Iron-, Cobalt

Iron-, Cobalt- and Chromium-Catalyzed Cross-Coupling Reactions of Aromatics and Heterocycles ... (“Deadlock - it's a great excuse to break down the wa...

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Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München

Iron-, Cobalt- and Chromium-Catalyzed Cross-Coupling Reactions of Aromatics and Heterocycles

von

Olesya Kuzmina

aus Moskau, Russland

2014

Erklärung Diese Dissertation wurde im Sinne von § 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Paul Knochel betreut.

Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe bearbeitet.

München, 27. June 2014

…..……………………………………

Olesya Kuzmina

Dissertation eingereicht am: 27. June 2014 1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. Konstantin Karaghiosoff

Mündliche Prüfung am: 28. July 2014

2

This work was carried out from October 2011 to June 2014 under the guidance of Prof. Dr. Paul Knochel at the Faculty of Chemistry and Pharmacy of the Ludwig-Maximilians Universität, Munich.

Firstly, I would like to thank Prof. Dr. Paul Knochel for giving me the great opportunity to do my Ph.D. in his group and for his guidance and support in the course of my scientific research. I am also very grateful to Prof. Dr. Konstantin Karaghiosoff for agreeing to be my “Zweitgutachter” as well as Prof. Dr. Franz Bracher, Prof. Dr. Manfred Heuschmann, Prof. Dr. Herbet Mayr and Prof. Dr. Ania Hoffmann-Röder for their interest shown in this manuscript by accepting to be referees. I really would like to thank Andreas Steib, Dr. Simon Herbert, Robert Greiner, Julia Nafe and Sophie Hansen for the careful correction of this manuscript. I thank all past and present co-workers I have met in the Knochel group for their kindness and their help especially at the beginning of my PhD. Special thanks to old members of F2.012 Dr. Andreas Unsinn, Dr. Gabriel Monzon, Dr. Christoph Sämann. Especially I would like to thank my former hood neighbor Dr. Ilaria Tirotta, who made my daily life in the lab more funny. I also thank all my actual lab mates Diana Haas, Johannes Nickel, Dr. Maitane Fernandez and Dr. Dorian Didier. I am very greatful to Andreas Steib, Andi, Andi Steib, A. Steib et al, I would like to thank all of them for their great help during my PhD and for many fruitfull collaborations on iron and chromium chemistry. Special thank to Dr. John Markiewicz for his help on the iron project, for all “sexy Grignards” he prepared, and to Sarah Fernandez for her assistance on chromium-catalyzed cross-couplings and for being my hood neighbor (unfortunatlly the “Friday column day” did not work so well). Moreover, I would like to thank my чувиха Nadja Barl that she never let me forget russian. I would also like to thank Dr. Vladimir Malakhov, Renate Schröder and Yulia Tsvik for their help in organizing everyday life in the lab and in the office, as well as the analytical team of the LMU for their invaluable help. I thank Stephan Dorsch and Alexander John for their contributions to this work in course of their internship in the Knochel group. Thank you guys for making these three years a great time for me. I hope we will stay in touch wherever life will take us!

Parts of this PhD thesis have been published 1)

Kuzmina, O. M. & Knochel, P., Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines, manuscript submitted.

2)

Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D. & Knochel, P., Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Csp2-Centers. J. Am. Chem. Soc. 135 (2013), 15346.

3)

Kuzmina, O. M.; Steib, A. K.; Markiewicz, J. T.; Flubacher, D. & Knochel, P., Ligand-Accelerated Fe- and Co-Catalyzed Cross-Coupling Reactions between NHeterocyclic Halides and Aryl Magnesium Reagents. Angew. Chem. Int. Ed. 52 (2013), 4945.

4)

Kuzmina, O. M.; Steib, A. K.; Flubacher, D. & Knochel, P., Iron-Catalyzed CrossCoupling of N-Heterocyclic Chlorides and Bromides with Arylmagnesium Reagents. Org. Lett. 14 (2012), 4818.

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“Тупик — это отличный предлог, чтобы ломать стены” (“Deadlock - it's a great excuse to break down the walls”) Братья Стругацкие (Brothers Strugackie)

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Моей Бабушке и Маме (To My Grandmother and Mother)

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Table of Contents A.

Introduction ................................................................................................................................................. 2

1.

General Introduction ........................................................................................................................................... 3

2.

Iron-Catalyzed Cross-Coupling Reactions.......................................................................................................... 7

2.1

Cross-Coupling of Alkenyl Electrophiles with Grignard Reagents ...................................................................... 8

2.2

Cross-Coupling of Aryl Electrophiles with Grignard Reagents ......................................................................... 19

3.

Chromium-Catalyzed Cross-Coupling Reactions ............................................................................................. 28

4.

C-H Bond Activation Reactions Using Alternative Transition Metals ............................................................. 31

5.

Objectives ......................................................................................................................................................... 38

B.

Results and Discussion .............................................................................................................................. 41

1.

Iron-Catalyzed Cross-Coupling of N-Heterocyclic Halides with Grignard Reagents. ...................................... 43

1.1

Introduction ........................................................................................................................................................ 43

1.2

Results and Discussion ....................................................................................................................................... 43

2.

Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling between N-Heterocyclic Halides and Aryl

Magnesium Reagents. .................................................................................................................................................. 53 2.1

Introduction ........................................................................................................................................................ 53

2.2

Results and Discussion ....................................................................................................................................... 54

3.

Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions ......................................................................... 67

3.1

Introduction ........................................................................................................................................................ 67

3.2

Results and Discussion ....................................................................................................................................... 67

4.

Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines .... 74

4.1

Introduction ........................................................................................................................................................ 74

4.2

Results and Discussion ....................................................................................................................................... 74

5.

Summary 81

5.1

Iron-Catalyzed Cross-Coupling of N-Heterocyclic Halides with Grignard Reagents ........................................ 81

5.2

Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling between N-Heterocyclic Halides and Aryl Magnesium Reagents.......................................................................................................................................... 82

5.3

Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions........................................................................... 83

5.4

Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines ...... 85

C.

Experimental Section ................................................................................................................................ 89

1. 1.1

General Considerations ..................................................................................................................................... 91 Solvents 91

i

1.2

Reagents 92

1.3

Content Determination of Organometallic Reagents .......................................................................................... 93

1.4

Chromotography ................................................................................................................................................. 93

1.5

Analytical Data ................................................................................................................................................... 93

2.

Typical Procedures (TP) ................................................................................................................................... 94

2.1

Typical Procedure for Fe-Catalyzed Cross-Coupling Reactions of N-Heterocyclic Chlorides and Bromides with Arylmagnesium Reagents (TP1)......................................................................................................................... 94

2.2

Typical Procedure for Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling Reactions between NHeteroaryl Halides and Aryl Magnesium Reagents (TP2) ................................................................................. 94

2.3

Typical Procedure for Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Aryl Halides and Aryl or Alkyl Grignard Reagents (TP3) ............................................................................................................. 95

2.4

Typical Procedure for Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Imine Halide 16 and Aryl Grignard Reagents (TP4) ..................................................................................................................... 95

2.5

Typical Procedure for Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Alkenyl Iodide 18 and Aryl Grignard Reagents (TP5) ................................................................................................................ 95

2.6

Typical Procedure for Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines and Aryl Oxazolines (TP6) ................................................................................................................................................ 96

2.7 3.

Typical Procedure for Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Imines (TP7) ........... 96 Fe-Catalyzed Cross-Coupling Reactions of N-heterocyclic Chlorides and Bromides with Arylmagnesium

Reagents 97 3.1

Preparation of Cross-Coupling Products Using TP1 .......................................................................................... 97

4.

Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling Reactions between N-Heterocyclic Halides

and Aryl Magnesium Reagents .................................................................................................................................. 114 4.1

Preparation of Starting Materials ...................................................................................................................... 114

4.2

Preparation of Cross-Coupling Products Using TP2 ........................................................................................ 121

5.

Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Csp2 Centers ................................... 143

5.1

Preparation of Cross-Coupling Products Using TP3 ........................................................................................ 143

5.2

Preparation of Cross-Coupling Products Using TP4 ........................................................................................ 156

5.3

Preparation of Cross-Coupling Products Using TP5 ........................................................................................ 159

6.

Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines. . 164

6.1

Preparation of Starting Materials ...................................................................................................................... 164

6.2

Preparation of Arylated Products Using TP6 ................................................................................................... 168

6.3

Preparation of Arylated Products Using TP7 ................................................................................................... 185

ii

iii

List of Abbreviations

Ac

Acetyl

LDA

lithium diisopropylamide

acac

acetylacetonate

M

molarity

aq.

aqueous

m

meta

Ar

aryl

m

multiplet

Alk

alkyl

MCPE

methoxycyclopentane

Bn

benzyl

Me

methyl

Boc

t-butyloxycarbonyl

Met/M

metal

Bu

butyl

min

minute

nBu

n-butyl

mmol

millimole

tBu

t-butyl

m.p.

melting point

calc.

calculated

MS

mass spectroscopy

conc.

concentrated

NEP

N-ethyl-2-pyrrolidone

Cy

cyclohexyl

NMP

N-methyl-2-pyrrolidone

δ

chemical shifts in parts per

NMR

nuclear magnetic resonance

million

o

ortho

d

doublet

OTf

triflate

dba

trans,trans-dibenzylideneacetone

p

para

DCB

2,3-dichlorobutane

Ph

phenyl

DME

dimethoxyethane

Piv

pivaloyl

DMPU

1,3-dimethyltetrahydropyrimidin-

iPr

iso-propyl

2(1H)-one

q

quartet

DG

directing group

R

organic substituent

dppe

diphenylphosphinoethane

r.t.

room temperature

dppf

1,1'-bis(diphenylphosphino)

sat.

saturated

ferrocene

s

singulet

E

electrophile

Tol

tolyl

EI

electron-impact ionization

tfp

tri-2-furylphosphine

ESI

electrospray ionization

THF

tetrahydrofuran

equiv

equivalent

TLC

thin layer chromatography

Et

ethyl

TMEDA

tetramethylethylenediamine

FG

functional group

TMHD

2,2,6,6-tetramethyl-3,5-heptane-dionate

GC

gas chromatography

TMS

trimethylsilyl

h

hour

TMP

2,2,6,6-tetramethylpiperidyl

Hal

halogene

TP

typical procedure

Het

heteroaryl

iv

HRMS

high resolution mass spectroscopy

IR

infra-red

J

coupling constant (NMR)

v

i

A. Introduction

A.Introduction

1. General Introduction Over the past two centuries, the discoveries made in organic chemistry have led us to a world with vastly increased life expectancy due to the medical wonder drugs we are now able to produce. Organometallic chemistry is at the same time an old and a new branch of chemistry. It is old because the first organometallic compound was prepared about 250 years ago; organometallic chemistry is new, since in the last 60 years organometallic compounds have become a subject of general interest, and the field is now recognized as an independent branch of chemistry.1 The history of organometallic chemistry could be described as a one of unexpected discoveries.2 The first organometallic compound prepared was in 1760 by Louis Claude Cadet,3 who worked on synthetic inks based on cobalt salts. He used cobalt minerals, which also contain arsenic. Reaction of arsenic(III) oxide and potassium acetate gave “Cadet´s fuming liquid”, which contains cacodyloxide [(CH3)2As]2O. Later, in 1840, R. W. Bunsen investigated these kind of compounds, which he called “alkarsines” more closely.4 The first olefin complex was prepared by William Christopher Zeise,5 a Danish chemist, in 1827 by the reaction of ethanol with a mixture of PtCl2 and PtCl4 in the presence of KCl. It is interesting to mention that this was about at the same time as the first successful synthesis of urea in 1828 by F. Wöhler6 and 40 years prior to the proposal of the Periodic Table by A. D. Mendeleev in 1869, who later, used organometallic compounds as the test cases for his Periodic Table. The compound prepared and formulated as PtCl2(C2H4)·KCl·H2O by Zeise must have been regarded as quite bizarre at that time. How can ethylene, a gaseous compound under ordinary conditions combine with platinum? It is no wonder, that when the synthesis of this compound was reported, some of his contemporaries criticised Zeise. The first organometallic compound having a direct metal-to-alkyl σ-bond was synthesized by E. Frankland,7 a student of Bunsen´s at Marburg, in 1849. What Frankland was trying to prove, was the existence of organic radicals. Reasoning that abstraction of iodine from ethyl

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Basic Organometallic Chemistry, I. Haiduc, J. J. Zuckerman, Walter de Gruyter, Berlin, 1985. Organotransition metal Chemistry. Fundemental Concepts and Applications; A. Yamamoto, Wiley-VCH: Weinheim, 1986. 3 L. C. Cadet de Gassicourt, Mem. Mat. Phys. 1760, 3, 363. 4 R. Bunsen, Liebigs Ann. Chem. 1837, 24, 471. 5 W. C. Zeise, Pogg. Ann. 1827, 9, 632. 6 F. Wöhler, Annalen der Physik und Chemie 1828, 88, 253. 7 E. Frankland, Liebigs Ann. Chem. 1849, 71, 171. 2

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iodide by zinc should give an ethyl radical, he heated a mixture of ethyl iodide and zinc. He obtained a volatile, colorless liquid and first thought that he had demonstrated the occurrence of a radical. However, the determination of the molecular weight showed that it was not an ethyl radical, but butane that was formed by the decomposition of an ethylzinc compound generated by the reaction of zinc with ethyl iodide. This experiment, which was called “the most fruitful failure”, led to a method for preparing alkylzinc compounds. A number of discoveries of different organometallic compounds such as bis-alkylmercury, bis-alkyltin, bis-alkylboron, allylaluminum iodides, organochlosilanes, halide-free magnesium alkyls passed by, until P. Barbier in 1890 replaced zinc with magnesium in reactions with alkyl iodides.8 His student V. Grignard went on with this investigation and expanded significantly the usage of organo-magnesium reagents,9 which were subsequently named Grignard reagents. Since then, Grignard reagents became a powerful tool in organic synthesis (Scheme 1).

Scheme 1. Some important discoveries in the history of organometallic chemistry

8 9

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P. A. Barbier, C. R. Acad. Sci. 1899, 128, 110. V. Grignard, C. R. Acad. Sci. 1900, 130, 1322.

A.Introduction The history of organometallic chemistry continues with the discovery by Paul Sabatier in 1910, who showed that finely divided metals such as nickel, palladium or platinum could catalyze the hydrogenation of alkenes. This discovery was a great advance for the use of transition metals in organic synthesis.10 However, a real turning point was the determination of the structure of ferrocene by Wilkinson and Fischer11 many years later. A clear image and the high stability of ferrocene gave chemists the possibility of studying and better understanding these kind of organometallic compounds. These discoveries coupled with tremendous advances such as nuclear magnetic resonance (NMR)12 and X-ray crystallography13 paved the way for the investigation of transition-metal complexes, their reactivity and usage in synthetic chemistry. The era of transition metal-catalyzed chemistry had begun. The work of Nobel Laureates such as Sharpless,14 Noyori15 and Knowles16 (2001), Grubbs17, Schrock18 and Chawin19 (2005) and, most recently, Heck,20 Negishi21 and Suzuki22 (2010), made the approaches of this area one of the most applicable in synthetic organic chemistry. Transition metal-catalyzed cross-coupling type reactions represent one of the most powerful tools for the synthesis of any desired molecular structures. Over the last decades, Pd, Ni and Cu-catalyzed cross-couplings were widely applied due to the generality and high functional-group tolerance. A great number of natural products, building blocks for supramolecular chemistry and self-assembly, organic materials and polymers were produced using these metals as catalysts in cross-coupling reactions.23 Most of the palladium or nickel-catalyzed reactions are believed to follow a similar catalytic cycle (Scheme 2).

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Organic Synthesis Using Transition Metals; Bates, R. John Wiley & Sons Ltd., United Kingdom 2012. Wilkinson, J. Am. Chem. Soc. 1954, 76, 209. 12 Nuclear Magnetic Resonance; Hore, P.J. Oxford University Press, Oxford, 1995. 13 Understanding Single-Crystal X-ray Crystallography; Bennett, D. W. Wiley-VCH: Weinheim, 2010. 14 Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. 15 a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Douchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932; b) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117. 16 Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946. 17 Dias, E. L.; Nqyuyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887. 18 McCullough, L. G.; Schrock, R. R. J. Am. Chem. Soc. 1984, 106, 4067. 19 Martinato, A.; Chauvin, Y.; Lefebvre, G. Compt. Rend. 1964, 258, 4271. 20 Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. 21 Baba, S., Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729. 22 Suzuki, A. Pure Appl. Chem. 1991, 63, 419. 23 Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.; Diederich, F. Wiley-VCH: Weinheim, 2004. 11

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Scheme 2. General mechanism for palladium- or nickel-catalyzed cross-coupling reactions

The first step of the catalysis includes the in situ reduction of the precatalyst M1(II)L4 and the generation of the active species of the catalyst M1(0)L2, due to the excess of the organometallic reagent R2-M2. Next, the oxidative addition of the C-X bond of the electrophile R1-X to M1(0)L2 leads to the formation of the complex 1. As a consequence of transmetalation, R2 goes to M1 and the complex 2 is created. The last step is a reductive elimination, whereby the cross-coupling product R1-R2 is produced and the catalyst M1(0)L2 is regenerated.24 The catalytic species can be formed in situ using metal sources such as Pd2(dba)3, Pd(OAc)2 or Ni(dppe)Cl2 in the presence of an appropriate ligand. It also can be introduced as a performed catalyst such as Pd(Ph3)4, Pd(PtBu3)2 or Ni(COD)2. Many ligand families for palladium or nickel are available today. Electron-rich phosphine ligands facilitate the oxidative addition through increasing the electron density of the catalyst´s active complex. Electron-poor ligands facilitate transmetalation as well as reductive elimination. The choice of the ligand depends on which step of catalytic cycle is rate limiting. The oxidative addition of aryliodides usually proceeds fast; thereby electron-poor ligands are 24

a) Handbook of Functionalized Organometallics, (Hrsg.: P. Knochel), Wiley-VCH, Weinheim, 2005; b) Metal Catalyzed Cross-Coupling Reactions, 2nd Ed., (Hrsg.: A. de Meijere, F. Diederich), Wiley-VCH: Weinheim, 2004; c) Handbook of Organopalladium Chemistry for Organic Synthesis, (Hrsg.: E. Negishi), WileyInterscience, New York, 2002; d) Transition Metal for Organic Synthesis, 2nd Ed., (Hrsg.: M. Beller, C. Bolm), Wiley-VCH, Weincheim, 2004

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A.Introduction mostly used. Whereas the cross-coupling reaction with arylchlorides commonly requires electron-rich ligands to accelerate the oxidative addition. Coupled with the right ligand, palladium and nickel catalyzed cross-coupling reactions represent a powerful tool in synthetic organic chemistry today. However, due to economic and ecological disadvantages there is still exists a need for the examination of alternative catalysts. It is not a secret that the price of the most applicable palladium –catalyst, also for the large scale reactions, is around $300 per ounce. At the same time, the toxicity of nickel prevents application of nickel-catalyzed processes for consumer goods and health-care products.25 Moreover, both palladium and nickel catalitic systems require the addition of complicated and expensive ligands.

2. Iron-Catalyzed Cross-Coupling Reactions Iron catalysts have recently received a lot of attention due to a number of advantages, which this metal brings. For instance, for $100 one can buy 0.5 g of ruthenium, 2.0 g of platinum, 2.2 g of gold, 5571 g of nickel, 15 000 g of copper and, finally, 500 000 g of iron.26 Iron is the most abundant metal in the universe and the second-most abundant metal in the earth´s crust. Furthermore, iron is the most abundant transition metal in the human body (4g/person) and it is an essential metal in the life cycle of all living things. This factor actually represents a big advantage for using iron catalysts in health-care related chemistry, since no severe toxicity and side effects exist. The environmentally friendly properties and moderate price make iron the catalyst of the future and therefore provide ample motivation for further developments in the field of ironcatalyzed cross-coupling. The first iron-catalyzed homo-coupling reaction of aryl Grignard reagents was described by Kharash and Fields as far back as 1941.27 Although, the true epoch started in the 1970´s, predating the palladium and nickel relatives, with Kochi investigating the reaction between alkenyl halides and Grignard reagents.28 Kochi also proposed the first mechanistic rationale for iron-catalyzed cross-coupling with an analogy to palladium and nickel catalytic cycles. This mechanistic rationale includes the formation of a reduced iron complex, which

25

a) Handbook of the Toxicity of Metals; Friberg L.; Nordberg, G. F.; Vouk, V. B. Elsevier, Amsterdam, 1986; b) Hughes, M. N. Compr. Coord, Chem. 1987, 67, 643; c) Nickel and the Skin: Absorbtion, Immunology, Epidemiology, and Metallurgy; Hostynek, J. J.; Maibach, H. I. CRC Press, Boca Raton, 2002. 26 For prices of the metals see: http://www.boerse-go.de. 27 Kharash, M. S., Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316. 28 a) Kumada, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487; b) Kochi, J. K.; Acc. Chem. Res. 1974, 7, 351.

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undergoes oxidative addition of the organohalide, with subsequent transmetalation from the organomagnesium species and reductive elimination to give the cross-coupling product. During 1990´s, iron-catalyzed cross-couplings (with the exception of a few publications) received little attention, until in the early 2000´s Fürstner and Leitner breathed new life into the development of this field. They reported a highly selective iron-catalyzed cross-coupling of aryl halides and alkyl Grignard reagents in the presence of NMP as co-solvent.29 This work paved the way for a number of publications, which continue to increase each year. All these discoveries made a strong foundation for a better development of iron-catalyzed crosscouplings, which today represent an effective tool for the C-C and C-X-bond formation with good tolerance of functional groups. 2.1 Cross-Coupling of Alkenyl Electrophiles with Grignard Reagents In 1971 Kochi reported that an excess of alken-1-yl halides react with Grignard reagents in the presence of catalytic amount of FeCl3 to give at 0 °C or 25 °C the cross-coupling products in good yields (up to 89 %) and stereoselectivity after several hours (see Scheme 3).28

Scheme 3. Example of first iron-catalyzed cross-coupling of vinyl bromides with primary Grignard reagents by Kochi et al.

In the same year, the Kochi group extended this cross-coupling reaction to secondary and tertiary alkyl and aryl Grignard reagents and tested different iron complexes for the catalytic activity.30 Furthermore, Kochi proposed the active iron catalyst as an iron(I) species formed by the facile reduction of the iron(III) by the Grignard reagent. These species are metastable and probably are deactivated by aggregation over a length of time. One can say that iron(I) species consist of a d7 electron configuration, isoelectronic with manganese(0) and cobalt(II). Based on the kinetic studies and electron paramagnetic resonance investigations, Kochi suggested a mechanism of iron-catalyzed cross-coupling reaction of vinyl bromides with Grignard reagents. This mechanism, presented in Scheme 4, includes (a) an oxidative addition

29

Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2002, 41, 609. a) Kochi, J. K.; Tamura, M. Synthesis 1971, 303; b) Tamura, M.; Kochi, J. K. Bull. Chem. Soc. Jpn. 1971, 44, 3063. 30

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A.Introduction of 1-bromopropene to iron(I) followed by (b) an exchange with ethylmagnesium bromide and (c) a reductive elimination.31

Scheme 4. Proposed mechanism for the iron-catalyzed cross-coupling reactions by Kochi et al.

Previously, Kochi and co-workers studied the mechanism of iron-catalyzed cross-coupling reactions of alkyl halides with alkyl Grignard reagents. Interestingly, the kinetic results show that this type of reaction is largely independent of the concentration of the alkylmagnesium halide and the rate is first-order in both alkyl halide and iron catalyst. A catalytic cycle with the following aspects was proposed, first - the oxidation of the iron species by alkyl halides takes place, second - regeneration of the catalyst by decomposition of alkyliron intermediates and the last aspect is the role of alkyl radicals in the chain process (see Scheme 5).

Scheme 5. Tentatively proposed mechanism for iron-catalyzed cross-coupling reactions of alkyl halides and alkyl Grignard reagents by Kochi et al.

31

Smith, R. S.; Kochi, J. K. J. Org. Chem. 1976, 41, 502.

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The kinetics support oxidative addition as the rate-limiting step in the catalytic process. The reaction proceeds most readily with mononuclear iron species and to a lesser degree with iron aggregates. Kochi proposed that the aggregation to a less active polynuclear iron species occurred with the liberation of Grignard reagents and ethereal ligands; he also observed the same deactivation effect for iron catalyst in the presence of high concentrations of triphenylphosphine.32

Scheme 6. Proposed aggregation of the iron species by Kochi et al.

Returning to cross-couplings with alkenyl electrophiles, in 1978 Felkin and Meunier published a stereoselective cross-coupling between alkenyl bromides and phenyl Grignard reagents using iron-phosphine catalysts.33 The cross-coupling product is formed in 84 % yield in the presence of 5 % of the iron-catalyst. Julia and co-workers described that vinyl sulfones react with Grignard reagents, forming trisubstituted olefins of defined stereochemistry in good yields (see Scheme 7).34 R2

Fe(acac)3 (1 %) R2 +

O2SR

RMgX

R1

R = t-Bu, Ph R1 = R2 = H, CH3 R3 = Ph, n-C8H17, n-C4H9

R

R1

yields up to 63 % E/Z = up to 100/0

Scheme 7. Cross-coupling reaction of vinyl sulfones with Grignard reagents by Julia et al.

Later, the stereoselective synthesis of 2-isopropyl-1,4-dienes through the iron-catalyzed crosscoupling reaction of 2-benzenesulfonyl-1,4-dienes and isopropylmagnesium chloride was also published by the Julia group.35 Molander and co-workers further studied the cross-coupling reaction of alkenyl halides with aryl Grignard reagents, described first by Kochi.36 The Molander group found that the use of

32

Tamura, M.; Kochi, J. J. Org. Chem. 1971, 31, 289. Felkin, H.; Meunier, B. J. Organomet. Chem. 1978, 146, 169. 34 Fabre, J.-L.; Julia, M.; Verpeaux, J.-N. Tetrahedron Lett. 1982, 23, 2469. 35 a) Alvarez, E.; Cuvigny, T.; du Penhoat, C. H.; Julia, M. Tetrahedron 1988, 44, 111; b) Alvarez, E.; Cuvigny, T.; du Penhoat, C. H.; Julia, M. Tetrahedron 1988, 44, 119. 36 Neumann, S. M.; Kochi, J. K. J. Org. Chem. 1975, 40, 599. 33

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A.Introduction DME as a solvent and a lower reaction temperature (-20 °C) consistently provided highest yields and no excess of alkenyl halide was required (Scheme 8).37

Scheme 8. Cross-coupling reaction between alkenyl halides and Grignard reagents by Molander et al.

Naso and co-workers described a stereospecific cross-coupling reaction of secondary alkyl Grignard reagents with Z or E-1-bromo-2-phenylthioethene in the presence of an iron catalyst. Different iron compounds such as FeCl3, Fe(acac)3, Fe(DBM)3, Fe(DPM)3 were found to be effective catalysts and cross-coupling products were obtained in up to 80 % yield at -78 °C after 8 to 12 h with high chemo- and stereoselectivity.38 In 1998, Cahiez and co-workers reported, that in the presence of Fe(acac)3, Grignard reagents react readily with alkenyl halides in a THF/NMP mixture to give the cross-coupling products in high yields with excellent stereoselectivity of up to 90 %.39 Numerous functional groups were tolerated (Scheme 9).

Scheme 9. Iron-catalyzed alkenylation of organomagnesium compounds by Cahiez et al. 37

Molander, G. A.; Rahn, B. J.; Shubert, D. C. Tetrahedron Lett. 1983, 24, 5449. Fiandanese, V.; Miccoli, G.; Naso, F.; Ronzini, L. J. Organomet. Chem. 1986, 312, 343. 39 Cahiez, G; Avedissian, H. Synthesis 1998, 1199. 38

11

A solvent screening including DMPU, DMF, DMA, diethyl carbonate, sulfolane, tetramethylurea and DME, showed that 9 equivalents of DMF had the best co-solvent effect. The nature of iron salts was not essential as no difference was observed when Fe(dpm)3, Fe(dpb)3 or FeCl3 was used instead of Fe(acac)3. In some cases the catalyst amount could be lowered to 0.01 %. Enol phosphates could also be used as electrophile in the reaction with butylmagnesium chloride. A collaboration work between the Knochel and the Cahiez groups in 2001 showed that alkenyl halides undergo cross-coupling reaction with functionalized arylmagnesium compounds, using 5 % of Fe(acac)3 as catalyst at -20 °C. Functional groups such as ester, cyano, nonaflates and trialkylsiloxy could be tolerated and the cross-coupling products were formed in satisfactory yields. Excellent yields could be achieved by performing the crosscoupling reaction on the solid phase by generating the Grignard reagent on Wang resin (Scheme 10).40

Scheme 10. Iron-catalyzed cross-coupling between functionalized arylmagnesium compounds by Cahiez and Knochel

Begtrup and co-workers applied the NMP-protocol described by Cahiez as one of the steps of the synthesis of 3-substituted pyrrolidines.41 Hoffmann and co-workers published the Kumada-Corriu coupling of Grignard reagents with vinyl bromides, probed with a chiral Grignard reagent, using transition metals catalysts. Investigations showed that Ni(II)- and 40 41

Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901. Østergaard, N.; Pedersen, B. T.; Skjærbæk, N.; Vedsø, P.; Begtrup, M. Synlett 2002, 1889.

12

A.Introduction Pd(II)-catalyzed reactions proceed with essentially full retention of configuration, whereas when low-valent Fe or Co generated from Fe(acac)3 or Co(acac)2 were used, the enantiomeric excess of the coupling product was significantly reduced. The authors proposed that partial racemization could take place due to single electron transfer (SET) processes involved in the transmetallation step.42 Itami and Yoshida described iron-catalyzed cross-couplings of alkenyl sulfides with Grignard reagents. Aryl and alkyl Grignard reagents are applicable and crosscoupling proceeds efficiently at alkenyl-S bonds, but almost no cross-coupling takes place at aryl-S bonds. An addition/elimination mechanism was proposed.43 In 2004, Fürstner and co-workers reported selective iron-catalyzed cross-coupling reactions of Grignard reagents with alkenyl triflates. A variety of alkenyl triflates derived from ketones, βketo esters or cyclic 1,3-diketones could undergo a cross-coupling reactions in the presence of 5 % of Fe(acac)3 in THF/NMP at -30 °C, yielding the desired products in good to excellent yields (Scheme 11).44

Scheme 11. Iron-catalyzed cross-coupling reaction of alkenyl triflates with Grignard reagents by Fürstner

This methodology, which also works with enol triflates as electrophiles, was applied in a number of natural product syntheses.45 Fürstner and co-workers published the preparation, structure and reactivity of nonstabilized organoiron compounds and the implications for iron-catalyzed cross-coupling reactions.46

42

Hölzer, B.; Hoffmann, R. W. Chem. Commun. 2003, 732. Itami, K.; Higashi, S.; Mineno, M.; Yoshida, J.-I. Org. Lett. 2005, 7, 1220. 44 Scheiper, B.; Bonnekessel, M.; Krause, H.; Fürstner, A. J. Org. Chem. 2004, 69, 3943. 45 a) Fürstner, A; De Souzy, D.; Parra-Rapado, L.; Jensen, J. T. Angew. Chem. Int. Ed. 2003, 42, 5358; b) Fürstner, A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006; c) Camacho-Dávilla, A. A. Synth. Commun. 2008, 38, 3823; d) Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205; e) Maulide, N.; Vanherck, J.-C.; Marrkó, I. E. Eur. J. Org. Chem. 2004, 3962; f) Fürstner, A.; Schleker, A. Chem. Eur. J. 2008, 14, 9181. 43

13

Two distinctly different mechanisms were proposed, depending on the nature of the Grignard reagent. When MeMgX or PhMgX were used for cross-coupling, the reaction was proposed to proceed through the formation of discrete organoferrate complexes as reactive intermediates. EtMgCl and higher homologues generate a low-valent iron cluster species (step A of Scheme 12) that activates the electrophile. The authors assumed that the reaction of [Fe(MgX)2]n with an organic halide (step B of Scheme 12) sets up a σ-bond metathesis rather than an oxidative insertion. Also, such a process does not generate an oraganoiron halide, which means that the reaction with RMgX must occure by alkylation rather than by transmetalation of the intermediate primarily produced (step C of Scheme 12). Finally, the formed diorganoiron species undergoes reductive elimination to generate the desired product and regenerates the catalyst (step D, see Scheme 12). This hypothesis about such a difference in mechanism was based on conclusions made by Bogdanović and co-workers, who suggested that anhydrous FeX2 reacts with RMgX to give bimetallic clusters [Fe(MgX)2]n, provided that the R group of the chosen Grignard reagent is able to undergo β-hydroelimination followed by formation of an “inorganic Grignard reagent” (Scheme 12).47

Scheme 12. Proposed basic scenarios for iron-catalyzed cross-coupling reactions by Fürstner et al.

46 Fürstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773. 47 Bogdanović, B.; Schwickardi, M. Angew. Chem. Int. Ed. 2000, 39, 4610.

14

A.Introduction The iron center in this intermediate is distinguished by a “formally negative” oxidation state Fe(-2) (see Scheme 13). Since MeMgX or PhMgX cannot follow the Bogdanović activation pathway due to their inability to undergo β-hydroelimination, these compounds would generate metastable “iron-ate” complexes, which rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate or arylate the metal center (Scheme 13). MgX

2 R FeX2

+2 Fe

R

R R

-2MgX2

Fe H

R R 0 Fe

2 R

R

MgX

-2 Fe·(MgX)2

+ R

Scheme 13. Proposed elementary steps leading to the formation of an “inorganic Grignard reagent” of iron

In order to confirm these assumptions a number of iron complexes such as [(Me4Fe)(MeLi)][Li(OEt2)]2, [Ph4Fe][Li(OEt2)]4, [Ph4Fe][Li(OEt2)]4[Li(1,4-dioxane)] were prepared, analyzed and tested for catalytic activity also with alkenyl electrophiles (Scheme 14). 5 MeLi + FeCl3

-70 °C, Et2O

TfO

[(Me4Fe)(MeLi)][Li(OEt2)]2 + 3 LiCl + 1/2 ethane

[(Me4Fe)(MeLi)][Li(OEt2)]2 O

Me

THF, -40 °C to -30 °C

O yield 70 %

TfO

[(Me4Fe)(MeLi)][Li(OEt2)]2

Me

THF, -40 °C to -30 °C

yield 80 %

Scheme 14. [(Me4Fe)(MeLi)][Li(OEt2)]2-catalyzed cross-coupling reactions with alkenyl elecrophiles by Fürstner et al.

15

Fürstner and co-workers also showed that the cyclobutenyl iodides could be further functionalized under iron catalysis.48 Figadère and Alami published an iron-catalyzed coupling reaction between 1,1-dichloro-1-alkenes and Grignard reagents. This reaction led mainly to the coupled products in good to excellent yields. When c-hexyl Grignard reagent was used in reaction with quinoline derivatives, the mono-coupled adduct was obtained (Scheme 15).49 c-HexMgBr (3 equiv)

Cl N

Cl

Fe(acac)3 (10 %), THF, -30 °C, 3 h

Cl N yield 64 % (5:1)

Cl N

RMgBr (3 equiv) Cl Fe(acac)3 (10 %), THF, -30 °C, 1.5 h-3 h

R N

R

yields 70 % - 80 % R = Bu, Et, p-MePh, 2-Thienyl

Scheme 15. Iron-catalyzed cross-coupling with 1,1-dichloro-1-alkenes by Figadère and Alami

Knochel showed that arylcopper compounds prepared from Grignard reagents could also be applicable in iron-catalyzed cross-coupling reactions with alkenyl and dienyl sulfonates (Scheme 16).50

Scheme 16. Cross-coupling between alkenyl and dienyl sulfonates with arylcopper compounds prepared from Grignard reagents, by Knochel et al.

48

Fürstner, A.; Schleker, A.; Lehmann, C. W. Chem. Commun. 2007, 4277. Dos Santos, M.; Franck, X.; Hocquemiller, R.; Figadère, B.; Peyrat, J.-O., Provot, O.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2004, 45, 1881. 50 Dunet, G.; Knochel, P. Synlett 2006, 407. 49

16

A.Introduction Olsson and co-workers reported an iron catalyzed cross-coupling of imidoyl chlorides with Grignard reagents under mild conditions. Functionalities such as aryl chloride or ester were well tolerated. This protocol represents a good alternative for the synthesis of imines due to mild reaction conditions (Scheme 17).51

Scheme 17. Synthesis of Clozapine analogues by Olsson et al.

Syntheses of substituted quinolines by iron-catalyzed coupling reactions between chloroenynes and Grignard reagents were performed by Figadère and Alami in 2004.52 Several functional groups such as propargyl acetate, ethyl benzoate, aryl bromide and hydroxyl were tolerated (Scheme 18).

