is a triplet 1,4-diradical, which must undergo spin inversion before product formation is complete. Stereospeci®city is lost if the intermediate 1,4110. M. E. Kuehne and L. Foley, J. Org. Chem. 30:4280 (1965). 111. J. K. Williams, D. W. Wiley, and B. C. McKusick, J. Am. Chem. Soc. 84:2210 (1962). 112. R. Huisgen, Acc. Chem. Res. 10:117, 199 (1977).

371

diradical undergoes bond rotation faster than ring closure.

C



C

3

* C

C

intersystem crossing

3

C

C

* C

C

* C

C

1

C

+

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

Intermolecular photocycloadditions of alkenes can be carried out by photosensitization with mercury or directly with short-wavelength light.113 Relatively little preparative use has been made of this reaction for simple alkenes. Dienes can be photosensitized using benzophenone, butane-2,3-dione, or acetophenone.114 The photodimerization of derivatives of cinnamic acid was among the earliest photochemical reactions to be studied.115 Good yields of dimers are obtained when irradiation is carried out in the crystalline state. In solution, cis±trans isomerization is the dominant reaction. Ph CO2H PhCH

CHCO2H

hν H2O

56%

HO2C

Ph

The presence of Cu(I) salts promotes intermolecular photocycloaddition of simple alkenes. Copper(I) tri¯ate is especially effective.116 It is believed that the photoreactive species is a 2 : 1 alkene : Cu(I) complex in which the two alkene molecules are brought together prior to photoexcitation.117

2 RCH CH2 + Cu1

H H C

H R C CuI C R H HC H

H

H

CuO3SCF3

R H

H

H

H

+



H

113. 114. 115. 116. 117.

R hν

H

H. Yamazaki and R. J. Cvetanovic, J. Am. Chem. Soc. 91:520 (1969). G. S. Hammond, N. J. Turro, and R. S. H. Liu, J. Org. Chem. 28:3297 (1963). A. Mustafa, Chem. Rev. 51:1 (1962). R. G. Salomon, Tetrahedron 39:485 (1983); R. G. Salomon and S. Ghosh, Org. Synth. 62:125 (1984). R. G. Salomon, K. Folking, W. E. Streib, and J. K. Kochi, J. Am. Chem. Soc. 96:1145 (1974).

SECTION 6.4. PHOTOCHEMICAL CYCLOADDITION REACTIONS

372 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Intramolecular [2 ‡ 2] photocycloaddition of dienes is an important method of formation of bicyclic compounds containing four-membered rings.118 Direct irradiation of simple nonconjugated dienes leads to cyclobutanes.119 Strain makes the reaction unfavorable for 1,4-dienes, but when the alkene units are separated by at least two carbon atoms, cycloaddition becomes possible.

+

Ref. 120

The most widely exploited photochemical cycloadditions involve irradiation of dienes in which the two double bonds are fairly close and result in formation of polycyclic cage compounds. Some examples are given in Scheme 6.7. Copper(I) tri¯ate facilitates these intramolecular additions, as was the case for intermolecular reactions. OH

CH

OH

CH2 CuO3SCF3

CH2CH

H

Ref. 121

51%



CH2

H

Another class of molecules that undergo photochemical cycloadditions is a,bunsaturated ketones.122 The reactive excited state is either an n±p* or a p±p* triplet. The reaction is most successful with cyclopentenones and cyclohexenones. The excited states of acyclic enones and larger ring compounds are rapidly deactivated by cis±trans isomerization and do not readily add to alkenes. Photoexcited enones can also add to alkynes.123 Unsymmetrical alkenes can undergo two regioisomeric modes of addition. It is generally observed that alkenes with donor groups are oriented such that the substituted carbon becomes bound to the b carbon, whereas with acceptor substituents the other orientation is preferred.124 Selectivity is low for alkenes without strong donor or acceptor substituents.125 O

O

O

X +

X



or X favored for X = electron donor

favored for X = electron acceptor

118. P. deMayo, Acc. Chem. Res. 4:41 (1971). 119. R. Srinivasan, J. Am. Chem. Soc. 84:4141 (1962); R. Srinivasan, J. Am. Chem. Soc. 90:4498 (1968). 120. J. Meinwald and G. W. Smith, J. Am. Chem. Soc. 89:4923 (1967); R. Srinivasan and K. H. Carlough, J. Am. Chem. Soc. 89:4932 (1967). 121. K. Avasthi and R. G. Salomon, J. Org. Chem. 51:2556 (1986). 122. A. C. Weedon, in Synthetic Organic Photochemistry, W. M. Horspool, ed., Plenum, New York, 1984, Chapter 2; D. I. Schuster, G. Lem, and N. A. Kaprinidis, Chem. Rev. 93:3 (1993); M. T. Crimmins and T. L. Reinhold, Org. React. 44:297 (1993). 123. R. L. Cargill, T. Y. King, A. B. Sears, and M. R. Willcott, J. Org. Chem. 36:1423 (1971); W. C. Agosta and W. W. Lowrance, J. Org. Chem. 35:3851 (1970). 124. E. J. Corey, J. D. Bass, R. Le Mahieu, and R. B. Mitra, J. Am. Chem. Soc. 86:5570 (1984). 125. J. D. White and D. N. Gupta, J. Am. Chem. Soc. 88:5364 (1966); P. E. Eaton, Acc. Chem. Res. 1:50 (1968).

Scheme 6.7. Intramolecular [2 ‡ 2] Photochemical Cycloaddition Reactions of Dienes

SECTION 6.4. PHOTOCHEMICAL CYCLOADDITION REACTIONS

1a hν CuCl

2b

43%

H

CH3 CH2

CHCHCCH2CH CH2

hν CuO3SCF3

HO CH3

H3C 90%

H3C H

HO H

HO

3c HO

H

HO

CuO3SCF3

+

70%



CH3

CH3 85:15

4d

H

O2CCH3

H

O2CCH3

hν pentane

5e

74%

CO2C2H5

CO2C2H5

H5C2O2C

H5C2O2C hν acetone

80%

O

O H

6f H TBDMSO a. b. c. d. e. f.



H

373

H

83%

TBDMSO

P. Srinivasan, Org. Photochem. Synth. 1:101 (1971); J. Am. Chem. Soc. 86:3318 (1964). R. G. Salomon and S. Ghosh, Org. Synth. 62:125 (1984). K. Langer and J. Mattay, J. Org. Chem. 60:7256 (1995). P. G. Gassman and D. S. Patton, J. Am. Chem. Soc. 90:7276 (1968). B. M. Jacobson, J. Am. Chem. Soc. 95:2579 (1973). M. Thommen and R. Keese, Synlett. 1997:231.

The cycloadditions are believed to proceed through 1,4-diradical intermediates. Trapping experiments with hydrogen-atom donors indicated that the initial bond formation can take place at either the a or b carbon of the enone. The ®nal product ratio re¯ects both the rate of formation of the diradical and the ef®ciency of ring closure.126 126. D. I. Schuster, G. E. Heibel, P. B. Brown, N. J. Turro, and C. V. Kumar, J. Am. Chem. Soc. 110:8261 (1988); D. Andrew, D. J. Hastings, and A. C. Weedon, J. Am. Chem. Soc. 116:10870 (1994).

374 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Intramolecular enone±alkene cycloadditions are also possible. O

O

(CH3)2CHCH2

(CH3)2CHCH2



Ref. 127

H3C CH3

In the case of b-(5-pentenyl) substituents, there is a general preference for exo-type cyclization to form a ®ve-membered ring.127,128 This is consistent with the general pattern for radical cyclizations and implies initial bonding at the b carbon of the enone. O

O

O



not

Some examples of photochemical enone±alkene cycloadditions are given in Scheme 6.8. With many other ketones and aldehydes, reaction between the photoexcited carbonyl chromophore and alkene can result in formation of four-membered cyclic ethers (oxetanes). This reaction is often referred to as the Paterno±BuÈchi reaction.129 R R2C

O + R′CH

CHR′

R

R′ O R′

The reaction is stereospeci®c for at least some aliphatic ketones but not for aromatic carbonyl compounds.130 This result suggests that the reactive excited state is a singlet for aliphatics and a triplet for aromatics. With aromatic aldehydes and ketones, the regioselecitivity of addition can usually be predicted on the basis of formation of the more stable of the two possible diradical intermediates by bond formation between oxygen and the alkene. X O PhCH ⋅

CH2 ⋅CH

X

>

O PhCH ⋅

CH ⋅CH2

127. P. J. Connolly and C. H. Heathcock, J. Org. Chem. 50:4135 (1985). 128. W. C. Agosta and S. Wolff, J. Org. Chem. 45:3139 (1980); M. C. Pirrung, J. Am. Chem. Soc. 103:82 (1981). 129. D. R. Arnold, Adv. Photochem. 6:301 (1968); H. A. J. Carless, in Synthetic Organic Photochemistry, W. M. Horspool, ed., Plenum, New York, 1984, Chapter 8. 130. N. C. Yang and W. Eisenhardt, J. Am. Chem. Soc. 93:1277 (1971); D. R. Arnold, R. L. Hinman, and A. H. Glick, Tetrahedron Lett. 1964:1425; N. J. Turro and P. A. Wriede, J. Am. Chem. Soc. 90:6863 (1968); J. A. Barltrop and H. A. J. Carless, J. Am. Chem. Soc. 94:8761 (1972).

Scheme 6.8. Photochemical Cycloaddition Reactions of Enones with Alkenes and Alkynes 1a

N C

+ H2C



CH2

62%

O

O

2b + H2C



CH2

50%

O

O 3c

O

O

H3C

H

H3C

(CH3)2CH H

hν CH2Cl2

+

H3C

60%

67%

CO2CH3

CO2CH3

O

O CH3

O + CH3CH2C

hν Ph2CO

CCH3

O CH3CH2

O 6f

79%

O

O

O

OCCH3

OCCH3 hν cyclohexane

78%

C O 7g

O O

O CH3 CH2

hν hexane

CH3 CH3

77%

CH2CH2CH2CCH3 CH3 a. b. c. d. e. f. g.

H

H

+

CH(CH3)2

4d

O

H

hν benzene

+

5e

SECTION 6.4. PHOTOCHEMICAL CYCLOADDITION REACTIONS

C

N

375

H3C

W. C. Agosta and W. W. Lowrance, Jr., J. Org. Chem. 35:3851 (1970). P. E. Eaton and K. Nyi, J. Am. Chem. Soc. 93:2786 (1971). P. Singh, J. Org. Chem. 36:3334 (1971). P. A. Wender and J. C. Lechleiter, J. Am. Chem. Soc. 99:267 (1977). R. M. Scarborough, Jr., B. H. Toder, and A. B. Smith III, J. Am. Chem. Soc. 102:3904 (1980). W. Oppolzer and T. Godel, J. Am. Chem. Soc. 100:2583 (1978). M. C. Pirrung, J. Am. Chem. Soc. 101:7130 (1979).

(CH3)2CH H

30%

376 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Stereochemistry can also be interpereted in terms of conformational effects in the 1,4diradical intermediates.131 Vinyl enol ethers and enamides add to benzaldehyde to give 3-substituted oxetanes, usually with the cis isomer preferred.132±135 OTMS PhCH

O + CH2

O hν

C

C(CH3)3 Ph

C(CH3)3

59%

Ref. 132

OTMS O

PhCH



O +

Ph H3C

O

32%

H3C

Ref. 133

O

O PhCH



O +

Ph

Ref. 134

N

N

COCH3

COCH3

Some other examples of Paterno±BuÈchi reactions are given in Scheme 6.9.

6.5. [3,3] Sigmatropic Rearrangements The mechanistic basis of sigmatropic rearrangements was introduced in Chapter 11 of Part A. The sigmatropic process that is most widely applied in synthesis is the [3,3] sigmatropic rearrangement. The principles of orbital symmetry establish that concerted [3,3] sigmatropic rearrangements are allowed processes. Stereochemical predictions and analyses are based on the cyclic transition state implied by a concerted reaction mechanism. Some of the various [3,3] sigmatropic rearrangements that are used in synthesis are presented in outline form in Scheme 6.10.136 6.5.1. Cope Rearrangements The Cope rearrangement is the conversion of a 1,5-hexadiene derivative to an isomeric 1,5-hexadiene by the [3,3] sigmatropic mechanism. The reaction is both stereospeci®c and stereoselective. It is stereospeci®c in that a Z or E con®gurational relationship at either double bond is maintained in the transition state and governs the stereochemical relationship at the newly formed single bond in the product.137 However, the relationship depends upon the conformation of the transition state. When a chair transition state is favored, the E,E- and Z,Z-dienes lead to anti-3,4-diastereomers whereas the E,Z and Z,E-isomers give the 3,4-syn product. Transition-state conformation also 131. 132. 133. 134. 135. 136.

A. G. Griesbeck and S. StadtmuÈller, J. Am. Chem. Soc. 113:6923 (1991). T. Bach, Tetrahedron Lett. 32:7037 (1991). A. G. Griesbeck and S. StadtmuÈller, J. Am. Chem. Soc. 113:6923 (1991). T. Bach, Liebigs Ann. Chem. 1997:1627. T. Bach, Synthesis 1998:683. For reviews of synthetic application of [3,3] sigmatropic rearrangements, see G. B. Bennett, Synthesis 1977:58; F. E. Ziegler, Acc. Chem. Res. 10:227 (1977). 137. W. v. E. Doering and W. R. Roth, Tetrahedron 18:67 (1962).