Scheme 18. Cross-coupling reactions with chloroenynes and Grignard reagents by Figadère and Alami

Nakamura and co-workers published an iron-catalyzed enyne cross-coupling reaction. This type of cross-coupling proceeds in the presence of 0.5-1 % of FeCl3 and stoichiometric amounts of LiBr as a crucial additive in high to excellent yields.53 Alkenyl Grignard reagents 51

Ottesen, L. K.; Ek, F.; Olsson, R. Org. Lett. 2006, 8, 1771. Seck, M.; Franck, X.; Hocquemiller, R.; Figadère, B.; Peyrat, J.-F.; Provot, O.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2004, 45, 1881. 53 Hatakeyama, T.; Yoshimoto, Y.; Gabriel, T; Nakamura, Masaharu Org. Lett. 2008, 10, 5341. 52

17

were prepared from the corresponding alkynes and methylmagnesium bromide. Various terminal alkynes and alkenyl electrophiles were well tolerated (Scheme 19). 1) MeMgBr (1.2 equiv) LiBr (1.2 equiv) R1

R2 R1

H 2) FeBr3 (0.5 - 1 %) THF, 60 °C R2 X R3 X = Br, OTf

R3 yield up to 99 %

Selected Examples: TMS TBDMSO yield 82 %

C6H13

Ph yield 91 %

yield 76 %

Scheme 19. Iron-catalyzed enyne cross-coupling reaction by Nakamura et al.

The mechanism proposed by the authors is shown in Scheme 20. It is based on initial formation of the diyne upon mixing the alkynyl organometalic species and the precatalyst FeCl3. The authors assumed that the trivalent iron would possibly first be reduced to a lowvalent state (A), such as Fe(0) or Fe(I), which probably possesses one or more alkynyl groups. The presence of LiBr is probably important due to the notable stability of Fe(II) alkenyl-ate complexes, which could make the initial reduction more difficult. The oxidative addition of an alkenyl bromide to a low-valent ferrat complex A provides the higher-valent complex B, which could undergo the reductive elimination to furnish the desired enyne. Ferrate complex C would react with alkenyl Grignard reagent to generate A. The authors also noticed that the particular loss of the stereochemical purity of E- and Z-propenylbromides indicates the likely involvement of an electron transfer process at the oxidative addition step.

18

A.Introduction

Scheme 20. Possible mechanism of iron-catalyzed enyne coupling by Nakamura et al.

2.2 Cross-Coupling of Aryl Electrophiles with Grignard Reagents

2.2.1

Alkyl Grignard Reagents

In 1989, Pridgen and co-workers described a transition metal catalyzed cross-coupling of ortho-halogenated aryl imines and Grignard reagents, where Fe(acac)3 shows a better tolerance to the “reducing” Grignard reagents, containing β-hydrogen atoms, than Ni(acac)2 (see Scheme 21).54

Scheme 21. Cross-coupling with ortho-halogenated aryl imines by Pridgen et al.

Fürstner et al deeply investigated iron-ctalyzed cross-coupling reactions with aryl or heteroaryl electrophiles and alkyl Grignard reagents.55 High yields of the desired products 54 55

Pridgen, L. N.; Snyder, L.; Prol, J. J. Org. Chem. 1989, 54, 1523. Fürstner, A.; Leitner, A; Méndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856.

19

were obtained using Fe(acac)3 or Fe(salen)Cl complex as a catalysts in THF/NMP solvent mixtures. A number of functional groups such as ether, sulfonate or nitrile were also tolerated.

Scheme 22. Cross-coupling of alkyl Grignard reagents with aryl and heteroaryl chlorides, tosylates and triflates by Fürstner et al.

In order to elucidate the mechanism of this iron-catalyzed process, the reaction between 4chlorobenzoic acid methyl ester and n-tetradecylmagnesium bromide in the presence of 5 % of FeClx (x = 2, 3) as a precatalyst was investigated. The cross-coupling product was obtained in a quantitative yield (>95 % GC-yield) within 5 min at ambient temperature, when FeCl3 was used. In striking contrast, highly dispersed and nonpassivated iron metal Fe(0)* powder prepared by reduction of FeCl3 with potassium does not insert at all into this substrate at 20 °C and reacts only after several hours under more harsh conditions. However the suspension of finely dispersed Fe(0)* particles in THF slowly dissolves on treatment with n-C14H29MgBr. The resulting mixture could catalyze this cross-coupling reaction. This fact means that during the cross-coupling reaction, the iron species get reduced by the Grignard reagent, but this process does not stop at Fe(0), it probably goes on generating a soluble complex, which likely contains iron in a formal oxidation state < 0, as postulated for the “inorganic Grignard reagent” [Fe(MgX)2] (see Scheme 23). This iron complex participates in the catalytic cycle for iron-catalyzed cross-coupling reactions with alkyl Grignard reagents, proposed by Fürstner (see Scheme 12).46

20

A.Introduction

Scheme 23. Investigation of possible catalytically active iron species by Fürstner et al.

This procedure for iron-catalyzed aryl-alkyl cross-couplings could be applied in the synthesis of natural products, which was demonstrated by Fürstner in the total synthesis of (R)-(+)Muscopyridine.56 Nagano and Hayashi published the functionalization of aryl triflates using Fe(acac)3 in Et2O under reflux conditions.57 The Hocek group examined the regioselectivity of iron-catalyzed cross-coupling reactions of 2,6-dichloropurines and 6,8-dichloropurines with the methyl Grignard reagent.58 Fürstner and co-workers also reported the selective ironcatalyzed mono-substitution of dichloro-substituted arenes and heteroarenes.44

2.2.2

Aryl Grignard Reagents

The first aryl-aryl homo-coupling reaction was already described by Kharash and Fields in 1941 (Scheme 24).27 Br

MgBr FeCl3 (5 %) + Et2O, 35 °C, 1 h yield 47 %

Scheme 24. Iron-catalyzed biaryl coupling by Kharash et al.

Bromobenzene was used as an oxidizing agent in converting the phenylmagnesium bromide to biphenyl as shown in Scheme 24. The authors proposed the following chain mechanism for cobalt chloride, but they admitted that iron could act in the same manner. The essential feature 56

Fürstner, A.; Leitner, A. Angew. Chem. Int. Ed. 2003, 42, 308. Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297. 58 a) Hocek,M.; Dvoȓȧkovȧ, H. J. Org. Chem. 2003, 68, 5773; b) Hocek, M.; Hockova, D.; Dvoȓȧkovȧ, H Syntheis 2004, 889; c) Hocek, M.; Pohl, R. Synthesis 2004, 2869. 57

21

of this mechanism is that the reaction proceeds through the agency of a cobalt or iron subhalide, the active chain carrier. The biaryl is formed exclusively from the aryl Grignard reagent and the bromine atom of the phenyl bromide is converted into a bromide ion by the cobalt or iron subhalide (see Scheme 25).59

Scheme 25. Chain mechanism proposed by Kharash et al.59

Fürstner and co-workers reported a cross-coupling reaction of aryl Grignard reagents and heteroaryl chlorides using 5 % of Fe(acac)3 in THF. Electron-rich aryl halides tended to fail, giving only rise to the homo-coupling of the ArMgX, but various electron-deficient heterocycles could be used giving the desired cross-coupling products in good yields. However, the authors admitted that in all cases varying amounts of biphenyl were formed as byproducts. Sterically hindered Grignard reagents like mesitylmagnesium bromide failed in this cross-coupling, whereas 2-thienylmagnesium bromide and pyridine-3-magnesium bromide showed good results (see Scheme 26).55

59

Scheme 25 represents a mechanism described for CoCl2, like it was in the original paper from Kharash and Fields, but since authors suggested the same mechanism for FeCl3, it makes sense to point it out here.

22

A.Introduction MgBr Fe(acac)3 (5 %) or Fe(salen)Cl (5 %)

R N

+

Cl

R

R

THF, -30 °C

N

R

Fe(salen)Cl:

H N

H N

Fe O Cl O

Selected Examples: Ph N N yield 69 %

S

Ph N

N

N SMe

yield 53 %

MeO

N N

OMe

yield 63 %

Scheme 26. Cross-coupling reactions using heteroaryl chlorides by Fürstner et al.

Figadère and co-workers studied iron-catalyzed arylations of heteroaryl halides by Grignard reagents. Iron salts such as Fe(acac)3, FeCl3 and FeCl2 were tested for the catalytic activity in the reaction of 3-bromoquinoline with PhMgBr.60 The effect of different additives like NMP, DMPU, CH3CN, bipyridine, Ph3P, MnCl2, ZnCl2 and CuCN was also investigated. The optimum conditions were determined to be Fe(acac)3 in THF at -30 °C, 3-phenylquinoline could be achieved in 45 % yield. These conditions were applied to cross-coupling reactions with 2-chloroquinoline and 2-bromoquinoline with PhMgBr (see Scheme 27).

Scheme 27. Iron-catalyzed arylation of heteroaryl halides with PhMgBr by Figadère et al.

60

Quintin, J.; Franck, X.; Hocquemiller, R.; Figadère Tetrahedron Lett. 2002, 43, 3547.

23

Pie and co-workers described iron-catalyzed cross-coupling reactions of pyridine or diazine chlorides with aryl Grignard reagents. The synthesis of various unsymmetrical polyaryl or polyheteroaryl products was achieved.61 The Knochel group successfully used iron powder as a catalyst for the cross-coupling reaction of 2-chloroquinoline with PhMgCl, producing the desired product after 12 h in 86 % yield (see Scheme 28).62

Scheme 28. Cross-coupling with catalytic iron powder by Knochel et al.

Several protocols for homo-coupling reactions of Grignard reagents under iron-catalysis were reported, using oxidizing agents such as 1,2-dichloroethane or oxygen.63 The combination of the catalytic system of the Fe(acac)3 or Fe(DBM)3 with 2 equivalent of Mg in the absence of an oxidizing agent also furnishes homo-coupling products.64 Later, Knochel et al showed that the homo-coupling of the Grignard reagent could be suppressed if the arylmagnesium compound is transmetalated to the corresponding arylcopper reagent, using stoichiometric amounts of CuCN·2LiCl, prior to the iron-catalyzed crosscoupling reaction with aryl halides.65

61

Boully, L.; Darabantu, M.; Turck, A., Pié, N. J. Heterocycl. Chem. 2005, 42, 1423. Korn, T. J.; Cahiez, G.; Knochel, P. Synlett 2003, 1892. 63 a) Nagano, T; Hayashi, T. Org. Lett. 2005, 7, 491; b) Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am. Chem. Soc. 2007, 129, 13788. 64 Xu, X.; Cheng, D.; Pei, W. J. Org. Chem. 2006, 71, 6637. 65 Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulou, C.; Knochel, P. Angew. Chem. Int. Ed. 2005, 44, 1654. 62

24

A.Introduction

MgCl

1) CuCN·2 LiCl, -20 °C

FG2

2) Fe(acac)3 (10 %) DME/THF (3/2), 25 °C to 80 °C I Het

FG1

FG2

FG1 yields up to 93 %

FG1 = CO2Et, CO2Me, OMe, OTf FG2 = CO2Et, COPh, COMe, CN, CONR2 Selected Examples:

Ph

CN CN

O Ph

CO2Et

EtO2C yield 93 %

N yield 72 %

Ph yield 85 %

Scheme 29. Iron-catalyzed aryl-aryl cross-coupling with magnesium-derived copper reagents by Knochel et al.

In 2007, Nakamura reported a novel combination of iron fluoride salts with a N-heterocyclic carbene (NHC) ligand, which specifically suppressed homo-coupling reactions. The optimum conditions include 3 % of FeF3·H2O and 9 % of SIPr·HCl (NHC ligand). Ferrous fluoride (FeF2·4H2O) showed comparable catalytic activity, indicating that the in situ reduction of FeF2·4H2O or FeF3·H2O probably gives the same catalytically active iron species. The authors assumed that the water or hydroxide could react with the solid surface of FeF3 and make it partially soluble in THF to promote the generation of catalytically active species to some extent.66 In 2009, Nakamura continued the investigation of this “fluorine effect”, expanded the scope of this methodology. They also proposed a mechanism for this cross-coupling reaction, based on DFT-calculations.67 The authors found that EtMgBr could be used as a base in order to deprotonate the NHC precursors and hydrates of iron fluorides. Electron-rich arylhalides as well as electron-deficient ones could be tolerated in this cross-coupling reactions and gave the desired products in good yields. Heteroaromatic electrophiles undergo cross-coupling reactions using this catalytic system, although compared to other catalytic systems discussed before, a higher temperature (80 °C to 100 °C) and a longer reaction time (8 h to 24 h) was required.

66 67

Hatakayama, T; Nakamura, M J. Am. Chem. Soc. 2007, 129, 9844. Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J. Am. Chem. Soc. 2009, 131, 11949.

25

Scheme 30. Aryl-aryl cross-coupling using catalytic system of FeF3·H2O with NHC ligand by Nakamura et al.

Two possible catalytic cycles, the “(II)-(IV)” and the “(0)-(II)”, were proposed by Nakamura et al. The first cycle includes the formation of a heteroleptic metal (II)-ate complex A (Scheme 31) from a divalent fluoride and an arylmagnesium reagent (Ar1MgX). The complex A undergoes oxidative addition with the aryl halide to generate an elusive higher-valent (formally IV oxidation state) species B having Ar1 and Ar2. Reductive elimination would give unsymmetrical biaryl Ar1-Ar2 and iron (II) complex C bearing two fluorides and one halogen ligand derived from Ar2X on the metal center. Subsequent reaction of C with Ar1MgX would regenerate species A. The “(0)-(II) mechanism” involves oxidative addition of the aryl halide to the iron (0) intermediate D, transmetalation between aryliron halide E and Ar1MgX and reductive elimination of Ar1-Ar2 from diaryliron(II) F. The authors assumed that the described crosscoupling reaction proceeds via the higher-valent iron intermediate of the first catalytic cycle “(II)-(IV)”, this statement was supported by DFT calculations.

26

A.Introduction (0)-(II) mechanism

(II)-(IV) mechanism FeIIF2

FeIIX2 2 Ar1MgX

Ar1MgX L = NHC F MgX L FeII F Ar1 A

Ar2X

Ar1-Ar1 Ar2X

LnM0

MgX2

B

Ln reductive slow elimination Ar1 FeII Ln Ar1

Ln

fast

reductive elimination

F MgX L FeII F X C

Ar1-Ar2 cross-coupling

Ar1-Ar2 cross-coupling

D Ar1MgX

X F MgX L FeIV F Ar1 Ar2

L = ligand or solvent

Ar1-Ar1 homo-coupling

Ar1 FeII Ar2

X FeII Ar2 E

F Ar1MgX

MgX2

Ln Ar1 FeII Ar1 Ar2 MgBr G

Scheme 31.

Proposed mechanisms involving a metal-fluoride-ate complex as reactive

intermediate by Nakamura et al.

Von Wangelin and co-workers recently described an iron-catalyzed hetero-biaryl coupling reaction using chlorostyrenes.68 The authors assumed that the mechanism of this transformation involves the coordination of the vinyl substituent to the iron catalyst and the subsequent haptotropic migration to the site of C-Cl bond activation is decisive. The general procedure is quite practical (THF/NMP, 20-30 °C, 2 h) and based on Fe(acac)3 (1-5 %) as a precatalyst (Scheme 32).

Scheme 32. Chlorostyrenes in iron-catalyzed biaryl coupling reactions by von Wangelin et al.

68

Gülak, S.; von Wangelin, A. J. Angew. Chem. Int. Ed. 2012, 51, 1357.

27

3. Chromium-Catalyzed Cross-Coupling Reactions The first chromium reagent was prepared from the phenyl Grignard reagent with CrCl3 in Et2O by Hein as far back as 1919,69 although the correct interpretation of the structure of this compound was described later.70 In 1986, Kishi et al71 and Nozaki et al72 independently discovered that traces of nickel salts exert a catalytic effect on the formation of the C-Cr(III) bond. This finding became a standard tool when less reactive substrates such as alkenyl and aryl halides or triflates have to be used for Barbier type addition reactions. Many applications using stoichiometric amounts or excess of chromium salts for various coupling reactions were published.73 In 1996, Fürstner and co-workers reported a method, which allowed, the Nozaki-HiyamaKishi reaction to be performed with catalytic quantities of chromium. The catalytic system includes 7 – 15 % of CrCl2 or CrCl3 doped with NiCl2, Mn powder as a stoichiometric reductive agent and chlorosilane as an additive for ligand exchange (see Scheme 33). Other chromium sources such as Cp2Cr or CpCrCl2·THF also could be applied as a “pre-catalyst”.

Scheme 33. Nozaki-Hiyama-Kishi reactions with a catalytic amount of CrCl2 by Fürstner et al 69

Hein, F. Ber. Dtsch. Chem. Ges. 1919, 52, 195. Zeiss, H. H.; Tsutsui, M. J. Am. Chem. Soc. 1957, 79, 3062. 71 Jin, H.; Uenishi, J.-i.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. 72 Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. 73 Selected publications for application of stehiometric amount of chromium salts: a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1976, 99, 3179; b) Okude, Y.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1977, 3829; c) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki H. Tetrahedron Lett. 1983, 24, 5281; d) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem. Int. Ed. 1998, 37, 152; e) Takai, K.; Toshikawa, S.; Inoue, A.; Kokumai, R.; Hirano, M. J. Organomet. Chem. 2007, 692, 520; f) Fürstner, A. Chem. Rev. 1999, 99, 991. 70

28

A.Introduction A possible catalytic cycle for this transformation is shown in Scheme 34. It starts with the reaction of the organo halide with 2 CrCl2. Since Cr+2 is a one-electron donor, 2 mol of this reagent/mol of halide are required for the formation of an oraganochromium nuchleophile A and CrX3. Species A then adds to the aldehyde with formation of chromium alkoxide B. At this point, the higher stability of its O-Cr3+ bond impedes the ability of undertaking this reaction with a catalytic amount of chromium. Therefore, the addition of chlorosilane provides the ligand exchange with B and such an σ-bond metathesis would afford the silyl ether of the desired product C and liberate the second mol of CrX3, which could be then reduced to CrX2 with reductive agent (Mn powder) and participate again in the catalytic cycle.74

Scheme 34. Likely mechanism with a catalytic amount of CrCl2 using chlorosilane as an additive by Fürstner et al.

However, one of the limiting features of this method is the incomplete ligand exchange between the chromium alkoxide and admixed chlorosilane. In

2007,

Yorimitsu,

Oshima

and

co-workers

reported

the

chromium-catalyzed

arylmagnesiation of unfunctionalized alkynes in the presence of pivalic acid. The arylmagnesium intermediate reacted with various electrophiles to afford the corresponding tetrasubstituted olefins in good yields (Scheme 35).75

74 75

Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. Murakami, K.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1569.

29

Scheme 35. Chromium-catalyzed arylmagnesiation of alkynes by Yorimitsu et al.

This procedure seems to be a highly effective manner to construct multisubstituted ethene units. To our knowledge there are no protocols described for chromium-catalyzed cross-coupling reactions. Therefore, this field represents a new extension of the chromium chemistry and brings new features to the transition metal-catalyzed cross-coupling.

30

A.Introduction

4. C-H Bond Activation Reactions Using Alternative Transition Metals The direct transformation of C-H bonds into C-C bonds makes the prefunctionalization of starting materials unnecessary and therefore represents a more environmentally friendly way of performing the desirable molecular core then cross-coupling reactions. However, in order to let a C-H bond activation occure selectively, one of the all C-H bonds in the organic molecule should be activated more than the others. The solution would be to have a directing group in the molecule. Some important directing groups are presented in Scheme 36.

Scheme 36. Some important functional groups that act as directing group

Over the last decades C-H bond activation has widely been developed.76 Transition metals such as Pd77, Ru78 and Rh79 were extensively applied as catalysts for this type of reaction. But due to the high prices and toxicity the replacement of these salts is highly desired.

76 For reviews about C-H bond activation see: a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731; b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48, 9792; d) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087; e) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094; f) Modern Arylation Methods; Ackermann, L.; Woley-VCH: Weinheim, 2009; g) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147; h) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624; i) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 10236; j) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726. 77 For palladium-catalyzed C-H bond activation see: a) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302; b) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. . J. Am. Chem. Soc. 2005, 127, 7330; c) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 17676; d) Zhou, W.; Li, H.; Wang, L. Org. Lett. 2012, 14, 4594.

31

In 2008 Nakamura et al published an iron-catalyzed arylation through directed C-H bond activation.80 The authors showed that benzo[h]quinoline could be arylated at position 10 using 10 % of Fe(acac)3 with 6 equivalents of

PhMgBr in the presence of 3 equivalents

ZnCl2·TMEDA and 2 equivalents of 1,2-dichloro-2-methylpropane (as an oxidant). 1,10Phenantroline was used as a ligand. Other phenylsubstituted heterocycles such as 2phenylpyridines gave mixtures of mono- and disubstituted products, except 2-(otolyl)pyridine, which was arylated exclusively on the side opposite to the methyl group, probably due to steric hindrance (Scheme 37). All the reactions were carried out at 0 °C with reaction times of 6 – 48 h.

ArMgBr (6 equiv) ZnCl2·TMEDA (3 equiv) Fe(acac)3 (10 %) 1,10-phenanthroline (10 %) Het

R Cl

Het

Me Me Cl (2 equiv)

R

Ph

THF, 0 °C, 6 - 48 h Selected Examples:

Ph

Ph N

N

N

Ph

Ph

Ph

yield 99 %, 16 h

N

F

yield 80 + 20 % (mono + di) 48 h

yield 82 + 12 % (mono + di) 15 h N

Me

Ph

N Ph

F

MeO yield 76 %, 36 h

yield 81 + 9 % (mono + di) 48 h

Scheme 37. Iron-catalyzed direct arylation through directed C-H bond activation by Nakamura et al.

78

For ruthenium-catalyzed C-H bond activation see: a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529; b) Harris, P. W. R.; Rickard, C. E. F.; Woodgate, P. D. J. of Organom. Chem., 1999, 589, 168; c) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chantani, N. Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858; d) Muralirajan, K.; Parthasarathy, K; Cheng, C.-H. Org. Lett. 2012, 14, 4262; e) Ogiwara, Y.; Kochi, T.; Kakiuchi, F. Chem. Lett. 2014, 43, 667. 79 For rhodium-catalyzed C-H bond activation see: a) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem. Int. Ed. 2011, 50, 4969; b) Patureau, F. W.; Nimphius, C.; Glorius, F. Org. Lett. 2011, 13, 6343; c) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. 80 Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 5858.

32

A.Introduction Later, Nakamura et al extended this type of reaction to a C-H bond activation for the orthoarylation of imines with Grignard reagents.81 In 2011, the Yoshikai group described a cobalt-catalyzed hydroarylation of alkynes through chelation-assisted C-H bond activation (Scheme 38).82 This addition reaction of arylpyridines and imines to internal alkynes gave olefins with high regio- and stereoselectivities using 10 % of CoBr2 with 20 % of PMePh2 (as a ligand) and 2.5 equivalent of an appropriate alkyne. MeMgCl (1.0 equiv) was used as a reducing agent. Reactions using arylpyridines were carried out at 100 °C for 12 – 24 h. Aryl imines were also amenable to hydroarylation reactions using a catalytic system which involved CoBr2 (5 %), P(3-ClC6H4)3 (10 %) as a ligand, tBuCH2MgBr (50 %) as a reducing agent and pyridine (80 %) as an additive.

R1

R

N

CoBr2 (10 %) PMePh2 (20 %) MeMgCl (1 equiv)

R

N

R1

+ THF, 100 °C, 12 - 24 h R2 (2.5 equiv)

Het

R2

Het

R = H, Me R1 = Pr, tBu, SiMe3, C3H6OBn, Ph R2 = Pr, Me, nBu, SiMe3, C3H6OBn, Ph Selected Examples:

N

Pr N

Pr Pr

N

iPr

Pr

N Pr

N

Ph

Me

Ph Pr

OMe

OMe

yield 75 %

yield 68 %

PMP N Ph

CoBr2 (5 %) P(3-ClC6H4)3 (10 %) tBuMgBr (0.5 equiv) pyridine (80 %)

yield 57 %

yield 72 %

O

Ph Ph

HCl (3 M)

+ R

THF, 20 °C, 12 h Ph (1.5 equiv)

R yields 76 - 90 %

R = H, OMe PMP = p-methoxyphenyl

Scheme 38. Cobalt-catalyzed hydroarylation of alkynes through chelation-assisted C-H bond activation by Yoshikai et al.

81 82

Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.; Nakamura, E. Chem. Asian J. 2011, 6, 3059. Gao, K.; Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2010, 132, 12249.

33

In the same year, the Yoshikai group published a cobalt-catalyzed addition of azoles to alkynes.83 The authors reported that the ternary catalytic system consisting of a cobalt salt, a diphosphine ligand, and the Grignard reagent promotes syn-addition of the azole C(2)-H bond across an unactivated internal alkyne with high chemo-, regio-, and stereoselectivities under mild conditions (Scheme 39). Mechanistic experiments suggest that the reaction involves oxidative addition of the oxazolyl C-H bond to the cobalt center, alkyne insertion into Co-H bond, and reductive elimination of the resulting diorganocobalt species.

Scheme 39. Cobalt-catalyzed hydroarylation of alkynes through chelation-assisted C-H bond activation by Yoshikai et al.

The Yoshikai group also achieved a similar cobalt-catalyzed addition of aromatic imines to alkynes via directed C-H bond activation.84 Nakamura and Yoshikai described a cobalt-catalyzed coupling of alkyl Grignard reagents with benzamide and 2-phenylpyridine derivatives through directed C-H bond activation (Scheme 40). The authors showed that aromatic carboxamides and 2-phenylpyridine derivatives could be ortho-alkylated with Grignard reagents in the presence of a cobalt catalyst and DMPU as a ligand, using air as a sole oxidant at 25 °C in THF.85

83

Ding, Z.; Yoshikai, N. Org. Lett. 2010, 12, 4180. Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 17283. 85 Chen, Q.; Ilies, L.; Yoshikai, N.; Nakamura, E. Org. Lett. 2011, 13, 3232. 84

34

A.Introduction

Scheme 40.

Cobalt-catalyzed oxidative alkylation of aromatic carboxamides and

arylpyridines with Grignard reagents by Nakamura and Yoshikai

In 2011, Nakamura described an iron-catalyzed stereospecific activation of olefinic C-H bonds with Grignard reagents for the synthesis of substituted olefins.86 Arylated products were synthesized in good yields (up to 99 %), using 10 % of Fe(acac)3, 15 % of dtbpy and 2 equivalents of 1,2-dichloro-2-methylpropane in PhCl with slow addition of 3.2 equivalents of ArMgBr in THF at 0 °C over 5 min. Wang and Shi reported the direct cross-coupling of C-H bonds with Grignard reagents through cobalt catalysis (Scheme 41).87 Various arylated benzo[h]quinolines could be produced in good yields (up to 92 %). Reaction conditions included 10 % of Co(acac)3 with 1 equivalent of TMEDA and 1.5 equivalent of 2,3-dichlorobutane (as an oxidant).

86 87

Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2011, 133, 7672. Li, B.; Wu, Z.-H.; Gu, Y.-F.; Sun, C.-L.; Wang, B.-Q.; Shi, Z.-J. Angew. Chem. Int. Ed. 2011, 50, 1109.

35

Scheme 41. Directed cross-coupling of C-H bonds with Grignard reagents through cobalt catalysis by Wang and Shi

In 2013, the Yoshikai group described another example for cobalt-catalyzed ortho-alkylation reaction of aromatic imines with primary and secondary alkyl halides.88,89 A cobalt-Nheterocyclic carbene (NHC) catalyst system allowed the authors to perform alkylations of aromatic imines at 23 °C with reaction times of 4 – 24 h. The You group showed that the iron-catalyzed oxidative C-H/C-H cross-coupling could be an efficient route to α-amino acid derivatives.90 Nakamura and Ilies reported the iron-catalyzed ortho-allylation of aromatic carboxamides with allyl ethers.91 They found that substrates bearing a bidentate directing group, N(quinolin-8-yl)benzamide selectively afford the allylation products in good yields (up to 99 %). In 2014, DeBoef et al found out that iron-catalyzed arylation of heterocycles via directed C-H bond activation could be successfully carried out on a variety of N-, S-, and O-containing

88

Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279. Gao, K.; Yosikai, N. Acc. Chem. Res. 2014, 47, 1208. 90 Li, K., Tan, G.; Huang, J.; Song, F.; You, J. Angew. Chem. Int. Ed. 2013, 52, 12942. 91 Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 17755. 89

36

A.Introduction heterocycles at 0 °C over 15 min.92 A number of heterocyclic arylated imines or aldehydes were synthesized with yields up to 88 %. The group of Ackermann showed that C(sp2)-H and C(sp3)-H arylation could be achieved by triazole assistance (Scheme 42).93

Scheme 42.

Iron-catalyzed C(sp2)-H and C(sp3)-H arylation by triazole assistance by

Ackermann and et al.

Among alternatives of the catalytic systems for the C-H bond activation reaction, iron and cobalt salts are predominant. To our knowledge, no chromium-catalyzed C-H bond activation has been described in the literature so far.

92 93

Sirois, J. J.; Davis, R.; DeBoef, B. Org. Lett. 2014, 16, 868. Gu, Q.; Al Mamari, H.H.; Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem. Int. Ed. 2014, 53, 3868.

37

5. Objectives Transition-metal-catalyzed cross-coupling reactions are one of the most used C-C bond forming reactions, where palladium and nickel catalysts play a main role. However, the constantly increasing world market price of palladium, the toxicity of nickel salts, and the laborious synthesis of arylboronic acids are prompting the search for powerful alternatives, also for industrial process. Therefore, the development of alternative transition metal catalysts for cross-coupling reactions represents our general goal. Iron-catalysts have received a lot of attention in the area of cross-coupling reactions due to environmentally friendly properties of iron salts combined with their moderate prices and absence of air-sensitive expensive ligands. Alkyl-aryl, alkyl-alkenyl, aryl-alkenyl, and alkynyl-coupling reactions are well documented. The corresponding aryl-aryl cross-couplings are much more challenging due to the formation of homo-coupling side-products. Therefore, our next aim would be to find simple and practical reaction conditions for sp2-sp2 type crosscoupling reactions using iron as a catalyst. Particularly, the cross-coupling between Nheterocyclic halides (chlorides or bromides) with arylmagnesium reagents should be investigated due to the potential biological activity of the resulting arylated heterocycles (Scheme 43).

Scheme 43. Iron-catalyzed cross-coupling reactions of N-heterocyclic halides with Grignard reagents

Other transition metals salts such as CoCl2, MnCl2, VCl3, VCl4 and eventually CrCl2 should be tested for catalytic activity in cross-coupling reactions of aryl or alkenyl halides with arylmagnesium reagents (Scheme 44).

Scheme 44. Alternative metal-catalyzed cross-coupling reactions of aryl or alkenyl halides with Grignard reagents 38

A.Introduction In addition, mechanistic insights should not be neglected. Over the last decades, the direct coupling of C-H bonds via C-H bond activation has developed from an exotic phenomenon to an indispensable tool for organic chemists. Pd-, Rhand Ru-catalysts are the metals of choice, if one aims to perform direct coupling reactions. As discussed above, the replacement of these metals by readily available and less-toxic salts is highly desirable. One further task of this work is to investigate the ability of Cr-salts to catalyze directed C-H bond activation reactions. Benzo[h]quinoline, 2-phenylpyridine, phenyloxazoline and imines should be tested in Cr-catalyzed C-H arylations with Grignard reagents (Scheme 45).

Scheme 45. Chromium-catalyzed C-H bond activation using arylmagnesium reagents

39

B. Results and Discussion

1. Iron-Catalyzed Cross-Coupling of N-Heterocyclic Halides with Grignard Reagents.

1.1 Introduction In 1941, Kharash described the first iron-catalyzed reaction of PhMgCl, which provided the homo-coupling product biphenyl.27 This discovery paved the way for the field of ironcatalyzed coupling reactions, but it also demonstrated the big challenge of performance of cross-coupling reactions between Csp2-Csp2 precursors due to the formation of the undesired homo-coupling side-products of the Grignard reagent such as biphenyl. The use of iron fluorides in combination with carbene ligands improves such aryl-aryl crosscoupling dramatically as shown by Nakamura et al.66 Although, long reaction time (8 - 48 h) and additional heat (60 – 100 °C) were required. To our knowledge, only few examples of cross-coupling of N-heterocyclic halides with arylmagnesium reagents are described in the literature and no general methodology have been established.55,56,61,62 The scope of Grignard reagents, which were used for this kind of transformation, also seems to be limited. 1.2 Results and Discussion 1.2.1

Optimization of reaction conditions

In preliminary experiments, we examined the cross-coupling between 2-chloropyridine (1a) and PhMgCl (2a) (see Sheme 46).

Scheme 46. Cross-coupling of pyridyl chloride (1a) with PhMgCl (2a) in the presence of various Fe-salts

43

We investigated the effect of catalytic amounts (5 %) of various iron salts, which are represented in Table 1. Surprisingly, the common Fe(acac)2 or Fe(acac)3 in THF gave only 46 % and 55 % (GC-yield) of the desired 2-phenylpyridine (3a) respectively at room temperature (entries 1 and 2). The related iron salt Fe(TMHD)3 (TMHD = 2,2,6,6-tetramethyl-3,5heptanedionate) provided 53 % of the desired product 3a after 2 h at room temperature (entry 3). Different iron halides such as FeCl2, FeCl3, FeBr2 or FeBr3 (entries 4 – 7) as well as Fe(OTf)3 (entry 8) gave only moderate yields of cross-coupling product 3a. As expected, iron fluorides gave only traces of product apparently due to insolubility in THF (entry 9 and 10) as well as FeI2 (entry 11). We have to admit that polar co-solvents such as NMP (Nmethylpyrrolidone) hampered the cross-coupling, since the reaction of the Grignard reagent and NMP was dominant (entry 12).

Table 1. Optimization of the conditions for the reaction of pyridyl chloride (1a) with PhMgCl (2a) catalyzed by iron salts Entry

Fe-salta

Reaction timeb

Yield (%)c

1

Fe(acac)2

2h

46

2

Fe(acac)3

2h

55

3

Fe(TMHD)3

2h

53

4

FeCl2

5h

56

5

FeCl3

2h

55

6

FeBr2

2h

62

7

FeBr3

1.5 h

63

8

Fe(OTf)3

5h

60

9

FeF2

20 h

tracesd

10

FeF3

20 h

tracesd

11

FeI2

20 h

tracesd

12

FeBr3

2h

tracese

13

FeBr3·3LiCl

1.5 h

51

14

FeBr3·3LiBr

1.5 h

56

15

Fe(acac)3·3LiCl

1.5 h

50

(a) 5 % of Fe-salt was used. (b) Reaction time until reaction completion according to GC analysis. (c) Calibrated GC-yield using undecane (C11H24) as internal standard. (d) Starting

44

B.Results and Discussion material was not consumed even after 20 h. (e) A mixture of THF/NMP (5:1) was used. The reaction of PhMgCl with NMP was dominant.

Solutions of iron salts in THF prepared in the presence of LiCl or LiBr such as FeBr3·3LiCl, FeBr3·3LiBr or Fe(acac)3·3LiCl were tested as well, but did not provide significant improvements (entries 13 – 15). We noticed that the use of Fe(II) or Fe(III) salt led to similar results. Reducing the Fe(III) catalyst in situ with i-PrMgCl prior to cross-coupling deactivated the catalytic system and hampered the coupling reaction. We also investigated the influence of different Lewis acids, since they showed good results in the cross-coupling of pyridines with aryl bromides via metalation with TMPZnCl·LiCl base, reported by Knochel et al.94 Results represented in Table 2 indicate that none of Lewis acids improved the yield of the cross-coupling product 3a.

Table 2. Influence of various Lewis acids for cross-coupling reaction of 2-chloropyridine (1a) with PhMgCl (2a)

Entry

Lewis acid

Fe-salta

Yield (%)b

1

without

Fe(acac)3

55

2

BF3·OEt2

Fe(acac)3

37

3

BF3·OEt2

FeBr3

3

4

Sc(OTf)3

Fe(acac)3

20

5

Sc(OTf)3

FeBr3

34

6

(CF3SO3)3Yb

Fe(acac)3

28

7

(CF3SO3)3Yb

FeBr3

31

(a) The reaction was carried out using 5 % of Fe-salt, 2.3 equivalents of PhMgCl and THF as a solvent at 0 °C to 23 °C for 24 h. (b) Calibrated GC-yield using undecane (C11H24) as an internal standard.

94

Duez, S.; Steib, A. K.; Manolikakes, S. M.; Knochel, P. Angew. Chem. Int. Ed. 2011, 50, 7686.

45

Based on the screening of various iron salts we decided to use FeBr3 in the subsequent reactions, since it showed the best result in THF (see Table 1) at 23 °C. We observed that carrying out the coupling reaction between 2-chloropyridine (1a) and 2.3 equivalents PhMgCl (2a) in the presence of 5 % FeBr3 at -70 °C, -30 °C and 0 °C showed 4 %, 21 % and 30 % GC-yield of the desired product respectively after 1.5 h. The amount of the Grignard reagent was also screened. The use of 2.3 equivalents of 2a have shown to be reasonable, since the employment of 1.2 equivalent of the Grignard reagent 2a gave less good results; on the other hand 3 equivalents of the reagent 2a did not improve the yield significantly. Next, we screened different solvents in order to examine solvent effects for this kind of transformation. Nonpolar solvents like n-hexane or toluene, did not display any considerable improvements in comparison to THF (entries 1-3, Table 3). The use of acetonitril led to only 14 % yield of the desired product due to a side reaction of this solvent and PhMgCl (2a; entry 4). However, the usage of ethereal solvents such as diethylether or tBuOMe allowed us to dramatically improve the yield and reach full conversion of the starting material. Thus, we isolated the desired product 3a using Et2O or t-BuOMe in 84 % and 82 % yield respectively (entries 7 - 8). Dibutylether also showed good results (entry 9) in contrast with dimethylether, which provided only 28 % of 2-phenylpyridine (3a, entry 6). A reasonable GC-yield was achieved using MCPE (methoxycyclopentane) as a solvent. Only 58 % yield of the crosscoupling product 3a was determined using 2-Me-THF (2-methyltetrohydrofurane) (entry 11). Since comparably good yields were obtained using tBuOMe or Et2O, we have pursued our investigations using the industry-friendly solvent tBuOMe.

Table 3. Solvent screening for the cross-coupling reaction of 2-chloropyridine (1a) with PhMgCl (2a)

46

Entrya

Solvent

Reaction timeb

Yield (%)c

1

THF

1.5 h

63

2

n-hexane

2h

53

3

toluene

1.5 h

14

4

CH3CN

1.5 h

18

5

1,2-dioxane

3h

49

B.Results and Discussion 6

DME

2h

48

7

Et2O

1.5 h

73, 87,d (84)d

8

t-BuOMe

1.5 h

75, 87,d (82)d

9

Bu2O

1.5 h

72

10

CPME

5h

80d

11

2-Me-THF

1.5 h

58d

(a) 5 % of Fe-salt was used. (b) The reaction time until reaction completion according to GC analysis. (c) Calibrated GC-yield using undecane (C11H24) as internal standard. Numbers in brackets indicate isolated yields. (d) 3 % of FeBr3 was used.

Based on the results obtained after optimization of the reaction conditions, we went on with our investigations using 3 % of FeBr3, 2.3 equivalent of the Grignard reagent and tBuOMe as solvent at 23 °C.

1.2.2

Investigation of the reaction scope

The use of ethereal solvents proved to be a key determinant and allowed us to extend this cross-coupling to various other N-heterocycles. In order to study the reaction scope we have, first varied the N-heterocyclic chlorides or bromides and investigated their reactions with PhMgCl (2a) in tBuOMe at 23 °C. Since PhMgCl as well as all Grignard reagents, which we used, were prepared in THF, the cross-coupling reactions in fact performed in a mixture of THF and tBuOMe (ca 2:5). Therefore, we observed that 2-bromopyridine (1b) reacted with PhMgCl (2a) at a faster rate for completion than 2-chloropyridine (1a) (70 min instead of 90 min) and produced 3a in the same yield (83 %, entry 2 of Table 4). Substituted bromo- or chloro-pyridines such as 2chloro-4-picoline (1c) and 2-bromo-5-chloropyridine (1d) reacted smoothly with similar reaction times leading to the pyridines 3b and 3c in 78 – 84 % yield (entries 3 and 4). Table 4. Scope of iron-catalyzed cross-coupling of N-heteroarylchlorides/-bromides (1a – j) with PhMgCl (2a) Entrya

Substrate

Reaction time

Product

Yield (%)b

1

1a: X = Cl

1.5 h

3a

82

47

2

1b: X = Br

70 min

3a

83

3

1c

2h

3b

84

4

1d

70 min

3c

78

5

1e

5 min

3d

60

6

1f

5 min

3e

88

7

1g

5 min

3f

90

8

1h

2h

3g

76

9

1i

5h

3h

22c

10

1j

3h

3i

24c

(a) The reaction was performed on a 1 mmol scale with 3 mol% of FeBr3 in THF:tBuOMe (ca. 2:5) at room temperature. (b) Isolated yield. (c) GC-yield.

Interestingly, the presence of a tert-butoxycarbonyl group in position 3 (1e) dramatically increased the reaction rate leading to full conversion within 5 min (entry 5). The crosscoupling product 3d was isolated in 60 % yield. No starting chloride 1e was detected, and the relatively moderate yield may be due to a polymerization of 1e. The annulation of the pyridine ring with a benzene moiety also accelerated the reaction rate, and the cross-coupling 48

B.Results and Discussion of PhMgCl (2a) with 2-chloroquinoline (1f) or 1-chloroisoquinoline (1g) were completed in 5 min and gave the expected phenylated N-heterocycles 3e and 3f in 88 – 90 % yield (entries 6 and 7). Diazines were also tested for cross-coupling reactions. For instance, 2chloropyrimidine derivative 1h reacted with PhMgCl (2a) within 2 h providing the arylated pyrimidine 3g in 76 % yield (entry 8). The more sensitive chloropyridazine 1i and –pyrazine 1j required 3 - 5 h for the full conversion of starting material, but led to the phenylated products 3h - i in only 22 – 24 % yields (entries 9 and 10). Unfortunately, the use of other heterocyclic halides, such as 3- and 4-chloropyridine, 2-chlorothiophene, or 2-bromofuran, as well as standard haloarenes resulted in only low yields. Thereafter, we have varied the nature of the Grignard reagent, using typical N-heterocyclic chlorides and bromides (1b, 1f and 1g) as electrophiles (Table 5).

Table 5. Iron-catalyzed cross-coupling of N-heteroarylchlorides/-bromides 1b, 1g and 1f with various Grignard reagents Entrya

Grignard reagent

Substrate;

Product; Yieldb

Reaction time

m-TolMgBr·LiCl 1

2b

1b; 1.5 h

3j; 80%

1g; 2 min

3k; 93%

p-TolMgBr· LiCl 2

2c

o-TolMgBr· LiCl 3

2d

1f; 45 min

3l; 84%

4

2e

1f; 15 min

3m; 92%

49

50

5

2e

1b; 2 h

3n; 66%

6

2f

1g; 5 h

3o; 75%

7

2g

1b; 5 min

3p; 68%

8

2g

1g; 5 min

3q; 90%

9

2h

1f; 5 min

3r; 84%

10

2i

1b; 10 min

3s; 82%

11

2i

1f; 5 min

3t; 87%

12

2j

1g; 5 min

3u; 71%

B.Results and Discussion 13

2k

1f; 5min

3v; 81%

14

2l

1g; 15 min

3w; 80%

15

2m

1f; 15 min

3x; 84%

16

2n

1f; 5 min

3y; 82%

(a) The reaction was performed on a 1 mmol scale with 3 mol% of FeBr3 in THF:tBuOMe (ca. 2:5) at room temperature. (b) Isolated yield.

In all cases presented in Table 5, the Fe-catalyzed cross-couplings were relatively fast and led to full conversion of the starting material. Both electron-rich and -poor Grignard reagents could be tolerated. For steric hindrance reasons, we first examined the substitution pattern of the arylmagnesium reagent. We have found that ortho-, meta-, and para-substituted Grignard reagents can be applied. Whereas m-TolMgBr·LiCl (2b) and p-TolMgBr·LiCl (2c) react at similar rates as the unsubstituted magnesium reagent, the presence of an ortho-methyl substituents in o-TolMgBr·LiCl (2d) reduced the reaction rate (compare entry 3 of Table 5 with entry 6 of Table 4). However, in all cases excellent yields (80 – 93 %; entries 1 – 3 of Table 5) were obtained. Various electron-poor substituted Grignard reagents were examined and proved to be applicable in this kind of transformation. Therefore, substituents such as a trifluoromethyl group (as in 3-trifluoromethyl-magnesium bromide 2e and in 3,5-ditrifluoromethylmagnesium bromide 2f; entries 4-6), a fluorine group (as in 4-fluorophenylmagnesium bromide 2g; entries 7 and 8), and a chlorine group (as in 2h; entry 9) were well tolerated in the cross-coupling providing the desired products 3m – r in 66 – 92 % yields (entries 4 – 9). Remarkably, electron-rich substituents were also compatible with rapid iron-catalyzed crosscouplings. Thus, methoxy-, methylenedioxy- as well as pivalate-functionalized Grignard reagents 2i – l undergo cross-coupling reactions giving 71 – 87 % yields of the expected 51

products 3s - w (entries 10 – 14 of Table 5). More sensitive Boc-protected Grignard reagent 2m also smoothly underwent cross-coupling with 2-chloroquinoline (1f) leading to the 2arylated quinoline 3x in 84 % yield (entry 15). We were interested to test the amino-substituted Grignard reagent due to its potential importance in the drug´s structures. We observed that a di-alkylated amino substituent did not disturb the cross-coupling, and the Grignard reagent 2n reacted with 1f within 5 min providing the product 3y in 82 % yield (entry 16).

52

B.Results and Discussion

2. Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling between N-Heterocyclic Halides and Aryl Magnesium Reagents.

2.1 Introduction In order to further optimize our reaction conditions, we looked more close at possible additives or ligands for iron-catalyzed cross-coupling between Csp2-Csp2 centers. Nakamura and co-workers have shown that N-heterocyclic carbene (NHC) ligands can suppress the homo-coupling reaction to less than 5 %.67 Although this is a large improvement, NHC ligands are expensive, and even optimized conditions, elevated temperatures and long reaction times are often required to complete the coupling reaction. Clearly, there is a need to discover new classes of ligands for Fe catalysis. During the course of our work, we have made the serendipitous discovery that quinoline or isoquinoline could be used as ligands to promote Fe-catalyzed cross-coupling, improving both the yield and reaction rate. Moreover, these new ligand-accelerated cross-coupling reactions could be extended to Co catalysts. Thus, cross-coupling of 2-chloroquinoline (1f) with PhMgCl (2a) in the presence of 3 % FeBr3 in tBuOMe/THF was completed at 25 °C in 5 min (producing the phenylated product 3e in 90 % yield; Scheme 47). Cross-coupling of the 2-chloropyrimidine 1h under the same reaction conditions requires 2 h for completion and provides the arylated pyrimidine 3g in 76 % yield.

Scheme 47. Rate acceleration and improved yield of Fe-catalyzed cross-coupling in the presence of quinoline 53

However, carrying out the same reaction in the presence of 7 % of quinoline leads to a reaction completion within 5 min (about 50 times faster) and an increased yield of 3g (89 % yield of isolated product; Scheme 47).

2.2 Results and Discussion

Prompted by the rate acceleration effect observed with quinoline, we screened other ligands. We observed that NMP and TMEDA, which have been traditionally used for iron catalysis, had a detrimental effect under our conditions (compare entries 1-4 of Table 6).29 We systematically examined substituted quinolines. Erosion of the rate enhancement occurs when a methyl group is attached to either the 2- or 8-position (entries 5 and 6), and only a slight improvement can be observed when a methyl group is placed at position 6 (entry 7) Benzo[h]quinoline and acridine led even to a decrease in yield (entries 8 and 9). Remarkably, electron-donating groups have a positive effect while electron-withdrawing groups decrease the catalytic activity of the quinoline core (compare entries 10-14). Finally, it was discovered that isoquinoline gave the best results with 92% yield after 15 min (entry 15). 1-Methyl isoquinoline had a similar catalytic activity as isoquinoline, but surprisingly, electron-rich 1benzyl-6,7-dimethoxyisoquinoline performed very poorly (compare entries 16 and 17). Two nitrogen-containing heterocycles hindered the reaction (entries 18 and 19). In 2002, Knochel and coworkers have shown that 4-fluorostyrene promotes Co-catalyzed coupling reactions.95 However, styrene had no effect (entry 20), and various substituted styrene derivatives caused only a moderate rate enhancement (entries 21-23). Additionally, the amount of isoquinoline was varied from 1-100% and it was found that 10% of the ligand was optimum. Pleasingly, isoquinoline (or quinoline) was not consumed during the cross-coupling according to the GC-analysis. Using isoquinoline, we tested the ability of other metallic salts to undergo rate-enhanced cross-coupling reactions. In response to the current debate as to whether trace impurities of

95

a) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79; b) Rohbogner, C. J.; Diène, C. R.; Korn, T. J.; Knochel, P. Angew. Chem. Int. Ed. 2010, 49, 18.

54

B.Results and Discussion Cu in commercial samples of Fe salts can be the cause of catalytic activity,96 CuBr2 was tested and none to minimal activity was found (compare entries 1-2 with 3-4 of Table 7).

Table 6. Screening different additives for the Fe-catalyzed cross-coupling reaction of 2chloropyridine (1a) with PhMgCl (2a)

Entry

Additive

Yield of 3a (%)a

1

without additive

40

2

quinoline

75

3

NMP

0

4

TMEDA

32

5

2-methylquinoline

67

6

8-methylquinoline

48

7

6-methylquinoline

82

8

benzo[h]quinoline

30

9

acridine

32

10

4-methoxyquinoline

73

11

6-methoxyquinoline

82

12

4-((tert-butyldimethylsilyl)oxy)quinoline

75

13

6-((tert-butyldimethylsilyl)oxy)quinoline

83

14

quinoline-3-carbonitrile

43

15

isoquinoline

16

1-methylisoquinoline

91

17

1-benzyl-6,7-dimethoxyisoquinoline

28

18

2,9-diphenyl-1,10-phenanthroline

27

19

4-(dimethylamino)pyridine

25

20

styrene

40

21

1-methoxy-3-vinylbenzene

67

22

1-methoxy-4-vinylbenzene

68

92 (89)b

96

For the role of metal contaminants in iron catalysis, see: a) Buchwald, S. L.; Bolm, C. Angew. Chem. Int. Ed. 2009, 48, 5586. (b) Larsson, P.-F.; Correa, A.; Carril, M.; Norrby, P.-O.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691. (c) Thomé, I.; Nijs, A.; Bolm, C. Chem. Soc. Rev. 2012, 41, 979.

55

23

2-vinylpyridine

37

(a) Yield determined after 15 min by integration of a GC-chromatogram and comparison against undecane as a calibrated internal standard. (b) Isolated yield after purification by flash column chromatography

A mixture of FeBr3 and CuBr2 displayed no synergistic benefit, as the yield was essentially the same as when no Cu is added (entry 5). Vanadium salts also had very little catalytic activity (entries 6 - 9). Finally, we were pleased to find that isoquinoline can also be used as a ligand to accelerate Co-catalyzed reactions (entries 12 and 13 of Table 7).

Table 7. Performance of different transition metals with isoquinoline-promoted crosscoupling

Metal salt

Isoquinoline (mol%)

Yield of 3a (%)a

1

FeBr3

0

40

2

FeBr3

10

92 (89)b

3

CuBr2c

0

0

4

CuBr2

10

2

5

FeBr3 + CuBr2

10

89

6

VCl3

0

0

7

VCl3

10

2

8

VCl4

0

5

9

VCl4

10

9

10

MnCl2

0

28

11

MnCl2

10

14

12

CoCl2

0

46

13

CoCl2

10

90

Entry

(a) Yield determined after 15 min by integration of a GC-chromatogram and comparison against undecane as a calibrated internal standard. (b) Isolated yield after purification by flash column chromatography. (c) Cu2O was also used and gave the same results.

56

B.Results and Discussion Since both Fe and Co had a similar activity, both of these transition metals were used, while exploring the scope of this new catalytic system. Using isoquinoline as a ligand (10 %), it is possible to obtain the expected cross-coupled products with a variety of chloro- or bromo-substituted pyridines as well as with a fair range of Grignard reagents. Good yields of the substituted pyridines 5a - f (65 - 91 %) were obtained especially with electron-rich Grignard reagents (entries 1 - 6 of Table 8) as well as with electron-poor 4-fluorophenylmagnesium bromide 2g to give pyridine 54g (77 - 79 % yield, entry 7). It is possible to couple the polyfunctional pyridine 4h with the sensitive estersubstituted Grignard compound 2l to produce pyridine 5h in 65 % yield (entry 8). Often both Co- and Fe-catalyzed couplings proceed with comparable yield, and it is difficult to propose that one metallic salt is a superior catalyst for all substrates. Pyrimidines, which are common motifs in pharmaceuticals, can be obtained from the same set of Grignard reagents to yield functionalized N-heterocycles 5k - n in 60 - 95 % yield (entries 11 - 14). Triazines are of great importance as material building blocks and as agrochemicals. This new method allows various chlorotriazines to be cross-coupled with magnesium reagents, leading to the desired products (5o - r) in 61 - 84 % yield (entries 15 - 18).

Table 8. Scope of Co- and Fe-catalyzed cross-coupling reactions utilizing isoquinoline as a ligand ArMgX LiCl (2; 2 equiv), FeBr3 or CoCl2 (3 %) 10 % isoquinoline R

R N 4

X

tBuOMe/THF 23 °C, 15 min

N

Ar

5

Entry

Starting material

Grignard reagent

Producta

1

4a

2i

5a; Fe: 91 % Co: 85 %

2

4b

2n

5b; Fe: 82 % 57

Co: 77 %

3

4c

2o

5c; Fe: 65 % Co: 70 %

4

4d

2p

5d; Fe: 71 % Co: 79 %

5b

4e

2q

5e; Co: 82 %

6c

4f

2r

5f; Co: 65 %

7

4g

2g

5g; Fe: 77 % Co: 79 %

58

B.Results and Discussion 8

4h

2l

5h; Fe: 65 %

9

4i

2i

5i; Co: 78 %

10

4j

2g

5j; Fe: 82 % Co: 67 %

11d

1h

2s

5k; Fe: 78 % Co: 63 %

12e

4k

2p

5l; Fe: 95 %

13

4l

2t

5m; Co: 68 %

14

4m

2u

5n; Fe: 61% Co: 60 % 59

15

4n

2i

5o; Fe: 81 % Co: 79 %

16f

4o

2a

5p; Fe: 76 %

17g

4p

2v

5q; Fe: 84 % Co: 79 %

18

4q

2t

5r; Fe: 61 %

(a) Isolated yield after purification by flash column chromatography. (b) Reaction run at 23 °C for 5 h. (c) Reaction run at 23 °C for 1 h. d) Reaction run at 23 °C for 30 min. (e) 4 equivalent of 2p were used. (f) Reaction run at 50 °C for 12 h. (g) Reaction run at 23 °C for 12 h.

The synthesis of heteroaryl-heteroaryl coupling products is often challenging. In the case of Pd- or Ni-catalysis, deactivation of the catalyst is observed due to chelation of the product with the catalyst.97 However, it was noted that both Fe- and Co-catalysts promoted by 10 % isoquinoline allow smooth cross-couplings with either the 3-magnesiated benzothiophene 2w or the 2-magnesiated heterocycle 2x to afford heterobyaryls 5s and 5t in 61 - 66 % isolated yield (Scheme 48). 97 a) Hanan, G. S.; Schubert, U. S.; Volkmer, D.; Rivière, E.; Lehn, J.-M.; Kyritsakas, N.; Fischer, J. Can. J. Chem. 1997, 75, 169 ; b) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553; c) Bedel, S.; Ulrich, G.; Picard, C.; Tisnès, P. Synthesis 2002, 1564; d) Comprehensive Coordination Chemistry II, Vol 1; McCleverty, J. A.; Meyer, T. J.; Eds.; Elsevier, Oxford, 2004, 1.

60

B.Results and Discussion MgBr·LiCl

TMS N

Br

4a

S 2w (2 equiv) FeBr3 or CoCl2 (3 %) isoquinoline (10 %) tBuOMe/THF 23 ºC, 24 h

TMS Fe: 64 % Co: 66 %

N 5s

S

S MgCl·LiCl TMS N

Br

4a

2x (2 equiv) FeBr3 or CoCl2 (3 %) isoquinoline (10 %) tBuOMe/THF 23 ºC, 12 h

TMS N

S

Fe: 61 %a Co: 66 %

5t

(a) reaction run at 50 °C

Scheme 48. Heteroaryl-heteroaryl cross-coupling reactions between bromopyridine 4a and benzothiophenes 2w and 2x

Delicate functional groups, such as alkynes, which could undergo carbometallation under iron catalysis,98 provide poor yields of the desired product. Nevertheless, we observed that the use of 3 % CoCl2 and 10 % isoquinoline improved the yield and allows the isolation of pyridine 5u in 62 % yield (Scheme 49).

Scheme 49. Cross-coupling reactions of acetylene-containing pyridines

To probe the mechanism of Fe- and Co-catalyzed cross-coupling reactions, we prepared the radical clock 4s.99 Treatment of this unsaturated pyridine 4s with PhMgCl (2a), using either

98

a) ) Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi, A. Angew. Chem. Int. Ed. 2001, 40, 621; b) Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 15050; c) Shirakawa, E.; Ikeda, D.; Masui, S.; Yoshida, M.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 272; d) Ilies, L.; Yoshida, T.; Nakamura, E. J. Am. Chem. Soc. 2012, 134, 16951. 99 a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374; b) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886; c) Manolikakes, G.; Knochel, P. Angew. Chem.

61

FeBr3 or CoCl2, produces a 4:1 mixture of the expected cross-coupling product 5v and the cyclized pyridine 6 indicative of a radical intermediate. The addition of isoquinoline did not change the product ratio, but as expected, it improved the yields (compare entries 1-4 of Table 9). These results indicate that both Fe- and Co-catalyzed cross-couplings undergo the radical pathway, at least partially. Interestingly, the corresponding Pd- and Ni-catalyzed crosscouplings, using 3 % Pd(Ph3P)4 or 3 % NiCl2(dppe) provided much less, if any, of the cyclized product.

Table 9. Scope of Co- and Fe-catalyzed cross-coupling reactions utilizing isoquinoline as a ligand

Entry

Catalyst

5v:6

Yield (%)a

1

FeBr3

80:20

47

2

FeBr3 /isoquinoline

80:20

62

3

CoCl2

80:20

72

4

CoCl2 /isoquinoline

80:20

78

5b

Pd(Ph3P)4

100:0

64

6

NiCl2(dppe)

95:5

67

(a) Isolated yield after purification by flash column chromatography. (b) Reaction was performed at 50 °C.

In spite of remarkable results, which we obtained using isoquinoline in Fe- and Co-catalyzed coupling reactions, we aimed to further optimize the reaction conditions. Therefore, we went on with our hunt for appropriate ligands using coupling between 2-chloropyridine (1a) and PhMgCl (2a) as a standard reaction. First of all, we tested various quinoline derivatives. Vinyl-substituted quinolines did not have any effect (entries 2 and 3 of Table 10). 2,3´-Biquinoline (7c) provided no improvement and even slowed down the reaction (17 % yield after 15 min; entry 4). Polycyclic compounds Int. Ed. 2009, 48, 205; d) Guisán-Ceinos, M.; Tato, F.; Bunuel, E.; Calle, P.; Cárdenas, D. J. Chem. Sci. 2013, 4, 109

62

B.Results and Discussion contained two nitrogens, such as cinnoline (7d) and quinoxaline (7e) hampered the reaction (entries 5 and 6). The quinoline derivative having a methoxy group in position eight (7f) demonstrated no acceleration effect (entry 7). 6-Chloroquinoline (7g) slightly promoted the reaction (58 % yield; entry 9), whereas 6-bromoquinoline (7h) gave a good yield already after 15 min (73 % yield; entries 8). Previously we observed that quinoline having a methoxy group in position six resulted in a positive effect. However, papaverin (7i) led to only 59 % GC-Yield of cross-coupling product 3a (entry 10). Various six-membered ring N-heterocycles 7j – l demonstrated moderate activity (entries 11 – 13).

Table 10. Screening different additives for the Fe-catalyzed cross-coupling reaction of 2chloropyridine (1a) with PhMgCl (2a)

Entry

Additive

Additive

Time, h

Number 1

without additive

2

7a

GC-Yield of 3a (%)

15 min

40

1.5 h

78

15 min

43

1.5 h

70

15 min

38

1.5 h

63

15 min

17

1.5 h

61

15 min

18

1.5 h

33

15 min

14

1.5 h

35

N

3

4

5

6

7b

7c

7d

7e

63

7

8

9

10

11

12

13

14

15

64

7f

7h

7g

7i

7j

7k

7l

7m

7n

15 min

40

1.5 h

69

15 min

73

1.5 h

74

15 min

58

1.5 h

76

15 min

59

1.5 h

62

15 min

66

1.5 h

67

15 min

22

1.5 h

61

15 min

60

1.5 h

71

15 min

35

1.5 h

62

15 min

19

1.5 h

40

B.Results and Discussion Bis(imino)pyridine ligand 7m is often used for iron-catalyzed polymerization100 reactions or as hydrogenation and hydrosilylation catalyst.101 Recently, it has been also used in regioselective syntheses of α-aryl carboxylic acids.

102

Nevertheless, in our cross-coupling

reaction this ligand 7m did not show any activity (entry 14). The tetradentate amine complex with Co 7n, hampered the reaction between 2-chloropyridine (1a) and PhMgCl (2a) (entry 15).103 Based on this small screenshot of all tested ligands, the following trend could be highlighted. The quinoline or isoquinoline core seemed to be the most reactive in this kind of coupling reactions. Electron-donating substituents of quinoline showed better results than electronwithdrawing ones. The second positions of quinoline should not have any residues besides hydrogen. A positive trend was observed when the electron-rich groups were placed in the sixth position of quinoline. Finally, chelating ligands disprove their activity in this kind of coupling reactions, probably due to aggregation and therefore deactivation of the iron catalyst.

Scheme 50. Positive effect of quinoline for reduced iron-species

100

a) Britovsek, G. J. P.; Gibson, V. C.; Kimberley, B. S.; Maddox, P. J.; McTavish, S. J.; Solan, G. A.; White, A. J. P.; Williams, D. J. Chem. Commun. 1998, 849; b) Small, B. L.; Brookhart, M.; Bennett, A. M. A. J. Am. Chem. Soc. 1998, 120, 4049. 101 a) Bart, S. C.; Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc. 2004, 126, 13794. b) Tondreau, A. M.; Atienza, C. C. H.; Weller, K. J.; Nye, S. A.; Lewis, K. M.; Delis, J. G. P.; Chirik, P. J. Science 2012, 335, 567. 102 Greenhalgh, M. D.; Thomas, S. P. J. Am. Chem. Soc. 2012, 134, 11900. 103 This salen ligand was previously used for the reductive cross-coupling of vinyl halides and Grignard reagents Le Bailly, B. A. F.; Greenhalgh, M. D.; Thomas, S. P. Chem. Commun. 2012, 48, 1580.

65

Bedford and coworkers described the catalytic activity of iron nano-particles in crosscoupling reactions. Therefore, we aimed to investigate reduced iron(0)-species in the coupling reaction between N-heterocyclic halides and aromatic Grignard reagents. Iron(0)-species, produced via in situ reduction of FeBr3 with nBuLi showed no catalytic activity in reaction between 2-chloropyridine (1a) and PhMgCl (2a). The addition of 7 % of quinoline to this reaction significantly improved this reaction, yielding the desired product 3a in 70 % (GCYield) after 1 h reaction time. It can be concluded that quinoline forms catalytically active species with in situ reduced iron(0) (Scheme 50).

66

B.Results and Discussion

3. Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions

3.1 Introduction

On the way of our search for alternative metal catalysts having an acceptably low toxicity, we have examined the potential use of chromium salts.104 Palladium

and

nickel-catalyzed

cross-coupling

reactions

between

aromatic

and

heteroaromatic groups are well established and have many applications.105 Although CrVI is highly toxic (ORL-RAT LD50 = 50-150 mg/kg), CrII has a much lower toxicity (ORL-RAT LD50 = 1870 mg/kg), also compared to other metals: ORL-RAT LD50(NiCl2) = 105 mg/kg, (PdCl2) = 2700 mg/kg, (CoCl2) = 766 mg/kg, (MnCl2) =1480 mg/kg, (FeCl2) = 450 mg/kg.106

3.2 Results and Discussion

Preliminary experiments showed that chromium-catalyzed cross-couplings between Csp2centers proceed quite smoothly and lead to significantly lower amounts of homo-coupled side-products compared to iron or cobalt. Thus, the reaction of 2-chloropyridine (1a, 1.0 equiv) with PhMgCl (2a, 2.3 equiv) in THF in the presence of 3 % CrCl2 (purity 99.99 %) is complete within 15 min at 23 °C, affording the desired cross-coupled product 3a in 90% yield. GC-analysis of the crude reaction mixture indicated that less than 1 % of the homocoupling product (biphenyl) is obtained (Scheme 51). Performing the same reaction with 3 % FeBr3 or 3 % CoCl2 under optimized conditions leads to about 15 % of the homo-coupled 104

For key coupling reactions using chromium(II) salts, see: a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179; b) Okude, Y.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1977, 3829; c) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281; d) Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644; e) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048; f) Matsubara, S.; Horiuchi, M.; Takai, K.; Utimoto, K. Chem. Lett. 1995, 259; g) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349; h) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew. Chem. Int. Ed. Engl. 1998, 37, 152; i) Fürstner, A. Chem. Rev. 1999, 99, 991; j) Takai, K.; Toshikawa, S.; Inoue, A.; Kokumai, R. J. Am. Chem. Soc. 2003, 125, 12990; k) Takai, K.; Toshikawa, S.; Inoue, A.; Kokumai, R.; Hirano, M. J. Organomet. Chem. 2007, 692, 520; l) Murakami, K.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1569; m) Holzwarth, M. S.; Plietker, B. ChemCatChem 2013, 5, 1650. 105 a) Cross-Coupling Reactions. A Practical Guide; Miyara, N., Ed.; Springer: Berlin, 2002; b) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; c) Organotrasition Metal Chemistry; Harwig, J. F., Ed.; University Scienca Books: Sausalito, CA, 2010. 106 according to IFA (Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung; July 2013).

67

product. A solvent screening (THF, n-hexane, toluene and tBuOMe) showed that THF was the optimal solvent. The optimization of the reagent stoichiometry indicated that only a small excess of Grignard reagent (1.2 equiv) was required. For all subsequent reactions standard grade CrCl2 (purity 97 %) was used, since no difference with CrCl2 (purity 99.99 %) was observed. Also, performing the cross-coupling with 5 % MnCl2 leads, under optimum conditions, to only 58 % yield of 3a107 compared to 90 % yield obtained with 3 % CrCl2. The reaction scope of this new cross-coupling proved to be quite broad. Thus, a range of N-heterocyclic chlorides and bromides can be readily used (Table 11). PhMgCl (2a) also undergoes a smooth cross-coupling with 2-bromo-3-(but-3-en-1-yl)pyridine (4s; 23 °C 15 min), leading to the 2,3-disubstituted pyridine 5v in 95 % yield (entry 1). Interestingly, no radical cyclization product is observed in this cross-coupling (similar iron and cobalt crosscouplings produce 20 % of the radical cyclization product). Both electron-rich and electronpoor Grignard reagents can be used for such cross-couplings. Thus, the sterically hindered bromo-pyridine 4b reacts with 4-N,N-dimethyl-aminophenylmagnesium bromide (2n) within 1.5 h at 23 °C, producing the 2,3-diarylated pyridine 5b (80 % yield; entry 2).

Scheme 51. Chromium-catalyzed cross-coupling between 2-chloropyridine (1a) and PhMgCl (2a)

Also, the electron-poor Grignard reagent 2y reacts with 2-bromo-3-chloropyridine (4t) in 15 min at 23 °C, leading to the pyridine 8a in 76 % yield (entry 3). A similar cross-coupling performed with 3 % of FeBr3 gives only traces of product and significant amounts of homocoupling. 2-Chloro-5-fluoropyridine (4u) also undergoes the cross-coupling reaction with the sensitive ester-substituted Grignard reagent 2l to give the pyridine 8b in 66 % yield (entry 4). Further N-heterocyclic halides such as the 2-chloroquinoline 4j and the 4-chloroquinoline 4v, react well with Grignard reagents 2k and 2n, affording the expected products 8c and 8d (74 78 %; entries 5 and 6). In contrast, the corresponding iron-catalyzed cross-coupling with the 4-chloroquinoline 4v fails, indicating that this Cr(II)-catalyzed cross-coupling may have a

107

68

Rueping, M.; Ieawsuwan, W. Synlett 2007, 247.

B.Results and Discussion broader reaction scope than the corresponding Fe- and Co-catalyzed cross-couplings. Halogenated diazenes, such as the 2-chloropyrimidines 1h and 4m as well as the 2chloropyrazine 1j, rapidly react with the magnesium organometallics 2z, 2p and 2i to provide the substituted diazenes 8e-g (71 - 85 %; entries 7 - 9).

Table 11. Room-temperature Cr-catalyzed cross-coupling reactions between N-heterocyclic halides and arylmagnesium reagents

Entry

Starting material

Grignard reagent

Producta

1

4s

2a

5v; 95 %; 15 min

2

4b

2n

5b; 80 %; 90 min

3

4t

2y

8a; 76 %; 15 min

4

4u

2l

8b; 66 %; 15 min

5

4j

2k

8c; 74 %; 1 h

69

6

4v

2n

8d; 78 %; 15 min

7

1h

2z

8e; 71 %; 2 h

8

4m

2p

8f; 85 %; 15 min

9

1j

2i

8g; 72 %; 30 min

(a) Isolated yield after purification by flash column chromatography.

Table 12. Cr-catalyzed cross-coupling reactions between 2-chlorobenzophenone (9) and phenylmagnesium reagents

70

Entry

Grignard reagent

Product

Yielda

1

10a

11a

79 %; 15 min

B.Results and Discussion

2b

10b

11b

71 %; 2 h

3

2y

11c

93 %; 15 min

4

2n

11d

94 %; 15 min

5c

2w

11e

89 %; 2 h

(a) Isolated yields after purification by flash column chromatography. (b) 0.7 equiv of 10b were used. (c) Reaction run at 50 °C for 2 h.

Remarkably, 2-halogenated aromatic ketones also undergo the chromium-catalyzed crosscoupling at room temperature within 15 min to 2 h (Table 12).108 Thus, 2chlorobenzophenone (9) reacts with a range of aryl- and heteroaryl-magnesium reagents (2n, 2w, 2y, 10a, 10b) yielding the corresponding polyfunctional ketones 11a-e (71-94%; entries 1-5 of Table 12). Interestingly, the (2-bromophenyl)(6-chloropyridin-3-yl)-methanone (12) reacts with the Grignard reagent 2a with complete regioselectivity (no chloride-substitution occurs) and gives the pyridyl ketone 13 in 72% yield (Scheme 52). Heterocyclic ketones, such as 14, also couple well with 3-thienylmagnesium chloride 10b affording the new ketone 15 in 90% yield (Scheme 52). These reactions show a remarkable functional group tolerance, since ester,

108

For related Mn-catalyzed reactions see: (a) Cahiez, G.; Lepifre, F.; Ramiandrasoa, P. Synthesis 1999, 2138. (b) Cahiez, G.; Luart, D.; Lecomte, F. Org. Lett. 2004, 6, 4395.

71

nitriles and ketones are compatible with this Cr-catalyzed cross-coupling. Interestingly, the imine-protected 2-chlorobenzaldehyde 16 reacts readily with various Grignard reagents (2a, 2i, 10c) at 23 °C, which after acidic work-up provides the aldehydes 17a-c in 69-84% yield (Scheme 53). The presence of the sulfur-containing Grignard reagent 10c considerably extends the reactionrate and a 16 h reaction time is required to complete the cross-coupling leading to 17c.

Scheme 52. Cr-catalyzed cross-coupling reactions between heteroaryl-substituted ketones and Grignard reagents

Thus, this cross-coupling constitutes a simple way for functionalizing aromatic aldehydes in the ortho-position.

Scheme 53. Cr-catalyzed cross-coupling reactions between imine-protected aldehyde 16 and Grignard reagent

Alkenyl iodides, such as 18, also undergo a fast stereoselective chromium-catalyzed arylation with a range of Grignard reagents (2i, 2n, 2p, 2t), affording in all cases the functionalized

72

B.Results and Discussion styrenes 19a-d in 69 - 80% yield with an E:Z ratio better than 99:1. Remarkably, all reactions were performed at 23 °C and were completed within 15 min (Scheme 54).

Scheme 54. Cr-catalyzed cross-coupling reactions between alkenyl iodide 18 and Grignard reagents

Furthermore, such chromium(II)-catalyzed cross-coupling reactions could be performed using alkyl Grignard reagents (Scheme 55). 2-Chloroquinoline (1f) reacts with alkylmagnesium reagents 20a – c affording after 15 min at 23 °C alkylated heterocycles 21a – c in 74 – 82 % yield.