Scheme 6.9. Photochemical Cycloaddition Reactions of Carbonyl Compounds with Alkenes 1a PhCH

O



O +

377 SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

38%

Ph H 2b + Ph2CH

O

hν benzene

O

81%

Ph Ph

3c H

hν benzene

CCH3

83%

O CH3

O 4d PhCH

O + PhCH

CH2

O



31%

Ph

Ph

a. J. S. Bradshaw, J. Org. Chem. 31:237 (1966). b. D. R. Arnold, A. H. Glick, and V. Y. Abraitys, Org. Photochem. Synth. 1:51 (1971). c. R. R. Sauers, W. Schinski, and B. Sickles, Org. Photochem. Synth. 1:76 (1971). d. H. A. J. Carless, A. K. Maitra, and H. S. Trivedi, J. Chem. Soc., Chem. Commun. 1979:984.

determines the stereochemistry of the new double bond. If both E- and Z-stereoisomers are possible for the product, the product ratio will normally re¯ect product (and transitionstate) stability. Thus, an E arrangement is normally favored for the newly formed double bonds. The stereochemical aspects of the Cope rearrangements for relatively simple reactants are consistent with a chairlike transition state in which the larger substituent at C-3 (or C-4) adopts an equatorial-like conformation.

favored

E,E-isomer

E,Z-isomer equal

disfavored

syn-stereoisomer

Z,Z-isomer

anti-stereoisomer

E,Z-isomer

Scheme 6.10. [3,3] Sigmatropic Rearrangements

378 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

1a

Cope rearrangement

2b

Oxy-Cope rearrangement HO

O

HO

3c Anionic oxy-Cope rearrangement –



O

O

O H+

4d Claisen rearrangement of allyl vinyl ethers O

O

5d Claisen rearrangement of allyl phenyl ethers O

6e

O

OH

Ortho ester Claisen rearrangement RO

OR

OR

O

–ROH

O

OR O

7f Claisen rearrangement of O-allyl-O′-trimethylsilyl ketene acetals OSiMe3 O

8g

OSiMe3 O

Ester enolate Claisen rearrangement O– O

9h

O– O

Claisen rearrangement of O-allyl-N,N-dialkyl ketene aminals NR2 O

NR2 O

379

Scheme 6.10. (continued )

SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

10i Aza-Claisen rearrangement of O-allyl imidates R O

a. b. c. d. e. f. g. h. i.

R NH

NH

O

S. J. Rhoads and N. R. Raulins, Org. React. 22:1 (1975). J. A. Berson and M. Jones, Jr., J. Am. Chem. Soc. 86:5019 (1964). D. A. Evans and A. M. Golob, J. Am. Chem. Soc. 97:4765 (1975). D. S. Tarbell, Org. React. 2:1 (1944). W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom, T. Li, D. J. Faulkner, and M. R. Petersen, J. Am. Chem. Soc. 92:741 (1970). R. E. Ireland and R. H. Mueller, J. Am. Chem. Soc. 94:5898 (1972). R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. Soc. 98:2868 (1976). D. Felix, K. Gschwend-Steen, A. E. Wick, and A. Eschenmoser, Helv. Chim. Acta 52:1030 (1969). L. E. Overman, Acc. Chem. Res. 13:218 (1980).

Because of the concerted mechanism, chirality at C-3 (or C-4) leads to enantiospeci®c formation of new chiral centers at C-1 (or C-6).138 These relationships are illustrated in the example below. Both the con®guration of the new chiral center and that of the new double bond are those expected on the basis of a chairlike transition state. Because there are two stereogenic centers, the double bond and the asymmetric carbon, there are four possible stereoisomers of the product. Only two are formed. The E-double-bond isomer has the Scon®guration at C-4 whereas the Z-isomer has the R-con®guration. These are the products expected for a chair transition state. The stereochemistry of the new double bond is determined by the relative stability of the two chair transition states. Transition state B is less favorable than A because of the axial placement of the larger phenyl substituent. H

Ph Ph H3C

CH3

B

H3C

R

E

H

CH3

Ph

H CH3

Ph

H

Z

S

H3C

CH3 R 13%

A

CH3

H

Ph

CH3

E

CH3

87%

The products corresponding to boatlike transition states are usually not observed for acyclic dienes. However, the boatlike transition state is allowed, and if steric factors make a 138. R. K. Hill and N. W. Gilman, J. Chem. Soc., Chem. Commun. 1967:619; R. K. Hill, in Asymmetric Synthesis, Vol. 4, J. D. Morrison, ed., Academic Press, New York, 1984, pp. 503±572.

380

boat transition state preferable to a chair, reaction will proceed through a boat.

CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

CH3

CH3

CH3 R

E

R

Ph

E

Ph

CH3 Ph

Ph

CH3 Ph

Ph

CH3

R

CH3

CH3 E

CH3

H CH3

H Z

CH3

S

CH3

Cope rearrangements are reversible reactions, and, because there are no changes in the number or types of bonds as a result of the reaction, to a ®rst approximation the total bond energy is unchanged. The position of the ®nal equilibrium is governed by the relative stability of the starting material and the product. In the example just cited, the equilibrium is favorable for product formation because the product is stabilized by conjugation of the alkene with the phenyl ring. Some other examples of Cope rearrangements are given in Scheme 6.11. In entry 1, the equilibrium is biased toward product by the fact that the double bonds in the product are more highly substituted, and therefore more stable, than those in the reactant. In entry 2, a gain in conjugation is offset by the formation of a less highly substituted double bond, and the equilibrium mixture contains both dienes. When ring strain is relieved, Cope rearrangements can occur at much lower temperatures and with complete conversion to ring-opened products. A striking example of such a process is the conversion of cis-divinylcyclopropane to 1,4-cycloheptadiene, a reaction which occurs readily at temperatures below 40 C.139

Entry 3 in Scheme 6.11 illustrates the application of a cis-divinylcyclopropane rearrangement in the prepartion of an intermediate for the synthesis of pseudoguaiane-type natural products. Several transition-metal species, especially Pd(II) salts, have been found to catalyze Cope rearrangements.140 The catalyst that has been adopted for synthetic purposes is PdCl2(CH3CN)2. With this catalyst, the rearrangement of 8 to 9 and 10 occurs at room temperature, as contrasted to 240 C in its absence.141 The catalyzed reaction shows

139. W. v. E. Doering and W. R. Roth, Tetrahedron 19:715 (1963). 140. R. P. Lutz, Chem. Rev. 84:205 (1984). 141. L. E. Overman and F. M. Knoll, J. Am. Chem. Soc. 102:865 (1980).

Scheme 6.11. Cope Rearrangements of 1,5-Dienes

381

A. Thermal 1a

350°C 1h

100%

CH2 CH2 2b

SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

CH2 CH2 CH3

H3C K = 0.25

H3C 3c

H

CH3

275°C

CO2C2H5

CO2C2H5

CH3

H 98°C

80–90%

CH3 CH3 O 4d

O OH

CH

O

CH2 320°C

90%

CH

CH2

B. Anionic oxy-Cope 5e H

KH, THF

98%

reflux, 18 h

OH

H O

6f

CH3 C

CH3 CH2 KH

H3C

7g

CH3O

OH

CH

CH2

18-crown-6, 25°C, 18 h

75%

H3C

O

OCH3 CH3 H OH

H

KH, THF

C2H5

25°C

C2H5

H CH3O

O OCH3

CH3 a. b. c. d. e.

K. J. Shea and R. B. Phillips, J. Am. Chem. Soc. 102:3156 (1980). F. E. Zeigler and J. J. Piwinski, J. Am. Chem. Soc. 101:1612 (1979). P. A. Wender, M. A. Eissenstat, and M. P. Filosa, J. Am. Chem. Soc. 101:2196 (1979). E. N. Marvell and W. Whalley, Tetrahedron Lett. 1970:509. D. A. Evans, A. M. Golob, N. S. Mandel, and G. S. Mandel, J. Am. Chem. Soc. 100:8170 (1978). f. W. C. Still, J. Am. Chem. Soc. 99:4186 (1977). g. L. A. Paquette, K. S. Learn, J. L. Romine, and H.-S. Lin, J. Am. Chem. Soc. 110:879 (1988); L. A. Paquette, J. L. Romine, H.-S. Lin, and J. Wright, J. Am. Chem. Soc. 112:9284 (1990).

382 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

enhanced stereoselectivity and is consistent with a chairlike transition-state structure. CH3

H3C

Ph

CH3 CH3

CH3 Ph

CH3 CH3

+

CH3

Ph

8

9

H3C 10 thermal 1:1 catalyzed 7:3

>90% enantioselectivity under both conditions

The mechanism for catalysis is formulated as a stepwise process in which the electrophilic character of Pd(II) facilitates the reaction.142 R

R

R

R +

Pd2+

Pd2+

+ Pd2+

Pd+

When there is a hydroxyl substituent at C-3 of the diene system, the Cope rearrangement product is an enol, which is subsequently converted to the corresponding carbonyl compound. This is called the oxy-Cope rearrangement.143 The formation of the carbonyl compound provides a net driving force for the reaction.144 –O

–O

H+

O H

Entry 4 in Scheme 6.11 illustrates the use of the oxy-Cope rearrangement in formation of a medium-sized ring. An important improvement in the oxy-Cope reaction was made when it was found that the reactions are markedly catalyzed by base.145 When the C-3 hydroxyl group is converted to its alkoxide, the reaction is accelerated by factors of 1010±1017. These basecatalyzed reactions are called anionic oxy-Cope rearrangements. The rates of anionic oxyCope rearrangements depend on the degree of cation coordination at the oxy anion. The reactivity trend is K‡ > Na‡ > Li‡ . Catalytic amounts of tetra-n-butylammonium salts lead to accelerated rates in some cases. This presumably results from the dissociation of less reactive ion-pair species promoted by the tetra-n-butylammonium ion.146 Entries 5, 6, and 7 in Scheme 6.11 illustrate the mild conditions under which rearrangement occurs. Silyl ethers of vinyl allyl alcohols can also be used in oxy-Cope rearrangements. This methodology has been used in connection with syn-selective aldol additions in stereo142. L. E. Overman and A. F. Renaldo, J. Am. Chem. Soc. 112:3945 (1990). 143. S. R. Wilson, Org. React. 43:93 (1993); L. A. Paquette, Angew. Chem. Int. Ed. Engl. 29:609 (1990); L. A. Paquette, Tetrahedron 53:13971 (1997). 144. A. Viola, E. J. Iorio, K. K. Chen, G. M. Glover, U. Nayak, and P. J. Kocienski, J. Am. Chem. Soc. 89:3462 (1967). 145. D. A. Evans and A. M. Golob, J. Am. Chem. Soc. 97:4765 (1975); D. A. Evans, D. J. Balillargeon, and J. V. Nelson, J. Am. Chem. Soc. 100:2242 (1978). 146. M. George, T.-F. Tam, and B. Fraser-Reid, J. Org. Chem. 50:5747 (1985).

selective synthesis.147 The use of the silyloxy group prevents reversal of the aldol addition, which would otherwise occur under anionic conditions. The reactions proceed at convenient rates at 140±180 C. R3SiO

CH2Ph

O

R3SiO

CH3

CH2Ph

O

180°C, 3 h

N

N

O

Ref. 148

O

CH3

O

O

TESO O 105°C, 1 h

O

O

O

TESO

>95%

Ref. 149

O O (TES = triethylsilyl)

6.5.2. Claisen Rearrangements The [3,3] sigmatropic rearrangement of allyl vinyl ethers leads to g,d-enones and is known as the Claisen rearrangement.150 The reaction is mechanistically analogous to the Cope rearrangement. Because the product is a carbonyl compound, the equilbrium is usually favorable for product formation. The reactants can be made from allylic alcohols by mercuric ion-catalyzed exchange with ethyl vinyl ether.151 The allyl vinyl ether need not be isolated but is usually prepared under conditions which lead to its rearrangement. The simplest of all Claisen rearrangements, the conversion of allyl vinyl ether to 4pentenal, typi®es this process. CH2

CHCH2OH

CH2

O Hg(OAc)2

+



[CH2

CHCH2OCH

CH2]

CH2

CHCH2CH2CH

Ref. 152

96%

CHOCH2CH3

Acid-catalyzed exchange can also be used to prepare the vinyl ethers. RCH

CHCH2OH + CH3CH2OCH

CH2

H+

RCH

CHCH2OCH

CH2

Ref. 153

Allyl vinyl ethers can also be generated by thermal elimination reactions. For example, base-catalyzed conjugate addition of allyl alcohols to phenyl vinyl sulfone generates 2147. C. Schneider and M. Rehfeuter, Synlett 1996:212; C. Schneider and M. Rehfeuter, Tetrahedron 53:133 (1997); W. C. Black, A. Giroux, and G. Greidanus, Tetrahedron Lett. 37:4471 (1996). 148. C. Schneider, Eur. J. Org. Chem. 1998:1661. 149. M. M. Bio and J. L. Leighton, J. Am. Chem. Soc. 121:890 (1999). 150. F. E. Ziegler, Chem. Rev. 88:1423 (1988). 151. W. H. Watanabe and L. E. Conlon, J. Am. Chem. Soc. 79:2828 (1957); D. B. Tulshian, R. Tsang, and B. Fraser-Reid, J. Org. Chem. 49:2347 (1984). 152. S. E. Wilson, Tetrahedron Lett. 1975:4651. 153. G. Saucy and R. Marbet, Helv. Chim. Acta 50:2091 (1967); R. Marbet and G. Saucy, Helv. Chim. Acta 50:2095 (1967).