Scheme 55. Cr-catalyzed cross-coupling reactions of 2-chloroquinoline (1f) with alkyl Grignard reagents

73

4. Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines

4.1 Introduction

The formation of C-C bond involving a transition-metal catalyzed C-H activation has been widely developed in recent years.76 A range of transition metals such as Pd, Ru, Rh,77-79 Co and Fe catalyze these cross-couplings. Iron-catalysts and to some extend cobalt-catalysts are of special interest due to the moderate price of these metals. Iron salts are furthermore of low toxicity and the pioneering work of Nakamura and Yoshikai has attracted much attention.80-86 Although very attractive, the large amounts of Grignard reagents required to reach full conversion, long reaction times87,93 and the addition of appropriate ligands (such as cis-1,2bis(diphenylphosphino)ethylene,

1,10-phenantroline,

4,4´-di-tert-2,2´-bipyridiyl

or

N-

heterocyclic carbenes)80,87-89,91 are drawbacks and improvements are still desirable. Preliminary experiments showed that CrCl2 is an excellent catalyst for performing crosscouplings between aryl or heteroaryl halides and Grignard reagents.109 The key feature of this cross-coupling is the very small amount of the homo-coupling product formed, implying that almost no excess of Grignard reagent is required. Furthermore, these chromium(II)-catalyzed cross-couplings are very fast reactions. In this context it was of interest to examine directed C-H bond activation reactions involving CrCl2. This Cr-catalyzed directed arylation could be performed with N-heterocyles,

77b,77d,78c,78e,80,82,85,87

aryl

oxazolines78c,78e and aryl imines.84,86,88-89,92

4.2 Results and Discussion

The optimization of the reaction conditions was done using the reaction of the benzo[h]quinoline (22) with PhMgBr (2a, 1.5 – 4 equiv.) with catalytic amounts of CrCl2 and an oxidant at 23 °C for 24 h (Table 13). In the absence of the CrCl2-catalyst, no 10phenylbenzo[h]quinoline (23) is formed (entry 1). The use of 5 mol % of CrCl2 (99.99 %

109

Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D.; Knochel P. J. Am. Chem. Soc. 2013, 135, 1534615349.

74

B.Results and Discussion pure) led to the desired phenylated product 23 in 57 % yield, using 2,3-dichlorobutane (DCB) (entry 2). Using 10 mol % of CrCl2 increased the yield of 23 to 98 % (calibrated GC-yield) (entry 3). Lowering the amount of Grignard reagent to 1.5 equiv or 2.5 equiv (instead of 4 equiv) decreased the yield to 19 % and 63 %, respectively (entries 4 and 5). Changing the nature of the oxidant (from DCB to 1,2-dichloroethane or 1,2-dichloro-2-methylpropane) led to lower yields (45 – 87 %; entries 6 and 7). In the absence of an oxidant, only 10 % of product 23 was observed (entry 8 of Table 13).

Table 13. Optimization of the conditions for reaction of benzo[h]quinoline (22) with PhMgBr (2a) catalyzed by CrCl2

Entry

CrCl2

PhMgBr (2a)

Oxidant

Yield of

(%)

(equiv)

(1.5 equiv)

23 (%)a

1

0

4

DCB

0

2

5

4

DCB

57

3

10

4

DCB

98 (95) b

4

10

1.5

DCB

19

5

10

2.5

DCB

63

6

10

4

1,2-dichloroethane

45

7

10

4

1,2-dichloro-2-

87

methylpropane 8

10

4

without

10

(a) Yield determined after 24 h by integration of a GC-chromatogram and comparison against undecane as a calibrated internal standard. (b) Yield of isolated product after purification by flash column chromatography.

Treatment of benzo[h]quinoline (22) with PhMgBr (2a; 4 equiv) with the optimized conditions provides the arylated heterocycle 23 in 95 % isolated yield (entry 3 of Table 13). Similarly other arylmagnesium reagents either donor or acceptor undergo a high yield arylation at position 10 furnishing the arylated benzo[h]quinolines 23b - f in 66 - 90 % yield 75

(Table 14). Using the same conditions, it was also possible to arylate the 2-(2trimethylsilylphenyl)pyridine (24) with various arylmagnesium reagents affording the expected pyridines 25a-e in 79 - 92 % yield. Interestingly, these chromium(II)-catalyzed arylations proceed within a few hours at 23 ºC (Table 14).

Table

14.

Chromium-catalyzed

arylation

of

benzo[h]quinoline

(22)

and

2-(2-

trimethylsilylphenyl)pyridine (24) ArMgX (4 equiv) N H 22

N

CrCl2 (10 %) DCB (1.5 equiv) THF, 23 °C 24 - 38 h

Ar 23a - f

ArMgX (4 equiv)

TMS

TMS N

N H 24

Entry

76

Substrate

CrCl2 (10 %) DCB (1.5 equiv) THF, 23 °C 3-4h

ArMgX

Ar 25a - e

Reaction

Product;

Time (h)

Yield (%)a

1

22

PhMgBr (2a)

24

23a: Ar = Ph; 95 %

2

22

3-MeO-C6H4MgBr (10d)

24

23b: Ar = 3-MeO-C6H4; 90 %

3

22

4- Me2N-C6H4MgBr (2n)

24

23c: Ar = 4-Me2N-C6H4; 87 %

4

22

2k

24

23d: 67 %

5

22

4- F3C-C6H4MgBr (2y)

38

23e: Ar = 4-F3C-C6H4; 66 %

6

22

4-F-C6H4MgBr (2g)

24

23f: Ar = 4-F-C6H4; 86 %

B.Results and Discussion

7

24

PhMgBr (2a)

3

25a: Ar = Ph; 92 %

8

24

3-MeO-C6H4MgBr (10d)

3

25b: Ar = 3-MeO-C6H4; 79 %

9

24

4- Me2N-C6H4MgBr (2u)

4

25c: Ar = 4-Me2N-C6H4; 85 %

11

24

3-OTBS-C6H4MgBr (2p)

3

25d: Ar = 3-OTBS-C6H4; 83 %

12

24

4-F-C6H4MgBr (2g)

3

25e: Ar = 4-F-C6H4; 84 %

(a) Yield of the isolated product after purification by flash column chromatography.

The role of the TMS-group (TMS = trimethylsilyl) at position 2 is to avoid double arylation. Interestingly, this group can be further used to introduce a second different aryl substituent as shown in Scheme 49. Thus, the treatment of 24 with 3-tolylmagnesium bromide (2b) in the presence of 10 % CrCl2 and DCB (1.5 equiv) afforded the arylated product 25f in 89 % yield. Treatment with ICl in refluxing CH2Cl2 (12 h), followed by Negishi cross-coupling110 with the cyano-substituted phenylzinc derivative 26 in the presence of 3 % Pd(dba)2 (dba = dibenzylideneacetone) and 6 % tfp (tri(2-furyl)phosphine) at 50 ºC for 15 h furnishes the bisarylated pyridine 27 in 63 % yield over two steps (Scheme 56).

Scheme 56. Selective bis-arylation of the phenylpyridine 24 using chromium and palladium catalysts

The oxazoline directing group is a very popular group for directed C-H bond activation. Using the 2-TMS-phenyl oxazoline 28, we have achieved an efficient C-H activation and arylation with various Grignard reagents as shown in Scheme 57. Functional groups such as methoxy,

110

(a) Negishi, E.-I. Metal-Catalyzed Cross-Coupling Reactions (Eds.: Diederich, F.; Stang, P. J.) Woley, New York, 1998, chap. 1; (b) Negishi, E.-i.; Valente, L. F.; Kobayashi, M. Am. Chem. Soc. 1980, 102, 3298; (c) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340.

77

dimethylamino or TBS-protected alcohol could be tolerated well and the arylated oxazolines 29a – d were synthesized in 72 – 91 % yield.

Me Me N TMS

Me Me CrCl2 (10 %) DCB (1.5 equiv)

O H

+

Me Me

N

O

TMS

THF, 23 °C 3 - 15 h

2a: Ar=Ph 10d: Ar=3-MeO-C6H4 2n: =4-Me2N-C6H4 2p: =3-OTBS-C6H4

28

Me Me

ArMgBr (4 equiv)

Ar

29a-d

Me Me

Me Me

OMe N

O

TMS

N TMS

29a: 91 %, 3 h

OTBS

O

N

O

TMS

29b: 85 %, 5 h

N

NMe2

O

TMS

29c: 72 %, 15 h

29d: 78 %, 12 h

Scheme 57. Chromium-catalyzed arylation of 2-(2-(trimethylsilyl)phenyl)oxazoline 28 with Grignard reagents

In order to transform the TMS-group into a second aryl substituent, the oxazoline 29e was synthesized using 10 % of the CrCl2 and DCB (1.5 equiv) in 87 % yield. Treatment with ICl in refluxing CH2Cl2 (6 h), and subsequent Negishi cross-coupling reaction with the estersubstituted phenylzinc derivative 30 in the presence of 3 % Pd(dba)2 and 6 % tfp at 50 ºC for 15 h furnishes the bis-arylated pyridine 31 in 89 % yield over two steps (Scheme 58).

Scheme 58. Selective bis-arylation of the 2-(2-(trimethylsilyl)phenyl)oxazoline 28 using chromium and palladium catalysts

78

B.Results and Discussion Imine-protected aldehydes undergo chromium-catalyzed C-H bond activation reaction, furnishing compounds 34aa - ad and 34ba - bd in 61 – 88 % yield (Scheme 59). Interestingly, the reaction time was strongly dependent on the nature of the imine protection group. When p-methoxyphenyl imine 32 was used, chromium-catalyzed arylation reactions proceeded with reaction times of 16 – 25 h (34aa - ad). N-Butyl imine 33 reacted with the Grignard reagents 2n, 2g, 2z and 10f at faster rates (1.5 h – 3h) giving after acidic work up the arylated aldehydes 34ba - bd in 73 – 88 % yield.

OMe

TMS

TMS O

ArMgBr (4 equiv)

H

N CrCl2 (10 %) DCB (1.5 equiv) THF, 23 °C 16 - 25 h

H 32

Ar 34

TMS

ArMgBr (4 equiv)

n-Bu

N

CrCl2 (10 %) DCB (1.5 equiv) THF, 23 °C 1.5 - 3 h

H 33

2n: Ar =4-Me2N-C6H4 2g: =4-F-C6H4 10e: =4-CF3-3-Cl-C6H3 2z: =4-OCF3-C6H4 10f: =4-tBu-C6H4 2k:

= O O

TMS O H

TMS O

TMS O

TMS O

H

H

H

Cl NMe2 34aa: 76 %, 16 h (from 32)

34ab: 61 %, 16 h (from 32) TMS O

TMS O

NMe2 34ba: 73 %, 3 h (from 33)

34ac: 75 %, 25 h (from 32) TMS O

H

H

34bb: 88 %, 2 h (from 33)

O 34ad: 67 %, 16 h (from 32) TMS O

H

F

O

CF3

F

H

OCF3 34bc: 75 %, 3 h (from 33)

tBu 34bd: 74 %, 1.5 h (from 33)

Scheme 59. Chromium-Catalyzed Arylation of Imines 32 and 33 with Grignard Reagents

In order to show the practicability of our chromium-methodology, we aimed to perform biarylation of the imine-protected 2-chloro-benzaldehyde 35 via a one-pot Cr-catalyzed crosscoupling with subsequent Cr-catalyzed C-H bond activation (Scheme 60). In the first step, 35 undergoes a Cr-catalyzed coupling reaction with the Grignard reagent 2i to yield the arylated 79

product 36, which undergoes subsequent Cr-catalyzed direct C-H arylation with the Grignard reagent 2g to produce, after acetic work-up, bis-arylated aldehyde 37 in a one-pot fashion in 65% yield.

Scheme 60. One pot bis-arylation of aldehyde 37 using chromium catalyzed cross-coupling reaction and C-H bond activation reaction

80

B.Results and Discussion

5. Summary 5.1 Iron-Catalyzed Cross-Coupling of N-Heterocyclic Halides with Grignard

Reagents A simple and practical iron-catalyzed cross-coupling of N-heterocyclic chlorides and bromides with arylmagnesium reagents was developed. The reactions were performed at room temperature and proceeded at fast rates. The desired substituted N-heterocyclic products were obtained in high yields and various functional groups like electron-withdrawing groups such as trifluoromethyl-, fluoro- and pivalate-functions, as well as electron-donating groups like methoxy-, methylenedioxy- and dimethylamino-moieties were well tolerated. The addition of an ethereal co-solvent like diethyl ether or tert-butyl methyl ether was found to be essential to prevent homocoupling and to obtain high yields (Scheme 61).

Scheme 61. Iron-catalyzed cross-coupling reactions between N-hetrocyclic halides and aryl Grignard reagents

81

5.2 Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling between N-Heterocyclic Halides and Aryl Magnesium Reagents The cross-coupling of N-heterocyclic halides and Grignard reagents was further investigated. It was found that isoquinoline (and quinoline) has an ability to act as a new ligand for ironbut also for cobalt-catalyzed cross-coupling reactions. The rate and yield of iron- or cobaltcatalyzed cross-coupling reactions were dramatically increased while simultaneously decreasing the amount of homocoupling. With this new method, it was possible to widen the scope of these reactions considerably to couple a variety of functionalized Grignard reagents with an assortment of N-heterocycles.

Most important advances: • Increased reaction rate and yield

• Functionalized Grignard reagents could be used

82

B.Results and Discussion • An extension to the formation of heteroaryl-heteroaryl bonds was performed

In the case of FeBr3 S

OEt N EtO

N N

In the case of CoCl2 S MgCl

OEt N

(2 equiv) Cl

FeBr3 (3 %) isoquinoline (10 %) tBuOMe/THF 23 ºC, 12 h

EtO

TMS

N N

S

84 % yield

N

Br

TMS

(2 equiv) MgCl CoCl2 (3 %) isoquinoline (10 %) tBuOMe/THF 23 ºC, 24 h

N S 66 % yield

• A mechanistic study indicates that radical intermediates are involved

5.3 Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions An efficient chromium(II)-catalyzed cross-coupling reaction between heterocyclic and aromatic Grignard reagents and various aromatic and N-heterocyclic halides was investigated. This new cross-coupling reaction does not require additional ligands, proceeds at 25 °C within 15 min to 2 h and produces the desired cross-coupled products in good yields. Homo-coupling side-products were produced in much lower amounts compared to Fe-, Co- or even Mn-crosscouplings. As electrophiles, various halogenated N-heterocycles (chlorides and bromides), aromatic halogenated ketones or imines and alkenyl iodides could be used. Against common wisdom, toxicological data indicate that CrCl2 is a chromium-salt of low toxicity, as it is sold as a low-toxic chemical by major international suppliers (compare LD50 values of CrCl2 (1870 mg/kg), FeCl2 (450 mg/kg) and CoCl2 (766 mg/kg)).

83

Features of the method: •

N-Heterocyclic bromides and chlorides undergo CrCl2-catalyzed cross-couplings without the formation of homo-coupling side-products

84



Aromatic chloro-and bromo-ketones as well as chloro-imines react smoothly



E-Alkenyl iodides undergo stereoselective Cr(II)-catalyzed cross-couplings

B.Results and Discussion •

Cr(II)-catalyzed cross-coupling between Csp2-Csp3 centers also could be achieved

5.4 Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines Direct C-H bond activation reactions with aromatic Grignard reagents catalyzed by CrCl2 were examined. This type of reaction proceeds usually rapidly at 23 °C and does not require any additional ligands. Different compounds such as benzo[h]quinoline, 2-phenylpyridine, phenyloxazoline and imines were successfully arylated in good yields. A TMS-group was used to avoid double arylation, which after treatment with ICl was further used to introduce a second aryl substituent.

Most important advances:



Benzo[h]quinoline and 2-(2-trimethylsilylphenyl)pyridine could be arylated

85



2-(2-(Trimethylsilyl)phenyl)oxazoline underwent mild chromium(II)-catalyzed C-H bond activations in relatively fast rates.

Me Me N

Me Me CrCl2 (10 %) DCB (1.5 equiv)

O H

TMS

+ ArMgBr (4 equiv)

THF, 23 °C 3 - 15 h

N

O Ar

TMS

up to 91 % yield Me Me

Me Me

Me Me

Me Me

OMe N

O

TMS

N

F TMS

87 % yield; 3 h



N

O

TMS

85 % yield; 5 h

N

NMe2

O

TMS

72 % yield; 15 h

78 % yield; 12 h

Arylated aldehydes could be furnished in good yields, wherein imine B reacted in faster rates than imine A.

86

OTBS

O

B.Results and Discussion •

The TMS-group could be further transformed to iodide and used in Negishi crosscoupling reactions.

CN TMS N

TMS 1) ICl (3.5 equiv) CH2Cl2, reflux, 12 h

3-TolMgBr (4 equiv)

N

N

CrCl2 (10 %) DCB (1.5 equiv) THF, 23 °C, 4 h

H

2) 3-CN-PhZnCl (1.5 equiv) Pd(dba)2 (3 %) tfp (6 %), THF, 50 °C, 15 h Me 89 % yield

Me Me N TMS

Me 63 % yield (over two steps)

Me Me 4-F-C6H4MgBr (4 equiv)

O H

CrCl2 (10 %) DCB (1.5 equiv) THF, 23 °C, 3 h

N

O

1) ICl (3.5 equiv) CH2Cl2, reflux, 6 h F

F

2) 3-CO2Et-C6H4ZnCl (1.5 equiv) Pd(dba)2 (3 %) tfp (6 %), THF 50 °C, 15 h

TMS

87 % yield



Me Me CO2Et N O

89 % yield (over two steps)

The One pot bis-arylation of aldehydes could be achieved using a chromium catalyzed cross-coupling reaction and a C-H bond activation reaction

87

C. Experimental Section

C.Experimental Section

1. General Considerations All reactions were carried out with magnetic stirring and, if the reagents were air or moisture sensitive, in flame-dried glassware under argon. Syringes which were used to transfer reagents and solvents were purged with argon prior to use.

1.1 Solvents Solvents were dried according to standard procedures by distillation over drying agents and stored under argon. tBuOMe was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. CPME was predried over CaCl2 and distilled from CaH2. Et2O was predried over CaH2 and dried with the solvent purification system SPS-400-2 from INNOVATIVE TECHNOLOGIES INC. Hexane was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. NEP was heated to reflux for 14 h over CaH2 and distilled from CaH2. NMP was heated to reflux for 14 h over CaH2 and distilled from CaH2. THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. Toluene was predried over CaCl2 and distilled from CaH2. DCM was predried over CaCl2 and distilled from CaH2. CH3CN was heated to reflux for 14 h over CaH2 and distilled from CaH2. 1,2-dioxane was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. Bu2O was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. DME was continuously refluxed and freshly distilled from sodium benzophenone ketyl under nitrogen. Solvents for column chromatography were distilled prior to use.

91

1.2 Reagents All reagents were obtained from commercial sources and used without further purification unless otherwise stated. CoCl2 was dried under high vacuum at 150 °C for 2 min prior reactions (until the colour turned blue). CrCl2 was dried under high vacuum at 150 °C for 2 min prior reactions (until the colour turned white-grey). BF3·OEt2 was distilled under Ar prior to use. nBuLi solution in hexane was purchased from Rockwood Lithium GmbH. iPrMgCl·LiCl solution in THF was purchased from Rockwood Lithium GmbH. PhMgCl solution in THF was purchased from Rockwood Lithium GmbH. TMSCl was distilled under Ar prior to use. ZnCl2 solution (1.0

M)

was prepared by drying ZnCl2 (100 mmol, 13.6 g) in a Schlenk-flask

under vacuum at 140 °C for 5 h. After cooling, 100 mL dry THF were added and stirring was continued until the salt was dissolved. TMPH was distilled under Ar prior to use. TMPMgCl·LiCl was prepared in the following way: A dry and argon flushed 250 mL flask, equipped with a magnetic stirrer and a septum, was charged with freshly titrated iPrMgCl·LiCl (100 mL, 1.2 M in THF, 120 mmol). TMPH) (19.8 g, 126 mmol, 1.05 equiv) was added dropwise at room temperature. The reaction mixture was stirred at r.t. until gas evolution was completed (ca. 48 h). The freshly prepared TMPMgCl·LiCl solution was titrated prior to use at 25 °C with benzoic acid using 4(phenylazo)diphenylamine as indicator. A concentration of ca. 1.1 M in THF was obtained. Grignard reagents 2b - u, 2w, 2y - z, 10d - f, 21a - c were prepared via LiCl-assisted Mginsertion into the corresponding aromatic halides.111 Grignard reagents 2v, 2x, 10a - c were prepared via halogen-magnesium exchange reaction.112 Aryl Zn-compounds 26 and 30 were prepared via LiCl-assisted Zn-insertion into the corresponding aromatic halides113 or via Mg/Zn transmetalation reaction using ZnCl2 (1.0 M in THF). 111

Piller, F. M.; Metzger, A. ; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel, P. Chem. Eur. J., 2009, 15, 7192. 112 a) A. Krasovskiy, P. Knochel, Angew. Chem. Int. Ed. 2004, 43, 3333; b) A. Krasovskiy, B. F. Straub, P. Knochel, Angew. Chem. Int. Ed. 2006, 45, 159. 113 Krasovskiy, A.; Malakhov, V.; Gavryushin; A. Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 6040.

92

C.Experimental Section 1.3 Content Determination of Organometallic Reagents Organzinc and organomagnesium reagents were titrated against I2 in THF. Organolithium reagents were titrated against menthol using 1,10-phenanthroline as indicator in THF.

1.4 Chromotography Flash column chromatography was performed using silica gel 60 (0.040-0.063 mm) from Merck. Thin layer chromatography was performed using SiO2 pre-coated aluminium plates (Merck 60, F-254). The chromatograms were examined under UV light at 254 nm and/or by staining of the TLC plate with one of the solutions given below followed by heating with a heat gun: -

KMnO4 (3.0 g), 5 drops of conc. H2SO4 in water (300 mL).

-

Phosphomolybdic acid (5.0 g), Ce(SO4)2 (2.0 g) and conc. H2SO4 (12 mL) in water (230 mL).

1.5 Analytical Data NMR spectra were recorded on VARIAN Mercury 200, BRUKER AXR 300, VARIAN VXR 400 S and BRUKER AMX 600 instruments. Chemical shifts are reported as δ-values in ppm relative to the residual solvent peak of CHCl3 (δH : 7.25, δC : 77.0). For the characterization of the observed signal multiplicities the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet) as well as br (broad). Mass spectroscopy: High resolution (HRMS) and low resolution (MS) spectra were recorded on a FINNIGAN MAT 95Q instrument. Electron impact ionization (EI) was conducted with an electron energy of 70 eV.

For the combination of gas chromatography with mass spectroscopic detection, a GC/MS from Hewlett-Packard HP 6890 / MSD 5973 was used.

93

Infrared spectra (IR) were recorded from 4500 cm-1 to 650 cm-1 on a PERKIN ELMER Spectrum BX-59343 instrument. For detection a SMITHS DETECTION DuraSamplIR II Diamond ATR sensor was used. The absorption bands are reported in wavenumbers (cm-1) Melting points (M.p.) were determined on a BÜCHI B-540 apparatus and are uncorrected.

2. Typical Procedures (TP)

2.1 Typical Procedure for Fe-Catalyzed Cross-Coupling Reactions of N-Heterocyclic Chlorides and Bromides with Arylmagnesium Reagents (TP1) In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, the appropriate halogenated N-heterocycle (1.0 mmol, 1.0 equiv) and iron(III) bromide (4.4 mg, 0.015 mmol, 0.03 equiv) were dissolved in dry tBuOMe (5 mL). Then, the appropriate Grignard reagent (2.3 mmol, 2.3 equiv) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture. When the conversion was complete it was quenched with brine or with a mixture of aqueous saturated solution of NH4Cl and ammonia (10:1) and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained after purification by flash chromatography.

2.2 Typical Procedure for Ligand-Accelerated Iron- and Cobalt-Catalyzed CrossCoupling Reactions between N-Heteroaryl Halides and Aryl Magnesium Reagents (TP2) A solution of the appropriate Grignard reagent (concentration in THF varying depending on the identity of the Grignard reagent, 1.0 mmol, 2.0 equiv) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and the aryl halide (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for the indicated time before being quenched with NaHCO3 sat. aq. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, NaCl sat. aq. was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield the final compound as an analytically pure substance. 94

C.Experimental Section 2.3 Typical Procedure for Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Aryl Halides and Aryl or Alkyl Grignard Reagents (TP3) A solution of the appropriate Grignard reagent (concentration in THF varying depending on the nature of the Grignard reagent, 1.2 mmol, 1.2 equiv) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv.; 97% purity) and the aryl halide (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for the indicated time before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield the final compound as an analytically pure substance.

2.4 Typical Procedure for Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Imine Halide 16 and Aryl Grignard Reagents (TP4) A solution of the appropriate Grignard reagent (concentration in THF varying depending on the nature of the Grignard reagent, 1.2 mmol, 1.2 equiv) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and imine 16 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for the indicated time before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield the final compound as an analytically pure substance.

2.5 Typical Procedure for Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Alkenyl Iodide 18 and Aryl Grignard Reagents (TP5) A solution of the appropriate Grignard reagent (concentration in THF varying depending on the nature of the Grignard reagent, 1.5 mmol, 1.5 equiv) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and alkenyl iodide 18 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for the indicated time before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield the final compound as an analytically pure substance.

95

2.6 Typical Procedure for Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines and Aryl Oxazolines (TP6) A solution of the appropriate Grignard reagent (concentration in THF varying depending on the nature of the Grignard reagent, 2 mmol, 4 equiv) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv; 97% purity) and the appropriate aryl compound (0.5 mmol, 1.0 equiv) at 23 °C. 2,3-Dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The suspension was stirred at 23 °C for the indicated time before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield the final compound as an analytically pure substance.

2.7 Typical Procedure for Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Imines (TP7) A solution of the appropriate Grignard reagent (concentration in THF varying depending on the nature of the Grignard reagent, 2 mmol, 4 equiv) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv; 97% purity) and the appropriate aryl imine (0.5 mmol, 1.0 equiv) at 23 °C. 2,3-Dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv.) was added dropwise at 23 °C. The suspension was stirred at 23 °C for the indicated time before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield the final compound as an analytically pure substance.

96

C.Experimental Section

3. Fe-Catalyzed Cross-Coupling Reactions of N-heterocyclic Chlorides and Bromides with Arylmagnesium Reagents

3.1 Preparation of Cross-Coupling Products Using TP1 Synthesis of 2-phenylpyridine (3a):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloro- or 2-bromo-pyridine (1a or 1b; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 1.5 h (for 2-chloropyridine) or 70 min (for 2bromopyridine). The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 82 % yield (for 2-chloropyridine) or in 83 % yield (for 2-bromopyridine) as a colorless oil after purification by flash chromatography (silica gel, 6:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

1H

NMR (300 MHz, CDCl3) δ/ppm: 7.23 (m, 1 H), 7.45 (m, 3 H), 7.75 (m, 2 H), 8.01 (m, 2

H), 8.70 (d, J=4.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 120.60, 122.10, 126.92, 128.74, 128.99, 136.84, 139.24,

149.53, 157.39. MS (70 eV, EI) m/z (%): 155 (100) [M]+, 154 (60), 128 (10), 127 (10), 77 (9), 59 (10), 43 (7). IR ATR ν (cm-1): 3062, 3036, 3008, 2927, 1586, 1580, 1564, 1468, 1449, 1424, 1293, 1152, 1074, 1020, 988, 800, 737, 692.

HRMS (EI) for C11H9N (155.1735) [M]+: 155.1731. Synthesis of 4-methyl-2-phenylpyridine (3b):

97

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloro-4-methylpyridine (1c; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 84 % yield as a colorless oil after purification by flash chromatography (silica gel, 6:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

1H

NMR (300 MHz, CDCl3) δ/ppm: 2.41 (s, 3 H), 7.06 (d, J=4.1 Hz, 1 H), 7.44 (m, 3 H),

7.55 (s, 1 H), 7.98 (d, J=7.2 Hz, 2 H), 8.55 (d, J=4.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 21.24, 121.59, 123.14, 126.94, 128.68, 128.88, 139.26,

147.99, 149.18, 157.21. MS (70 eV, EI) m/z (%): 169 (100) [M]+, 168 (38), 128 (10), 167 (18), 154 (27), 115 (6), 77 (3). IR ATR ν (cm-1): 3058, 2921, 1601, 1582, 1557, 1472, 1446, 1400, 1386, 1377, 1073, 1030, 989, 866, 826, 774, 734, 692.

HRMS (EI) for C12H11N (169.0891) [M]+: 169.0884. Synthesis of 5-chloro-2-phenylpyridine (3c): Cl N

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-bromo-5-chloropyridine (1d; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 70 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 78 % yield as a white solid after purification by flash chromatography (silica gel, 30:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

98

C.Experimental Section m.p.: 65.1 – 66.8 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.47 (m, 3 H), 7.71 (m, 2 H), 7.95 (s, 1 H), 7.98 (d,

J=1.4 Hz, 1 H), 8.65 (d, J=1.9 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 121.17, 126.82, 128.85, 129.33, 130.63, 136.60, 138.00,

148.34, 155.48. MS (70 eV, EI) m/z (%): 189 (100) [M]+, 188 (18), 154 (37), 153 (8), 127 (13), 126 (7), 77 (8). IR ATR ν (cm-1): 3059, 3033, 2921, 1573, 1554, 1459, 1442, 1365, 1290, 1136, 1111, 1074, 1006, 920, 835, 774, 730, 691.

HRMS (EI) for C11H8ClN (189.0345) [M]+: 189.0339. Synthesis of tert-butyl 2-phenylnicotinate (3d): O Ot-Bu N

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, tert-butyl 2-chloronicotinate (1e; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 60% yield as a white solid after purification by flash chromatography (silica gel, 8:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 70.2 – 72.2 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.29 (s, 9 H), 7.31 (dd, J=7.7, 4.7 Hz, 1 H), 7.42 (m, 3

H), 7.52 (m, 2 H), 8.07 (dd, J=7.7, 1.7 Hz, 1 H), 8.73 (dd, J=5.0, 1.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 27.51, 82.17, 121.54, 128.03, 128.38, 128.67, 128.93,

137.73, 140.64, 150.68, 158.75, 167.20. MS (70 eV, EI) m/z (%): 255 (19) [M]+ , 200 (23), 199 (100), 198 (40), 182 (28), 155 (62), 154 (26), 127 (16), 57 (10). IR ATR ν (cm-1): 2977, 2362, 2349, 1701, 1580, 1560, 1428, 1369, 1311, 1293, 1255, 1168, 1128, 1077, 1056, 850, 792, 755, 732, 701. 99

HRMS (EI) for C16H17NO2 (255.1259) [M]+: 255.1247. Synthesis of 2-phenylquinoline (3e):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 88 % yield as a beige solid after purification by flash chromatography (silica gel, 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 81.9 – 83.6 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.50 (m, 4 H), 7.75 (m, 1 H), 7.86 (m, 2 H), 8.22 (m, 4

H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 119.04, 126.38, 127.18, 127.45, 127.65, 128.85, 129.44,

129.52, 129.81, 137.03, 139.35, 147.98, 157.27. MS (70 eV, EI) m/z (%): 206 (20), 205 (100) [M]+, 204 (70), 203 (13), 175 (12), 169 (15), 102 (9), 84 (8), 44 (27). IR ATR ν (cm-1): 2923, 2853, 2362, 1740, 1596, 1490, 1446, 1318, 1240, 1213, 1186, 1126, 1050, 1024, 923, 829, 770, 747, 690, 676.

HRMS (EI) for C15H11N (205.0891) [M]+: 205.0884. Synthesis of 1-phenylisoquinoline (3f): N

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 1-chloroisoquinoline (1g; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were 100

C.Experimental Section dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 90% yield as a white solid after purification by flash chromatography (silica gel, 10:1 ihexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 97.6 – 99.5 ºC. NMR (300 MHz, CDCl3) δ/ppm: 7.53 (m, 4 H), 7.69 (m, 4 H), 7.89 (d, J=8.3 Hz, 1 H),

1H

8.12 (d, J=8.6 Hz, 1 H), 8.62 (d, J=5.5 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 120.01, 126.68, 126.99, 127.26, 127.64, 128.36, 128.69,

129.93, 130.16, 136.93, 139.23, 141.86, 160.60. MS (70 eV, EI) m/z (%): 206 (7), 205 (46) [M]+, 204 (100), 203 (13), 176 (7), 102 (8). IR ATR ν (cm-1): 3053, 2921, 2364, 2337, 1618, 1582, 1552, 1500, 1440, 1380, 1352, 1319, 1304, 1167, 1020, 973, 954, 875, 823, 803, 798, 767, 754, 706, 699, 675.

HRMS (EI) for C15H11N (205.0891) [M]+: 205.0864. Synthesis of 4,6-dimethyl-2-phenylpyrimidine (3g):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloro-4,6-dimethylpyrimidine (1h; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol%) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, phenylmagnesium chloride (2a; 2.3 equiv, 1.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 76 % yield as a white solid after purification by flash chromatography (silica gel, 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 82.8 – 84.0 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.54 (s, 6 H), 6.92 (s, 1 H), 7.47 (m, 3 H), 8.43 (d, J=1.9

Hz, 1 H), 8.45 (d, J=4.4 Hz, 1 H). 101

13C

NMR (75 MHz, CDCl3) δ/ppm: 24.11, 117.97, 128.24, 128.42, 130.31, 137.94, 164.06,

166.77. MS (70 eV, EI) m/z (%): 185 (16), 184 (100) [M]+ , 169 (20), 104 (19), 103 (27), 77 (6). IR ATR ν (cm-1): 3068, 2924, 2853, 2361, 1595, 1574, 1550, 1534, 1442, 1434, 1379, 1364, 1342, 1173, 1025, 932, 854, 749, 693, 662.

HRMS (EI) for C12H12N2 (184.1000) [M]+: 184.0995. Synthesis of 2-(m-tolyl)pyridine (3j): N

CH3

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-bromopyridine (1b; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, m-tolyl-magnesium bromide (2b; 2.3 equiv, 1.1 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 1.5 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 80% yield as a yellow oil after purification by flash chromatography (silica gel, 5:1 i-hexane/ethyl acetate + 0.5% triethylamine).

1H

NMR (300 MHz, CDCl3) δ/ppm: 2.44 (s, 3 H), 7.22 (m, 2 H), 7.37 (t, J=7.6 Hz, 1 H),

7.73 (m, 3 H), 7.85 (s, 1 H), 8.69 (d, J=4.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 21.51, 120.61, 121.61, 123.99, 127.64, 128.62, 129.70,

136.67, 138.39, 139.35, 149.58, 157.63. MS (70 eV, EI) m/z (%): 170 (14), 168 (52), 167 (23), 154 (10), 115 (5). IR ATR ν (cm-1): 3049, 3008, 2918, 2860, 1584, 1565, 1473, 1460, 1431, 1302, 1293, 1152, 1087, 1043, 991, 883, 804, 762, 742, 724, 694.

HRMS (EI) for C12H11N (169.0891) [M+H]+: 169.0886.

102

C.Experimental Section Synthesis of 1-(p-tolyl)isoquinoline (3k):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 1-chloroisoquinoline (1g; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, p-tolyl-magnesium bromide (2b; 2.3 equiv, 1.2 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 2 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 93 % yield as a yellow oil after purification by flash chromatography (silica gel, 12:1 ihexane/ethyl acetate + 0.5 % triethylamine).

1H

NMR (300 MHz, CDCl3) δ/ppm: 2.47 (s, 3 H), 7.35 (d, J=8.0 Hz, 2 H), 7.54 (t, J=7.6 Hz,

1 H), 7.66 (m, 4 H), 7.88 (d, J=8.0 Hz, 1 H), 8.14 (d, J=8.6 Hz, 1 H), 8.61 (d, J=5.8 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 21.35, 119.77, 126.72, 126.96, 127.13, 127.74, 129.04,

129.87, 130.07, 136.37, 136.94, 138.58, 141.86, 160.66. MS (70 eV, EI) m/z (%): 219 (80) [M]+, 218 (100), 217 (21), 216 (20), 205 (11), 204 (59), 203 (11), 175 (9), 108 (13), 43 (13). IR ATR ν (cm-1): 3049, 2919, 2852, 1618, 1583, 1552, 1497, 1452, 1384, 1355, 1320, 1305, 1182, 1166, 1138, 1111, 1021, 974, 873, 848, 821, 799, 787, 749, 722, 677.

HRMS (EI) for C16H13N (219.1048) [M]+: 219.1023. Synthesis of 2-(o-tolyl)quinoline (3l): CH3 N

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, o-tolyl-magnesium bromide (2b; 2.3 equiv, 0.9 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 45 min. The reaction mixture was quenched with brine and extracted 103

with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 84 % yield as a beige solid after purification by flash chromatography (silica gel, 5:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 78.3 – 80.4 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.43 (s, 3 H), 7.34 (s, 3 H), 7.54 (m, 3 H), 7.75 (t, J=7.7

Hz, 1 H), 7.87 (d, J=8.3 Hz, 1 H), 8.21 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 20.34, 122.37, 126.01, 126.44, 126.73, 127.49, 128.54,

129.50, 129.68, 129.70, 130.86, 136.00, 136.18, 140.56, 147.75, 160.22. MS (70 eV, EI) m/z (%): 218 (100) [M-H]+, 217 (27), 216 (8), 85 (27), 83 (35). IR ATR ν (cm-1): 2951, 2921, 2852, 1740, 1602, 1592, 1553, 1501, 1485, 1455, 1420, 1378, 1334, 1311, 1276, 1264, 1238, 1217, 1204, 1118, 1037, 1014, 976, 941, 836, 798, 772, 762, 754, 722, 688, 674.