383 SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

384 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

(phenylsul®nyl)ethyl ethers, which can undergo elimination at 200 C.154 The sigmatropic rearrangement proceeds under these conditions. Allyl vinyl ethers can also be prepared by Wittig reactions using ylides generated from allyloxymethylphosphonium salts.155 O RCH

CHCH2OH + CH2 R2C

CHSPh

NaH

RCH

O + Ph3P+CH2OCH2CH

CHCH2OCH2CH2SPh K+ –O-t-Bu

CH2

R 2C

200°C

RCH

CHOCH2CH

CHCH2OCH

CH2

CH2

Catalysis of Claisen rearrangements has been achieved using highly hindered bis(phenoxy)methylaluminum as a Lewis acid.156 Reagents of this type also have the ability to control the E :Z ratio of the products. Very bulky catalysts tend to favor the Zisomer by forcing the a substituent of the allyl group into an axial conformation. R

R

R O+

O O

O+



R O

–AlR 3

AlR3 R

Z-isomer

E-isomer

Some representative Claisen rearrangements are shown in Scheme 6.12. Entry 1 illustrates the application of the Claisen rearrangement in introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In entry 2, rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. There are several variations of the Claisen rearrangement that make it a powerful tool for the synthesis of g,d-unsaturated carboxylic acids. The ortho ester modi®cation of the Claisen rearrangement allows carboalkoxymethyl groups to be introduced at the g-position of allylic alcohols.157 A mixed ortho ester is formed as an intermediate and undergoes sequential elimination and sigmatropic rearrangement. OCH3 RCH

CHCH2OH + CH3C(OCH3)3

RCH

CHCH2OCCH3

RCH

CHCH2OC

OCH3

CH2

OCH3

CH2CO2CH3 RCHCH

CH2

154. T. Mandai, S. Matsumoto, M. Kohama, M. Kawada, J. Tsuji, S. Saito, and T. Moriwake, J. Org. Chem. 55:5671 (1990); T. Mandai, M. Ueda, S. Hagesawa, M. Kawada, J. Tsuji, and S. Saito, Tetrahedron Lett. 31:4041 (1990). 155. M. G. Kulkarni, D. S. Pendharkar, and R. M. Rasne, Tetrahedron Lett. 38:1459 (1997). 156. K. Nonoshita, H. Banno, K. Maruoka, and H. Yamamoto, J. Am. Chem. Soc. 112:316 (1990). 157. W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom, T. Li, D. J. Faulkner, and M. R. Petersen, J. Am. Chem. Soc. 92:741 (1970).

Scheme 6.12. Claisen Rearrangements

385

A. Rearrangements of allyl vinyl ethers 1a

CH2CH

SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

O

195°C

OCH

87%

CH2 CH3

2b

(CH3)2CCH

CH2 + H2C

O H+ 125°C

COCH3

(CH3)2C

CHCH2CH2CCH3

94%

HO CH3 3c

CH2

CH3

CCHCH2CH3 + CH2 OH

CC

O

CH2

110°C

CH2

H+

CCCH2CH2C CHCH2CH3

OCH3

CH3

CH3 4d

CH3CH

O 140–145°C

CHCH2OC

CH3CCHCO2CH2CH CHCH3

CCO2CH2CH CHCH3

CH3CHCH

H 5e

H3C

~70%

CH3

H3C

H3C

CH2CH2CH2CN CH2

CH2OH

CHOCH2CH

61%

CH2

H3C CH2CH2CH2CN

CH2

200°C

CH2

CH2OCH

Hg(O2CF3)2

73%

H3C

H3C CH2CH2CH2CN CH2 95%

CH2CH

O

OCH3 CH2

OH

6f

CCH3

POCl3

(i-Bu)3Al

89%

0°C

OH B. Rearrangements via ortho esters OH 7g

H2C

H

CHCH2CH2CHC

CH2

CH3C(OC2H5)3 H+, 140°C

H2C

CHCH2CH2C

83–88%

CCH2CH2CO2C2H5

CH3

CH3 C2H5 8h

CH2

CH3

OH

C2H5 CH3C(OCH3)3

CCHCH2CH2C CCO2CH3 H

110°C

CH3

CH3O2CCH2CH2C

CCH2CH2C H

85%

CCO2CH3 H (continued)

Scheme 6.12. (continued )

386 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

9i

CH2Ph

CH2Ph

N

N CH3C(OC2H5)3 74%

140°C

10j

CH2CH3 CH2CO2C2H5

CH2CH3

HO CH3 N

CH3 O

N

O

CH3CH2CH2C(OCH3)3

96%

145°C

CH2OH

CH2 CH3CH2 CHCO2CH3

11k

PhthNCH2 C

12l

CH2OH

C

C

68%

CH3

CH3

OH

H C

H

CH3CH2CO2H, heat

CHCH3

(Phth = phthaloyl)

13m

CH3C(OC2H5)3

C

H

N H Ph C

PhthNCH2 CHCH2CO2C2H5

CH3

H

CH3C(OC2H5)3 CH3CH2CO2H, 155°C

CH2 CH3

N H Ph C

C

CH2CH2CO2CH3

93%

CH2 CH3 CH2CO2C2H5

OH CH3C(OC2H5)3 S

S

CH3CH2CO2H, 120–130ºC

Cl

Cl

C. Rearrangements of ester enolates and silyl enol ethers 14n

CH3

H C

1) 67°C

C

H

CH2OC

CH2

2) CH3OH 3) HO–

CHCHCH2CO2H

CH2

70%

CH3

OSiMe3 15o

CH3 CH3(CH2)5CHC

CH2

1) 70°C 2) H3O

CH3(CH2)5

O C

CH3 C

+

C

H

53%

CH2CH2CO2H

CH2

OSiMe3 16n

CH3 H2C O

C

C O

(CH2)5CH3 C

H CH2CH3

– 1) Li+[(CH3)2CHNC6H11] 2) 25°C, 3 h

CH3 CH2

CCH(CH2)5CH3

71%

CH3 CHCO2H ;

Scheme 6.12. (continued ) 17p

H3C

387

CH3

O

H3C

O

H C

H

OCH2

PhCH2O

O

18q

O

H

O

1) LDA, TMS–Cl 2) CH2N2

CH3 C

CH3 O

O

CO2-t-Bu

CH3 80%

CH

PhCH2O

O

O CH2C(CH3)2

SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

CH2

CO2CH3

CO2H

1) LDA, TMS–Cl 2) CH2N2

51%

t-BuO2C Ph

19r

Ph

ArSO2N

NSO2Ar B

O

HO2C

Br (C2H5)3N, –78°C

O

20s

CF3 O

TMSO O

CH3 CF3 O

O N

PdCl2(PhCN)2

O

85% yield, >99% e.e.

O N

reflux

O

60%

HO2C

21t

O O

NHCOCF3

1) 4.5 equiv LHDMS, 2 equiv quinine 1.2 equiv Mg(OC2H5)2 –78° to 0°C

CH3 CO2H NHCOCF3 97% yield, 88% e.e.

22u

OCH2OCH3 O2CCH2NHCO2C(CH3)3

F2C

1) 3 LDA –78°C

CH3OCH2O

NHCO2C(CH3)3 92%

Ph

2) ZnCl2

CO2H

Ph

F

F

D. Rearrangement of ortho amides 23i

CH2Ph

CH2Ph (CH3)2NC(OCH3)2

N

CH3 diglyme, 160°C

HO

CH2CH3

N CH2CH3

45%

CH2CN(CH3)2 O (continued)

Scheme 6.12. (continued )

388 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

CH2CON(CH3)2 24v

CH3

PhCH2O

(CH3O)2CHN(CH3)2

CH3

PhCH2O

92%

160°C, 48 h

OH a. A. W. Burgstahler and I. C. Nordin, J. Am. Chem. Soc. 83:198 (1961). b. G. Saucy and R. Marbet, Helv. Chim. Acta 50:2091 (1967). c. D. J. Faulkner and M. R. Petersen, J. Am. Chem. Soc. 95:553 (1973). d. J. W. Ralls, R. E. Lundin, and G. F. Bailey, J. Org. Chem. 28:3521 (1963). e. L. A. Paquette, T.-Z. Wang, S. Wang, and C. M. G. Philippo, Tetrahedron Lett. 34:3523 (1993). f. S. D. Rychnovsky and J. L. Lee, J. Org. Chem. 60:4318 (1995). g. R. I. Trust and R. E. Ireland, Org. Synth. 53:116 (1973). h. C. A. Hendrick, R. Schaub, and J. B. Siddall, J. Am. Chem. Soc. 94:5374 (1972). i. F. E. Ziegler and G. B. Bennett, J. Am. Chem. Soc. 95:7458 (1973). j. J. J. Plattner, R. D. Glass, and H. Rapoport, J. Am. Chem. Soc. 94:8614 (1972). k. L. Serfass and P. J. Casara, Biorg. Med. Chem. Lett. 8:2599 (1998). l. D. N. A. Fox, D. Lathbury, M. F. Mahon, K. C. Molloy, and T. Gallagher, J. Am. Chem. Soc. 113:2652 (1991). m. E. Brenna, N. Caraccia, C. Fuganti, and P. Grasselli, Tetrahedron Asymmetry 8:3801 (1997). n. R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. Soc. 98:2868 (1976). o. J. A. Katzenellenbogen and K. J. Christy, J. Org. Chem. 39:3315 (1974). p. R. E. Ireland and D. W. Norbeck, J. Am. Chem. Soc. 107:3279 (1985). q. L. M. Pratt, S. A. Bowler, S. F. Courney, C. Hidden, C. N. Lewis, F. M. Martin, and R. S. Todd, Synlett 1998:531. r. E. J. Corey, B. E. Roberts, and B. R. Dixon, J. Am. Chem. Soc. 117:193 (1995). s. T. Yamazaki, N. Shinohara, T. Ktazume, and S. Sato, J. Org. Chem. 60::8140 (1995). t. A. Kazmaier and A. Krebs, Tetrahedron Lett. 40:479 (1999). u. J. M. Percy, M. E. Prime, and M. J. Broadhurst, J. Org. Chem. 63:8049 (1998). v. A. R. Daniewski, P. M. Waskulich, and M. R. Uskokovic, J. Org. Chem. 57:7133 (1992).

Both the exchange and elimination are catalyzed by addition of a small amount of a weak acid, such as propionic acid. Entries 7±13 in Scheme 6.12 are representative examples. The mechanism and stereochemistry of the ortho ester Claisen rearrangement are analogous to those of the Cope rearrangement. The reaction is stereospeci®c with respect to the double bond present in the initial allylic alcohol. In acyclic molecules, the stereochemistry of the product can usually be predicted on the basis of a chairlike transition state.158 When steric effects or ring geometry preclude a chairlike structure, the reaction can proceed through a boatlike transition state.159 High levels of enantiospeci®city have been observed in the rearrangement of chiral reactants. This method can be used to establish the con®guration of the newly formed carbon±carbon bond on the basis of the chirality of the C O bond in the starting allylic alcohol. Treatment of (2R,3E)-3-penten-2-ol with ethyl orthoacetate gives the ethyl ester of (3R,4E)-3-methyl-4-hexenoic acid in 90% enantiomeric purity.160 The con®guration of the new chiral center is that predicted by a chairlike transition state with the methyl group occupying a pseudoequatorial position. H HO

CH3 C

H3C

C

R

H

C

CH3C(OEt)3

H

H O H3C

CH2 CH3

H

CH2CO2C2H5

H3C

CH3

OC2H5 H

H

H

H

R

158. G. W. Daub, J. P. Edwards, C. R. Okada, J. W. Allen, C. T. Maxey, M. S. Wells, A. S. Goldstien, M. J. Dibley, C. J. Wang, D. P. Ostercamp, S. Chung, P. S. Cunningham, and M. A. Berliner, J. Org. Chem. 62:1976 (1997). 159. R. J. Cave, B. Lythgoe, D. A. Metcalf, and I. Waterhouse, J. Chem. Soc., Perkin Trans. 1 1997:1218; G. BuÈchi and J. E. Powell, Jr., J. Am. Chem. Soc. 92:3126 (1970); J. J. Gajewski and J. L. Jiminez, J. Am. Chem. Soc. 108:468 (1986). 160. R. K. Hill, R. Soman, and S. Sawada, J. Org. Chem. 37:3737 (1972); 38:4218 (1973).

Esters of allylic alcohols can be rearranged to g,d-unsaturated carboxylic acids via the O-trimethylsilyl ether of the ester enolate.161 This rearrangement takes place under much milder conditions than the ortho ester method. The reaction occurs at or slightly above room temperature. Entries 14 and 15 of Scheme 6.12 are examples. The example in entry 16 is a rearrangement of the enolate without intervention of the silyl enol ether. The stereochemistry of the silyl enol ether Claisen rearrangement is controlled not only by the stereochemistry of the double bond in the allylic alcohol but also by the stereochemistry of the silyl enol ether. For the chair transition state, the con®guration at the newly formed C C bond is predicted to be determined by the E- or Z-con®guration of the silyl enol ether. R O

R R

O

OTMS

H

R R R

H

O

H

O

OTMS

OTMS

Z-silyl ether

R

syn isomer

R

H

H

OTMS

E-silyl ether

anti isomer

The stereochemistry of the silyl enol ether can be controlled by the conditions of preparation. The base that is usually used for enolate formation is LDA. If the enolate is prepared in pure THF, the E-enolate is generated, and this stereochemistry is maintained in the silylated derivative. The preferential formation of the E-enolate can be explained in terms of a cyclic transition state in which the proton is abstracted from the stereoelectronically preferred orientation. O R

Li

R N–

O

OR

H

H

Li

R

H

R

OR

R N–

H

R transition state for E-enolate

transition state for Z-enolate

If HMPA is included in the solvent, the Z-enolate predominates.162 DMPU also favors the Z-enolate. The switch to the Z-enolate with HMPA or DMPU can be attributed to a loose, perhaps acyclic, transition state being favored as the result of strong solvation of the lithium ion by HMPA or DMPU. The steric factors favoring the E transition state are therefore diminished.163 These general principles of solvent control of enolate stereochemistry are applicable to other systems.164 A number of steric effects on the rate of rearrangement have been observed and can be accommodated by the chairlike transition-state model.165 The E-silyl enol ethers 161. R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. Soc. 98: 2868 (1976); S. Pereira and M. Srebnik, Aldrichimica Acta 26:17 (1993). 162. R. E. Ireland and A. K. Willard, Tetrahedron Lett. 1975:3975; R. E. Ireland, P. Wipf, and J. D. Armstrong III, J. Org. Chem. 56:650 (1991). 163. C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn, and J. Lamp, J. Org. Chem. 45:1066 (1980). 164. J. Corset, F. Froment, M.-F. Lutie, N. Ratovelomanana, J. Seyden-Penne, T. Strzalko, and M. C. RouxSchmitt, J. Am. Chem. Soc. 115:1684 (1993). 165. C. S. Wilcox and R. E. Babston, J. Am. Chem. Soc. 108:6636 (1986).

389 SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

390 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

rearrange somewhat more slowly than the corresponding Z-isomers. This is interpreted as resulting from the pseudoaxial placement of the methyl group in the E transition state. H

R

O

O CH3

R3SiO

R3SiO

Z-isomer

CH3

R

H E-isomer

The size of the substituent R also in¯uences the rate, with the rate increasing somewhat for both isomers as R becomes larger. It is believed that steric interactions with R are relieved as the C O bond stretches. The rate acceleration would re¯ect the higher ground-state energy resulting from these steric interactions. diminished steric interaction in transition state

steric factors in reactant increase in magnitude with the size of R

The silyl ketene acetal rearrangement can also be carried out by reaction of the ester with a silyl tri¯ate and tertiary amine, without formation of the ester enolate. Optimum results have been obtained with bulky silyl tri¯ates and amines, for example, t-butyldimethylsilyl tri¯ate and N -methyl-N ,N -dicyclohexylamine. Under these conditions, the reaction is stereoselective for the Z-silyl ketene acetal, and the stereochemistry of the allylic double bond determines the syn or anti con®guration. O

TBDMSO O

TBDMSOTf (c-C6H11)2NCH3

O

O

CO2H Ref. 166

TBDMSO O

TBDMSOTf (c-C6H11)2NCH3

O

CO2H

The possibility of using chiral auxiliaries or chiral catalysts to achieve enantioselective Claisen rearrangements has been explored.167 One approach is to use boron enolates with chirality installed at the boron atom. For example, enolates prepared with L2*BBr led 166. M. Kobayashi, K. Matsumoto, E. Nakai, and T. Nakai, Tetrahedron Lett. 37:3005 (1996). 167. D. Enders, M. Knopp, and R. Schiffers, Tetrahedron Asymmetry 7:1847 (1996).

to rearranged products of >95% enantiomeric excess.168

391 SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

OBL*2 CO2H

O L*2BBr

O

65% yield, 96% e.e.

(C2H5)3N

O

(i-Pr)2NC2H5

OBL*2

L*2BBr

CO2H

O Ph

Ph L*2BBr =

ArSO2N

75% yield, >97% e.e.

NSO2Ar

Ar = 3,5-bis(trifluoromethyl)phenyl

B Br

As with other ester enolate rearrangements, the presence of chiral ligands can render the reaction enantioselective. Use of quinine or quinidine with the chelating metal leads to enantioselectivity (see entry 21 in Scheme 6.12). The stereoselectivity of ester enolate Claisen rearrangements can also be controlled by speci®c intramolecular interactions.169 The enolates of a-alkoxy esters give the Z-silyl derivatives because of chelation by the alkoxy substituent. O

Li+

RO

ROCH2COCH2CH CHR′

LDA

C

O– ClSiR3

C

H

OCH2CH

RO

OSiR3 C

CHR′

H

C OCH2CH

CHR′

Z-isomer

The con®guration at the newly formed C C bond is then controlled by the stereochemistry of the double bond in the allylic alcohol. The E-isomer gives a syn orientation whereas the Z-isomer gives rise to anti stereochemistry.170 H O R′ E

OR

O

OSiR3

OR

OR R′ OSiR3

CO2SiR3 R′

H O Z

OSiR3 R′

OR

O R3SiO

OR OR

R′

CO2SiR3 R′

168. E. J. Corey and D.-H. Lee, J. Am. Chem. Soc. 113:4026 (1991); E. J. Corey, B. E. Roberts, and B. R. Dixon, J. Am. Chem. Soc. 117:193 (1995). 169. H. Frauenrath, in Stereoselective Synthesis, G. Helmchen, R. W. Hoffmann, J. Mulzer, and E. Schaumann, eds., Georg Thieme Verlag, Stuttgart, 1996. 170. T. J. Gould, M. Balestra, M. D. Wittman, J. A. Gary, L. T. Rossano, and J. Kallmerten, J. Org. Chem. 52:3889 (1987); S. D. Burke, W. F. Fobare, and G. J. Pacofsky, J. Org. Chem. 48:5221 (1983); P. A. Bartlett, D. J. Tanzella, and J. F. Barstow, J. Org. Chem. 47:3941 (1982).

392 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Similar chelation effects appear to be present in a-alkoxymethyl derivatives. Magnesium enolates give predominantly the Z-enolate as a result of this chelation. The corresponding trimethylsilyl enol ethers give E=Z mixtures because of a relatively weak steric differentiation between the ethyl and alkoxymethyl substituents.171 R O

CH2OR

Mg C2H5NMgBr

O

CH2OR

O

O

CO2H Z

O

85% yield, >95% Z

R = CH3 or CH2OCH3

Enolates of allyl esters of a-amino acids are also subject to chelation-controlled Claisen rearrangement.172 O

CH3

CH3

CF3CNHCHCO2CH2C

CPh

O

2.5 equiv LDA

CH3

CH3

O

N Zn

CH3

HO2C

Ph

1.1 equiv ZnCl2

CH3

Ph

CH2

H3C CF3CONH

CH3

COCF3

CH3

Various salts can promote chelation, but ZnCl2 and MgCl2 are suitable for most cases. The rearrangement is a useful reaction for preparing amino acid analogs and has also been applied to modi®ed dipeptides.173 Ph t-BocNH

O O

N H

Ph

1) 4 equiv LDA 2) MnCl2 3) CH2N2

t-BocNH

O N

CO2CH3

H

O

90% yield, 62:38 mixture

A reaction which is related to the ortho ester Claisen rearrangement utilizes an amide acetal, such as dimethylacetamide dimethyl acetal, rather than an ortho ester in the exchange reaction with allylic alcohols.174 The stereochemistry of the reaction is analogous to that of the other variants of the Claisen rearrangement.175 OCH3 RC H

CHCH2OH + (CH3)2NCOCH3 CH3

OCH3 (CH3)2NCOCH2CH CH3

CHR

(CH3)2NCOCH2CH

CHR

CH2

O (CH3)2NCCH2CHCH

CH2

R 171. M. E. Krafft, S. Jarrett, and O. A. Dasse, Tetrahedron Lett. 34:8209 (1993). 172. U. Kazmaier, Liebigs Ann. Chem. 1997:285; U. Kazmaier, J. Org. Chem. 61:3694 (1996); U. Kazmaier and S. Maier, Tetrahedron 52:941 (1996). 173. U. Kazmaier and S. Maier, J.. Chem. Soc., Chem. Commun. 1998:2535. 174. A. E. Wick, D. Felix, K. Steen, and A. Eschenmoser, Helv. Chim. Acta 47:2425 (1964); D. Felix, K. Gschwend-Steen, A. E. Wick, and A. Eschenmoser, Helv. Chim. Acta 52:1030 (1969). 175. W. Sucrow, M. Slopianka, and P. P. Calderia, Chem. Ber. 108:1101 (1975).

O-Allyl imidate esters undergo [3,3] sigmatropic rearrangements to N -allyl amides. Trichloroacetimidates can be easily made from allylic alcohols by reaction with trichloroacetonitrile. The rearrangement then provides trichloroacetamides of N -allylamines.176 R R

CCl3CN

OH

NHCOCCl3 HN

O R CCl3

Yields in the reaction are sometimes improved by inclusion of K2CO3 in the reaction mixture.177 NH

NHCOCCl3 xylene reflux

O

CCl3

73%

K2CO3

Tri¯uoroacetimidates show similar reactivity.178 Imidate rearrangements are catalyzed by palladium salts.179 The mechanism is presumably similar to that for the Cope rearrangement (see p. 382). M2+ R

M+ R

HN

O CCl3

R HN

+

O

HN

CCl3

O CCl3

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The anions of these imidates, prepared using lithium diethylamide, rearrange at around 0 C. When a chiral amine is used, this reaction can give rise to enantioselective formation of g,d-unsaturated amides. Good results were obtained with a chiral binaphthylamine.180 The methoxy substitutent is believed to play a role as a Li‡ ligand in the reactive enolate.

CH3 CH3

OCH3 Li N

O CH3

NHR*

Li N

O

CH3

O

O

176. 177. 178. 179.

L. E. Overman, J. Am. Chem. Soc. 98:2901 (1976); L. E. Overman, Acc. Chem. Res. 13:218 (1980). T. Nishikawa, M. Asai, N. Ohyabu, and M. Isobe, J. Org. Chem. 63:188 (1998). A. Chen, I. Savage, E. J. Thomas, and P. D. Wilson, Tetrahedron Lett. 34:6769 (1993). L. E. Overman, Angew. Chem. Int. Ed. Engl. 23:579 (1984); T. G. Schenck and B. Bosnich, J. Am. Chem. Soc. 107:2058 (1985). 180. P. Metz and B. Hungerhoff, J. Org. Chem. 62:4442 (1997).

393 SECTION 6.5. [3,3] SIGMATROPIC REARRANGEMENTS

394 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Aryl allyl ethers can also undergo [3,3] sigmatropic rearrangement. Claisen rearrangements of allyl phenyl ethers to ortho-allyl phenols were the ®rst [3,3] sigmatropic rearrangements to be thoroughly studied.181 The reaction proceeds through a cyclohexadienone that enolizes to the stable phenol.

C O

C

O

C

H

HO

C C

C

C

C

C

If both ortho positions are substituted, the allyl group undergoes a second sigmatropic migration, giving the para-substituted phenol: OCH2CH CH3O

CH2

OH

OCH3

CH3O

OCH3

180°C

CH2CH

CH2

88%

Ref. 182 CH3O CH2

HC

O

O OCH3

OCH3

CH3O

H2C H

CH2CH

CH2

6.6. [2,3] Sigmatropic Rearrangements The [2,3] sigmatropic class of rearrangements is represented by two generic charge types: Y –

+

X

Y

X

Neutral

or

RCH

CHCH2

X

CHZ –

RCHCH CH2 ZCHX–

Anionic

The rearrangements of allylic sulfoxides, selenoxides, and nitrones are the most useful examples of the ®rst type whereas rearrangements of carbanions of allyl ethers are the major examples of the anionic type. 181. S. J. Rhoads, in Molecular Rearrangements, Vol. 1, P. de Mayo, ed., Interscience, New York, l963, pp. 655± 684.

The sigmatropic rearrangement of allylic sulfoxides to allylic sulfenates ®rst received study in connection with the mechanism of racemization of allyl aryl sulfoxides.183 Although the allyl sulfoxide structure is strongly favored at equilibrium, rearrangement through the achiral allyl sulfenate provides a low-energy pathway for racemization.