HRMS (EI) for C16H13N (219.1048) [M+H]+: 219.0957. Synthesis of 2-(3-(trifluoromethyl)phenyl)quinoline (3m):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved

in

dry

t-BuOMe

(5 mL)

following

TP1.

Then,

(3-(

trifluoromethyl)phenyl)magnesium bromide (2e; 2.3 equiv, 0.9 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 15 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 92 % yield as a beige solid after purification by flash chromatography (silica gel, 5:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 76.5 – 78.5 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.56 (t, J=7.5 Hz, 1 H), 7.64 (t, J=7.7 Hz, 1 H), 7.75 (m,

2 H), 7.86 (m, 2 H), 8.22 (dd, J=15.5, 8.6 Hz, 2 H), 8.36 (d, J=7.7 Hz, 1 H), 8.48 (s, 1 H).

104

C.Experimental Section 13C

NMR (75 MHz, CDCl3) δ/ppm: 118.52, 124.16 (q, J=272.65 Hz), 124.39 (q, J=3.92 Hz),

125.84 (q, J=3.93 Hz), 126.74, 127.37, 127.48, 129.27, 129.81, 129.94, 130.66, 131.23 (q, J=32.26 Hz), 137.11, 140.35, 148.24, 155.52. MS (70 eV, EI) m/z (%): 274 (19), 273 (100) [M]+, 272 (29), 252 (10), 204 (21), 203 (6). IR ATR ν (cm-1): 3060, 2362, 1741, 1592, 1509, 1483, 1466, 1428, 1336, 1274, 1261, 1236, 1168, 1142, 1115, 1096, 1074, 1051, 806, 786, 757, 704, 693, 652.

HRMS (EI) for C16H10F3N (273.0765) [M]+: 273.0763. Synthesis of 2-(3-(trifluoromethyl)phenyl)pyridine (3n):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-bromopyridine (1b; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved

in

dry

t-BuOMe

(5 mL)

following

TP1.

Then,

(3-

(trifluoromethyl)phenyl)magnesium bromide (2e; 2.3 equiv, 0.9 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 66 % yield as a yellow oil after purification by flash chromatography (silica gel, 5:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

1H

NMR (300 MHz, CDCl3) δ/ppm: 7.28 (m, 1 H), 7.58 (t, J=7.7 Hz, 1 H), 7.67 (m, 1 H),

7.78 (m, 2 H), 8.18 (d, J=7.7 Hz, 1 H), 8.29 (s, 1 H), 8.72 (d, J=4.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 120.55, 122.79, 123.76 (q, J=3.93 Hz), 124.16 (q,

J=272.36 Hz), 125.50 (q, J=3.93 Hz), 129.18, 130.01, 131.20 (q, J=32.54 Hz), 136.95, 140.10, 149.86, 155.81. MS (70 eV, EI) m/z (%): 224 (10), 223 (100) [M]+, 222 (12), 202 (7), 154 (21). IR ATR ν (cm-1): 3074, 3054, 3011, 1586, 1464, 1437, 1418, 1333, 1272, 1262, 1163, 1117, 1094, 1073, 1064, 1040, 991, 919, 826, 811, 773, 739, 696, 662.

HRMS (EI) for C12H8F3N (223.0609) [M]+: 223.0609.

105

Synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)isoquinoline (3o): N

F3C

CF3

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 1-chloroisoquinoline (1g; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved

in

dry

t-BuOMe

(5 mL)

following

TP1.

Then,

(3,5-

bis(trifluoromethyl)phenyl)magnesium bromide (2f; 2.3 equiv, 1.0 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 75 % yield as a beige solid after purification by flash chromatography (silica gel, 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 75.0 – 76.6 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.63 (t, J=7.9 Hz, 1 H), 7.76 (m, 2 H), 7.95 (d, J=8.3

Hz, 2 H), 8.03 (s, 1 H), 8.20 (s, 2 H), 8.65 (d, J=5.8 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 121.17, 122.38, 123.27 (q, J=272.72 Hz), 126.07,

126.32, 127.44, 128.19, 130.14, 130.52, 131.83 (q, J=37.59 Hz), 136.95, 141.56, 142.29, 157.22. MS (70 eV, EI) m/z (%): 342 (62), 341 (100) [M]+ , 320 (8), 272 (15), 271 (7). IR ATR ν (cm-1): 3059, 2360, 1623, 1567, 1368, 1335, 1275, 1184, 1164, 1123, 1107, 1069, 898, 877, 846, 829, 746, 714, 703, 690, 678.

HRMS (EI) for C17H9F6N (341. 0639) [M]+: 341.0549. Synthesis of 2-(4-fluorophenyl)pyridine (3p):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-bromopyridine (1b; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, (4-fluorophenyl)magnesium bromide 106

C.Experimental Section (2g; 2.3 equiv, 1.0 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 68% yield as a beige solid after purification by flash chromatography (silica gel, 6:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 40.6 – 41.8 ºC. NMR (300 MHz, CDCl3) δ/ppm: 7.20 (m, 3 H), 7.72 (m, 2 H), 7.98 (m, 2 H), 8.67 (d,

1H

J=4.4 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 115.62 (d, J=21.63 Hz), 120.17, 122.00, 128.65 (d,

J=8.26 Hz), 135.54 (d, J=4.4 Hz), 136.77, 149.66, 156.44, 163.47 (d, J=248.25 Hz). MS (70 eV, EI) m/z (%): 174 (11), 173 (100) [M]+, 172 (50), 146 (7), 145 (5). IR ATR ν (cm-1): 3053, 2924, 2854, 1599, 1584, 1567, 1510, 1466, 1434, 1409, 1393, 1297, 1219, 1160, 1152, 1098, 989, 844, 826, 818, 773, 737, 724, 706.

HRMS (EI) for C11H8FN (173.0641) [M]+: 173.0641. Synthesis of 1-(4-fluorophenyl)isoquinoline (3q):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 1-chloroisoquinoline (1g; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, ((4-fluorophenyl)magnesium bromide (2g; 2.3 equiv, 1.0 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 90 % yield as a beige solid after purification by flash chromatography (silica gel, 8:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 79.8 – 81.5 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.22 (t, J=8.7 Hz, 2 H), 7.54 (t, J=7.6 Hz, 1 H), 7.68 (m,

4 H), 7.88 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.6 Hz, 1 H), 8.60 (d, J=5.8 Hz, 1 H). 107

13C

NMR (75 MHz, CDCl3) δ/ppm: 115.37 (d, J=21.64 Hz), 120.00, 126.64, 127.06, 127.24,

127.30, 130.06, 131.70 (d, J=8.26 Hz), 135.65 (d, J=3.41 Hz), 136.88, 142.17, 159.59, 163.08 (d, J=247.96 Hz). MS (70 eV, EI) m/z (%): 223 (100) [M+H]+, 202 (7), 194 (4), 111 (3), 83 (22). IR ATR ν (cm-1): 3056, 2924, 2854, 1795, 1604, 1582, 1553, 1509, 1498, 1384, 1353, 1233, 1221, 1159, 975, 877, 844, 834, 804, 798, 757, 724, 674.

HRMS (EI) for C15H10FN (223.0797) [M+H]+: 223.0701. Synthesis of 2-(4-chlorophenyl)quinoline (3r):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, (4-chlorophenyl)magnesium bromide (2h; 2.3 equiv, 1.2 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 84 % yield as a white solid after purification by flash chromatography (silica gel, 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 114.8 – 116.2 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.52 (m, 3 H), 7.76 (m, 3 H), 8.15 (m, 4 H).

13C

NMR (75 MHz, CDCl3) δ/ppm: 118.49, 126.47, 127.20, 127.47, 128.79, 129.99, 129.70,

129.81, 135.53, 136.91, 138.02, 148.22, 155.93. MS (70 eV, EI) m/z (%): 241 (5), 239 (100) [M]+, 203 (2), 102 (1). IR ATR ν (cm-1): 3055, 2361, 2338, 1596, 1588, 1577, 1552, 1486, 1430, 1399, 1285, 1089, 1050, 1008, 939, 815, 788, 770, 752, 732, 715, 672, 652.

HRMS (EI) for C15H10ClN (239.0502) [M]+: 239.0507. Synthesis of 2-(4-methoxyphenyl)pyridine (3s):

108

C.Experimental Section

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-bromopyridine (1b; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, (4-methoxyphenyl)magnesium bromide (2i; 2.3 equiv, 1.3 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 10 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 82 % yield as a white solid after purification by flash chromatography (silica gel, 5:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 58.7 – 60.4 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.86 (s, 3 H), 7.00 (d, J=8.8 Hz, 2 H), 7.18 (m, 1 H),

7.71 (m, 2 H), 7.95 (d, J=8.8 Hz, 2 H), 8.66 (d, J=4.4 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 55.34, 114.14, 119.91, 121.42, 128.21, 131.71, 136.87,

149.28, 156.98, 160.53. MS (70 eV, EI) m/z (%): 186 (13), 185 (100) [M]+, 142 (26), 141 (16), 115 (5). IR ATR ν (cm-1): 3062, 2997, 2963, 2837, 1601, 1586, 1579, 1562, 1513, 1458, 1431, 1407, 1306, 1302, 1272, 1243, 1176, 1151, 1113, 1058, 1036, 1021, 1005, 838, 776, 736, 718.

HRMS (EI) for C12H11NO (185.0841) [M]+: 185.0840. Synthesis of 2-(4-methoxyphenyl)quinoline (3t):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, (4-methoxyphenyl)magnesium bromide (2i; 2.3 equiv, 1.3 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 87 % yield as a white solid after purification by flash chromatography (silica gel, 7:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

109

m.p.: 123.7 – 125.6 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.87 (s, 3 H), 7.05 (d, J=8.8 Hz, 2 H), 7.49 (t, J=7.5 Hz,

1 H), 7.75 (m, 3 H), 8.16 (m, 4 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 55.37, 114.23, 118.51, 125.90, 126.90, 127.43, 128.89,

129.49, 129.57, 132.18, 136.63, 148.24, 156.85, 160.84. MS (70 eV, EI) m/z (%): 235 (100) [M]+, 220 (18), 192 (17), 191 (18), 95 (3). IR ATR ν (cm-1): 3047, 2961, 2841, 1603, 1595, 1582, 1497, 1468, 1430, 1321, 1290, 1284, 1247, 1175, 1156, 1124, 1112, 1028, 1013, 948, 847, 834, 816, 789, 770, 761, 748, 726, 678.

HRMS (EI) for C16H13NO (235.0997) [M]+: 235. 0993. Synthesis of 1-(3,5-dimethoxyphenyl)isoquinoline (3u): N

MeO

OMe

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 1-chloroisoquinoline (1g; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, (3,5-dimethoxyphenyl)magnesium bromide (2j; 2.3 equiv, 1.2 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 71 % yield as a yellow oil after purification by flash chromatography (silica gel, 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

1H

NMR (300 MHz, CDCl3) δ/ppm: 3.84 (s, 6 H), 6.61 (t, J=2.3 Hz, 1 H), 6.83 (d, J=2.4 Hz,

2 H), 7.52 (m, 1 H), 7.67 (m, 2 H), 7.86 (d, J=8.3 Hz, 1 H), 8.14 (d, J=8.6 Hz, 1 H), 8.59 (d, J=5.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 55.48, 101.04, 107.98, 120.08, 126.66, 126.91, 127.18,

127.57, 130.05, 136.80, 141.39, 141.99, 160.55, 160.66. MS (70 eV, EI) m/z (%): 266 (13), 265 (100) [M]+, 264 (91), 250 (19), 235 (14), 234 (22), 206 (11), 191 (13). IR ATR ν (cm-1): 3051, 3000, 2936, 2838, 1591, 1585, 1557, 1453, 1424, 1383, 1358, 1318, 1203, 1151, 1061, 1051, 1003, 927, 824, 799, 775, 750, 700, 686, 654. 110

C.Experimental Section

HRMS (EI) for C17H15NO2 (265.1103) [M]+: 265.1090. Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)quinoline (3v):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, benzo[d][1,3]dioxol-5-ylmagnesium bromide (2k; 2.3 equiv, 1.2 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 81 % yield as a white solid after purification by flash chromatography (silica gel, 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 97.9 – 99.1 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 6.03 (s, 2 H), 6.95 (d, J=8.3 Hz, 1 H), 7.50 (t, J=7.0 Hz,

1 H), 7.72 (m, 5 H), 8.14 (dd, J=8.4, 4.0 Hz, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 101.35, 107.91, 108.45, 118.56, 121.73, 126.03, 126.98,

127.39, 129.54, 129.62, 134.11, 136.64, 148.17, 148.38, 148.82, 156.62. MS (70 eV, EI) m/z (%): 250 (15), 249 (100) [M]+, 248 (15), 191 (12), 190 (9), 163 (2). IR ATR ν (cm-1): 3051, 3008, 2895, 2780, 1594, 1494, 1486, 1454, 1443, 1425, 1353, 1290, 1251, 1245, 1233, 1222, 1206, 1116, 1108, 1097, 1035, 930, 916, 906, 892, 837, 826, 813, 799, 782, 742, 718, 682.

HRMS (EI) for C16H11NO2 (249. 0790) [M]+: 249.0782. Synthesis of 4-(isoquinolin-1-yl)phenyl pivalate (3w):

111

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 1-chloroisoquinoline (1g; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved in dry t-BuOMe (5 mL) following TP1. Then, (4-(pivaloyloxy)phenyl)magnesium bromide (2l; 2.3 equiv, 0.8 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 15 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 80 % yield as a white solid after purification by flash chromatography (silica gel, 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine). m.p.: 97.1 – 96.3 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.41 (s, 9 H), 7.25 (d, J=8.6 Hz, 2 H), 7.54 (t, J=7.2 Hz,

1 H), 7.70 (m, 4 H), 7.88 (d, J=8.0 Hz, 1 H), 8.11 (d, J=8.3 Hz, 1 H), 8.60 (d, J=5.5 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 27.16, 39.17, 120.19, 121.50, 126.71, 127.01, 127.39,

127.52, 130.23, 131.01, 136.59, 136.93, 141.80, 151.58, 159.77, 177.00. MS (70 eV, EI) m/z (%): 305 (68) [M]+ , 222 (12), 221 (70), 220 (100), 204 (22), 192 (20), 191 (35), 110 (26), 57 (32). IR ATR ν (cm-1): 3469, 2974, 2872, 1749, 1740, 1554, 1498, 1478, 1457, 1384, 1354, 1275, 1199, 1164, 1111, 1026, 1016, 974, 900, 882, 858, 844, 834, 820, 798, 788, 754, 726, 678.

HRMS (EI) for C20H19NO2 (305. 1416) [M]+: 305. 1409. Synthesis of tert-butyl 3-(quinolin-2-yl)phenyl carbonate (3x):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved

in

dry

t-BuOMe

(5 mL)

following

TP1.

Then,

(3-(tert-

butoxycarbonyloxy)phenyl)magnesium bromide (2m; 2.3 equiv, 0.7 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 15 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 84 % yield as a white solid after purification by flash chromatography (silica gel, 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 95.1 – 96.3 ºC. 112

C.Experimental Section NMR (300 MHz, CDCl3) δ/ppm: 1.60 (s, 9 H), 7.29 (m, 1 H), 7.53 (t, J=7.9 Hz, 2 H),

1H

7.73 (m, 1 H), 7.83 (m, 2 H), 8.04 (dd, J=4.1, 2.2 Hz, 2 H), 8.19 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 27.75, 83.58, 118.80, 120.43, 122.23, 124.80, 126.50,

127.30, 127.45, 129.71, 129.77, 136.93, 141.13, 148.12, 151.67, 151.83, 156.03. MS (70 eV, EI) m/z (%): 321 (9) [M]+, 222 (13), 221 (100), 220 (82), 204 (22), 191 (16), 57 (26). IR ATR ν (cm-1): 3496, 3076, 2982, 1747, 1598, 1454, 1445, 1369, 1295, 1274, 1264, 1252, 1242, 1183, 1142, 1083, 1047, 928, 869, 825, 804, 787, 780, 769, 742, 692, 686.

HRMS (EI) for C20H19NO3 (321. 1365) [M]+: 321. 1360. N,N-dimethyl-4-(quinolin-2-yl)aniline (3y) (CAS Number: 16032-41-0):

In a dry and argon flushed 10 mL Schlenk-tube, equipped with a magnetic stirring bar and a septum, 2-chloroquinoline (1f; 1.0 mmol, 1.0 equiv) and iron (III) bromide (3 mol %) were dissolved

in

dry

t-BuOMe

(5 mL)

following

TP1.

Then,

(4-

(dimethylamino)phenyl)magnesium bromide (2n; 2.3 equiv, 1.3 M) dissolved in THF was added dropwise at room temperature while stirring the reaction mixture for 5 min. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was separated and dried over Na2SO4. The product was obtained in 82 % yield as a red solid after purification by flash chromatography (silica gel, 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine).

m.p.: 175.8 – 177.5 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.04 (s, 6 H), 6.84 (d, J=8.8 Hz, 2 H), 7.46 (t, J=7.2 Hz,

1 H), 7.69 (m, 1 H), 7.77 (d, J=7.9 Hz, 1 H), 7.83 (d, J=8.6 Hz, 1 H), 8.12 (dd, J=8.5, 6.6 Hz, 4 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 40.34, 112.24, 118.26, 125.33, 126.69, 127.33, 127.37,

128.46, 129.33, 136.26, 148.41, 151.35, 157.33. MS (70 eV, EI) m/z (%): 248 (100) [M]+, 247 (35), 204 (11), 124 (4). IR ATR ν (cm-1): 3058, 2887, 2809, 1595, 1564, 1545, 1539, 1498, 1434, 1360, 1326, 1286, 1226, 1198, 1168, 1140, 1130, 1120, 947, 811, 789, 762. 113

HRMS (EI) for C17H16N2 (248. 1313) [M]+: 248.1309.

4. Ligand-Accelerated Iron- and Cobalt-Catalyzed Cross-Coupling Reactions between N-Heterocyclic Halides and Aryl Magnesium Reagents

4.1 Preparation of Starting Materials Substance 7a was prepared according to the procedure described in the literature.114 Substance 7b was prepared according to the procedure described in the literature.115

Synthesis of 2-bromo-3-(4-chlorophenyl)pyridine (4b):

Diisopropylamine (1.0 equiv, 20 mmol) in THF (50 mL) was cooled to -78 °C, and n-BuLi (1.0 equiv, 20 mmol) was added dropwise at -78 °C. The reaction mixture was stirred for 15 min at -78 °C, slowly warmed up to -5 °C and then cooled to -95 °C. A solution of 2bromo-pyridine (1.0 equiv, 20 mmol) in THF (20 mL) was added dropwise, and the reaction mixture was stirred for 4 h at -95 °C. A solution of ZnCl2 (1.1 equiv, 22 mmol, 1 M in THF) was added dropwise and the reaction mixture was warmed up to 23 °C. 1-Chloro-4iodobenzene (0.75 equiv, 15 mmol) and Pd(Ph3P)4 (5 mol%) were added and the reaction mixture was heated to 50 °C for 2 h. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 10:1 i-hexane/ethyl acetate) to furnish 2.01 g (50%) of the product as a pink solid.

m.p.: 136 – 139 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.29 - 7.48 (m, 5 H), 7.59 (dd, J=7.46, 1.66 Hz, 1 H),

8.38 (dd, J=4.56, 1.52 Hz, 1 H).

114 115

Rodriguez, J. G., Benito, Y. J. Heterocycl. Chem. 1988, 25, 819. Joucla, L.; Cusati, G.; Pinel, C.; Djakovitch, L. Applied Catalysis 2009, 360, 145.

114

C.Experimental Section 13C

NMR (75 MHz, CDCl3) δ/ppm: 122.74, 128.56, 130.62, 134.56, 137.24, 138.60, 138.90,

142.21, 149.01. MS (70 eV, EI) m/z (%): 267 (48), 190 (27), 188 (100), 153 (52), 152 (27), 126 (15). IR ATR ν (cm-1): 3045, 3036, 2000, 1911, 1572, 1554, 1494, 1442, 1408, 1376, 1301, 1098, 1090, 1053, 1020, 997, 833, 822, 803, 778, 744, 715, 700. HRMS (EI) for C11H7BrClN (266.9450) [M]+: 266.9444.

Synthesis of 2-bromo-4-(3-bromophenyl)-5-chloropyridine (4e):

Diisopropylamine (1.1 equiv, 16.5 mmol) in THF (24 mL) was cooled to -78 °C and n-BuLi (1.1 equiv, 16.5 mmol) was added dropwise at -78 °C. The reaction mixture was stirred for 15 minutes at -78 °C, slowly warmed up to -5 °C and then cooled to -78 °C. A solution of 2bromo-5-chloropyridine (1.0 equiv, 15 mmol) in THF (7 mL) was added dropwise, and the reaction mixture was stirred for 2 h. A solution of ZnCl2 (1.2 equiv, 18 mmol, 1 M in THF) was added at -78 °C and the reaction mixture was allowed to warm up to 23 °C. 1-Bromo-3iodobenzene (1.1 equiv, 16.5 mmol) and Pd(Ph3P)4 (5 mol%) were added, and the reaction mixture was heated to 50 °C over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 11:1 i-hexane/ethyl acetate) to furnish 3.6 g (68%) of the product as a yellow solid.

m.p.: 109 – 111 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.34 - 7.42 (m, 2 H), 7.47 (s, 1 H), 7.58 - 7.65 (m, 2 H),

8.45 (s, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 122.60, 127.47, 129.13, 129.74, 130.11, 131.68, 132.45,

137.09, 140.03, 148.61, 150.05. MS (70 eV, EI) m/z (%): 345 (18), 268 (20), 267 (16), 187 (47), 152 (12). IR ATR ν (cm-1): 3045, 2361, 1564, 1512, 1443, 1412, 1322, 1282, 1112, 1095, 1067, 1023, 995, 920, 890, 880, 784, 746, 730, 691, 664. HRMS (EI) for C11H6Br2ClN (344.8556) [M]+: 344.8541.

115

Synthesis of 2-bromo-5-chloro-4-(4-fluorophenyl)pyridine (4h):

Diisopropylamine (1.1 equiv, 16.5 mmol) in THF (24 mL) was cooled to -78 °C and n-BuLi (1.1 equiv, 16.5 mmol) was added dropwise at -78 °C. The reaction mixture was stirred for 15 minutes at -78 °C, slowly warmed up to -5 °C and then cooled to -78 °C. A solution of 2bromo-5-chloropyridine (1.0 equiv, 15 mmol) in THF (7 mL) was added dropwise, and the reaction mixture was stirred for 2 h. A solution of ZnCl2 (1.2 equiv, 18 mmol, 1 M in THF) was added at -78 °C and reaction mixture was allowed to warm up to 23 °C. 1-Fluoro-4iodobenzene (1.1 equiv, 16.5 mmol) and Pd(Ph3P)4 (5 mol%) were added. The reaction mixture was heated to 50 °C over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 10:1 i-hexane/ethyl acetate) to furnish 3 g (70%) of the product as a white solid.

m.p.: 130 – 132 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 11.25 (t, J=8.67 Hz, 2 H), 11.51 - 11.56 (m, 3 H), 12.50

(s, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 115.78 (d, J=21.88 Hz, 1 C) 129.22, 129.83, 130.82 (d,

J=8.45 Hz, 1 C), 131.18 (d, J=3.07 Hz, 1 C), 139.99, 149.15, 149.99, 163.30 (d, J=250.29 Hz, 1 C). MS (70 eV, EI) m/z (%): 285 (34), 206 (37), 171 (50), 144 (13), 73 (29), 61 (100). IR ATR ν (cm-1): 3076, 3041, 2362, 1907, 1773, 1604, 1569, 1507, 1446, 1334, 1234, 1223, 1159, 1109, 1098, 1020, 886, 843, 832. HRMS (EI) for C11H6BrClFN (284.9356) [M]+: 284.9332.

Synthesis of 2-bromo-3-(4-methoxyphenyl)quinoline (4i):

116

C.Experimental Section Diisopropylamine (1.1 equiv, 8.8 mmol) in THF (13 mL) was cooled to -78 °C and n-BuLi (1.1 equiv, 8.8 mmol) was added dropwise at -78 °C. The reaction mixture was stirred for 15 minutes at -78 °C, slowly warmed up to -5 °C and then cooled to -90 °C. A solution of 2bromoquinoline (1.0 equiv, 8 mmol) in THF (4 mL) was added dropwise, and the reaction mixture was stirred for 4 h. A Solution of ZnCl2 (1.2 equiv, 9.6 mmol, 1 M in THF) was added at -90 °C and reaction mixture was allowed to warm up to 25 °C. 1-Iodo-4methoxybenzene (1.1 equiv,

8.8 mmol) and Pd(Ph3P)4 (5 mol%) were added. The reaction

mixture was heated to 50 °C over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4, and the crude material was purified by column chromatography (silica gel, 12:1 i-hexane/ethyl acetate) to produce 0.5 g (20%) of the product as a white solid.

m.p.: 91 – 95 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.89 (s, 3 H), 7.01 (m, 2 H), 7.44 (m, 2 H), 7.58 (ddd,

J=8.11, 6.91, 1.19 Hz, 1 H), 7.73 (ddd, J=8.52, 6.97, 1.43 Hz, 1 H), 7.81 (dd, J=8.11, 1.19 Hz, 1 H), 8.03 (s, 1 H), 8.06 - 8.12 (m, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 55.34, 113.64, 127.32, 127.34, 127.52, 128.41, 130.22,

130.94, 131.39, 136.77, 137.80, 143.23, 147.35, 159.67. MS (70 eV, EI) m/z (%): 313 (31), 234 (22), 219 (14), 191 (11), 190 (14). IR ATR ν (cm-1): 3044, 2965, 2914, 2839, 1608, 1584, 1512, 1484, 1390, 1340, 1285, 1238, 1177, 1133, 1078, 1027, 1014, 958, 878, 827, 810, 794, 781, 767, 656. HRMS (EI) for C16H12BrNO (313.0102) [M]+: 313.0091.

Synthesis of 2-bromo-4-(4-chloro-2-fluorophenyl)pyrimidine (4l):

2-Bromopyridine (1.0 equiv, 6 mmol) in THF (6 mL) was reacted with a solution of TMPMgCl⋅LiCl (1.1 equiv, 6.6 mmol, 1.00 M in THF) at -55 °C for 1.5 h. A solution of ZnCl2 (1.2 equiv, 7.2 mmol, 1 M in THF) was added, and the reaction mixture was allowed to warm up to 25 °C. 4-Chloro-2-fluoro-1-iodobenzene (1.3 equiv, 7.8 mmol), Pd(dba)2 (3 mol%) and P(o-furyl)3 (6 mol%) were added, and the reaction mixture was heated to 50 °C 117

over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 5:1 i-hexane/ethyl acetate) to furnish 1.7 g (78%) of the product as a white solid.

m.p.: 125 - 127 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.22 - 7.35 (m, 2 H), 7.83 (dd, J=5.36, 1.55 Hz, 1 H),

8.23 (t, J=8.46 Hz, 1 H), 8.62 (d, J=5.25 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 117.32 (d, J=26.37 Hz, 1 C), 119.33 (d, J=13.46 Hz, 1

C), 125.55, 131.84, 138.74 (d, J=10.94 Hz, 1 C), 153.29, 159.84, 161.19 (d, J=256.93 Hz), 161.63, 161.68. MS (70 eV, EI) m/z (%): 285 (1), 88 (5), 73 (5), 70 (10), 61 (17). IR ATR ν (cm-1): 3112, 3101, 3032, 2360, 1612, 1561, 1527, 1483, 1418, 1402, 1348, 1345, 1340, 1212, 1191, 1172, 1086, 901, 858, 845, 820, 788, 771, 706, 661. HRMS (EI) for C10H5BrClFN2 (285.9309) [M]+: 285.9307.

Synthesis of 2-bromo-4-(4-(trifluoromethyl)phenyl)pyrimidine (4m):

2-Bromopyridine (1.0 equiv, 6 mmol) in THF (6 mL) was reacted with a solution of TMPMgCl⋅LiCl (1.1 equiv, 6.6 mmol, 1.00 M in THF) at -55 °C for 1.5 h. A solution of ZnCl2 (1.2 equiv., 7.2 mmol, 1 M in THF) was added and the reaction mixture was allowed to warm up to 23 °C. 1-Iodo-4-(trifluoromethyl)benzene (1.3 equiv, 7.8 mmol), Pd(dba)2 (3 mol%) and P(o-furyl)3 (6 mol%) were added and the reaction mixture was heated to 50 °C over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 4:1 i-hexane/ethyl acetate) to furnish 1.3 g (70%) of the product as a white solid.

m.p.: 89 – 93 °C.

118

C.Experimental Section NMR (300 MHz, CDCl3) δ/ppm: 7.73 (d, J=5.24 Hz, 1 H), 7.78 (m, J=8.23 Hz, 2 H),

1H

8.20 (m, J=8.04 Hz, 2 H), 8.65 (d, J=5.05 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 115.87, 123.67 (q, J=272.36 Hz, 1 C), 126.07 (q, J=3.93

Hz, 1 C), 127.80, 133.46 (q, J=32.82 Hz, 1 C), 138.27, 153.80, 160.03, 165.32. MS (70 eV, EI) m/z (%): 223 (4), 171 (1), 88 (4), 73 (4), 70 (9). IR ATR ν (cm-1): 3132, 3060, 2362, 2332, 1563, 1430, 1320, 1180, 1171, 1162, 1119, 1077, 1055, 1018, 982, 842, 830, 816, 770, 764, 740, 702. HRMS (EI) for C11H6BrF3N2 (301.9666) [M]+: 303.9646.

Synthesis of 2-chloro-4,6-bis(ethylthio)-1,3,5-triazine (4q):

nBuLi (2.2 equiv, 475 mmol) was added to a solution of EtSH (2.5 equiv, 534 mmol) in THF (200 mL) at -78 °C. The mixture was immediately warmed to 23 °C. The milky-white mixture was transferred via syringe to a solution of cyanuric chloride (1.0 equiv, 216 mmol) in THF (50 mL) at -78 °C. The mixture was immediately warmed to 23 °C and quenched with NH4Cl sat. aq. The mixture was extracted with Et2O, dried with MgSO4, filtered, and concentrated in vacuo to yield the crude substance as an orange oil, which was composed of the title compound mixed with 2,4,6-tris(ethylthio)-1,3,5-triazine. Purification was accomplished using vacuum distillation (bp 97-98 °C, 0.001 mbar) to provide the titled compound as a pale yellow oil that was 18.7 g (37%) pure by GC analysis.

1H

NMR (300 MHz, CDCl3) δ/ppm: 1.35 (td, J=7.26, 2.90 Hz, 6 H), 2.93 - 3.26 (m, J=7.36,

7.36, 7.26, 2.90 Hz, 4 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 14.03, 25.13, 167.95, 182.82.

MS (70 eV, EI) m/z (%): 235 (100), 206 (18), 202 (23), 172 (40), 146 (60), 88 (30). IR ATR ν (cm-1): 2972, 2930, 2873, 1499, 1453, 1412, 1374, 1279, 1233, 1152, 1135, 1056, 966, 838, 787, 750. HRMS (EI) for C7H10ClN3S2 (235.0005) [M]+: 234.9994.

119

Synthesis of 2-bromo-4-((trimethylsilyl)ethynyl)pyridine (4r):

Triethylamine (60 mL) and toluene (30 mL) were added to 2-bromo-4-iodopyridine (1 equiv, 9 mmol). Pd(Ph3P)4 (5 mol%) and CuI (10 mol%) were added and the reaction mixture was cooled to 0 °C. Trimethylsilylacetylene (1 equiv, 9 mmol) was added and the reaction mixture was stirred at room temperature over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 9:1 i-hexane/ethyl acetate) to furnish 1.37 g (60%) of the product as a slightly yellow liquid.

1H

NMR (300 MHz, CDCl3) δ/ppm: 0.26 (s, 9 H), 7.24 (dd, J=5.11, 1.24 Hz, 1 H), 7.51 (s, 1

H), 8.30 (d, J=4.98 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: -0.43, 100.32, 101.96, 124.71, 130.03, 133.74, 142.13,

149.82. MS (70 eV, EI) m/z (%): 252 (5), 240 (63), 239 (10), 144 (5), 131 (4), 80 (9). IR ATR ν (cm-1): 2960, 2900, 2172, 1580, 1570, 1518, 1456, 1365, 1250, 1112, 1077, 983, 873, 835, 759, 710. HRMS (EI) for C10H12BrNSi (252.9922) [M+H]+: 253.9824.

Synthesis of 2-bromo-3-(but-3-en-1-yl)pyridine (4s):

2-Bromo-3-(bromomethyl)pyridine (1.0 equiv, 1 mmol) was dissolved in THF (3 mL) and a solution of allyl magnesium chloride (1.1 equiv, 1.1 mmol, 1.2 M in THF) was added dropwise at -78 °C. The reaction mixture was allowed to warm up to room temperature over night. The reaction mixture was quenched with brine and extracted with EtOAc. The organic phase was dried with Na2SO4 and the crude material was purified by column chromatography (silica gel, 6:1 i-hexane/ethyl acetate) to furnish 81 mg (38%) of the product as a colorless liquid.

120

C.Experimental Section 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.40 (q, J=7.31 Hz, 2 H), 2.81 (t, J=7.75 Hz, 2 H), 4.84

- 5.22 (m, 2 H), 5.73 - 5.96 (m, 1 H), 7.18 (dd, J=7.39, 4.77 Hz, 1 H), 7.48 (dd, J=7.39, 1.43 Hz, 1 H), 8.21 (dd, J=4.53, 1.67 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 33.08, 34.59, 115.86, 122.72, 136.82, 138.18, 138.32,

144.37, 147.63. MS (70 eV, EI) m/z (%): 170 (100), 132 (82), 131 (39), 91 (24), 90 (18). IR ATR ν (cm-1): 3077, 2979, 2930, 2862, 1641, 1578, 1557, 1446, 1401, 1180, 1088, 1064, 1049, 994, 912, 796, 740, 674, 659. HRMS (EI) for C9H10BrN (210.9997) [M]+: 211.0013.

4.2 Preparation of Cross-Coupling Products Using TP2 Synthesis of 4,6-dimethyl-2-phenylpyrimidine (3g):

A solution of 2a in THF (1.0 mmol, 2.0 equiv, 1.7 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 1h (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 5 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 3g as a white powder.

Isolated yield: with FeBr3: 89 % (82 mg). Reaction time: 5 min. Solvent for purification: 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 82.8 – 84.0 ºC. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.54 (s, 6 H), 6.92 (s, 1 H), 7.47 (m, 3 H), 8.43 (d, J=1.9

Hz, 1 H), 8.45 (d, J=4.4 Hz, 1 H). 121

13C

NMR (75 MHz, CDCl3) δ/ppm: 24.11, 117.97, 128.24, 128.42, 130.31, 137.94, 164.06,

166.77. MS (70 eV, EI) m/z (%): 185 (16), 184 (100) [M]+ , 169 (20), 104 (19), 103 (27), 77 (6). IR ATR ν (cm-1): 3068, 2924, 2853, 2361, 1595, 1574, 1550, 1534, 1442, 1434, 1379, 1364, 1342, 1173, 1025, 932, 854, 749, 693, 662.

HRMS (EI) for C12H12N2 (184.1000) [M]+: 184.0995. Synthesis of 2-phenylpyridine (3a):

A solution of 2a in THF (1.0 mmol, 2.0 equiv, 1.7 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 1a (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with NaHCO3 sat. aq. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 3a as a colorless oil.

Isolated yield: with FeBr3: 89 % (69 mg). Reaction time: 15 min. Solvent for purification: 6:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.23 (m, 1 H), 7.45 (m, 3 H), 7.75 (m, 2 H), 8.01 (m, 2

H), 8.70 (d, J=4.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 120.60, 122.10, 126.92, 128.74, 128.99, 136.84, 139.24,

149.53, 157.39. MS (70 eV, EI) m/z (%): 155 (100) [M]+, 154 (60), 128 (10), 127 (10), 77 (9), 59 (10), 43 (7). IR ATR ν (cm-1): 3062, 3036, 3008, 2927, 1586, 1580, 1564, 1468, 1449, 1424, 1293, 1152, 1074, 1020, 988, 800, 737, 692.

HRMS (EI) for C11H9N (155.1735) [M]+: 155.1731.

122

C.Experimental Section Synthesis of 2-(4-methoxyphenyl)-3-(trimethylsilyl)pyridine (5a):

A solution of 32i in THF (1.0 mmol, 2.0 equiv, 1.3 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4a (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5a as a colorless oil.