R

O–

CH2

S

CH

+

CH2

O

CH2

RS

CH CH2

The synthetic utility of the allyl sulfoxide±allyl sulfenate rearrangement is as a method of preparation of allylic alcohols.184 The reaction is carried out in the presence of a reagent, such as phenylthiolate or trimethyl phosphite, which reacts with the sulfenate to cleave the S O bond: O– (CH3)3C

OSPh

CHCH2SPh

PhS–

(CH3)3C

+

CH

CH2 Ref. 185 OH

(CH3)3C CH

CH2

95%

An analogous transposition occurs with allylic selenoxides when they are generated in situ by oxidation of allylic seleno ethers.186 PhCH2CH2CHCH

CHCH3

H2O2

PhCH2CH2CH

CHCHCH3

SePh

OH

Allylic sulfonium ylides readily undergo [2,3] sigmatropic rearrangement.187 (CH3)2C (CH3)2C



CHCH

(CH3)2CCH

CH +

CH2

(CH3)2C

CH2

CHCHSCH3 95%

S CH3

This reaction results in carbon±carbon bond formation. It has found synthetic application in ring-expansion sequences for generation of medium-sized rings. The reaction proceeds best when the ylide has a carbanion-stabilizing substituent. Part A of Scheme 6.13 shows some examples of the reaction. The corresponding nitrogen ylides can also be generated when one of the nitrogen substituents has an anion-stabilizing group on the a carbon. For example, quaternary salts 182. 183. 184. 185. 186.

I. A. Pearl, J. Am. Chem. Soc. 70:1746 (1948). R. Tang and K. Mislow, J. Am. Chem. Soc. 92:2100 (1970). D. A. Evans and G. C. Andrews, Acc. Chem. Res. 7:147 (1974). D. A. Evans, G. C. Andrews, and C. L. Sims, J. Am. Chem. Soc. 93:4956 (1971). H. J. Reich, J. Org. Chem. 40:2570 (1975); D. L. J. Clive, G. Chittatu, N. J. Curtis, and S. M. Menchen, J. Chem. Soc., Chem. Commun. 1978:770. 187. J. E. Baldwin, R. E. Hackler, and D. P. Kelly, J. Chem. Soc., Chem. Commun. 1968:537.

395 SECTION 6.6. [2,3] SIGMATROPIC REARRANGEMENTS

396 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Scheme 6.13. Carbon±Carbon Bond Formation via [2,3] Sigmatropic Rearrangements of Sulfur and Nitrogen Ylides A. Sulfonium ylides 1a

CH3 (CH3)2C

CHCH2

+

S

SCH3

CH2CO2C2H5

Na2CO3

(CH3)2CCHCO2C2H5 CH

2b

K+ OC(CH3)3

S

85%

–40°C

H

+

91%

CH2

S

C

CH3 H

C H O

3c

CH3CO CH3 CH3 H C C H + S H3C CH2CO2C2H5

CH3

OCCH3

CH3

DBU

O 40%

20°C

C2H5O2C

CH3

S

B. Ammonium ylides 4d

DBU

H +

N PhCH2

20°C

90%

N

CH CH2 CH2CO2C2H5

PhCH2

CO2C2H5

5e

N +

N (CH3)3C

CHCH2

CH2CN

K+ –O-t-Bu

CHCN (CH3)3C

94%

CH a. b. c. d. e.

CH2

K. Ogura, S. Furukawa, and G. Tsuchihashi, J. Am. Chem. Soc. 102:2125 (1980). V. Cere, C. Paolucci, S. Pollicino, E. Sandri, and A. Fava, J. Org. Chem. 43:4826 (1978). E. Vedejs and M. J. Mullins, J. Org. Chem. 44:2947 (1979). E. Vedejs, M. J. Arco, D. W. Powell, J. M. Renga, and S. P. Singer, J. Org. Chem. 43:4831 (1978). L. N. Mander and J. V. Turner, Aust. J. Chem. 33:1559 (1980).

of N -allyl a-aminoesters readily rearrange to a-allyl products.188 H3C R

N+

R

CH3 CO2CH3

K2CO3, DBu 10°C, DMF

CO2CH3 N(CH3)2

Entries 4 and 5 in Scheme 6.13 are other examples. Entry 4 illustrates the use of the reaction for ring expansion. 188. I. Coldham, M. L. Middleton, and P. L. Taylor, J. Chem. Soc., Perkin Trans. 1 1997:2951; I. Coldham, M. L. Middleton and P. L. Taylor, J. Chem. Soc., Perkin Trans. 1 1998:2817.

N -Allylamine oxides possess the general structure pattern for [2,3] sigmatropic rearrangement where X ˆ N and Y ˆ O . The rearrangement proceeds readily to provide O-allyl hydroxylamine derivatives. R R

+

N

R CH2CH

CH2

N

OCH2CH

CH2

R

O–

A useful method for ortho-alkylation of aromatic amines is based on [2,3] sigmatropic rearrangement of S-anilinosulfonium ylides. These ylides are generated from anilinosulfonium ions, which can be prepared from N -chloroanilines and sul®des.189 Cl

R

NR

R′

N

–H+

+ S

+S

R′

– CHZ

CH2Z

H

NR

NH2

CHSR′

CHSR′

Z

Z

This method is the basis for synthesis of nitrogen-containing heterocyclic compounds when Z is a carbonyl-containing group.190 The [2,3] sigmatropic rearrangement pattern is also observed with anionic species. The most important case for synthetic purposes is the Wittig rearrangement, in which a strong base converts allylic ethers to a-allyl alkoxides.191 ZCH2

R

O

OH

O–

O base

ZHC _

H+

ZHC

ZCHCHCH CH2 R

R

R

Because the deprotonation at the a0 carbon must compete with deprotonation of the a carbon in the allyl group, most examples involve a conjugated or electron-withdrawing substituent Z.192 The stereochemistry of the Wittig rearrangement can be predicted in terms of a cyclic ®ve-membered transition state in which the a substituent prefers an equatorial orientation.193 H

H R2

..

R2 O–

O Z

Z

189. P. G. Gassman and G. D. Gruetzmacher, J. Am. Chem. Soc. 96:5487 (1974); P. G. Gassman and H. R. Drewes, J. Am. Chem. Soc. 100:7600 (1978). 190. P. G. Gassman, T. J. van Bergen, D. P. Gilbert, and B. W. Cue, Jr., J. Am. Chem. Soc. 96:5495 (1974); P. G. Gassman and T. J. van Bergern, J. Am. Chem. Soc. 96:5508 (1974); P. G. Gassman, G. Gruetzmacher, and T. J. van Bergen, J. Am. Chem. Soc. 96:5512 (1974). 191. J. Kallmarten, in Stereoselective Synthesis, Houben Weyl Methods in Organic Chemistry Vol. E21d, R. W. Hoffmann, J. Mulzer, and E. Schaumann, eds., G. Thieme Verlag, Stuttgart, 1995, pp. 3810. 192. For reviews of [2,3] sigmatropic rearrangement of allyl ethers, see T. Nakai and K. Mikami, Chem. Rev. 86:885 (1986). 193. R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 18:563 (1979). K. Mikami, Y. Kimura, N. Kishi, and T. Nakai, J. Org. Chem. 48:279 (1983); K. Mikami, K. Azuma, and T. Nakai, Tetrahedron 40:2303 (1984); Y.-D. Wu, K. N. Houk, and J. A. Marshall, J. Org. Chem. 55:1421 (1990).

397 SECTION 6.6. [2,3] SIGMATROPIC REARRANGEMENTS

398 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

A consistent feature of the observed stereochemistry is a preference for E-stereochemistry at the newly formed double bond. The reaction can also show stereoselectivity at the newly formed single bond. This stereoselectivity has been carefully studied for the case in which the substituent Z is an acetylenic group. H

H



H3C

H

H O

OH OH

H3C

H

H

CH3

R

anti-isomer

R

R

E-isomer

H

H



H

H

H O

OH

H

H3C

OH

H3C

R

CH3 syn-isomer

R

R

Z-isomer

The preferred stereochemistry arises from the transition state that minimizes interaction between the ethynyl and isopropyl substituents. This stereoselectivity is revealed in the rearrangement of 11 to 12. H H

H

H H

R3SiOCH2

O

R3SiOCH2

H

CH2OSiR3



Ref. 194

OH OH

11

12

There are other means of generating the anions of allyl ethers. For synthetic purposes, one of the most important involves lithium±tin exchange on stannylmethyl ethers.195 R

O

SnR3

RLi

R

O

Li

R CH2OLi

Another method involves reduction of allylic acetals of aromatic aldehydes by SmI2.196 R ArCH(OCH2CH CHR)2

3 equiv SmI2

ArCHOCH2CH CHR –

ArCHCHCH CH2 OH

194. M. M. Midland and J. Gabriel, J. Org. Chem. 50:1143 (1985). 195. W. C. Still and A. Mitra, J. Am. Chem. Soc. 100:1927 (1978). 196. H. Hioki, K. Kono, S. Tani, and M. Kunishima, Tetrahedron Lett. 39:5229 (1998).

[2,3] Sigmatropic rearrangements of anions of N -allylamines have also been observed and are known as aza-Wittig rearrangements.197 The reaction requires anionstabilizing substituents and is favored by N -benzyl and by silyl or sulfenyl substituents on the allyl group.198 The trimethylsilyl substituents also can in¯uence the stereoselectivity of the reaction. The steric interactions between the benzyl group and allyl substituent govern the stereoselectivity, and which is markedly higher in the trimethylsilyl derivatives.199

X

X t-BocNCH2C

CHR

CH2Ph R CH3 C2H5 (CH3)2CH CH3 C2H5 (CH3)2CH

Ph

BuLi –40°C THF–HMPA

X

NH-t-Boc

R

X

R

R X

anti:syn

H H H Si(CH3)3 Si(CH3)3 Si(CH3)3

3:2 1:1 4:3 <1:20 1:18 1:11

Ph N

N

Boc

Boc

anti

syn

Ph

The [2,3] Wittig rearrangement has proven useful for ring contraction in the synthesis of a number of medium-ring unsaturated structures, as illustrated by entry 3 in Scheme 6.14.

6.7. Ene Reactions Certain electrophilic carbon±carbon and carbon±oxygen double bonds can undergo an addition reaction with alkenes in which an allylic hydrogen is transferred to the electrophile. This process is called the ene reaction, and the electrophile is called an enophile.200

H

EWG

H

EWG

ene + enophile (EWG = electron-withdrawing group)

197. 198. 199. 200.

C. Vogel, Synthesis 1997:497. J. C. Anderson, S. C. Smith, and M. E. Swarbrick, J. Chem. Soc., Perkin Trans 1 1997:1517. J. C. Anderson, D. C. Siddons, S. C. Smith, and M. E. Swarbrick, J. Org. Chem. 61:4820 (1996). For review of the ene reaction, see H. M. R. Hoffmann, Angew. Chem. Int. Ed. Engl. 8:856 (1969); W. Oppolzer, Pure Appl. Chem. 53:1181 (1981).

399 SECTION 6.7. ENE REACTIONS

Scheme 6.14. [2,3] Wittig Rearrangements

400 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

1a

H

H C

(CH3)2CH H

H

C

C

CH3

OCH2C

CH2

n-BuLi K+ –O-t-Bu

(CH3)2CH

C

H

CH3 OCH2SiMe3

2b

C

OH C

C

CH3

C

CH2

95%

CH3

CH2OH 1) BuLi, –78 → 0°C 2) NH4Cl

45%

O(CH2)2OTMS

O(CH2)2OTMS OH

3c

O n-BuLi

60%

HMPA

4d

H3C

H3C

OH C CH

CH

OCH2C

2 n-BuLi

75%

–78°C

OMe

OMe OH

5e n-BuLi

O

N

O

N a. b. c. d. e.

–78°C

O

D. J.-S. Tsai and M. M. Midland, J. Am. Chem. Soc. 107:3915 (1985). T. Sugimura and L. A. Paquette, J. Am. Chem. Soc. 109:3017 (1987). J. A. Marshall, T. M. Jenson, and B. S. De Hoff, J. Org. Chem. 51:4316 (1986). K. Mikami, K. Kawamoto, and T. Nakai, Tetrahedron Lett. 26:5799 (1985). M. H. Kress, B. F. Kaller, and Y. Kishi, Tetrahedron Lett. 34:8047 (1993).

The concerted mechanism is allowed by the Woodward±Hoffmann rules. The transition state involves the p electrons of the alkene and enophile and the s electrons of the C H bond. HOMO of allyl

H

1s orbital of hydrogen

H

LUMO of enophile A concerted ene reaction corresponds to the interaction of a hydrogen atom with the HOMO of an allyl radical and the LUMO of the enophile and is allowed.