Isolated yield: with FeBr3: 91 % (117 mg). with CoCl2: 85 % (109 mg). Reaction time: 15 min. Solvent for purification: 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.05 (s, 9 H), 3.84 (s, 3 H), 6.94 (m, J=8.85 Hz, 2 H),

7.20 (dd, J=7.46, 4.70 Hz, 1 H), 7.34 (m, J=8.57 Hz, 2 H), 7.89 (dd, J=7.60, 1.80 Hz, 1 H), 8.59 (dd, J=4.70, 1.94 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 0.25, 55.29, 113.29, 121.02, 130.11, 133.30, 136.29,

143.17, 148.91, 159.62, 165.10. MS (70 eV, EI) m/z (%): 257 (91), 242 (100), 227 (23), 211 (6), 199 (13). IR ATR ν (cm-1): 3045, 2954, 2898, 2836, 1609, 1548, 1515, 1402, 1298, 1245, 1172, 1038, 1025, 832, 809, 787, 753, 731, 688, 656. HRMS (EI) for C15H19NOSi (257.1236) [M]+: 257.1222.

Synthesis of 4-(3-(4-chlorophenyl)pyridin-2-yl)-N,N-dimethylaniline (5b):

123

A solution of 2n in THF (1.0 mmol, 2.0 equiv, 1.2 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4b (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5b as a slightly yellow oil.

Isolated yield: with FeBr3: 82 % (127 mg) with CoCl2: 77 % (119 mg) Reaction time: 15 min. Solvent for purification: 9:1 dichloromethane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.95 (s, 6 H), 6.59 (d, J=8.85 Hz, 2 H), 7.08 - 7.35 (m, 7

H), 7.61 (dd, J=7.74, 1.66 Hz, 1 H), 8.65 (dd, J=4.70, 1.66 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 40.28, 111.63, 120.91, 127.49, 128.56, 130.75, 130.85,

132.97, 133.96, 138.32, 139.32, 148.51, 150.10, 157.19. MS (70 eV, EI) m/z (%): 308 (100), 307 (45), 291 (19), 153 (9), 136 (12). IR ATR ν (cm-1): 3037, 2885, 2855, 2801, 1606, 1576, 1524, 1489, 1425, 1394, 1353, 1193, 1168, 1090, 999, 945, 834, 821, 799, 778, 758, 728, 718, 704. HRMS (EI) for C19H17ClN2 (308.1080) [M]+: 308.1060.

4-(thiophen-2-yl)-2-(4-(trimethylsilyl)phenyl)pyridine (5c):

A solution of 2o in THF (1.0 mmol, 2.0 equiv, 1.2 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4c (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. 124

C.Experimental Section aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5c as a slightly yellow oil.

Isolated yield: with FeBr3: 65 % (101 mg). with CoCl2: 70 % (108 mg). Reaction time: 15 min. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.33 (s, 9 H), 7.17 (dd, J=5.13, 3.70 Hz, 1 H), 7.44 (d,

J=5.25 Hz, 2 H), 7.54 - 7.60 (m, 1 H), 7.67 (m, J=8.11 Hz, 2 H), 7.92 (s, 1 H), 8.02 (m, J=8.11 Hz, 2 H), 8.68 (d, J=5.01 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: -1.12, 117.00, 118.52, 125.31, 126.19, 127.10, 128.43,

133.79, 139.57, 141.53, 141.67, 142.16, 150.26, 158.32. MS (70 eV, EI) m/z (%): 309 (20), 296 (9), 295 (27), 294 (100). IR ATR ν (cm-1): 3073, 3021, 2953, 2895, 1593, 1554, 1467, 1405, 1246, 1107, 989, 837, 815, 799, 785, 759, 754, 720, 699, 679. HRMS (EI) for C18H19NSSi (309.1007) [M]+: 309.0977.

Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)phenyl)-4-(4-fluorophenyl)pyridine (5d): F

N

OTBS

A solution of 2p in THF (1.0 mmol, 2.0 equiv, 1.05 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4d (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of 125

Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5d as a slightly yellow oil.

Isolated yield: with FeBr3: 71 % (131 mg). with CoCl2: 79 % (145 mg). Reaction time: 15 min. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.26 (s, 6 H), 1.03 (s, 9 H), 6.93 (dd, J=7.99, 1.79 Hz, 1

H), 7.21 (t, J=8.58 Hz, 2 H), 7.31 - 7.44 (m, 2 H), 7.54 (d, J=2.15 Hz, 1 H), 7.58 - 7.74 (m, 3 H), 7.84 (s, 1 H), 8.73 (d, J=5.25 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: -4.32, 18.23, 25.73, 116.15 (d, J=21.60 Hz, 1 C),

118.63, 118.88, 120.08, 120.69, 128.85 (d, J=8.41 Hz, 1 C), 129.70, 134.63, 134.68, 140.94, 148.18, 150.11, 156.15, 157.99, 163.42 (d, J=249.08 Hz, 1 C). MS (70 eV, EI) m/z (%): 322 (100), 281 (41), 209 (13), 207 (83), 97 (12). IR ATR ν (cm-1): 3064, 2955, 2930, 2895, 2858, 1597, 1581, 1512, 1464, 1444, 1270, 1253, 1233, 1204, 1160, 948, 825, 779, 724, 693, 666. HRMS (EI) for C23H26FNOSi (379.1768) [M]+: 379.1756.

Synthesis of 4-(3-bromophenyl)-5-chloro-2-mesitylpyridine (5e):

A solution of 2q in THF (1.0 mmol, 2.0 equiv, 1.1 M) was added dropwise to a suspension of CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4e (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 5 h before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was

126

C.Experimental Section dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5e as a slightly yellow oil.

Isolated yield: with CoCl2: 82 % (159 mg). Reaction time: 5 h. Solvent for purification: 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.04 - 2.13 (m, 6 H), 2.34 (s, 3 H), 6.95 (s, 2 H), 7.21 -

7.24 (m, 1 H), 7.33 - 7.41 (m, 1 H), 7.44 - 7.51 (m, 1 H), 7.55 - 7.65 (m, 1 H), 7.65 - 7.73 (m, 1 H), 8.76 - 8.81 (m, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 20.33, 21.18, 122.53, 126.20, 127.80, 128.01, 128.54,

130.06, 132.01, 135.59, 135.69, 136.29, 137.98, 138.58, 146.11, 150.09, 158.85. MS (70 eV, EI) m/z (%): 386 (100), 384 (74), 255 (5), 230 (24), 127 (8). IR ATR ν (cm-1): 2966, 2918, 2858, 1612, 1577, 1563, 1525, 1478, 1455, 1355, 1106, 1093, 1073, 1025, 996, 907, 881, 851, 840, 786, 732, 697, 679, 658. HRMS (EI) for C20H17BrClN (385.0233) [M]+:384.0152.

Synthesis of 5-(6-methoxypyridin-2-yl)-1-methyl-1H-indole (5f):

A solution of 2r in THF (1.0 mmol, 2.0 equiv, 0.9 M) was added dropwise to a suspension of CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4f (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 25 °C. The suspension was stirred at 23 °C for 1 h before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5f as a slightly yellow solid.

Isolated yield: with CoCl2: 65 % (77 mg). Reaction time: 1 h. Solvent for purification: 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 127

m.p.: 99 – 108 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.83 (s, 3 H), 4.10 (s, 3 H), 6.59 (dd, J=3.04, 0.83 Hz, 1

H), 6.65 (dd, J=8.16, 0.69 Hz, 1 H), 7.09 (d, J=3.04 Hz, 1 H), 7.37 - 7.43 (m, 2 H), 7.63 (dd, J=8.02, 7.46 Hz, 1 H), 7.99 (dd, J=8.57, 1.66 Hz, 1 H), 8.37 (dd, J=1.66, 0.55 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 32.93, 53.17, 101.85, 107.76, 109.18, 112.39, 119.54,

120.79, 128.77, 129.51, 130.75, 137.32, 139.04, 156.15, 163.63. MS (70 eV, EI) m/z (%): 238 (64), 237 (48), 209 (12), 207 (13), 104 (5). IR ATR ν (cm-1): 3001, 2944, 1591, 1580, 1566, 1463, 1446, 1428, 1419, 1410, 1335, 1321, 1278, 1243, 1178, 1150, 1081, 1061, 1020, 986, 940, 893, 859, 788, 767, 735, 726, 662. HRMS (EI) for C15H14N2O (238.1106) [M]+:238.1097.

Synthesis of 2-(4-fluorophenyl)-3-(2-methoxyphenyl)pyridine (5g):

A solution of 2g in THF (1.0 mmol, 2.0 equiv, 1.05 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4g (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5g as a slightly yellow oil.

Isolated yield: with FeBr3: 77 % (108 mg). with CoCl2: 79 % (110 mg). Reaction time: 15 min. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine.

128

C.Experimental Section 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.42 (s, 3 H), 6.78 (d, J=8.22 Hz, 1 H), 6.84 - 7.05 (m, 3

H), 7.16 (dd, J=7.40, 1.53 Hz, 1 H), 7.23 - 7.41 (m, 4 H), 7.69 (dd, J=7.63, 1.53 Hz, 1 H), 8.67 (dd, J=4.75, 1.47 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 54.96, 111.05, 114.42 (d, J=21.35 Hz, 1 C), 120.84,

121.87, 128.75, 129.36, 130.54 (d, J=8.26 Hz, 1 C), 131.14, 132.73, 137.06, 139.10, 148.21, 155.98, 157.02, 162.36 (d, J=246.54 Hz, 1 C). MS (70 eV, EI) m/z (%): 279 (15), 278 (15), 264 (4), 248 (9), 235 (4). IR ATR ν (cm-1): 3050, 2958, 2936, 2836, 1895, 1599, 1580, 1510, 1495, 1462, 1436, 1420, 1273, 1220, 1181, 1157, 1124, 1107, 1094, 1050, 1025, 1015, 999, 839, 824, 811, 802, 780, 751, 718, 678. HRMS (EI) for C18H14FNO (279.1059) [M]+: 278.0958.

Synthesis of 4-(5-chloro-4-(4-fluorophenyl)pyridin-2-yl)phenyl pivalate (5h):

A solution of 2l in THF (1.0 mmol, 2.0 equiv, 0.8 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4h (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 25 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5h as a white thick oil.

Isolated yield: with FeBr3: 65 % (125 mg). Reaction time: 15 min. Solvent for purification: 15:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.39 (s, 9 H), 7.12 - 7.25 (m, 4 H), 7.48 - 7.56 (m, 2 H),

7.64 - 7.69 (m, 1 H), 8.02 (d, J=8.57 Hz, 2 H), 8.72 (s, 1 H). 129

13C

NMR (75 MHz, CDCl3) δ/ppm: 27.13, 39.15, 115.60 (d, J=21.64 Hz, 1 C), 121.93,

127.45, 127.91, 128.03, 128.71, 130.86 (d, J=8.26 Hz, 1 C), 132.74, 132.79, 135.47, 147.19, 149.83, 152.19, 155.15, 163.07 (d, J=249.10 Hz, 1 C), 176.88. MS (70 eV, EI) m/z (%): 383 (14), 300 (18), 299 (100), 264 (11), 85 (14). IR ATR ν (cm-1): 2975, 2874, 1747, 1606, 1507, 1480, 1460, 1366, 1276, 1231, 1200, 1163, 1102, 1022, 1014, 908, 895, 856, 836, 816, 800, 788, 757, 729. HRMS (EI) for C22H19ClFNO2 (383.1088) [M]+: 383.1083.

Synthesis of 2,3-bis(4-methoxyphenyl)quinoline (5i): OMe

N OMe

A solution of 2i in THF (1.0 mmol, 2.0 equiv, 1.3 M) was added dropwise to a suspension of CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4i (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5i as a slightly yellow oil.

Isolated yield: with CoCl2: 78 % (133 mg). Reaction time: 15 min. Solvent for purification: 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.81 (s, 3 H), 3.82 (s, 3 H), 6.77 - 6.90 (m, 5H), 7.16 -

7.19 (m, 2 H), 7.42 - 7.44 (m, 2 H), 7.54 (ddd, J=8.04, 6.97, 1.17 Hz, 1 H), 7.70 - 7.75 (m, 1 H), 7.84 (dd, J=8.19, 1.17 Hz, 1 H), 8.14 (s, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 59.35, 59.42, 117.57, 117.90, 130.74, 131.28, 131.42,

132.80, 133.76, 134.89, 135.63, 136.24, 137.00, 138.23, 141.91, 147.53, 159.32, 163.00, 163.84. MS (70 eV, EI) m/z (%): 340 (100), 326 (11), 297 (14), 254 (12), 163 (5). 130

C.Experimental Section IR ATR ν (cm-1): 2999, 2955, 2945, 2917, 2835, 1607, 1511, 1483, 1463, 1455, 1422, 1402, 1370, 1289, 1242, 1173, 1144, 1109, 1027, 965, 829, 809, 792, 782, 757, 746, 731, 714, 666. HRMS (EI) for C23H19NO2 (340.1338) [M-H]+:340.1336.

Synthesis of 2-(4-fluorophenyl)-6,7-dimethoxy-4-methylquinoline (5j):

A solution of 2g in THF (1.0 mmol, 2.0 equiv, 1.05 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4j (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5j as a slightly yellow solid.

Isolated yield: with FeBr3: 82 % (122 mg). with CoCl2: 67 % (100 mg). Reaction time: 15 min. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 164 – 168 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.70 (s, 3 H), 4.05 (s, 3 H), 4.06 (s, 3 H), 7.12 - 7.23 (m,

3 H), 7.54 (d, J=2.76 Hz, 2 H), 8.09 (dd, J=8.98, 5.39 Hz, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 19.26, 56.02, 56.17, 101.46, 108.56, 115.64 (d, J=21.64

Hz, 1 C), 117.99, 122.38, 129.06 (d, J=8.54 Hz, 1 C), 135.88, 143.36, 144.79, 149.46, 152.36, 153.96, 163.48 (d, J=247.96 Hz, 1 C). MS (70 eV, EI) m/z (%): 297 (100), 282 (14), 254 (24), 252 (6), 211 (10). IR ATR ν (cm-1): 2923, 2854, 2833, 1623, 1597, 1503, 1489, 1465, 1433, 1422, 1399, 1353, 1260, 1246, 1208, 1189, 1166, 1150, 1096, 1065, 1034, 1014, 1000, 994, 910, 862, 850, 836, 808, 771, 726, 668. 131

HRMS (EI) for C18H16FNO2 (297.1165) [M]+:297.1165.

Synthesis of 3-(4,6-dimethylpyrimidin-2-yl)-N,N-dimethylaniline (5k):

A solution of 2s in THF (1.0 mmol, 2.0 equiv, 1.15 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 1h (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 30 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5k as a brownish solid.

Isolated yield: with FeBr3: 78 % (89 mg). with CoCl2: 63 % (72 mg). Reaction time: 30 min. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 105 – 108 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.54 (s, 6 H), 3.05 (s, 6 H), 6.92 (s, 2 H), 7.35 (t, J=7.88

Hz, 1 H), 7.77 - 7.92 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 24.18, 40.91, 112.49, 114.95, 117.16, 117.79, 129.13,

138.86, 150.82, 164.71, 166.57. MS (70 eV, EI) m/z (%): 227 (100), 212 (53), 184 (18), 114 (7), 43 (55). IR ATR ν (cm-1): 2986, 2918, 2887, 2800, 1600, 1586, 1570, 1539, 1494, 1486, 1436, 1414, 1396, 1362, 1345, 1319, 1233, 1177, 1064, 996, 955, 864, 775, 766, 697. HRMS (EI) for C14H17N3 (227.1422) [M]+:227.1417.

132

C.Experimental Section Synthesis of 4,6-bis(3-((tert-butyldimethylsilyl)oxy)phenyl)pyrimidine (5l):

A solution of 2p in THF (2.0 mmol, 4.0 equiv, 1.1 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4k (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5l as a red liquid.

Isolated yield: with FeBr3: 95 % (234 mg). Reaction time: 15 min, using 4 equiv of Grignard reagent. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine. MS (70 eV, EI) m/z (%): 492 (11), 436 (36), 435 (100), 393 (19), 379 (9), 189 (23). 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.27 (s, 12 H), 1.03 (s, 18 H), 7.01 (dd, J=7.87, 1.83 Hz,

2 H), 7.40 (t, J=7.97 Hz, 2 H), 7.65 (d, J=1.83 Hz, 2 H), 7.72 (d, J=7.87 Hz, 2 H), 8.02 (s, 1 H), 9.32 (s, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: -4.32, 18.24, 25.72, 112.98, 118.89, 120.17, 122.56,

129.99, 138.58, 156.37, 159.14, 164.47. IR ATR ν (cm-1): 2955, 2943, 2886, 2858, 1572, 1521, 1491, 1471, 1461, 1277, 1252, 1229, 1199, 1001, 968, 939, 870, 833, 777, 734, 708, 687, 666. HRMS (EI) for C28H40N2O2Si2 (492.2628) [M]+:492.2615.

133

Synthesis

of

4-(4-chloro-2-fluorophenyl)-2-(4-(dimethoxymethyl)phenyl)pyrimidine

(5m):

A solution of 2t in THF (1.0 mmol, 2.0 equiv, 0.9 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4l (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5m as a white solid.

Isolated yield: with CoCl2: 68 % (122 mg). Reaction time: 15 min. Purification: purified by HPLC with a column Chromolith SemiPrep RP-18e, 100-10 nm; 15 % H2O/85 % CH3CN; flow rate 8 ml/min. m.p.: 89 – 91 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.36 (s, 6 H), 5.49 (s, 1 H), 7.18 - 7.30 (m, 1 H), 7.34

(dddd, J=8.48, 6.38, 2.00, 0.68 Hz, 1 H), 7.60 (d, J=8.19 Hz, 1 H), 7.66 - 7.81 (m, 1 H), 7.95 8.09 (m, 1 H), 8.36 (td, J=8.38, 2.53 Hz, 1 H), 8.48 - 8.59 (m, 1 H), 8.65 - 8.76 (m, 1 H), 8.87 (dd, J=17.45, 5.36 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 52.61, 102.69, 117.24 (d, J=21.77 Hz, 1C), 125.39,

127.02, 128.11, 128.76, 129.88, 137.75, 140.72, 142.91, 158.15, 159.27, 161.31 (d, J=255.47 Hz, 1C), 163.38, 164.26. MS (70 eV, EI) m/z (%): 358 (1), 327 (100), 311 (18), 283 (8), 154 (1), 130(5).

134

C.Experimental Section IR ATR ν (cm-1): 2980, 2959, 2932, 2830, 1607, 1584, 1576, 1558, 1548, 1484, 1432, 1407, 1380, 1348, 1286, 1207, 1189, 1099, 1078, 1050, 1018, 982, 900, 851, 822, 810, 786, 738, 722, 712, 665. HRMS (EI) for C19H16ClFN2O2 (358.0884) [M]+:358.0872.

Synthesis of 2-(4-chloro-2-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)pyrimidine (5n):

A solution of 2u in THF (1.0 mmol, 2.0 equiv, 1.0 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4m (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5n as a white solid.

Isolated yield: with FeBr3: 61 % (108 mg). with CoCl2: 60 % (106 mg). Reaction time: 15 min. Solvent for purification: 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 120 – 122 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.24 - 7.32 (m, 2 H), 7.67 (d, J=5.28 Hz, 1 H), 7.79 (m,

J=8.14 Hz, 2 H), 8.20 (t, J=8.36 Hz, 1 H), 8.30 (m, J=8.14 Hz, 2 H), 8.94 (d, J=5.28 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 114.93, 117.71 (d, J=26.19 Hz), 123.86 (q, J=272.44),

124.64 (d, J=3.99 Hz), 124.92 (d, J=8.83 Hz), 125.96 (q, J=3.70 Hz), 127.60, 132.71, 132.75, 132.81 (q, J=32.74 Hz), 137.12 (d, J= 10.25 Hz,), 139.83 (q, J=1.14 Hz), 158.28, 161.33 (d, J=260.48 Hz), 162.60, 162.75, 162.82. 135

MS (70 eV, EI) m/z (%): 354 (31), 352 (100), 197 (34), 170 (36), 157 (10). IR ATR ν (cm-1): 1607, 1576, 1558, 1550, 1488, 1414, 1374, 1323, 1308, 1285, 1278, 1218, 1191, 1172, 1142, 1106, 1087, 1065, 1038, 1014, 902, 854, 838, 820, 792, 768, 718, 711. HRMS (EI) for C17H9ClF4N2 (352.0390) [M]+:352.0383.

Synthesis of 2-(4-methoxyphenyl)-4,6-diphenyl-1,3,5-triazine (5o): Ph N Ph

N N OMe

A solution of 2i in THF (1.0 mmol, 2.0 equiv, 1.3 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4n (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5o as a white solid.

Isolated yield: with FeBr3: 81 % (137 mg). with CoCl2: 79 % (134 mg). Reaction time: 15 min. Solvent for purification: 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 144 – 146 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.94 (s, 3 H), 7.08 (d, J=8.79 Hz, 2 H), 7.39 - 7.81 (m, 6

H), 8.62 - 9.07 (m, 6 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 55.45, 113.94, 128.55, 128.77, 128.87, 130.85, 132.31,

136.40, 163.31, 171.18, 171.38. MS (70 eV, EI) m/z (%): 339 (63), 214 (44), 199 (35), 171 (12), 133 (41), 103 (24). IR ATR ν (cm-1): 3312, 3038, 3015, 2958, 2840, 2362, 2331, 1605, 1499, 1438, 1274, 1249, 1183, 1040, 1012, 823, 809, 781, 770, 690. HRMS (EI) for C22H17N3O (339.1372) [M]+:339.1366. 136

C.Experimental Section 2-phenyl-4,6-di(pyrrolidin-1-yl)-1,3,5-triazine (5p):

A solution of 2a in THF (1.0 mmol, 2.0 equiv, 1.7 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4o (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 50 °C for 12 h before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5p as a white solid.

Isolated yield: with FeBr3: 76 % (112 mg). Reaction time: 12 h at 50 °C. Solvent for purification: 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 137 – 139 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.96 (ddd, J=6.28, 3.48, 3.26 Hz, 8 H), 3.61 (br. s., 4

H), 3.72 (br. s., 4 H), 7.35 - 7.52 (m, 3 H), 8.38 - 8.50 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 25.35, 45.98, 127.97, 128.21, 130.69, 138.07, 163.62,

169.50. MS (70 eV, EI) m/z (%): 295 (88), 267 (100), 253 (25), 239 (19), 226 (39), 197 (13). IR ATR ν (cm-1): 2969, 2871, 2361, 1557, 1540, 1507, 1491, 1471, 1454, 1383, 1338, 1293, 1279, 1238, 1221, 1180, 1167, 1154, 1008, 863, 815, 795, 780, 702. HRMS (EI) for C17H21N5 (295.1797) [M]+:295.1792.

Synthesis of 2,4-diethoxy-6-(thiophen-2-yl)-1,3,5-triazine (5q):

137

A solution of 2v in THF (1.0 mmol, 2.0 equiv, 0.8 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4p (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 12 h before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5q as a yellow solid.

Isolated yield: with FeBr3: 84 % (105 mg). with CoCl2: 79 % (99 mg). Reaction time: 12 h. Solvent for purification: 10:1 i-hexane/ethyl acetate + 0.5 % triethylamine. m.p.: 79 – 81 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.33 - 1.55 (m, 6 H), 4.52 (q, J=7.08 Hz, 4 H), 7.14 (dd,

J=4.97, 3.80 Hz, 1 H), 7.56 (dd, J=4.97, 1.27 Hz, 1 H), 8.14 (dd, J=3.80, 1.27 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 14.29, 64.22, 128.27, 131.71, 132.29, 140.81, 170.59,

172.03. MS (70 eV, EI) m/z (%): 251 (6), 207 (6), 110 (10), 71 (35), 61 (14). IR ATR ν (cm-1): 3102, 2983, 2927, 1531, 1490, 1466, 1439, 1416, 1378, 1346, 1324, 1290, 1233, 1218, 1121, 1100, 1078, 1044, 1034, 1008, 866, 841, 811, 754, 714, 692, 671. HRMS (EI) for C11H13N3O2S (251.0728) [M]+:251.0725.

Synthesis of 2-(4-(dimethoxymethyl)phenyl)-4,6-bis(ethylthio)-1,3,5-triazine (5r):

A solution of 2t in THF (1.0 mmol, 2.0 equiv, 0.9 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4q (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C 138

C.Experimental Section for 15 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5r as a colorless oil.

Isolated yield: with FeBr3: 61 % (107 mg). Reaction time: 15 min. Solvent for purification: 6:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.45 (t, J=7.46 Hz, 6 H), 3.22 (q, J=7.46 Hz, 4 H), 3.34

(s, 6 H), 5.47 (s, 1 H), 7.56 (d, J=8.29 Hz, 2 H), 8.45 (d, J=8.57 Hz, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 14.39, 24.85, 52.63, 102.51, 126.95, 128.88, 135.21,

142.59, 167.94, 181.30. MS (70 eV, EI) m/z (%): 351 (43), 320 (53), 230 (6), 146 (11), 75 (11). IR ATR ν (cm-1): 2962, 2947, 2829, 1483, 1410, 1377, 1348, 1309, 1284, 1235, 1205, 1098, 1051, 1018, 984, 971, 912, 898, 847, 832, 796, 751, 733, 690. HRMS (EI) for C16H21N3O2S2 (351.1075) [M]+:351.1061.

Synthesis of 2-(benzo[b]thiophen-3-yl)-3-(trimethylsilyl)pyridine (5s):

A solution of 2w in THF (1.0 mmol, 2.0 equiv, 0.8 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4a (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 24 h before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5s as a yellow oil. 139

Isolated yield: with FeBr3: 64 % (90 mg). with CoCl2: 66 % (93 mg). Reaction time: 24 h. Solvent for purification: 9:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.00 (s, 9 H), 7.28 - 7.42 (m, 4 H), 7.49 - 7.55 (m, 1 H),

7.87 - 7.93 (m, 1 H), 7.99 (dt, J=7.74, 1.52 Hz, 1 H), 8.72 (dt, J=3.04, 1.52 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: -0.15, 121.89, 122.43, 123.43, 124.42, 124.55, 125.39,

135.44, 138.94, 139.48, 139.68, 143.21, 149.46, 159.75. MS (70 eV, EI) m/z (%): 283 (36), 268 (100), 250 (10), 227 (21), 126 (14). IR ATR ν (cm-1): 3051, 3028, 2952, 2896, 1564, 1550, 1458, 1431, 1399, 1338, 1262, 1248, 1221, 1041, 953, 833, 797, 782, 752, 731, 712, 696. HRMS (EI) for C16H17NSSi (283.0851) [M]+:283.0840.

Synthesis of 2-(benzo[b]thiophen-2-yl)-3-(trimethylsilyl)pyridine (5t):

A solution of 2x in THF (1.0 mmol, 2.0 equiv, 0.8 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4a (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 50 °C for 12 h (for FeBr3) or at 23 °C for 12 h (for CoCl2) before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5t as a yellow oil.

Isolated yield: with FeBr3: 61 % (86 mg). with CoCl2: 66 % (93 mg). Reaction time: for FeBr3: 12 h at 50 °C. for CoCl2: 12 h at 25 °C. Solvent for purification: 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 140

C.Experimental Section 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.23 (s, 9 H), 7.25 - 7.30 (m, 1 H), 7.35 - 7.41 (m, 2 H),

7.42 (s, 1 H), 7.78 - 7.84 (m, 1 H), 7.86 - 7.91 (m, 1 H), 7.96 (dd, J=9.40, 1.11 Hz, 1 H), 8.66 (dd, J=3.04, 1.11 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 0.28, 122.01, 122.29, 123.88, 124.20, 124.37, 124.71,

134.24, 139.61, 140.62, 143.54, 145.80, 149.23, 158.26. MS (70 eV, EI) m/z (%): 283 (32), 270 (10), 268 (100), 252 (8), 238 (19), 127 (7). IR ATR ν (cm-1): 3052, 3027, 2953, 2896, 1561, 1548, 1458, 1391, 1248, 1166, 1156, 1129, 1041, 958, 835, 829, 798, 783, 743, 725, 709, 685. HRMS (EI) for C16H17NSSi (283.0851) [M]+:283.0837.

Synthesis of 2-(4-methoxyphenyl)-4-((trimethylsilyl)ethynyl)pyridine (5u):

A solution of 2i in THF (1.0 mmol, 2.0 equiv, 1.3 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4r (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 30 min before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5u as a slightly yellow oil.

Isolated yield: with FeBr3: 38 % (53 mg). with CoCl2: 62 % (87 mg). Reaction time: 30 min. Solvent for purification: 8:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.29 (s, 9 H), 3.86 (s, 3 H), 6.98 (dd, J=8.82, 1.19 Hz, 2

H), 7.18 (dt, J=5.01, 1.43 Hz, 1 H), 7.70 (d, J=0.72 Hz, 1 H), 7.95 (dd, J=8.58, 1.19 Hz, 2 H), 8.58 (d, J=5.01 Hz, 1 H). 141

13C

NMR (75 MHz, CDCl3) δ/ppm: -0.26, 55.34, 99.26, 102.51, 114.12, 122.00, 123.33,

128.17, 131.31, 131.72, 149.43, 157.15, 160.68. MS (70 eV, EI) m/z (%): 281 (68), 266 (100), 251 (6), 223 (8), 133 (12). IR ATR ν (cm-1): 2958, 2900, 2837, 2160, 1609, 1592, 1578, 1535, 1514, 1466, 1422, 1385, 1274, 1247, 1219, 1196, 1174, 1112, 1031, 890, 839, 826, 800, 758, 728, 700. HRMS (EI) for C17H19NOSi (281.1236) [M]+:281.1220.

Synthesis of 3-(but-3-en-1-yl)-2-phenylpyridine (5v):

A solution of 2a in THF (1.0 mmol, 2.0 equiv, 1.7 M) was added dropwise to a suspension of FeBr3 (4.4 mg, 0.015 mmol, 0.03 equiv) or CoCl2 (1.9 mg, 0.015 mmol, 0.03 equiv), isoquinoline (6.5 mg, 0.05 mmol, 0.10 equiv), and 4s (0.5 mmol, 1.0 equiv) in tBuOMe (2.5 mL) at 23 °C. The suspension was stirred at 23 °C for 1 h before being quenched with sat. aq. NaHCO3. The mixture was diluted with CH2Cl2 and an EDTA (1.0 M, H2O) solution was added. The mixture was stirred at 23 °C for 15 min, before being filtered through a pad of Celite®. After washing the pad of Celite® with CH2Cl2, sat. aq. NaCl was added, and the mixture was extracted with CH2Cl2. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5v as a colorless oil.

Isolated yield: with FeBr3: 62 % (65 mg). with CoCl2: 78 % (81 mg). Reaction time: 1 h. Solvent for purification: 4:1 i-hexane/ethyl acetate + 0.5 % triethylamine. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.18 - 2.34 (m, 2 H), 2.71 - 2.83 (m, 2 H), 4.81 - 5.02

(m, 2 H), 5.63 - 5.79 (m, 1 H), 7.21 - 7.28 (m, 1 H), 7.36 - 7.52 (m, 5 H), 7.61 (dd, J=7.88, 1.80 Hz, 1 H), 8.53 (dd, J=4.70, 1.66 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 31.81, 34.57, 115.34, 122.13, 127.84, 128.17, 128.78,

129.09, 134.60, 137.30, 140.62, 146.97, 158.97. MS (70 eV, EI) m/z (%): 209 (42), 208 (51), 180 (15), 168 (25). 167 (100),

142

C.Experimental Section IR ATR ν (cm-1): 3060, 3027, 2977, 2925, 2860, 1640, 1579, 1564, 1495, 1453, 1433, 1421, 1019, 995, 912, 791, 749, 732, 699. HRMS (EI) for C15H15N (209.1204) [M]+:208.1126.

5. Efficient Chromium(II)-Catalyzed Cross-Coupling Reactions between Csp2 Centers

5.1 Preparation of Cross-Coupling Products Using TP3

Synthesis of 2-phenylpyridine (3a):

A solution of 2a in THF (1.2 mmol, 1.2 equiv, 1.7 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 1a (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 3a as a colorless oil.

Isolated yield: 90 % (140 mg) Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 6:1 (+0.5 % NEt3). 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.23 (m, 1 H), 7.45 (m, 3 H), 7.75 (m, 2 H), 8.01 (m, 2

H), 8.70 (d, J=4.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 120.6, 122.1, 126.9, 128.7, 128.9, 136.8, 139.2, 149.5,

157.4. MS (70 eV, EI) m/z (%): 155 (100) [M]+, 154 (60), 128 (10), 127 (10), 77 (9), 59 (10), 43 (7). IR ATR ν (cm-1): 3062, 3036, 3008, 2927, 1586, 1580, 1564, 1468, 1449, 1424, 1293, 1152, 1074, 1020, 988, 800, 737, 692.

HRMS (EI) for C11H9N (155.1735) [M]+: 155.1731. 143

Synthesis of 3-(but-3-en-1-yl)-2-phenylpyridine (5v):

A solution of 2a in THF (1.2 mmol, 1.2 equiv, 1.7 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 4s (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 5v as a colorless oil.

Isolated yield: 95 % (199 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 6:1 (+0.5 % NEt3). 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.18 - 2.32 (m, 2 H), 2.68 - 2.84 (m, 2 H), 4.86 - 5.00

(m, 2 H), 5.63 - 5.80 (m, 1 H), 7.21 (dd, J=7.76, 4.77 Hz, 1 H), 7.32 - 7.54 (m, 5 H), 7.57 7.64 (m, 1 H), 8.53 (dd, J=4.86, 1.31 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 31.8, 34.6, 115.4, 122.1, 127.9, 128.2, 128.8, 134.6,

137.3, 140.6, 147.0, 159.0. MS (70 eV, EI) m/z (%): 209 (42), 208 (51), 180 (15), 168 (25). 167 (100). IR ATR ν (cm-1): 3060, 3027, 2977, 2925, 2860, 1640, 1579, 1564, 1495, 1453, 1433, 1421, 1019, 995, 912, 791, 749, 732, 699. HRMS (EI) for C15H15N (209.1204) [M]+:209.1191.

Synthesis of 4-(3-(4-chlorophenyl)pyridin-2-yl)-N,N-dimethylaniline (5b):

A solution of 2n in THF (1.2 mmol, 1.2 equiv, 1.2 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 4b (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 90 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and 144

C.Experimental Section concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8b as a slightly yellow oil.

Isolated yield: 80 % (247 mg). Reaction time: 90 min. Solvent for purification: dichloromethane/ethyl acetate 9:1 (+0.5 % NEt3). 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.95 (s, 6 H), 6.59 (d, J=8.85 Hz, 2 H), 7.08 - 7.35 (m, 7

H), 7.61 (dd, J=7.74, 1.66 Hz, 1 H), 8.65 (dd, J=4.70, 1.66 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 40.3, 111.6, 120.9, 127.5, 128.6, 130.8, 130.9, 132.9,

133.9, 138.3, 139.3, 148.5, 150.1, 157.2. MS (70 eV, EI) m/z (%): 308 (100), 307 (45), 291 (19), 153 (9), 136 (12). IR ATR ν (cm-1): 3037, 2885, 2855, 2801, 1606, 1576, 1524, 1489, 1425, 1394, 1353, 1193, 1168, 1090, 999, 945, 834, 821, 799, 778, 758, 728, 718, 704. HRMS (EI) for C19H17ClN2 (308.1080) [M]+: 308.1060.

Synthesis of 3-chloro-2-(4-(trifluoromethyl)phenyl)pyridine (8a):

A solution of 2y in THF (1.2 mmol, 1.2 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 4t (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8a as a white solid.

Isolated yield: 76 % (195 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 8:1 (+0.5 % NEt3). m.p.: 53.0-54.0 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.27 (dd, J=8.02, 4.70 Hz, 1 H), 7.69 - 7.78 (m, 2 H),

7.79 - 7.92 (m, 3 H), 8.62 (dd, J=4.70, 1.66 Hz, 1 H).

145

13C

NMR (75 MHz, CDCl3) δ/ppm: 123.7, 124.0 (q, J=272.1 Hz), 125.0 (q, J=3.9 Hz),

129.8, 130.3, 130.8 (q, J=32.5 Hz), 138.3, 141.6, 147.8, 155.1. MS (70 eV, EI) m/z (%): 257 (46), 237 (28), 222 (98), 81 (13), 71 (16), 43 (100). IR ATR ν (cm-1): 3052, 1616, 1564, 1436, 1428, 1402, 1324, 1164, 1132, 1108, 1090, 1066, 1040, 1026, 1012, 848, 792, 768, 758, 736, 690. HRMS (EI) for C12H7ClF3N (257.0219) [M]+: 257.0219.

Synthesis of 4-(5-fluoropyridin-2-yl)phenyl pivalate (8b):

A solution of 2l in THF (1.2 mmol, 1.2 equiv, 0.8 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 4u (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8b as a white solid.