Ene reactions have relatively high activation energies and intermolecular reaction is observed only for strongly electrophilic enophiles. Some examples are given in Scheme 6.15. The thermal ene reaction of carbonyl compounds generally requires electron-attracting substituents. Glyoxalate and oxomalonate esters are useful reagents for the ene reaction.201,202 Mechanistic studies have been designed to determine if the concerted cyclic transition state is a good representation of the mechanism. The reaction is only moderately sensitive to electronic effects. The r value for reaction of diethyl oxomalonate with a series of 1-arylcyclopentenes is 1:2, which would indicate there is little charge development in the transition state. The reaction shows a primary kinetic isotope effect indicative of C H bond-breaking in the rate-determining step.203 These observations are consistent with a concerted process. The ene reaction is strongly catalyzed by Lewis acids such as aluminum chloride and diethylaluminum chloride.204 Coordination by the aluminum at the carbonyl group increases the electrophilicity of the conjugated system and allows reaction to occur below room temperature, as illustrated in Entry 6. Intramolecular ene reactions can be carried out under either thermal (Entry 3) or catalyzed (Entry 7) conditions.205 Formaldehyde in acidic solution can form allylic alcohols, as in entry 1. Other carbonyl ene reactions are carried out with Lewis acid catalysts. Aromatic aldehydes and acrolein undergo the ene reaction with activated alkenes such as enol ethers in the presence of Yb(fod)3.206 Sc(O3SCF3)3 has also been used to catalyze ene reactions.207 CH2 + ArCH

O

Sc(O3SCF3)3

CH2CHAr O2CCF3

With chiral catalysts, the reaction becomes enantioselective. Among the successful catalysts are diisopropoxyTi(IV) BINOL and copper bis-oxazoline complexes. OH (CH3)2C

CH2 + O

CHCO2CH3

(i-PrO)2Ti/BINOL

O

O N t-Bu

CH2 + O

CHCO2C2H5

Ref. 208

CO2CH3 72% yield, 95% e.e.

N Cu

t-Bu

CO2C2H5

Ref. 209

OH 95% yield, 96% e.e.

201. K. Mikami and M. Shimizu, Chem. Rev. 92:1020 (1992). 202. M. F. Salomon, S. N. Pardo, and R. G. Salomon, J. Org. Chem. 49:2446 (1984); M. F. Salomon, S. N. Pardo, and R. G. Salomon, J. Am. Chem. Soc. 106:3797 (1984). 203. O. Achmatowicz and J. Szymoniak, J. Org. Chem. 45:4774 (1980); H. Kwart and M. Brechbiel, J. Org. Chem. 47:3353 (1982). 204. B. B. Snider, Acc. Chem. Res. 13:426 (1980). 205. W. Oppolzer and V. Snieckus, Angew. Chem. Int. Ed. Engl. 17:476 (1978). 206. M. A. Ciufolini, M. V. Deaton, S. Zhu, and M. Chen, Tetrahedron 53:16299 (1997); M. A. Ciufolini and S. Zhu, J. Org. Chem. 63:1668 (1998). 207. V. K. Aggarawal, G. P. Vennall, P. N. Davey, and C. Newman, Tetrahedron Lett. 39:1997 (1998). 208. K. Mikami, M. Terada, and T. Nakai, J. Am. Chem. Soc. 112:3949 (1990). 209. D. A. Evans, C. S. Burgey, N. A. Paras, T. Vojkovsky, and S. W. Tegay, J. Am. Chem. Soc. 120:5824 (1998).

401 SECTION 6.7. ENE REACTIONS

Scheme 6.15. Ene Reactions

402 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

1a

CH3

CH3 + CH2O

CH3C

BF3 Ac2O, CH2Cl2

CH2

2b (CH3)2C

84%

C

H2C

CH2 + HC

CCO2CH3

AlCl3

O CH2CH2OCCH3 CCH2CH

CH2

25°C

CHCO2CH3

61%

H3C 3c

CO2C2H5

CO2C2H5 CHCH2CH2CH

CH2

280°C

68%

CH3 (mixture of stereoisomers) 4d (CH3)2C

CHCH2

O

O

NCCF3 EtO2C

C(CO2Et)2 C

Et2AlCl

CO2Et 90%

–78°C

CH3

C

H

CCF3 N

H

CO2Et

C CH2

CH2CO2Et C2H5 OH

5e

(C2H5)2C

CH2 + O

CHCO2C(CH3)3

(i-PrO)2TiCl2

CH3

CO2C(CH3)3 OH

6f

CH2

+ O

CHC

CCO2CH3

OTBDMS 7g

CO2CH3

20 mol %(i-PrO)2TiCl2, BINOL 0°C

OTBDMS

TBDPSO

TBDPSO CO2C2H5

ZnBr2

CH(CO2C2H5)2

90%

CO2C2H5

a. b. c. d. e. f. g.

A. T. Blomquist and R. J. Himics, J. Org. Chem. 33:1156 (1968). B. B. Snider, D. J. Rodini, R. S. E. Conn, and S. Sealfon, J. Am. Chem. Soc. 101:5283 (1979). W. Oppolzer, K. K. Mahalanabis, and K. Battig, Helv. Chim. Acta 60:2388 (1977). W. Oppolzer and C. Robbiani, Helv. Chim. Acta 63:2010 (1980). M. A. Brimble and M. K. Edmonds, Synth. Commun. 26:243 (1996). K. Mikami, A. Yoshida, and Y. Matsumoto, Tetrahedron Lett. 37:8515 (1996). T. K. Sarkar, B. K. Ghorai, S. K. Nandy, B. Mukherjee, and A. Banerji, J. Org. Chem. 62:6006 (1997).

Intramolecular ene reactions can also be carried out with Lewis acid catalysts. Several examples are included in Scheme 6.15. Mechanistic analysis of Lewis acid-catalyzed reactions indicates they may more closely resemble an electrophilic substitution process related to reactions which will be discussed in Section 10.1.1.210

6.8. Unimolecular Thermal Elimination Reactions This section will describe reactions in which elimination to form a double bond or a new ring occurs as a result of thermal activation. There are several such thermal elimination reactions which ®nd use in synthesis. Some of these are concerted processes. The transition-state energy requirements and stereochemistry of concerted elimination processes can be analyzed in terms of orbital symmetry considerations. We will also consider an important group of unimolecular b-elimination reactions in Section 6.8.3.

6.8.1. Cheletropic Elimination Cheletropic processes are de®ned as reactions in which two bonds are broken at a single atom. Concerted cheletropic reactions are subject to orbital symmetry restrictions in the same way that cycloadditions and sigmatropic processes are. C

C

C

X

C

C

C

C X C

C C

C X C

In the elimination processes of interest here, the atom X is normally bound to other atoms in such a way that elimination will give rise to a stable molecule. The most common examples involve ®ve-membered rings. A good example of a concerted cheletropic elimination is the reaction of 3-pyrroline with N -nitrohydroxylamine, which gives rise to a diazene, that then undergoes elimination of nitrogen.

Na2N2O3

N

CH2

+

CHCH

CH2 + N2

N +

N

.. ..

H

H+

Use of substituted systems has shown that the reaction is completely stereospeci®c.211 The groups on C-2 and C-5 of the pyrroline ring rotate in the disrotatory mode on going to 210. B. B. Snider, D. M. Roush, D. J. Rodini, D. M. Gonzalez, and D. Spindell, J. Org. Chem. 45:2773 (1980); J. V. Duncia, P. T. Lansbury, Jr., T. Miller, and B. B. Snider, J. Org. Chem. 47:4538 (1982); B. B. Snider and G. B. Phillips, J. Org. Chem. 48:464 (1983); B. B. Snider and E. Ron, J. Am. Chem. Soc. 107:8160 (1985); O. Achmatowicz and E. Bialecka-Florjanczyk, Tetrahedron 52:8827 (1996). 211. D. M. Lemal and S. D. McGregor, J. Am. Chem. Soc. 88:1335 (1966).

403 SECTION 6.8. UNIMOLECULAR THERMAL ELIMINATION REACTIONS

404 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

product. This stereochemistry is consistent with conservation of orbital symmetry. H

H3C H

+

N

H3C H

CH3

H3C

H

CH3

H

CH3

N–

+

H 3C

CH3

H

N

H

H

N–

The most synthetically useful cheletropic elimination involves 2,5-dihydrothiophene-1,1-dioxides (sulfolene dioxides). At elevated temperatures, they fragment to give dienes and sulfur dioxide.212 The reaction is stereospeci®c. For example, the dimethyl derivatives 13 and 14 give the E,E- and Z,E-isomers of 2,4-hexadiene, respectively, at temperatures of 100±150 C.213 This sterespeci®city corresponds to disrotatory elimination. CH3

H3C H 13

S O2

H3C H

CH3

H

CH3

H

H

H3C 14

S O2

H

H

CH3 H3C

H

Elimination of sulfur dioxide has proven to be a useful method for generating dienes which can undergo subsequent Diels±Alder addition. O

CO2CH3

O CO2CH3

O

+ S O2

105°C

O

Ref. 214

O O

The method is particularly useful in formation of o-quinodimethanes. O

Ph

Ph 250°C air

SO2 + Ph

O

O

42%

Ph

Ref. 215

O

(oxidation product of initial adduct)

O

CH3 O

H3C CH2CH2 SO2

210°C

CH

CH2

H H

85%

Ref. 216

H

The elimination of carbon monoxide can occur by a concerted process in some cyclic ketones. The elimination of carbon monoxide from bicyclo[2.2.1]heptadien-7-ones is very 212. W. L. Mock, in Pericyclic Reactions, Vol. II, A. P. Marchand and R. E. Lehr, eds., Academic Press, New York, 1977, Chapter 3. 213. W. L. Mock, J. Am. Chem. Soc. 88:2857 (1966); S. D. McGregor and D. M. Lemal, J. Am. Chem. Soc. 88:2858 (1966). 214. J. M. McIntosh and R. A. Sieler, J. Org. Chem. 43:4431 (1978). 215. M. P. Cava, M. J. Mitchell, and A. A. Deana, J. Org. Chem. 25:1481 (1960). 216. K. C. Nicolaou, W. E. Barnette, and P. Ma, J. Org. Chem. 45:1463 (1980).

facile. In fact, generation of bicyclo[2.2.1]heptadien-7-ones is usually accompanied by spontaneous elimination. O R R

R

R

R

R R

R

+ CO R

R

R

R

The ring system can be generated by Diels±Alder addition of a substituted cyclopentadienone and an alkyne. A reaction sequence involving addition followed by CO elimination can be used for the synthesis of highly substituted benzene rings.217 Ph

Ph Ph

Ph O + PhC

Ph Ref. 218

CPh

Ph

Ph Ph

Ph Ph

Exceptionally facile elimination of CO also takes place from 15, in which homoaromaticity can stabilize the transition state: O

O

C + CO

Ref. 219

15

6.8.2. Decomposition of Cyclic Azo Compounds Another signi®cant group of elimination reactions involves processes in which a small molecule is eliminated from a ring system and the two reactive sites that remain react to re-form a ring. X

Y

The most widely studied example is decomposition of azo compounds, where X Y is NˆN .220 The elimination of nitrogen from cyclic azo compounds can be carried out either photochemically or thermally. Although the reaction generally does not proceed by a concerted mechanism, there are some special cases in which concerted elimination is possible. We will consider some of these cases ®rst and then consider the more general case. 217. M. A. Ogliaruso, M. G. Romanelli, and E. I. Becker, Chem. Rev. 65:261 (1965). 218. L. F. Fieser, Org. Synth. V:604 (1973). 219. B. A. Halton, M. A. Battiste, R. Rehberg, C. L. Deyrup, and M. E. Brennan, J. Am. Chem. Soc. 89:5964 (1967). 220. P. S. Engel, Chem. Rev. 80:99 (1980).

405 SECTION 6.8. UNIMOLECULAR THERMAL ELIMINATION REACTIONS

406 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

An interesting illustration of the importance of orbital symmetry effects is the contrasting stability of azo compounds 16 and 17. Compound 16 decomposes to norbornene and nitrogen only above 100 C. In contrast 17 eliminates nitrogen immediately on preparation, even at 78 C.221 N N

N N 16

17

The reason for this difference is that if 16 were to undergo a concerted elimination, it would have to follow the forbidden (high-energy) [2ps ‡ 2ps ] pathway. For 17, the elimination can take place by the allowed [2ps ‡ 4ps ] pathway. Thus, these reactions are the reverse of, respectively, the [2 ‡ 2] and [4 ‡ 2] cycloadditions, and only the latter is an allowed concerted process. The temperature at which 16 decomposes is fairly typical for strained azo compounds, and the decomposition presumably proceeds by a nonconcerted diradical mechanism. Because a C N bond must be broken without concomitant compensation by carbon±carbon bond formation, the activation energy is much higher than for a concerted process. Although the concerted mechanism is available only to those azo compounds with appropriate orbital arrangements, the nonconcerted mechanism occurs at low enough temperatures to be synthetically useful. The elimination can also be carried out photochemically. These reactions presumably occur by stepwise elimination of nitrogen. R

N

N

R′

slow

R

N

fast

N⋅ + ⋅R′

R⋅ N

N ⋅R′

R

R′

The stereochemistry of the nonconcerted reaction has been a topic of considerable study and discussion. Frequently, there is only partial randomization, indicating a short-lived diradical intermediate. The details vary from case to case, and both preferential inversion and retention of relative stereochemistry have been observed. H3C

CH3

H

H

N

N

H3C H

H3C

N

N

CH3 33%

Ref. 222

CH2CH3

CH3CH2

H3C

CH3

H3C

CH3

N

+ 66%

H N

H3C

+ 25%

H3C

CH3

145°C

CH3 43%

CH2CH3 CH3 CH2CH3 + CH3

CH3 72%

CH2CH3 CH3 CH3 CH2CH3

2.5%

Ref. 223 H3C CH3CH2

CH2CH3 N

N

145°C

CH3 3.5%

CH2CH3 CH3 CH2CH3 + CH3

42%

CH2CH3 CH3 CH3 CH2CH3

These results can be interpreted in terms of competition between recombination of the 221. N. Rieber, J. Alberts, J. A. Lipsky, and D. M. Lemal, J. Am. Chem. Soc. 91:5668 (1969). 222. R. J. Crawford and A. Mishra, J. Am. Chem. Soc. 88:3963 (1966). 223. P. D. Bartlett and N. A. Porter, J. Am. Chem. Soc. 90:5317 (1968).

diradical intermediate and conformational equilibration which would destroy the stereochemical relationships present in the azo compound. The main synthetic application of azo compound decomposition is in the synthesis of cyclopropanes and other strained ring systems. Some of the required azo compounds can be made by dipolar cycloadditions of diazo compounds. Elimination of nitrogen from Diels±Alder adducts of certain heteroaromatic rings has been useful in the synthesis of substituted aromatic compounds.224 Pyridazines, triazines, and tetrazines react with electron-rich dienophiles in inverse-electron-demand cycloadditions. The adducts then rearomatize with loss of nitrogen and the dienophile substituent.225

N

N

N

X

N

Y

N

+

Y

N

–N2

N

–HY

X

X

Pyridazine-3,6-dicarboxylate esters react with electron-rich alkenes to give adducts that undergo subsequent elimination to give benzene derivatives.226

CO2Me N N

MeO2C OMe + CH2

NMe2

NMe2

N

C

CO2Me

OMe –N2 –MeOH

N

NMe2

CO2Me

CO2Me

MeO2C

Similar reactions have been developed for 1,2,4-triazines and 1,2,4,5-tetrazines.

N N

N

+

N CO2Me

PhC

CH2

CO2Me N

N

N CO2Me

224. 225. 226. 227. 228.

N

MeO2C

Ph

Ref. 227

CO2Me

MeO2C + (MeO2)C CHCCH3

HN

Ph

O

MeO2C

CCH3

O N

–N2

N

N

N

N

N

N

N

N

H OMe

–N2 –MeOH

OMe CO2Me

D. L. Boger, Chem. Rev. 86:781 (1986). D. L. Boger, J. Heterocycl Chem. 33:1519 (1996). H. Neunhoeffer and G. Werner, Justus Liebigs Ann. Chem. 1973: 1955. D. L. Boger and J. S. Panek, J. Am. Chem. Soc. 107:5745 (1985). D. L. Boger and R. S. Coleman, J. Am. Chem. Soc. 109:2717 (1987).

N N

O CCH3 Ref. 228 OMe

CO2Me

407 SECTION 6.8. UNIMOLECULAR THERMAL ELIMINATION REACTIONS

408 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

The heterocycles frequently carry substituents such as chloro, methylthio, or alkoxycarbonyl. NHCOCH3 N

N

N

N

NHCOCH3 + CH2

N

C(OCH3)2

78%

N

Ref. 229

OCH3

SCH3

SCH3 Cl

Cl N

N

N

N

N

+

66%

Ref. 230

N CH3O Cl

Cl

Acetylenic dienophiles lead directly to aromatic adducts on loss of nitrogen. SCH3 SCH3

OTBDMS H H + NH

N

N

N

N

O

OTBDMS H H

N N

NH O

Ref. 231

SCH3

SCH3

6.8.3. b Eliminations Involving Cyclic Transition States Another important family of elimination reactions has as the common mechanistic feature cyclic transition states in which an intramolecular proton transfer accompanies elimination to form a new carbon±carbon double bond. Scheme 6.16 depicts examples of the most important of these reaction types. These reactions are thermally activated unimolecular reactions that normally do not involve acidic or basic catalysts. There is, however, a wide variation in the temperature at which elimination proceeds at a convenient rate. The cyclic transition states dictate that elimination occurs with syn stereochemistry. At least in a formal sense, all the reactions can proceed by a concerted mechanism. The reactions, as a group, are referred to as thermal syn eliminations. Amine oxide pyrolysis occurs at temperatures of 100±150 C. The reaction can proceed at room temperature in DMSO.232 If more than one type of b hydrogen can attain the eclipsed conformation of the cyclic transition state, a mixture of alkenes will be formed. The product ratio parallels the relative stability of the competing transition states. Usually, more of the E-alkene is formed because of the additional eclipsed interactions present in the transition state leading to the Z-alkene. The selectivity is usually not high, 229. 230. 231. 232.

D. L. Boger, R. P. Schaum, and R. M. Garbaccio, J. Org. Chem. 63:6329 (1998). T. J. Sparey and T. Harrison, Tetrahedron Lett. 39:5873 (1998). S. M. Sakya, T. W. Strohmeyer, S. A. Lang, and Y.-I. Lin, Tetrahedron Lett. 38:5913 (1997). D. J. Cram, M. R. V. Sahyun, and G. R. Knox, J. Am. Chem. Soc. 84:1734 (1962).

Scheme 6.16. Elimination via Cyclic Transition States Reactant

Transition state

1a H R

R

R

S H R

CHR + HON(CH3)2

100–150°C

SeR′

RCH

CHR + HOSeR′

0–100°C

RCH

CHR + CH3CO2H

400–600°C

RCH

CHR + CH3SH + SCO

150–250°C

CHR CH3

C

C

O

O

H

CH CHR

4d

SECTION 6.8. UNIMOLECULAR THERMAL ELIMINATION REACTIONS

δ+

RC H

CH3 O H

a. b. c. d.

δ−

H

CHR

RCH

CHR

O

SeR′

Temperature range

δ+

N(CH3)2

RC H

+

O

CH

3c

H

CHR



H

O

N(CH3)2

CH

2b

δ−

+



O

Product

409

C

R

O CHR H

SCH3

SCH3

C

C

S

O

H

CH CHR

C

R

O CHR H

A. C. Cope and E. R. Trumbull, Org. React. 11:317 (1960). D. L. J. Clive, Tetrahedron 34:1049 (1978). C. H. De Puy and R. W. King, Chem. Rev. 60:431 (1960). H. R. Nace, Org. React. 12:57 (1962).

however. H

O– +

R

N

H

R

H

CH3

O– N

H

R

E-alkene

CH3

R

H more favorable

CH3

+

H

CH3

Z-alkene

steric repulsion

less favorable

In cyclic systems, conformational effects and the requirement for a cyclic transition state determine the product composition. This effect can be seen in the product ratios from pyrolysis of N ,N -dimethyl-2-phenylcyclohexylamine N -oxide. O– +

O– +

N(CH3)2

N(CH3)2

+ Ph

+ Ph

Ph 85%

15%

Ph

Ph

Ph 2%

98%

Elimination to give a double bond conjugated with an aromatic ring is especially favorable. This presumably re¯ects both the increased acidity of the proton a to the phenyl ring and the stabilizing effect of the developing conjugation at the transition state. Amine oxides

410 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

can be readily prepared from amines by oxidation with hydrogen peroxide or a peroxycarboxylic acid. Some typical examples are given in section A of Scheme 6.17. Selenoxides are even more reactive than amine oxides toward b elimination. In fact, many selenoxides react spontaneously when generated at room temperature. Synthetic procedures based on selenoxide eliminations usually involve synthesis of the corresponding selenide followed by oxidation and in situ elimination. We have already discussed examples of these procedures in Section 4.7, where the conversion of ketones and esters to their a,b-unsaturated derivatives was considered. Selenides can also be prepared by electrophilic addition of selenenyl halides and related compounds to alkenes (see Section 4.5). Selenide anions are powerful nucleophiles that can displace halides or tosylates and open epoxides.233 Selenide substituents stabilize an adjacent carbanion so that a-selenenyl carbanions can be prepared. One versatile procedure involves conversion of a ketone to a bis-selenoketal which can then be cleaved by n-butyllithium.234 The carbanions in turn add to ketones to give b-hydroxyselenides.235 Elimination gives an allylic alcohol. Li RCH2C

O + 2 PhSeH

R′

RCH2C(SePh)2

BuLi

R′

RCH2CSePh

R′

R′′CH O

R′

RCH2C

CHR′′

PhSe OH [O]

R′ RCH

C

CHR′′ OH

Alcohols can be converted to o-nitrophenylselenides by reaction with o-nitrophenyl selenocyanate and tri-n-butylphosphine.236 RCH2OH +

SeCN NO2

Bu3P

RCH2Se O2N

The selenides prepared by any of these methods can be converted to selenoxides by such oxidants as hydrogen peroxide, sodium metaperiodate, peroxycarboxylic acids, t-butyl hydroperoxide, or ozone. Like amine oxide eliminations, selenoxide eliminations normally favor formation of the E-isomer in acyclic structures. In cyclic systems, the stereochemical requirements of the cyclic transition state govern the product structure. Section B of Scheme 6.17 gives some examples of selenoxide eliminations. A third category of syn eliminations involves pyrolytic decomposition of esters with elimination of a carboxylic acid. The pyrolysis of acetate esters normally requires temperatures above 400 C. The pyrolysis is usually a vapor-phase reaction. In the 233. D. L. J. Clive, Tetrahedron 34:1049 (1978). 234. W. Dumont, P. Bayet, and A. Krief, Angew. Chem. Int. Ed. Engl. 13:804 (1974). 235. D. Van Ende, W. Dumont, and A. Krief, Angew. Chem. Int. Ed. Engl. 14:700 (1975); W. Dumont, and A. Krief, Angew. Chem. Int. Ed. Engl. 14:350 (1975). 236. P. A. Grieco, S. Gilman, and M. Nishizawa, J. Org. Chem. 41:1485 (1976); A. Krief and A.-M. Laval, Bull. Soc. Chim. Fr. 134:869 (1997).

Scheme 6.17. Thermal Eliminations via Cyclic Transition States

411

A. Amine oxide pyrolyses

SECTION 6.8. UNIMOLECULAR THERMAL ELIMINATION REACTIONS

CH3 +

1a PhCHCHN(CH3)2 CH3

PhC

O–

CHCH3 + PhCHCH

CH3

CH2

CH3

92%

8%

O–

2b

+

CH2N(CH3)2

CH2

85%

3c O– +

67%

N(CH3)2

B. Selenoxide elimination O 4d

CH2CH2OSO2Ar O

CH2CH2SePh 1)

O

PhSe–

CCl4, 10 min

O

H

5e

O

77°C

2) O3

O

CH

H

O

CH2 60%

H

O CO2H

1) PhSe–

O

CO2H 3) pyridine 4) H+

2) O3

CH2SePh

CH2

O 6f

CH2CO2H

PhSeCl, Et3N

O

CH2Cl2

H2O2

O

THF

O

O 93%

92%

PhSe O

NO2 1)

7g O

SeCN, Ph3P

OH

2) O3

DBU

Se

O 5%

O

H O2N C. Acetate pyrolyses O2CCH3

8h N 9i

C

CHCH3

575–600°C

CH2O2CCH3

N

CH

CH2 555°C

CH2O2CCH3

C

CH2

76%

CH2 +

CH2

61%

CH2O2CCH3

24%

(continued)

Scheme 6.17. (continued )

412 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

CH3

10j

CH3 400ºC

CH3

O CH3

CH3

O

CH2O2CCH3

CH3

CH2

D. Xanthate ester pyrolyses 1) K 2) CS2

11k PhCHCHCH3

3) CH3I 4) ∆

H3C OH

PhC

CHCH3

91%

CH3

OH

12l

1) NaH 2) CS2

+

3) CH3I 4) ∆

13m (CH3)2CH

CH2O–Na+ CS2



(total yield 41%)

(CH3)2CH

CH2

(CH3)2CH

CH2

CH3I

(CH3)2CH 14n

CH2O–Na–

OH 1) NaH 2) CS2

71%

3) CH3I 4) ∆

1) NaH, CS2, 2) CH3I

15o

60%

3) ∆

O

OH

O

a. b. c. d. e.

D. J. Cram and J. E. McCarty, J. Am. Chem. Soc. 76:5740 (1954). A. C. Cope, E. Ciganek, and N. A. LeBel, J. Am. Chem. Soc. 81:2799 (1959). A. C. Cope and C. L. Bumgardner, J. Am. Chem. Soc. 78:2812 (1956). R. D. Clark and C. H. Heathcock, J. Org. Chem. 41:1396 (1976). D. Liotta and H. Santiesteban, Tetrahedron Lett. 1977:4369; R. M. Scarborough, Jr. and A. B. Smith III, Tetrahedron Lett. 1977:4361. f. K. C. Nicolaou and Z. Lysenko, J. Am. Chem. Soc. 99:3185 (1977). g. L. E. Friedrich and P. Y. S. Lam, J. Org. Chem. 46:306 (1981). h. C. G. Overberger and R. E. Allen, J. Am. Chem. Soc. 68:722 (1946). i. W. J. Bailey and J. Economy, J. Org. Chem. 23:1002 (1958). j. E. Piers and K. F. Cheng, Can. J. Chem. 46:377 (1968). k. D. J. Cram, J. Am. Chem. Soc. 71:3883 (1949). l. A. T. Blomquist and A. Golstein, J. Am. Chem. Soc. 77:1001 (1955). m. A. de Groot, B. Evenhuis, and H. Wynberg, J. Org. Chem. 33:2214 (1968). n. C. F. Wilcox, Jr. and C. G. Whitney, J. Org. Chem. 32:2933 (1967). o. L. A. Paquette and H.-C. Tsui, J. Org. Chem. 61:142 (1996).

laboratory, this can be carried out by using a glass tube in the heating zone of a small furnace. The vapors of the reactant are swept through the hot chamber by an inert gas and into a cold trap. Similar reactions occur with esters derived from long-chain acids. If the boiling point of the ester is above the decomposition temperature, the reaction can be carried out in the liquid phase.