Isolated yield: 66 % (180 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 6:1 (+0.5 % NEt3). m.p.: 76.6-76.8 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 1.38 (s, 9 H), 7.16 (m, 2 H), 7.46 (td, J=8.43, 3.32 Hz, 1

H), 7.69 (dd, J=8.85, 4.42 Hz, 1 H), 7.95 (m, 2 H), 8.53 (d, J=2.76 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 27.1, 39.1, 121.1, 121.2, 121.8, 123.5, 123.7, 127.8,

135.8, 137.5, 137.8, 151.8, 152.9, 152.9, 157.1, 160.5, 176.9. MS (70 eV, EI) m/z (%): 273 (9), 190 (11), 189 (100), 160 (4), 159 (3). IR ATR ν (cm-1): 2982, 2966, 2932, 2908, 2890, 1750, 1742, 1600, 1470, 1416, 1396, 1382, 1368, 1276, 1264, 1224, 1198, 1166, 1112, 1026, 1010, 974, 960, 942, 924, 898, 834, 826, 810, 796, 750. HRMS (EI) for C16H16FNO2 (273.1165) [M]+: 273.1154.

146

C.Experimental Section Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)-6,7-dimethoxy-4-methylquinoline (8c):

A solution of 2k in THF (1.2 mmol, 1.2 equiv, 1.1 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 4j (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 1 h before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8c as a yellow solid.

Isolated yield: 74 % (239 mg). Reaction time: 1 h. Solvent for purification: i-hexane/ethyl acetate 3:1 (+0.5 % NEt3). m.p.: 195-221 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 2.67 (s, 3 H), 4.04 (d, J=5.53 Hz, 6 H), 6.02 (s, 2 H),

6.92 (d, J=8.29 Hz, 1 H), 7.13 (s, 1 H), 7.50 (d, J=5.81 Hz, 2 H), 7.59 (dd, J=8.16, 1.80 Hz, 1 H), 7.65 (d, J=1.94 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 19.2, 56.0, 56.1, 101.2, 101.5, 107.7, 108.4, 108.6,

117.9, 121.3, 122.2, 134.3, 143.0, 144.8, 148.2, 148.4, 149.3, 152.2, 154.5. MS (70 eV, EI) m/z (%): 323 (100), 308 (18), 280 (15), 278 (6), 161 (9). IR ATR ν (cm-1): 2922, 2898, 2834, 1618, 1604, 1592, 1494, 1486, 1476, 1466, 1450, 1432, 1416, 1382, 1352, 1336, 1240, 1222, 1206, 1166, 1138, 1114, 1066, 1048, 1028, 998, 926, 876, 862, 852, 834, 808. HRMS (EI) for C19H17NO4 (323.1158) [M]+: 323.1149.

Synthesis of N,N-dimethyl-4-(2-phenylquinolin-4-yl)aniline (8d):

147

A solution of 2n in THF (1.2 mmol, 1.2 equiv, 1.1 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 4v (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8d as a red solid.

Isolated yield: 78 % (253 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 8:1 (+0.5 % NEt3). m.p.: 152.0-154.0 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.06 (s, 6 H), 6.89 (dd, J=8.71, 1.80 Hz, 2 H), 7.43 -

7.59 (m, 6 H), 7.70 - 7.77 (m, 1 H), 7.83 (d, J=1.66 Hz, 1 H), 8.09 (d, J=8.29 Hz, 1 H), 8.19 8.30 (m, 3 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 40.4, 112.2, 113.1, 119.1, 125.9, 126.1, 127.0, 127.6,

128.8, 129.2, 129.3, 130.0, 130.6, 139.9, 148.9, 149.5, 150.6, 156.9. MS (70 eV, EI) m/z (%): 324 (100), 323 (42), 307 (16), 280 (13), 240 (63), 225 (23), 161 (15), 119 (14). IR ATR ν (cm-1): 2922, 2866, 2806, 1610, 1592, 1542, 1524, 1504, 1492, 1460, 1442, 1424, 1414, 1402, 1356, 1226, 1196, 1162, 1138, 1120, 1064, 944, 818, 808, 788, 772, 762, 694, 680. HRMS (EI) for C23H20N2 (324.1626) [M]+: 324.1621.

Synthesis of 4,6-dimethyl-2-(4-(trifluoromethoxy)phenyl)pyrimidine (8e):

A solution of 2z in THF (1.2 mmol, 1.2 equiv, 0.8 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 1h (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 2 h before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8e as a white solid. 148

C.Experimental Section Isolated yield: 71 % (190 mg). Reaction time: 2 h. Solvent for purification: i-hexane/ethyl acetate 6:1 (+0.5 % NEt3). m.p.: 66.0-67.4 °C. NMR (300 MHz, CDCl3) δ/ppm: 2.53 (s, 6 H), 6.93 (s, 1 H), 7.29 (d, J=8.29 Hz, 2 H),

1H

8.48 (d, J=8.57 Hz, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 24.1, 118.2, 120.5, 120.5 (q, J=257.6 Hz), 129.9, 136.6,

150.9, 162.8, 166.9. MS (70 eV, EI) m/z (%): 269 (13), 268 (100), 253 (12), 189 (15), 187 (20). IR ATR ν (cm-1): 1602, 1582, 1544, 1504, 1434, 1368, 1288, 1256, 1196, 1148, 1102, 1030, 1012, 958, 920, 874, 866, 852, 810, 786, 734, 680. HRMS (EI) for C13H11F3N2O (268.0823) [M]+: 268.0803.

Synthesis of 2-(3-((tert-butyldimethylsilyl)oxy)phenyl)-4-(4-(trifluoromethyl)-phenyl)pyrimidine (8f):

A solution of 2p in THF (1.2 mmol, 1.2 equiv, 1.0 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 4m (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8f as a slightly yellow oil.

Isolated yield: 80 % (366 mg) Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 8:1 (+0.5 % NEt3). 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.29 (s, 6 H), 1.05 (s, 9 H), 7.02 (dd, J=7.60, 2.07 Hz, 1

H), 7.40 (t, J=7.88 Hz, 1 H), 7.63 (d, J=5.25 Hz, 1 H), 7.81 (m, J=8.02 Hz, 2 H), 8.08 (dd,

149

J=2.21, 1.66 Hz, 1 H), 8.17 - 8.22 (m, J=7.78, 1.11, 0.81, 0.81 Hz, 1 H), 8.33 (m, J=8.02 Hz, 2 H), 8.90 (d, J=5.25 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: -4.3, 18.3, 25.7, 107.6, 108.4, 112.6, 114.8, 119.9, 121.4,

122.9, 123.9 (q, J=272.6 Hz), 125.9 (q, J=3.9 Hz), 127.6, 129.6, 129.9, 132.4, 140.3, 156.1, 156.7, 158.0, 162.5, 164.5. MS (70 eV, EI) m/z (%): 430 (7), 374 (26), 373 (100), 224 (4), 167 (23). IR ATR ν (cm-1): 2958, 2932, 2860, 1712, 1566, 1550, 1452, 1426, 1410, 1382, 1362, 1326, 1284, 1272, 1256, 1220, 1168, 1146, 1128, 1094, 1070, 950, 838, 810, 784. HRMS (EI) for C23H25F3N2OSi (430.1688) [M]+: 430.1682.

Synthesis of 2-(4-methoxyphenyl)pyrazine (8g):

A solution of 2i in THF (1.2 mmol, 1.2 equiv, 1.3 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 1j (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 30 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 8g as a white solid.

Isolated yield: 72 % (134 mg). Reaction time: 30 min. Solvent for purification: i-hexane/ethyl acetate 6:1 (+0.5 % NEt3). m.p.: 93.8-95.2 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 3.87 (s, 3 H), 6.98 - 7.07 (m, 2 H), 7.95 - 8.01 (m, 2 H),

8.43 (d, J=2.49 Hz, 1 H), 8.58 (dd, J=2.49, 1.38 Hz, 1 H), 8.97 (d, J=1.38 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 55.4, 114.5, 128.3, 128.8, 141.5, 141.9, 144.0, 152.5,

161.2. MS (70 eV, EI) m/z (%): 186 (19), 149 (7), 133 (7), 109 (6), 83 (8), 71 (8), 69 (24). IR ATR ν (cm-1): 2956, 2914, 2836, 1604, 1586, 1516, 1474, 1458, 1424, 1400, 1302, 1246, 1178, 1148, 1108, 1078, 1034, 1014, 834, 818, 750. HRMS (EI) for C11H10N2O (186.0793) [M]+: 186.0785. 150

C.Experimental Section Synthesis of Ethyl 2'-benzoyl-[1,1'-biphenyl]-3-carboxylate (11a):

A solution of 10a in THF (1.2 mmol, 1.2 equiv, 0.8 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 9 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 11a as a white solid.

Isolated yield: 79 % (261 mg). Reaction time: 15 min. Solvent for purification: i-hexane/diethyl ether 9:1. m.p.: 65.1-66.7 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.98 (t, J=1.7 Hz, 1 H), 7.85 (dt, J=7.8, 1.5 Hz, 1 H),

7.69 – 7.38 (m, 8 H), 7.32 - 7.23 (m, 3 H), 4.32 (q, J=7.2 Hz, 2 H), 1.33 (t, J=7.1 Hz, 3 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 198.3, 166.1, 140.3, 140.2, 138.9, 137.3, 133.3, 132.9,

130.5, 130.5, 130.1, 129.9, 129.8, 128.9, 128.4, 128.2, 128.1, 127.4, 60.9, 14.2. MS (70 eV, EI) m/z (%): 330 (100), 285 (37), 257 (53), 253 (30), 207 (97), 152 (30), 105 (83), 77 (45). IR ATR ν (cm-1): 3054, 2971, 2912, 1714, 1662, 1595, 1580, 1567, 1447, 1440, 1428, 1306, 1283, 1264, 1238, 1180, 1167, 1153, 1120, 1112, 1106, 1075, 1054, 1033, 1023, 1000, 937, 923, 894, 882, 861, 805, 768, 747, 712, 704, 695, 669. HRMS (EI) for C22H18O3 (330.1256) [M]+: 330.1247.

Synthesis of 2'-benzoyl-[1,1'-biphenyl]-3-carbonitrile (11b):

151

A solution of 10b in THF (0.7 mmol, 0.7 equiv, 0.5 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 9 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 2 h before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 11b as colorless oil.

Isolated yield: 71 % (261 mg). Reaction time: 2 h. Solvent for purification: i-hexane/ethyl acetate 95:5. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.68 – 7.51 (m, 6H), 7.50 – 7.41 (m, 4H), 7.39 – 7.22

(m, 3H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 197.8, 141.5, 138.9, 138.8, 137.2, 133.4, 133.3, 132.2,

130.9, 130.8, 130.1, 129.9, 129.2, 129.0, 128.4, 128.0, 118.5, 112.5. MS (70 eV, EI) m/z (%): 283 (98), 282 (28), 206 (79), 151 (25), 105 (100), 77 (53). IR ATR ν (cm-1): 3061, 3028, 2230, 1661, 1595, 1579, 1470, 1448, 1412, 1314, 1284, 1276, 1264, 1177, 1152, 1110, 1074, 1026, 1000, 928, 905, 846, 802, 757, 727, 707, 690. HRMS (EI) for C20H13NO (283.0997) [M]+: 283.0988.

Synthesis of phenyl(4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methanone (11c):

A solution of 2y in THF (1.2 mmol, 1.2 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 9 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 11c as colorless oil.

Isolated yield: 93 % (305 mg). Reaction time: 15 min. 152

C.Experimental Section Solvent for purification: i-hexane/ethyl acetate 96:4. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.71 - 7.66 (m, 2 H), 7.65 - 7.43 (m, 7 H), 7.42 - 7.26

(m, 4 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 198.1, 143.9, 139.9, 138.9, 137.3, 133.2, 130.6, 130.1,

129.9, 129.4 (q, J=32.5 Hz), 129.3, 128.9, 128.3, 127.7, 125.2 (q, J=3.9 Hz), 124.1 (q, J=272.1 Hz). MS (70 eV, EI) m/z (%): 326 (100), 325 (27), 249 (91), 201 (34), 152 (24), 105 (74), 77 (42). IR ATR ν (cm-1): 3063, 1663, 1618, 1597, 1581, 1450, 1405, 1322, 1281, 1260, 1162, 1120, 1114, 1068, 1020, 1006, 926, 843, 806, 764, 737, 709, 698. HRMS (EI) for C20H13F3O (326.0918) [M]+: 326.0904.

Synthesis of (4'-(dimethylamino)-[1,1'-biphenyl]-2-yl)(phenyl)methanone (11d):

A solution of 2n in THF (1.2 mmol, 1.2 equiv, 1.1 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 9 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 11d as an orange solid.

Isolated yield: 94 % (282 mg). Reaction conditions: 15 min. Solvent for purification: i-hexane/ethyl acetate 97:3 (+ 4 % Et3N). m.p.: 112.4-113.8 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.75 - 7.68 (m, 2 H), 7.58 - 7.45 (m, 3 H), 7.44 - 7.35

(m, 2 H), 7.33 - 7.24 (m, 2 H), 7.21 - 7.14 (m, 2 H), 6.62 - 6.53 (m, 2 H), 2.87 (s, 6 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 199.3, 149.7, 141.2, 138.6, 137.5, 132.7, 130.2, 129.9,

129.8, 129.8, 128.6, 128.1, 128.1, 126.0, 112.3, 40.4. MS (70 eV, EI) m/z (%): 302 (21), 301 (100), 300 (36), 77 (12).

153

IR ATR ν (cm-1): 2924, 2854, 2802, 1663, 1611, 1594, 1580, 1570, 1525, 1479, 1447, 1349, 1315, 1293, 1281, 1247, 1222, 1204, 1168, 1161, 1150, 1130, 1104, 1062, 1028, 945, 938, 932, 921, 879, 823, 804, 775, 766, 726, 720, 703, 690, 676. HRMS (EI) for C21H19NO (301.1467) [M]+: 301.1452.

Synthesis of (2-(benzo[b]thiophen-3-yl)phenyl)(phenyl)methanone (11e):

A solution of 2w in THF (1.2 mmol, 1.2 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 9 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 50 °C for 2 h before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 11e as a red solid.

Isolated yield: 89 % (305 mg). Reaction conditions: 2 h, 50 °C. Solvent for purification: i-hexane/ethyl acetate 96:4. m.p.: 121.2-123.1 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.75 - 7.49 (m, 8 H), 7.38 - 7.20 (m, 3 H), 7.18 (s, 1 H),

7.05 - 7.13 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 198.5, 140.1, 139.9, 138.3, 137.2, 135.6, 134.5, 132.4,

130.4, 130.3, 129.1, 129.1, 127.8, 127.7, 126.0, 124.3, 124.3, 122.7, 122.5. MS (70 eV, EI) m/z (%): 314 (100), 313 (21), 285 (19), 234 (76), 165 (30), 105 (21), 77 (27). IR ATR ν (cm-1): 1663, 1593, 1577, 1448, 1424, 1316, 1285, 1270, 1255, 1210, 1183, 1163, 1147, 1062, 944, 926, 836, 808, 764, 758, 733, 717, 704. HRMS (EI) for C21H14OS (314.0765) [M]+: 314.0755.

154

C.Experimental Section Synthesis of [1,1'-biphenyl]-2-yl(6-chloropyridin-3-yl)methanone (13):

A solution of 2a in THF (1.2 mmol, 1.2 equiv, 1.7 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 12 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 13 as white crystals.

Isolated yield: 72 % (211 mg). Reaction time: 15 min. Solvent for purification: i-hexane/diethyl ether 2:1. m.p.: 108.6-111.2 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 8.42 (dd, J=2.5, 0.6 Hz, 1 H), 7.81 (dd, J=8.3, 2.5 Hz, 1

H), 7.68 - 7.48 (m, 4 H), 7.24 - 7.12 (m, 6 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 196.3, 154.8, 151.2, 141.2, 139.6, 138.9, 137.6, 131.8,

131.4, 130.1, 129.1, 129.0, 128.6, 127.8, 127.7, 123.8. MS (70 eV, EI) m/z (%): 293 (97), 292 (100), 266 (11), 264 (26), 182 (10), 153 (30), 152 (50), 151 (13), 140 (18). IR ATR ν (cm-1): 1671, 1594, 1576, 1564, 1478, 1460, 1448, 1433, 1376, 1363, 1289, 1276, 1266, 1251, 1139, 1115, 1100, 1076, 1052, 1041, 1020, 1008, 970, 961, 926, 918, 884, 844, 786, 774, 752, 744, 715, 699. HRMS (EI) for C18H12ClNO (293.0613) [M]+: 293.0569.

Synthesis of thiophen-2-yl(2-(thiophen-3-yl)phenyl)methanone (15):

155

A solution of 10c in THF (1.2 mmol, 1.2 equiv, 0.8 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97% purity) and 14 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 15 as a brownish solid.

Isolated yield: 90 % (165 mg). Reaction conditions: 15 min. Solvent for purification: i-hexane/diethyl ether 9:1. m.p.: 68.8-70.2 °C. 1H

NMR (300 MHz, CDCl3) δ/ppm: 7.65 - 7.47 (m, 4 H), 7.45 - 7.38 (m, 1 H), 7.28 - 7.17

(m, 3 H), 7.09 (dd, J=4.8, 1.5 Hz, 1 H), 6.94 (dd, J=4.8, 3.7 Hz, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 190.8, 144.5, 140.5, 138.7, 135.2, 134.8, 134.7, 130.3,

129.7, 128.2, 128.1, 127.9, 127.0, 125.9, 123.4. MS (70 eV, EI) m/z (%): 270 (100), 269 (33), 241 (32), 237 (85), 115 (31), 111 (38). IR ATR ν (cm-1): 3094, 2923, 2853, 1628, 1595, 1567, 1511, 1481, 1443, 1407, 1366, 1354, 1295, 1268, 1258, 1231, 1195, 1164, 1149, 1106, 1085, 1052, 1042, 1026, 889, 859, 842, 804, 795, 779, 756, 748, 728, 723, 706, 697, 669. HRMS (EI) for C15H10OS2 (270.0173) [M]+: 270.0169.

5.2 Preparation of Cross-Coupling Products Using TP4 Synthesis of [1,1'-biphenyl]-2-carbaldehyde (17a):

A solution of 2a in THF (1.2 mmol, 1.2 equiv, 1.7 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and imine 16 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with an aq. solution of HCl (2 M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 17a as a yellow oil. 156

C.Experimental Section Isolated yield: 84 % (152 mg). Reaction conditions: 15 min. Solvent for purification: i-hexane/diethyl ether 9:1. 1H

NMR (300 MHz, CDCl3) δ/ppm: 10.00 (d, J=0.8 Hz, 1 H), 8.04 (dd, J=7.7, 1.4 Hz, 1 H),

7.64 (td, J=7.5, 1.5 Hz, 1 H), 7.52 - 7.43 (m, 5 H), 7.41 - 7.37 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 192.4, 146.0, 137.7, 133.7, 133.5, 130.8, 130.1, 128.4,

128.1, 127.8, 127.6. MS (70 eV, EI) m/z (%): 182 (72), 181 (100), 154 (19), 153 (41), 152 (49), 76 (13). IR ATR ν (cm-1): 3060, 3028, 2845, 2752, 1688, 1655, 1596, 1498, 1473, 1453, 1437, 1392, 1301, 1252, 1194, 1160, 1101, 1075, 1048, 1033, 1008, 919, 827, 778, 756, 745, 700. HRMS (EI) for C13H10O (182.0732) [M]+: 182.0701.

Synthesis of 4'-methoxy-[1,1'-biphenyl]-2-carbaldehyde (17b):

A solution of 2i in THF (1.2 mmol, 1.2 equiv, 1.3 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and imine 16 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with an aq. solution of HCl (2 M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 17b as a yellow oil.

Isolated yield: 69 % (152 mg). Reaction conditions: 15 min. Solvent for purification: i-hexane/diethyl ether 95:5. 1H

NMR (300 MHz, CDCl3) δ/ppm: 10.00 (t, J=0.7 Hz, 1 H), 8.00 (dt, J=7.8, 0.7 Hz, 1 H),

7.65 - 7.57 (m, 1 H), 7.49 - 7.40 (m, 2 H), 7.34 - 7.25 (m, 2 H), 7.04 - 6.97 (m, 2 H), 3.87 (d, J=0.8 Hz, 3 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 192.6, 159.7, 145.6, 133.8, 133.5, 131.3, 130.8, 130.0,

127.6, 127.3, 113.9, 55.4. MS (70 eV, EI) m/z (%): 212 (100), 211 (30), 197 (20), 181 (27), 169 (59), 168 (19), 152 (21), 140 (20), 139 (51), 115 (57). 157

IR ATR ν (cm-1): 3031, 2957, 2935, 2837, 2750, 1688, 1657, 1609, 1596, 1578, 1514, 1474, 1449, 1442, 1391, 1297, 1271, 1243, 1192, 1177, 1160, 1112, 1100, 1047, 1033, 1016, 1000, 833, 803, 763, 742, 713. HRMS (EI) for C14H12O2: (212.0837) [M]+: 212.0838.

Synthesis of 2-(thiophen-3-yl)benzaldehyde (17c):

A solution of 10c in THF (1.2 mmol, 1.2 equiv, 0.8 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and imine 16 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 16 h before being quenched with an aq. solution of HCl (2 M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 17c as a yellow oil.

Isolated yield: 75 % (140 mg). Reaction conditions: 16 h. Solvent for purification: i-hexane/diethyl ether 95:5. 1H

NMR (300 MHz, CDCl3) δ/ppm: 10.10 (d, J=0.6 Hz, 1 H), 8.03 - 7.97 (m, 1 H), 7.65 -

7.58 (m, 1 H), 7.51 - 7.42 (m, 3 H), 7.29 (dd, J=2.9, 1.2 Hz, 1 H), 7.21 - 7.17 (m, 1 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 192.3, 140.4, 138.3, 134.0, 133.6, 130.6, 129.3, 127.8,

127.6, 126.3, 125.0. MS (70 eV, EI) m/z (%): 188 (100), 160 (100), 159 (24), 158 (21), 116 (20), 115 (85), 43 (31). IR ATR ν (cm-1): 3099, 2847, 2750, 1683, 1596, 1570, 1474, 1447, 1406, 1389, 1362, 1270, 1243, 1194, 1160, 1100, 1082, 1047, 1028, 859, 830, 813, 792, 756, 731, 684, 653. HRMS (EI) for C11H8OS: (188.0296) [M]+: 188.0300.

158

C.Experimental Section 5.3 Preparation of Cross-Coupling Products Using TP5 Synthesis of (E)-N,N-dimethyl-4-(oct-1-en-1-yl)aniline (19a):

A solution of 2n in THF (1.5 mmol, 1.5 equiv, 1.2 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and alkenyl iodide 18 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 19a as a slightly yellow oil.

Isolated yield: 70 % (162 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 9:1. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.84 - 0.96 (m, 3 H), 1.23 - 1.52 (m, 8 H), 2.10 - 2.26

(m, 2 H), 2.95 (s, 6 H), 5.97 - 6.10 (m, 1 H), 6.30 (d, J=16.03 Hz, 1 H), 6.66 - 6.74 (m, 2 H), 7.21 - 7.29 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 14.1, 22.7, 28.9, 29.7, 31.8, 33.1, 40.7, 112.8, 126.7,

127.2, 129.4, 149.6. MS (70 eV, EI) m/z (%): 232 (15), 231 (100), 161 (26), 160 (40), 145 (14), 134 (30). IR ATR ν (cm-1): 2954, 2923, 2871, 2852, 2801, 1610, 1519, 1480, 1466, 1454, 1444, 1348, 1221, 1187, 1164, 1129, 1061, 961, 947, 831, 801, 725. HRMS (EI) for C16H25N (231.1987) [M]+: 231.1964.

Synthesis of (E)-1-methoxy-4-(oct-1-en-1-yl)benzene (19b):

A solution of 2i in THF (1.5 mmol, 1.5 equiv, 1.3 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and alkenyl iodide 18 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with 159

MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 19b as a colorless oil.

Isolated yield: 75 % (164 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 20:1. NMR (300 MHz, CDCl3) δ/ppm: 0.87 - 0.99 (m, 3 H), 1.28 - 1.52 (m, 8 H), 2.14 - 2.27

1H

(m, 2 H), 3.81 (s, 3 H), 6.04 - 6.17 (m, 1 H), 6.29 - 6.39 (m, 1 H), 6.85 (m, 2 H), 7.29 (m, 2 H). 13C

NMR (75 MHz, CDCl3) δ/ppm: 14.1, 22.7, 28.9, 29.5, 31.8, 33.0, 55.3, 113.9, 126.9,

129.0, 129.1, 130.8, 158.6. MS (70 eV, EI) m/z (%): 218 (27), 148 (14), 147 (100), 134 (19), 121 (24), 115 (10), 91 (16). IR ATR ν (cm-1): 2955, 2924, 2871, 2854, 2836, 1608, 1510, 1465, 1441, 1287, 1244, 1174, 1105, 1037, 963, 840, 803, 758, 724. HRMS (EI) for C15H22O (218.1671) [M]+: 218.1666.

Synthesis of (E)-tert-butyldimethyl(3-(oct-1-en-1-yl)phenoxy)silane (19c):

A solution of 2p in THF (1.5 mmol, 1.5 equiv, 1.0 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and alkenyl iodide 18 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 19c as a colorless oil.

Isolated yield: 80 % (255 mg). Reaction time: 15 min. Solvent for purification: i-hexane. 1H

NMR (300 MHz, CDCl3) δ/ppm: 0.22 (s, 6 H), 0.87 - 0.97 (m, 3 H), 1.02 (s, 9 H), 1.22 -

1.58 (m, 8 H), 2.22 (q, J=7.28 Hz, 2 H), 6.15 - 6.26 (m, 1 H), 6.30 - 6.38 (m, 1 H), 6.70 (dd, J=8.02, 2.21 Hz, 1 H), 6.94 - 7.00 (m, 1 H), 7.12 - 7.28 (m, 2 H).

160

C.Experimental Section 13C

NMR (75 MHz, CDCl3) δ/ppm: -4.4, 14.1, 18.2, 22.6, 25.7, 28.9, 29.3, 31.8, 33.0, 117.5,

118.5, 119.1, 120.1, 129.5, 131.3, 139.5, 155.8. MS (70 eV, EI) m/z (%): 318 (13), 262 (20), 261 (100), 163 (9), 151 (6). IR ATR ν (cm-1): 2956, 2928, 2857, 1597, 1578, 1490, 1472, 1464, 1439, 1277, 1252, 1170, 1156, 1001, 965, 939, 916, 876, 837, 778, 713, 688, 665. HRMS (EI) for C20H34OSi (318.2379) [M]+: 318.2376.

Synthesis of (E)-1-(dimethoxymethyl)-4-(oct-1-en-1-yl)benzene (19d):

A solution of 2t in THF (1.5 mmol, 1.5 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and alkenyl iodide 18 (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 19d as a colorless oil.

Isolated yield: 69 % (181 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 20:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.81 - 0.87 (m, 3 H), 1.23 - 1.32 (m, 6 H), 1.36 - 1.45

(m, 2 H), 2.15 (q, J=6.63 Hz, 2 H), 3.32 (s, 6 H), 5.33 (s, 1 H), 6.24 - 6.39 (m, 2 H), 7.28 (m, 2 H), 7.36 (m, 2 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 14.4, 22.5, 28.8, 29.2, 31.6, 32.9, 52.8, 102.9, 125.9,

127.2, 129.6, 131.7, 137.1, 137.9. MS (70 eV, EI) m/z (%): 216 (24), 133 (11), 132 (100), 131 (30), 117 (66), 91 (24). IR ATR ν (cm-1): 2954, 2927, 2856, 1689, 1609, 1577, 1466, 1422, 1379, 1286, 1268, 1208, 1170, 1107, 1016, 893, 856, 828, 804, 790, 762, 733, 724, 702. HRMS (EI) for C17H26O2 (262.1933) [M]+: 262.1916.

Synthesis of 2-octylquinoline (21a):

161

A solution of 20a in THF (1.5 mmol, 1.5 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 2-chloroquinoline (1f) (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 21a as a brown oil.

Isolated yield: 77 % (185 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 95:5. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.87 (t, J=6.63 Hz, 3 H), 1.10 - 1.51 (m, 10 H), 1.81

(dt, J=15.20, 7.60 Hz, 2 H), 2.88 - 3.05 (m, 2 H), 7.24 - 7.32 (m, 1 H), 7.47 (t, J=7.46 Hz, 1 H), 7.59 - 7.83 (m, 2 H), 8.06 (dd, J=8.29, 3.87 Hz, 2 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 14.07, 22.63, 29.20, 29.47, 29.55, 30.05, 31.83, 39.26,

121.34, 125.66, 126.69, 127.44, 128.67, 129.36, 136.29, 147.69, 163.06. MS (70 eV, EI) m/z (%): 241 (13), 212 (12), 198 (22), 184 (14), 169 (57), 155 (100), 144 (59), 128 (35), 115 (19). IR ATR ν (cm-1): 2951, 2921, 1618, 1600, 1562, 1503, 1425, 1309, 1140, 1116, 825, 823, 768, 753, 751, 721. HRMS (EI) for C17H23N (241.1830) [M]+: 241.1829.

Synthesis of 2-octylquinoline (21b):

A solution of 20b in THF (1.5 mmol, 1.5 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 2-chloroquinoline (1f) (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 21b as yellowish crystals.

Isolated yield: 74 % (261 mg). Reaction time: 15 min. 162

C.Experimental Section Solvent for purification: i-hexane/ethyl acetate 95:5. m.p.: 49.4 – 51.2 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.88 (t, J=6.50 Hz, 3 H), 1.25 (s, 21 H), 1.29 - 1.40 (m,

5 H), 1.82 (dt, J=15.00, 7.57 Hz, 2 H), 2.95 - 3.04 (m, 2 H), 7.25 - 7.33 (m, 1 H), 7.49 (t, J=7.19 Hz, 1 H), 7.65 - 7.80 (m, 2 H), 8.05 - 8.15 (m, 2 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 14.09, 22.67, 29.34, 29.50, 29.53, 29.61, 29.64, 29.67,

30.04, 31.90, 39.06, 121.35, 125.81, 126.70, 127.45, 128.42, 129.55, 136.61, 147.31, 163.00. MS (70 eV, EI) m/z (%): 353 (22), 352 (37), 310 (10), 212 (14), 198 (16), 184 (13), 170 (46), 157 (23), 156 (100), 144 (63), 128 (16). IR ATR ν (cm-1): 2953, 2914, 2848, 1616, 1600, 1560, 1502, 1471, 1426, 831, 781, 758, 716. HRMS (EI) for C25H38N (352.3004) [M-1]+: 352.3003

Synthesis of 2-octylquinoline (21c):

A solution of 20c in THF (1.5 mmol, 1.5 equiv, 0.9 M) was added dropwise to a suspension of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv; 97 % purity) and 2-chloroquinoline (1f) (1 mmol, 1.0 equiv) in THF (5 mL) at 23 °C. The suspension was stirred at 23 °C for 15 min before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 21c as brown oil.

Isolated yield: 82 % (261 mg). Reaction time: 15 min. Solvent for purification: i-hexane/ethyl acetate 95:5. 1H

NMR (300 MHz, DMSO) δ/ppm: 3.10 - 3.24 (m, 2 H), 3.26 - 3.37 (m, 2 H), 7.15 - 7.37

(m, 6 H), 7.50 (t, J=7.46 Hz, 1 H), 7.65 - 7.83 (m, 2 H), 8.05 (d, J=8.57 Hz, 1 H), 8.12 (d, J=8.57 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ ppm 35.92, 40.87, 121.57, 125.86, 126.01, 126.81, 127.53,

128.40, 128.52, 128.75, 129.48, 136.35, 141.47, 147.83, 161.76. MS (70 eV, EI) m/z (%): 260 (10), 234 (28), 233 (100), 232 (93), 230 (34), 217 (15), 156 (37), 128 (16), 115 (15), 105 (11), 91 (22). 163

IR ATR ν (cm-1): 3054, 3924, 2917, 1618, 1598, 1592, 1498, 1495, 1452, 1425, 1309, 1139, 1114, 1075, 841, 818, 747, 721, 696. HRMS (EI) for C17H15N (233.1204) [M]+: 233.1197.

6. Room-Temperature Chromium(II)-Catalyzed Direct Arylation of Pyridines, Aryl Oxazolines and Imines.

6.1 Preparation of Starting Materials 2-(Trimethylsilyl)benzaldehyde was prepared according to the methods describe in the literature.116 Starting materials 22 is commercially available.

Synthesis of 2-(2-(trimethylsilyl)phenyl)pyridine (24):117

A solution of TMPMgCl·LiCl in THF (4 mmol, 2 equiv, 1.2 M) was added dropwise to a solution of 2-phenylpyridine (3a) (310 mg, 2 mmol, 1.0 equiv) in THF (10 ml). The reaction mixture was heated to 55 °C for 50 h. Then, the reaction mixture was cooled down to -30 °C and a solution of TMSCN (0.397 mg, 4 mmol, 2 equiv) in THF (4 ml) was added and slowly warmed up to 23 °C. Reaction mixture was quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 24 as a colorless oil.

Isolated yield: 54 % (245 mg). Solvent for purification: i-hexane/ethyl acetate 15:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.08 (s, 9 H), 7.25 - 7.30 (m, 1 H), 7.37 - 7.53 (m, 4 H),

7.68 - 7.80 (m, 2 H), 8.65 (d, J=4.70 Hz, 1 H).

116 117

So, S., S.; Burkett, J. A.; Mattson, A. E. Org. Lett. 2011, 13, 716. Jaric, M.; Haag, B. A.; Unsinn, A.; Karaghiosoff, K.; Knochel, P. Angew. Chem. Int. Ed. 2010, 49, 5451.

164

C.Experimental Section 13C

NMR (75 MHz, DMSO) δ/ppm: 0.81, 122.01, 123.09, 127.48, 128.61, 128.75, 135.46,

136.53, 139.35, 146.74, 148.28, 161.22 MS (70 eV, EI) m/z (%): 212 (100), 213 (19), 182 (34), 98 (9), 44 (42), 43 (12), 41 (6). IR ATR ν (cm-1): 3050, 2946, 1586, 1569, 1556, 1477, 1423, 1295, 1242, 1150, 1123, 1101, 1021, 990, 832, 797, 747, 726, 680. HRMS (EI) for C14H17NSi (226.1052) [M-H]+: 226.1058.

Synthesis of 4,4-dimethyl-2-(2-(trimethylsilyl)phenyl)-4,5-dihydrooxazole (28):

A solution of nBuLi in nhexane (6 mmol, 1 equiv, 2.55 M) was added dropwise to a solution of 4,4-dimethyl-2-phenyl-4,5-dihydrooxazole (1051 mg, 6 mmol, 1 equiv) in Et2O (6 ml) at 0 °C. The reaction mixture was stirred 15 min at 0 °C and 30 min at 23 °C. Then a solution of TMSCl (761 mg, 6 mmol, 1 equiv) in Et2O (30 ml) was added, and the reaction mixture was reflux for 3 h. After cooling down to 23 °C, the reaction mixture was quenched with brine and and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 28 as a colorless oil.

Isolated yield: 56% (829 mg). Solvent for purification: i-hexane/ethyl acetate 10:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 31 (s, 9 H), 1.38 (s, 6 H), 4.08 (s, 2 H), 7.34 - 7.41 (m,

2 H), 7.59 - 7.64 (m, 1 H), 7.86 (dd, J=7.19, 1.66 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.66, 28.49, 67.79, 79.06, 128.63, 129.50, 129.69,

133.82, 135.15, 140.17, 163.58. MS (70 eV, EI) m/z (%): 247 (14), 232 (86), 160 (56), 137 (28), 125 (30), 111 (66), 97 (84), 85 (59), 71 (75), 57 (100), 55 (70). IR ATR ν (cm-1): 2971, 2958, 2894, 1655, 1462, 1355, 1349, 1307, 1241, 1187, 1128, 1092, 1057, 1038, 989, 966, 923, 834, 779, 730, 687. HRMS (EI) for C14H21NOSi (247.1392) [M]+: 247.1379.

165

Synthesis of 4-methoxy-N-(2-(trimethylsilyl)benzylidene)aniline (32):

A mixture of 2-(trimethylsilyl)benzaldehyde116 (891 mg, 5 mmol, 1 equiv), anisidine (616 mg, 5 mmol, 1 equiv), Na2SO4 (53 mg) and molecular sieves (53 mg) in DCM (5 ml) was stirred at 23 °C for 12 h. The reaction mixture was then filtrated through a pad of Celite®. After washing the pad of Celite® with Et2O, the crude mixture was purifired using Kugelrohr destillation to yield the desired compound 32 as a light yellow oil.