Ester pyrolysis has been shown by use of deuterium labels to be a syn elimination in the case of formation of stilbene.237 CH3 C O

Ph

HO

H

H

LiAlD4

Ph

H

O

Ph

Ph H

O H

Ph

Ph H

Ph

HO LiAlD4

Ph H

H

C

Ph H

O

O Ph

H

D

Ph

D

H

Ph

CH3

CH3 O

D

D Ph

H

D

Ph

H

C



O Ph H

O D H Ph

Ph

H

H

Ph

Although the existence of the concerted cyclic mechanism is recognized, it has been proposed that most preparative pyrolyses proceed as surface-catalyzed reactions.238 Mixtures of alkenes are formed when more than one type of b hydrogen is present. In acyclic compounds, the product composition often approaches that expected on a statistical basis from the number of each type of hydrogen. The E-alkene usually predominates over the Z-alkene for a given isomeric pair. In cyclic structures, elimination is in the direction in which the cyclic mechanism can operate most favorably. CH2

OAc

CH3 CH2

CH3 CH3

CH3 CH3

+

CH3 +

Ref. 239

55%

45%

0%

46%

26%

28%

CH3 OAc CH3

Alcohols can be dehydrated via xanthate esters at temperatures that are much lower than those required for acetate pyrolysis. The preparation of xanthate esters involves reaction of the alkoxide with carbon disul®de. The resulting salt is alkylated with methyl iodide. S RO–

Na+

S

ROCS– Na+

+ CS2

CH3I

ROCSCH3

The elimination is often effected simply by distillation. H R

S

CH H

C

C O

SCH3



RCH

CHR +

HSCSCH3

CH3SH + COS

O

R

237. D. Y. Curtin and D. B. Kellom, J. Am. Chem. Soc. 75:6011 (1953). 238. D. H. Wertz and N. L. Allinger, J. Org. Chem. 42:698 (1977). 239. D. H. Froemsdorf, C. H. Collins, G. S. Hammond, and C. H. DePuy, J. Am. Chem. Soc. 81:643 (1959).

413 SECTION 6.8. UNIMOLECULAR THERMAL ELIMINATION REACTIONS

414 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

Product mixtures are observed when more than one type of b hydrogen can participate in the reaction. As with the other syn thermal eliminations, there are no intermediates that are prone to skeletal rearrangement.

General References W. Carruthers, Cycloaddition Reactions in Organic Synthesis, Pergamon Press, Oxford, 1990. A. P. Marchand and R. E. Lehr (eds.), Pericyclic Reactions, Vols. I and II, Academic Press, New York, 1977. A. Williams, Concerted Organic and Bro-Organic Mechanisms. CRC Press, Boca Raton, FL, 2000. R. B. Woodward and R. Hoffmann, The Conservation of Orbital Symmetry, Academic Press, New York, 1970.

Diels±Alder Reactions G. Brieger and J. N. Bennett, Chem. Rev. 80:63 (1980). E. Ciganek, Org. React. 32:1 (1984). W. Oppolzer, Angew Chem. Int. Ed. Engl. 23:876 (1984). W. Oppolzer, Synthesis 1978:793.

Cycloaddition Reactions A. Padwa (ed.), 1,3-Dipolar Cycloaddition Chemistry, Wiley, New York, 1984.

Sigmatropic Rearrangements E. Block, Reactions of Organosulfur Compounds. Academic Press, New York, 1978, Chapter 7. H.-J. Hansen, in Mechanisms of Molecular Migrations, Vol. 3, B. S. Thyagarajan (ed.), Wiley-Interscience, New York, 172, pp. 177±236. R. K. Hill, in Asymmetric Synthesis, Vol. 3, J. D. Morrison (ed.), Academic Press, New York, 1984, Chapter 8. S. J. Rhoads and N. R. Raulins, Org. React. 22:1 (1975). T. S. Stevens and W. E. Watts, Selected Molecular Rearrangements, Van Nostrand Reinhold, London, 1973, Chapter 8. B. M. Trost and L. S. Melvin, Jr., Sulfur Ylides, Academic Press, New York, 1975, Chapter 7.

Elimination Reactions W. H. Saunders, Jr. and A. F. Cockerill, Mechanisms of Elimination Reactions, Wiley, New York, 1973, Chapter VIII.

Problems (References for these problems will be found on page 931.) 1. Predict the product of each of the following reactions, clearly showing stereochemistry where relevant.

(a)

415

OAc

PROBLEMS

BF3, Et2O

CHCHO

+ CH2

toluene, –10°C

CH2CH3 OSiMe3

(b)

CHCHO

+ CH2 CH3 CH3 (c)

NHCO2C2H5 + (E)-CH3CH

(d)

CHCHO

110°C

H2C CH 60°C

H H (e) CH3 CH3

200ºC

CH3 H

O O

(f) H3C

O

C H

(g)

C

CH3

230°C

CO2CH3

O CH3CCH2CH2CH2CH

(h)

CH2 + CH3NHOH⋅HCl

OH 1) C2H5OCH CH2, Hg2+ 2) 210°C

H3C (i)

CH3 OH CCH2CH

KH dimethoxyethane, 80°C

CH2

CH3 (j)

O CH3 hν

CH2CH2CH2C CH3

CH2

CH3

416 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

(k)

1) n-BuLi

C6H5CH(SeCH3)2

2) 1,2-epoxybutane 3) H2O2

H

(l)

KH, THF 25°C

OH

(m)

HO

H

CH3

C

CH3 C

CH2CH(CH3)2

C

H

(CH3)2NC(OCH3)2 ∆

H

(n)

CH3 100°C

O

CH3 (o)

CH3

O

CH3 (p)

Li+ –N

CH3OCH2O H3C

1) LDA, HMPA 2) t-BuMe2SiCl

H

O

3) 105°C

O (q)

H3C O CH2

CH3 O



CH(CH2)3

(r)

O

O OMe O

CH2Br + CH2

CHCCH3

CH2Br O (s)

CH2

OMe

CCH2CH2CH2OCH2CO2H

1) ClCOCOCl 2) Et3N

CH3 (t)

1) MCPBA

CN

2) (C2H5)2NH

SPh (u)

N(CH2Ph)2 Ph

MCPBA

CO2C2H5

Zn

417

(v) Li+ –O

+ N+

heat THF

PROBLEMS

OCH3

CH3 (w) KO-t-Bu DMF

(CH3)2 N+CH2CO2C2H5 (x)

OCH2Ph

O2CCH2OCH2Ph LDA TMS–Cl

TBDPSO CH3 (y)

CH3 N

H

+

+

H

O–

CO2CH3

2. Intramolecular cycloaddition reactions occur under the reaction conditions speci®ed for each of the following reactants. Show the structure of the product, including all aspects of its stereochemistry, and indicate the structures of any intermediates which are involved in the reactions. (a)

NHOH

H

CH2

CH3

H (b)

O

C6H5 N CH3



CH2CH2CH2CH

(c)

H N

O

O N H

(d)

Ph (e)

CH2CNHNHCH3 S

C C

CH3O

C

H

O CCH2NC H

C6H5CH

O

80°C, 1 h

S

H Ph

CH2

CH3

H C

C

90°C

Ph

H

CN (CH2)4CH

CH2



418 CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

(f)

CH2

CH

H

H C

C

H

CH(CH3)2 C

C



H

CH2CH2CH2C O

(g)

CH3

O

CCH2CH2C

CH2



AcO

3. Indicate the mechanistic type to which each of the following reactions belongs. (a)

CH3 NO2

H (CH3)2C

CHN(CH3)2 +

C

C

C6H5

C6H5

H3C

H (CH3)2N

NO2

O

(b)

CH3CH

1) CH3SCH2CPh

CHCH2Br +

2) K2CO3

CH3CHCH

CH2

CH3S CHCPh O (c)

N N

H

N

20°C

+

N

PhCH2

CH2CO2C2H5

PhCH2 (d)

CO2C2H5 CO2CH3

CO2CH3 +

N

O–

+

N

CH2CH2OSO2CH3 O

CH3SO2O (e)

CH2

CHCH2CH3 + C2H5O2CN

NCO2C2H5

CH3CH

CHCH2NNHCO2C2H5 CO2C2H5

(f)

(CH3)2C

CHCH2CH2CHCH2CH2CO2CH3 + HC CH3 CH3

AlCl3

CH2

CCHCH2CH2CHCH2CH2CO2CH3 CH

CHCO2CH3

(g) Et3N CH3SO2Cl

H

CHN N

SO2

CCO2CH3

(h)

419

N

Ph N

N

PROBLEMS

PhN3 +

NCH

CHPh

N

Ph

O

CH3

(CH3)2CHC

CCH

(i) (CH3)2CHCHOCH2CH

C(CH3)2

1) LiNR2 2) H3O+

NC (j)

CH2

CH3

O

O

OCH3 + CH2

110°C

C(OCH3)2

CO2CH3

CO2CH3

4. By applying the principles of retrosynthetic analysis, show how each of the indicated target molecules could be prepared from the starting material(s) given. No more than three separate transformations are necessary in any of the syntheses. (a)

CH3O

OCH3 Cl

Cl Cl

Cl

Cl

Cl

Cl

CH3O (b)

O

Cl +

OCH3

CH3 CO2CH3 H3C

CH3 O + dimethyl acetylenedicarboxylate

CH3 CO CH 2 3 (c)

N(C2H5)2 C(O)Ph

crotonaldehyde, diethylamine, and trans-1,2dibenzoylethylene

C(O)Ph (d)

CH3CH2C

CCH

CHCH2CH2CO2CH3 CH3CH2C

(e)

CH + CH2 OH

OH CH2CH

HO

CH2

O + H2C

O O

HO (f)

CHCHO + CH3C(OCH3)3

H3C H3C H

CO2C2H5 Ph

Ph

H

CO2C2H5

trans-stilbene, diethyl malonate, and acetone

CHCH2Br

420

(g)

CO2CH3

H3C

CHAPTER 6 CYCLOADDITIONS, UNIMOLECULAR REARRANGEMENTS, AND THERMAL ELIMINATIONS

CO2CH3

CH3 CHO

H3C

CH3

H3C

CH3

and any other necessary reagents (h)

NO2 CO2CH3

O (i)

H3C

H3C

H3C

(j)

(E)-O2NCH CHCO2CH3 and any other necessary reagents

CH3O CH2CH

CH2

HO

CH3O (k)

CHO and any other necessary reagents CH3O

HO

CH3O O

HO

N

I TBDMSOCH2CH2 (l)

H

H

O

H

O

CH3

H3C

CH2OH

H

H

O

O H3C

TBDMSOCH2CH2

CO2CH3

CH3 CH3

HOCH2

(m)

H3C

CH2CH2CO2C2H5

H

H

O

HO CH3 CH3

H3C N

H

H

H

N H

CO2CH3

5. Reaction of a-pyrone (A) with methyl acrylate at re¯ux for extended periods gives a mixture of stereoisomers of B. Account for the formation of this product.

H3CO2CCH

O

CH2

H3CO2C

O

CO2CH3

A

B

6. When 2-methylpropene and acrolein are heated at 300 C under pressure, 3-methylenecyclohexanol and 6,6-dimethyldihydropyran are formed. Explain the formation of these products. O

CH3

CH2

CH3 HO 3-methylenecyclohexanol

6,6-dimethyldihydropyran

7. Vinylcyclopropane, when irradiated with benzophenone or benzaldehyde, gives a mixture of two types of products. Suggest the mechanism by which product of type C is formed.

Ph C R′

CH2 + O

O

C R′

R

Ph

+ Ph

R

R′

O

R

C

8. The addition reaction of tetracyanoethylene and ethyl vinyl ether in acetone gives 94% of the 2 ‡ 2 adduct and 6% of an adduct having the composition tetracyanoethylene ‡ ethyl vinyl ether ‡ acetone. If the 2 ‡ 2 adduct is kept in contact with acetone for several days, it is completely converted to the minor product. Suggest a structure for this product, and indicate its mode of formation (a) in the initial reaction and (b) on standing in acetone. 9. A convenient preparation of 2-allylcyclohexanone involves simply heating the diallylketal of cyclohexanone in toluene containing a trace of p-toluenesulfonic acid and collecting a distillate consisting of toluene and allyl alcohol. Distillation of the residue gives a 90% yield of 2-allylcyclohexanone. Outline the mechanism of this reaction. 10. The preparation of a key intermediate in an imaginative synthesis of prephenic acid is depicted below. Write a series of equations showing the important steps and intermediates in this process. Indicate the reagents requ