Isolated yield: 92% (166 mg). 1H

NMR (300 MHz, DMSO) δ/ppm: 0.40 (s, 9 H), 3.84 (s, 3 H), 6.96 (d, J=8.85 Hz, 2 H),

7.24 (d, J=8.57 Hz, 2 H), 7.44 (t, J=8.29 Hz, 2 H), 7.65 (d, J=7.46 Hz, 1 H), 8.08 (d, J=7.19 Hz, 1 H), 8.77 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ ppm 1.00, 55.49, 114.50, 114.83, 116.62, 122.12, 128.38,

129.35, 129.80, 130.59, 135.02, 141.05, 141.51, 144.75, 158.26, 158.95, 172.65. MS (70 eV, EI) m/z (%): 283 (5), 270 (6), 269 (20), 268 (100), 253 (6), 134 (7), 123 (13). IR ATR ν (cm-1): 2952, 2890, 1692, 1681, 1615, 1592, 1510, 1503, 1465, 1437, 1296, 1240, 1179, 1116, 1073, 1031, 825, 754, 725, 689. HRMS (EI) for C17H21NOSi (283.1392) [M]+: 283.1388.

Synthesis of N-(2-(trimethylsilyl)benzylidene)butan-1-amine (33):

A mixture of 2-(trimethylsilyl)benzaldehyde116 (891 mg, 5 mmol, 1 equiv), butan-1-amine (365 mg, 5 mmol, 1 equiv), Na2SO4 (53 mg) and molecular sieves (53 mg) in DCM (5 ml) was stirred at 23 °C for 12 h. The reaction mixture was, then, filtrated through a pad of Celite®. After washing the pad of Celite® with Et2O, the crude mixture was purifired using Kugelrohr destillation to yield the desired compound 33 as a colorless oil.

Isolated yield: 94% (166 mg). 166

C.Experimental Section 1H

NMR (300 MHz, DMSO) δ/ppm: 0.36 (s, 9 H), 0.96 (t, J=7.33 Hz, 3 H), 1.34 - 1.48 (m, 2

H), 1.65 - 1.79 (m, J=7.36, 7.36, 7.26, 7.05 Hz, 2 H), 3.63 (t, J=6.91 Hz, 2 H), 7.39 (quin, J=6.43 Hz, 2 H), 7.58 (d, J=6.63 Hz, 1 H), 7.92 (d, J=6.91 Hz, 1 H), 8.59 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.82, 13.88, 20.50, 32.85, 61.48, 127.47, 129.21,

129.28, 134.60, 140.05, 141.57, 161.41. MS (70 eV, EI) m/z (%): 218 (90), 190 (54), 163 (78), 162 (48), 253 (6), 161 (100), 111 (41), 97 (59), 83 (71), 69 (72), 55 (70), 43 (57). IR ATR ν (cm-1): 2957, 2928, 2874, 1656, 1639, 1465, 1433, 1376, 1250, 1241, 1120, 1077, 975, 832, 753, 721, 689. HRMS (EI) for C14H22NSi (233.1600) [M-H]+: 233.1512.

Synthesis of N-(2-(trimethylsilyl)benzylidene)butan-1-amine (35):

A mixture of 2-chlorobenzaldehyde (703 mg, 5 mmol, 1 equiv), butan-1-amine (365 mg, 5 mmol, 1 equiv), Na2SO4 (53 mg) and molecular sieves (53 mg) in DCM (5 ml) was stirred at 23 °C for 12 h. The reaction mixture was, then, filtrated through a pad of Celite®. After washing the pad of Celite® with Et2O, the crude mixture was purifired using Kugelrohr destillation to yield the desired compound 35 as a colorless oil.

Isolated yield: 87 % (170 mg). 1H

NMR (300 MHz, DMSO) δ/ppm: 0.95 (t, J=7.33 Hz, 3 H) 1.40 (dq, J=14.89, 7.38 Hz, 2

H) 1.58 - 1.78 (m, J=7.36, 7.36, 7.26, 7.05 Hz, 2 H) 3.65 (t, J=6.91 Hz, 2 H) 7.20 - 7.39 (m, 3 H) 8.01 (dd, J=7.19, 1.93 Hz, 1 H) 8.69 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 13.85, 20.42, 32.92, 61.56, 126.92, 128.26, 129.68,

131.21, 133.40, 134.88, 157.44. MS (70 eV, EI) m/z (%): 196 (100), 148 (4), 140 (7), 102 (3), 89 (8). IR ATR ν (cm-1): 2955, 2928, 2871, 2827, 1637, 1593, 1567, 1467, 1439, 1372, 1273, 1210, 1122, 1050, 1028, 899, 867, 751, 705. HRMS (EI) for C11H15ClN (196.0893) [M+H]+: 196.0885.

167

6.2 Preparation of Arylated Products Using TP6 Synthesis of 10-phenylbenzo[h]quinoline (23a):

According to TP6, a solution of PhMgCl (2a) in THF (1.12 mmol, 4 equiv, 1.62 M) was added dropwise to a mixture of anhydrous CrCl2 (3.4 mg, 0.028 mmol, 0.1 equiv) and benzo[h]quinoline (22) (50 mg, 0.28 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (5.3 mg, 0.42 mmol, 1.5 equiv) was added dropwise at 23 °C. Reaction mixture was stirred at 23 °C for 24 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 23a as a colorless oil.

Isolated yield: 95 %. Solvent for purification: i-hexane, than toluene. 1H

NMR (300 MHz, DMSO) δ/ppm: 7.15 - 7.49 (m, 6 H), 7.57 (dd, J=7.33, 1.24 Hz, 1 H),

7.61 - 7.77 (m, 2 H), 7.78 - 8.00 (m, 2 H), 8.10 (dd, J=8.02, 1.94 Hz, 1 H), 8.45 (dd, J=4.28, 1.80 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 121.06, 125.71, 125.88, 127.07, 127.23, 127.38, 127.93,

128.32, 128.72, 128.89, 131.49, 134.99, 135.29, 141.68, 146.29, 146.67, 146.79. MS (70 eV, EI) m/z (%): 255 (25), 254 (100), 127 (16), 127 (6), 126 (12), 45 (5), 42 (30). IR ATR ν (cm-1): 3046, 3023, 2957, 2928, 2859, 1619, 1587, 1565, 1509, 1492, 1442, 1416, 1393, 1323, 1181, 1132, 1081, 1026, 1014, 989, 960, 924, 833, 756, 729, 696. HRMS (EI) for C19H12N (254.0970) [M-H]+: 254.0964.

Synthesis of 10-phenylbenzo[h]quinoline (23b):

According to TP6, solution of 10d in THF (1.12 mmol, 4 equiv, 1.62 M) was added dropwise to a mixture of anhydrous CrCl2 (3.4 mg, 0.028 mmol, 0.1 equiv) and benzo[h]quinoline (22) 168

C.Experimental Section (50 mg, 0.28 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (5.3 mg, 0.42 mmol, 1.5 equiv) was added dropwise at 23 °C. Reaction mixture was stirred at 23 °C for 24 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 23b as a colorless oil.

Isolated yield: 90 %. Solvent for purification: i-hexane, than toluene. 1H

NMR (300 MHz, DMSO) δ/ppm: 3.81 (s, 3 H), 6.89 - 7.03 (m, 3 H,) 7.28 - 7.39 (m, 2 H),

7.59 (d, J=7.19 Hz, 1 H), 7.63 - 7.74 (m, 2 H), 7.86 (d, J=8.85 Hz, 1 H), 7.93 (d, J=7.74 Hz, 1 H), 8.08 (dd, J=7.88, 1.52 Hz, 1 H), 8.49 (dd, J=4.15, 1.66 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ ppm 55.24, 111.49, 114.39, 121.08, 121.47, 125.94, 127.00,

127.21, 128.00, 128.23, 128.30, 129.01, 131.30, 134.96, 135.13, 141.46, 146.73, 146.95, 147.84, 159.02. MS (70 eV, EI) m/z (%): 285 (35), 284 (100), 270 (11), 268 (7), 242 (11), 241 (31), 239 (4), 120 (14). IR ATR ν (cm-1): 3045, 2931, 1598, 1577, 1481, 1450, 1410, 1316, 1284, 1218, 1165, 1130, 1047, 1038, 859, 830, 777, 748, 728, 698, 666. HRMS (EI) for C20H15NO (284.1075) [M-H]+: 284.1069

Synthesis of 4-(benzo[h]quinolin-10-yl)-N,N-dimethylaniline (23c):

According to TP6, a solution of 2n in THF (2 mmol, 4 equiv, 0.76 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and benzo[h]quinoline (22) (90 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 24 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 23c as a light brownish oil.

Isolated yield: 87 %. 169

Solvent for purification: i-hexane, than toluene. 1H

NMR (300 MHz, DMSO) δ/ppm: 3.04 (s, 6 H), 6.83 (d, J=8.57 Hz, 2 H), 7.23 - 7.35 (m,

3 H), 7.55 - 7.61 (m, 1 H), 7.62 - 7.70 (m, 2 H), 7.85 (t, J=8.71 Hz, 2 H), 8.07 (dd, J=7.88, 1.52 Hz, 1 H), 8.53 (dd, J=4.15, 1.66 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 40.95, 112.04, 120.90, 125.75, 127.06, 127.13, 127.31,

128.36, 129.17, 129.57, 131.80, 135.01, 135.13, 135.17, 141.94, 146.86, 147.22, 149.08. MS (70 eV, EI) m/z (%): 299 (13), 298(62), 297 (100), 281 (32), 252 (16), 149 (16), 126 (10). IR ATR ν (cm-1): 3037, 2856, 2794, 1608, 1518, 1439, 1415, 1340, 1323, 1221, 1194, 1163, 1131, 1081, 1057, 945, 906, 836, 810, 760, 731. HRMS (EI) for C21H17N2 (297.1392) [M-H]+: 297.1385.

Synthesis of 10-(benzo[d][1,3]dioxol-5-yl)benzo[h]quinoline (23d):

According to TP6, a solution of 2k in THF (2 mmol, 4 equiv, 0.82 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and benzo[h]quinoline (22) (90 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. Reaction mixture was stirred at 23 °C for 24 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 23d as a yellow crystals.

Isolated yield: 67 % Solvent for purification: i-hexane, than toluene. m.p.: 134.8 – 136.4 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 6.04 (br. s., 2 H), 6.81 - 6.94 (m, 2 H), 7.38 (dd,

J=8.02, 4.42 Hz, 2 H), 7.56 (dd, J=7.33, 1.24 Hz, 1 H), 7.61 - 7.75 (m, 2 H), 7.81 - 7.96 (m, 2 H), 8.13 (dd, J=8.02, 1.66 Hz, 1 H), 8.60 (dd, J=4.42, 1.66 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 100.79, 107.70, 110.02, 121.14, 121.56, 125.86, 127.22,

127.36, 127.98, 128.47, 128.64, 131.62, 135.09, 135.76, 139.93, 141.13, 145.94, 146.27, 146.81, 146.94. 170

C.Experimental Section MS (70 eV, EI) m/z (%): 299 (36), 298(100), 241 (9), 240 (10), 239 (9), 120 (11), 119 (6). IR ATR ν (cm-1): 2920, 1447, 1332, 1220, 1181, 1033, 931, 836, 805, 766, 731. HRMS (EI) for C20H12NO2 (298.0868) [M-H]+: 298.0865.

Synthesis of 10-(4-(trifluoromethyl)phenyl)benzo[h]quinoline (23e):

According to TP6, a solution of 2y in THF (2 mmol, 4 equiv, 0.90 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and benzo[h]quinoline (22) (90 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 38 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 23e as beige crystals.

Isolated yield: 66 % Solvent for purification: i-hexane, than toluene. m.p.: 101.3 – 103.1 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 7.35 (dd, J=8.02, 4.15 Hz, 1 H) 7.40 - 7.57 (m, 3 H)

7.57 - 7.78 (m, 4 H) 7.89 (d, J=8.57 Hz, 1 H) 7.98 (d, J=7.74 Hz, 1 H) 8.12 (dd, J=8.02, 1.66 Hz, 1 H) 8.42 (dd, J=4.28, 1.52 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 121.27, 124.29 (q, J=3.65 Hz), 124.76 (q, J=271.80

Hz), 126.08, 127.14, 127.31, 127.83 (J=31.98 Hz), 128.28, 128.52, 128.68, 129.01, 131.14, 134.97, 135.50, 140.17, 146.16, 146.79, 150.02. MS (70 eV, EI) m/z (%): 323 (34), 322 (100), 352 (17), 161 (5), 151 (5), 126 (9), 43 (15). IR ATR ν (cm-1): 3048, 2962, 2923, 1615, 1590, 1567, 1508, 1421, 1403, 1320, 1151, 1103, 1061, 1014, 833, 827, 761, 729, 679. HRMS (EI) for C20H11NO2 (322.0844) [M-H]+: 322.0843.

171

Synthesis of 10-(4-fluorophenyl)benzo[h]quinoline (23f):

According to TP6, a solution of 2g in THF (2 mmol, 4 equiv, 1.05 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and benzo[h]quinoline (22) (90 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 24 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 23f as beige crystals.

Isolated yield: 86 %. Solvent for purification: i-hexane, than toluene. m.p.: 117.7 – 119.3 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 7.10 (t, J=8.71 Hz, 1 H), 7.19 - 7.47 (m, 4 H), 7.53 (d,

J=7.19 Hz, 1 H), 7.60 - 7.79 (m, 2 H), 7.86 (d, J=8.85 Hz, 1 H), 7.94 (d, J=7.74 Hz, 1 H), 8.09 (d, J=8.02 Hz, 1 H), 8.40 - 8.50 (m, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 113.96, 114.25, 121.13, 125.99, 127.02, 127.26, 128.13,

128.29, 129.00, 130.09, 130.20, 131.49, 135.01, 135.30, 140.65, 142.18, 142.23, 146.70, 146.83, 159.95, 163.17. MS (70 eV, EI) m/z (%): 323 (34), 322 (100), 352 (17), 161 (5), 151 (5), 126 (9), 43 (15). IR ATR ν (cm-1): 3048, 2923, 2847, 1587, 1513, 1502, 1420, 1209, 1156, 1132, 1090, 1015, 829, 810, 758, 730. HRMS (EI) for C19H11N1F1 (272.0876) [M-H]+: 272.0867.

Synthesis of 2-(3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)pyridine (25a):

172

C.Experimental Section According to TP6, a solution of 2a in THF (2 mmol, 4 equiv, 1.66 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and 2-(2-

(trimethylsilyl)phenyl)pyridine (24) (113.5 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 25a as white crystals.

Isolated yield: 92 %. Solvent for purification: i-hexane/ethyl acetate 10:1. m.p.: 84.8 – 86.8 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: -0.01 (s, 9 H), 6.90 (d, J=7.74 Hz, 1 H), 6.95 - 7.29 (m,

6 H), 7.32 - 7.53 (m, 3 H), 7.70 (dd, J=7.19, 1.38 Hz, 1 H), 8.62 (d, J=4.42 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.31, 121.78, 126.26, 126.36, 127.54, 127.58, 129.81,

130.81, 134.11, 135.40, 139.89, 140.80, 141.66, 145.16, 148.12, 160.67. MS (70 eV, EI) m/z (%): 290 (6), 289 (23), 288 (100), 258 (18), 149 (6), 135 (4). IR ATR ν (cm-1): 2948, 2923, 1726, 1584, 1471, 1402, 1239, 1142, 1054, 1021, 854, 833, 751, 699. HRMS (EI) for C20H20NSi (302.1365) [M-H]+: 302.1359.

Synthesis of 2-(3'-methoxy-3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)pyridine (25b):

According to TP6, a solution of 10d in THF (2 mmol, 4 equiv, 1.09 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 2-(2(trimethylsilyl)phenyl)pyridine (24) (113.5 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield

173

the crude compound, which was purified by column chromatography to yield 25b as a colorless oil.

Isolated yield: 79 %. Solvent for purification: i-hexane/ethyl acetate 10:1. 1H

NMR (300 MHz, DMSO) δ/ppm: -0.01 (s, 9 H), 3.59 (s, 3 H), 6.58 (d, J=1.66 Hz, 1 H),

6.64 - 6.74 (m, 2 H), 6.92 (d, J=7.74 Hz, 1 H), 7.01 - 7.18 (m, 2 H), 7.35 - 7.50 (m, 3 H), 7.70 (dd, J=6.77, 2.07 Hz, 1 H), 8.63 (d, J=4.42 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.31, 55.08, 112.87, 114.81, 121.77, 122.29, 126.28,

127.49, 128.60, 130.66, 134.19, 135.39, 139.91, 140.62, 143.05, 145.25, 148.15, 158.78, 160.84. MS (70 eV, EI) m/z (%): 320 (6), 319 (30), 318 (100), 302 (15), 274 (16), 244 (6), 158 (5). IR ATR ν (cm-1): 3057, 2949, 1599, 1585, 1564, 1487, 1474, 1463, 1430, 1400, 1315, 1299, 1245, 1222, 1178, 1146, 1037, 989, 887, 834, 762, 747, 702. HRMS (EI) for C21H23NOSi (333.1549) [M]+: 333.1552.

Synthesis of N,N-dimethyl-2'-(pyridin-2-yl)-3'-(trimethylsilyl)-[1,1'-biphenyl]-4-amine (25c):

According to TP6, a solution of 2u in THF (2 mmol, 4 equiv, 1.10 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and 2-(2-

(trimethylsilyl)phenyl)pyridine (24) (113.5 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 4 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 25c as redish crystals.

Isolated yield: 85 %. Solvent for purification: i-hexane/ethyl acetate 10:1. m.p.: 138.5 – 140.2 °C. 174

C.Experimental Section 1H

NMR (300 MHz, DMSO) δ/ppm: -0.02 (s, 9 H), 2.89 (s, 6 H), 6.56 (d, J=8.57 Hz, 2 H),

6.89 - 6.97 (m, 3 H), 7.12 (dd, J=6.36, 4.98 Hz, 1 H), 7.37 - 7.47 (m, 3 H), 7.64 (dd, J=6.63, 2.21 Hz, 1 H), 8.63 (d, J=4.15 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.34, 40.71, 112.12, 121.55, 126.33, 127.44, 130.42,

130.60, 130.92, 133.42, 135.20, 139.77, 140.66, 145.37, 148.35, 148.59, 161.35. MS (70 eV, EI) m/z (%): 333 (8), 332 (25), 331 (100), 317 (8), 316 (6), 315 (27), 165 (15), 43 (31). IR ATR ν (cm-1): 2949, 2928, 1610, 1587, 1522, 1477, 1401, 1350, 1239, 1194, 1155, 1057, 990, 946, 846, 836, 799, 762, 749. HRMS (EI) for C22H26N2Si (346.1865) [M]+: 346.1852.

Synthesis of 2-(3'-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)-[1,1'-biphenyl]-2yl)pyridine (25d):

According to TP6, a solution of 2p in THF (2 mmol, 4 equiv, 0.80 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and 2-(2-

(trimethylsilyl)phenyl)pyridine (24) (113.5 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 25d as white crystals.

Isolated yield: 83 %. Solvent for purification: i-hexane/ethyl acetate 15:1. m.p.: 60.8 – 62.5 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: -0.02 (s, 9 H), 0.08 (s, 6 H), 0.93 (s, 9 H), 6.53 - 6.74

(m, 3 H), 6.91 (d, J=7.99 Hz, 1 H), 7.00 (t, J=7.80 Hz, 1 H), 7.08 - 7.15 (m, 1 H), 7.36 - 7.40 (m, 2 H), 7.45 (t, J=7.51 Hz, 1 H), 7.69 (dd, J=7.41, 1.36 Hz, 1 H), 8.61 (d, J=4.09 Hz, 1 H).

175

13C

NMR (75 MHz, DMSO) δ/ppm: -4.43, 0.33, 18.13, 25.65, 118.15, 121.70, 121.74,

123.18, 126.14, 127.34, 128.49, 130.72, 134.17, 135.11, 139.89, 140.57, 143.21, 145.40, 148.42, 154.91, 160.82. MS (70 eV, EI) m/z (%): 420 (14), 419 (37), 418 (100), 402 (6), 180 (14), 73 (13). IR ATR ν (cm-1): 2955, 2929, 2853, 1599, 1583, 1563, 1483, 1471, 1454, 1398, 1299, 1250, 1213, 1191, 1160, 1051, 939, 881, 833, 776, 749, 675. HRMS (EI) for C26H35NOSi2 (433.2257) [M]+: 433.2235.

Synthesis of 2-(4'-fluoro-3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)pyridine (25e):

According to TP6, a solution of 2g in THF (2 mmol, 4 equiv., 0.80 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and 2-(2-

(trimethylsilyl)phenyl)pyridine (24) (113.5 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 25e as white crystals.

Isolated yield: 84 %. Solvent for purification: i-hexane/ethyl acetate 10:1. m.p.: 72.0 – 73.8 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: -0.02 (s, 9 H), 6.78 - 6.91 (m, 3 H), 7.03 (dd, J=8.57,

5.53 Hz, 2 H), 7.13 (dd, J=6.91, 5.25 Hz, 1 H), 7.36 - 7.49 (m, 3 H), 7.70 (d, J=7.46 Hz, 1 H), 8.61 (d, J=4.70 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.28, 114.33, 114.61, 121.76, 126.18, 127.48, 130.69,

131.23, 134.18, 135.23, 137.73, 139.74, 139.98, 145.60, 148.48, 159.90, 160.74, 163.16. MS (70 eV, EI) m/z (%): 308 (7), 307 (25), 306 (100), 276 (21), 153 (2). IR ATR ν (cm-1): 2949, 2925, 1584, 1508, 1474, 1416, 1245, 1237, 1219, 1157, 1093, 1044, 1013, 856, 836, 805, 793, 749, 686. 176

C.Experimental Section HRMS (EI) for C20H20FNSi (321.1349) [M]+: 321.1321.

Synthesis of 2-(3'-methyl-3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)pyridine (25f):

According to TP6, a solution of 2b in THF (2 mmol, 4 equiv, 0.90 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and 2-(2-

(trimethylsilyl)phenyl)pyridine (24) (113.5 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 6 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 25f as a colorless oil.

Isolated yield: 89 %. Solvent for purification: i-hexane/ethyl acetate 15:1. 1H

NMR (300 MHz, DMSO) δ/ppm: -0.03 (s, 9 H), 2.18 (s, 3 H), 6.79 - 7.15 (m, 6 H), 7.31 -

7.48 (m, 3 H), 7.67 (dd, J=6.91, 1.94 Hz, 1 H), 8.60 (d, J=4.42 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.32, 21.22, 121.59, 126.19, 126.84, 126.91, 127.36,

127.38, 130.71, 130.76, 133.97, 135.00, 137.06, 139.79, 140.80, 141.60, 145.59, 148.35, 161.03. MS (70 eV, EI) m/z (%): 316 (10), 306 (17), 304 (23), 303 (27), 302 (100), 272 (16), 245 (22), 244 (66), 127 (14), 105 (11), 57 (15), 44 (22). IR ATR ν (cm-1): 3053, 2948, 1604, 1586, 1564, 1474, 1400, 1260, 1244, 1144, 1062, 1021, 989, 882, 834, 781, 761, 744, 706, 671. HRMS (EI) for C21H22NSi (316.1522) [M-H]+: 316.1524

177

Synthesis of 2-(3-iodo-3'-methyl-[1,1'-biphenyl]-2-yl)pyridine (25fa):

To a solution of 25f (317.5 mg, 1 mmol, 1.0 equiv) in CH2Cl2 (5 ml) was added dropwise ICl (496 mg, 3.5 mmol, 3.5 equiv) at 0 °C. Reaction mixture was warm up to 23 °C and then was stirred under reflux for 12 h, before being quenched with sat. aq. Na2S2O3 and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 25fa as a colourless oil.

Isolated yield: 56 %. Solvent for purification: i-hexane/ethyl acetate 15:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 2.18 (s, 3 H) 6.74 - 7.05 (m, 5 H) 7.07 - 7.19 (m, 2 H)

7.39 (d, J=7.74 Hz, 1 H) 7.50 (td, J=7.67, 1.52 Hz, 1 H) 7.95 (d, J=7.74 Hz, 1 H) 8.62 (d, J=4.42 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 21.20, 99.24, 122.06, 125.26, 126.42, 127.46, 127.47,

129.66, 129.91, 130.22, 135.78, 137.22, 138.26, 140.68, 142.78, 143.62, 148.65, 161.31. MS (70 eV, EI) m/z (%): 372 (16), 371 (96), 370 (100), 244 (41), 243 (67), 242 (31), 149 (22), 71 (23), 43 (28). IR ATR ν (cm-1): 2956, 2918, 2856, 1722, 1587, 1564, 1547, 1445, 1418, 1270, 1126, 1121, 1072, 1020, 989, 960, 776, 744, 704. HRMS (EI) for C18H14IN (370.0093) [M-1]+: 370.0081.

Synthesis of 3''-methyl-2'-(pyridin-2-yl)-[1,1':3',1''-terphenyl]-3-carbonitrile (27):

178

C.Experimental Section A solution of 26 in THF (0.45 mmol, 1.5 equiv, 0.31 M) was added dropwise to a mixture of Pd(dba)2 (4.7 mg, 0.009 mmol, 0.03 equiv), tris(2-furyl)phosphine (4.2 mg, 0.018 mmol, 0.06 equiv) and 2-(3-iodo-3'-methyl-[1,1'-biphenyl]-2-yl)pyridine (25fa) (111.4 mg, 0.3 mmol, 1 equiv) in THF (0.3 ml) at 23 °C. The reaction mixture was stirred at 50 °C for 15 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 27 as white crystals.

Isolated yield: 70 %. Solvent for purification: i-hexane/ethyl acetate 15:1. m.p.: 125.5-127.2 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 2.20 (s, 3 H), 6.75 - 6.89 (m, 2 H), 6.89 - 7.14 (m, 4 H),

7.17 - 7.45 (m, 6 H), 7.46 - 7.58 (m, 2 H), 8.32 (d, J=4.70 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 21.22, 111.78, 118.68, 121.24, 126.59, 126.70, 127.27,

127.55, 128.39, 128.42, 128.99, 129.91, 130.28, 130.43, 132.98, 133.95, 135.19, 137.32, 138.44, 139.53, 140.84, 142.20, 142.96, 148.60, 158.18. MS (70 eV, EI) m/z (%): 379 (7), 347 (9), 346 (51), 345 (100), 343 (6), 303 (2), 172 (4), 165 (5). IR ATR ν (cm-1): 3051, 2919, 1590, 1575, 1473, 1436, 1401, 805, 780, 758, 734, 706, 698, 681. HRMS (EI) for C25H17N2 (345.1392) [M-1]+: 345.1387.

Synthesis of 4,4-dimethyl-2-(3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)-4,5-dihydrooxazole (29a):

According to TP6, a solution of 2a in THF (2 mmol, 4 equiv, 1.10 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 4,4-dimethyl-2-(2(trimethylsilyl)phenyl)-4,5-dihydrooxazole (28) (123.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with brine and extracted

179

with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 29a as a colorless oil.

Isolated yield: 91 %. Solvent for purification: i-hexane/ethyl acetate 10:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.35 (s, 9 H), 1.10 (s, 6 H), 3.81 (s, 2 H), 7.28 - 7.45

(m, 7 H), 7.55 - 7.59 (m, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.21, 27.97, 67.87, 78.82, 125.80, 126.99, 127.66,

128.11, 128.45, 129.07, 130.49, 133.38, 134.03, 139.20, 141.30, 142.26, 162.77 MS (70 eV, EI) m/z (%): 323 (29), 322 (100), 308 (30), 252 (8), 236 (19), 220 (10), 42 (11). IR ATR ν (cm-1): 3054, 2965, 2892, 1659, 1462, 1443, 1413, 1363, 1344, 1286, 1246, 1210, 1183, 1146, 1097, 1033, 961, 920, 854, 836, 760, 751, 697. HRMS (EI) for C20H24NOSi (322.1627) [M-H]+: 322.1631.

Synthesis of 2-(3'-methoxy-3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)-4,4-dimethyl-4,5dihydrooxazole (29b):

According to TP6, a solution of 10d in THF (2 mmol, 4 equiv, 0.84 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 4,4-dimethyl-2-(2(trimethylsilyl)phenyl)-4,5-dihydrooxazole (28) (123.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 5 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 29b as a beij oil.

Isolated yield: 85 %. Solvent for purification: i-hexane/ethyl acetate 6:1.

180

C.Experimental Section 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 1.11 (s, 6 H), 3.79 (s, 3 H), 3.84 (s, 2 H),

6.85 (d, J=8.23 Hz, 1 H), 6.94 (br. s., 1 H), 6.97 (d, J=7.68 Hz, 1 H), 7.24 (t, J=7.68 Hz, 1 H), 7.31 (d, J=7.41 Hz, 1 H), 7.40 (t, J=7.41 Hz, 1 H), 7.56 (d, J=7.41 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.20, 27.93, 55.25, 67.82, 78.92, 112.96, 114.49,

121.66, 128.47, 128.67, 130.39, 133.45, 133.83, 139.23, 142.14, 142.60, 158.99, 162.83. MS (70 eV, EI) m/z (%): 353 (17), 352 (58), 338 (18), 281 (17), 266 (42), 236 (16), 126 (59), 61 (16). IR ATR ν (cm-1): 3056, 2960, 2926, 1664, 1636, 1599, 1574, 1493, 1461, 1363, 1321, 1288, 1223, 1216, 1174, 1094, 1035, 960, 918, 868, 775, 759, 697. HRMS (EI) for C21H26NO2Si (352.1733) [M-H]+: 352.1725.

Synthesis of 2'-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N,N-dimethyl-3'-(trimethylsilyl)[1,1'-biphenyl]-4-amine (29c):

According to TP6, a solution of 2n in THF (2 mmol, 4 equiv, 1.10 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 4,4-dimethyl-2-(2(trimethylsilyl)phenyl)-4,5-dihydrooxazole (28) (123.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 15 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 29c as dark violet crystals.

Isolated yield: 72 %. Solvent for purification: i-hexane/ethyl acetate 7:1, then 4:1. m.p.: 162.8 – 164.6 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 1.19 (s, 6 H), 2.96 (s, 6 H), 3.86 (s, 2 H),

6.76 (d, J=8.29 Hz, 2 H), 7.25 - 7.32 (m, 3 H), 7.38 (t, J=7.60 Hz, 1 H), 7.49 - 7.54 (m, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.28, 28.13, 29.68, 40.91, 67.82, 78.90, 112.28, 128.46,

129.75, 130.81, 132.76, 134.04, 139.07, 142.23, 149.56, 163.28. MS (70 eV, EI) m/z (%): 366 (18), 365 (13), 352 (29), 351 (100), 279 (9), 139 (7). 181

IR ATR ν (cm-1): 2959, 2919, 2855, 1659, 1608, 1523, 1461, 1355, 1292, 1280, 1250, 1240, 1193, 1164, 1096, 1053, 1035, 961, 942, 920, 835, 813, 767. HRMS (EI) for C22H30N2OSi (366.2127) [M]+: 366.2130.

Synthesis of 2-(3'-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)4,4-dimethyl-4,5-dihydrooxazole (29d):

According to TP6, a solution of 2p in THF (2 mmol, 4 equiv, 0.77 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 4,4-dimethyl-2-(2(trimethylsilyl)phenyl)-4,5-dihydrooxazole (28) (123.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 12 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 29d as a colorless oil.

Isolated yield: 78 %. Solvent for purification: i-hexane/ethyl acetate 9:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.19 (s, 6 H), 0.35 (s, 9 H), 0.98 (s, 9 H), 1.15 (s, 6 H),

3.83 (s, 2 H), 6.79 (dd, J=8.02, 1.38 Hz, 1 H), 6.90 (t, J=1.80 Hz, 1 H), 6.98 (d, J=7.74 Hz, 1 H), 7.18 (t, J=8.02 Hz, 1 H), 7.24 - 7.32 (m, 1 H), 7.40 (t, J=7.60 Hz, 1 H), 7.53 - 7.59 (m, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: -4.40, 0.24, 18.14, 25.66, 28.00, 67.89, 78.90, 118.38,

120.94, 122.31, 128.43, 128.53, 130.40, 133.39, 139.19, 142.00, 142.70, 149.57, 155.02, 162.78. MS (70 eV, EI) m/z (%): 454 (18), 453 (43), 452 (100), 439 (14), 438 (34), 308 (10), 73 (28). IR ATR ν (cm-1): 2957, 2929, 2984, 2857, 1660, 1602, 1580, 1484, 1462, 1301, 1285, 1248, 1222, 1211, 1096, 1035, 949, 919, 830, 778, 763, 698. HRMS (EI) for C26H38NO2Si2 (452.2441) [M-H]+: 452.2429.

182

C.Experimental Section Synthesis of 2-(4'-fluoro-3-(trimethylsilyl)-[1,1'-biphenyl]-2-yl)-4,4-dimethyl-4,5dihydrooxazole (29e):

According to TP6, a solution of 2g in THF (2 mmol, 4 equiv, 0.77 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 4,4-dimethyl-2-(2(trimethylsilyl)phenyl)-4,5-dihydrooxazole (28) (123.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 29e as a colorless oil.

Isolated yield: 87 %. Solvent for purification: i-hexane/ethyl acetate 10:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 1.12 (s, 6 H), 3.84 (s, 2 H), 7.03 (t,

J=8.77 Hz, 2 H), 7.25 - 7.30 (m, 1 H), 7.31 - 7.44 (m, 3 H), 7.57 (dd, J=7.51, 1.07 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.17, 28.01, 67.86, 78.91, 114.42, 114.63, 128.57,

130.53, 130.68, 130.75, 133.58, 137.18, 137.21, 139.39, 141.16, 160.95, 163.39. MS (70 eV, EI) m/z (%): 342 (8), 341 (32), 340 (100), 327 (15), 326 (53), 255 (10), 254 (17), 165 (8). IR ATR ν (cm-1): 2966, 2894, 1659, 1602, 1511, 1462, 1451, 1421, 1364, 1344, 1286, 1246, 1220, 1158, 1093, 1046, 1034, 1015, 985, 961, 920, 857, 834, 796, 762, 711. HRMS (EI) for C20H23FNOSi (340.1533) [M-H]+: 340.1529.

Synthesis of 2-(4'-fluoro-3-iodo-[1,1'-biphenyl]-2-yl)-4,4-dimethyl-4,5-dihydrooxazole (29ea):

183

To a solution of 29e (341.5 mg, 1 mmol, 1 equiv) in DCM (0.2 M) was added dropwise ICl (568.3 mg, 3.5 mmol, 3.5 equiv) at 0 °C. Reaction mixture was warmed up to 23 °C and then heated under reflux for 6 h, before being quenched with sat. aq. Na2S2O3 and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 29ea as light yellow crystals.

Isolated yield: 86 %. Solvent for purification: i-hexane/ethyl acetate 10:1, then 3:1. m.p.: 101.5 – 102.6 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 1.18 (s, 6 H), 3.93 (s, 2 H), 7.04 (t, J=8.51 Hz, 2 H),

7.12 (t, J=7.82 Hz, 1 H), 7.29 (d, J=7.68 Hz, 1 H), 7.31 - 7.41 (m, 2 H), 7.83 (d, J=7.96 Hz, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 27.61, 68.00, 79.47, 96.83, 114.77, 114.91, 129.32,

130.44, 130.49, 130.89, 134.05, 135.85, 135.87, 138.08, 142.54, 161.69, 162.38, 163.33. MS (70 eV, EI) m/z (%): 394 (85), 308 (22), 252 (11), 197 (15), 191 (12), 126 (45), 70 (14), 61 (18), 57 (17), 44 (97), 43 (100). IR ATR ν (cm-1): 2970, 2960, 1673, 1604, 1595, 1509, 1449, 1363, 1347, 1289, 1211, 1160, 1094, 1039, 1024, 961, 922, 836, 784, 747. HRMS (EI) for C17H14FNOI (394.0104) [M-H]+: 394.0092.

Synthesis of ethyl 2'-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-4''-fluoro-[1,1':3',1''terphenyl]-3-carboxylate (31):

A solution of 30 in THF (0.45 mmol, 1.5 equiv, 0.71 M) was added dropwise to a mixture of Pd(dba)2 (4.7 mg, 0.009 mmol, 0.03 equiv), tris(2-furyl)phosphine (4.2 mg, 0.018 mmol, 0.06 equiv) and 2-(3-iodo-3'-methyl-[1,1'-biphenyl]-2-yl)pyridine (29ea) (118.0 mg, 0.3 mmol, 1 equiv) in THF (0.3 ml) at 23 °C. The reaction mixture was stirred at 50 °C for 15 h, before being quenched with brine and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 31 as a yellowish oil. 184

C.Experimental Section Isolated yield: 92 %. Solvent for purification: i-hexane/ethyl acetate 4:1, then 3:1. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.90 (s, 6 H), 1.35 (t, J=7.19 Hz, 3 H), 3.60 (s, 2 H),

4.35 (q, J=7.19 Hz, 2 H), 7.05 (t, J=8.71 Hz, 2 H), 7.32 - 7.53 (m, 6 H), 7.64 (d, J=7.74 Hz, 1 H), 8.03 (d, J=7.74 Hz, 1 H), 8.13 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 14.34, 27.38, 61.00, 67.67, 79.01, 114.63, 114.91,

127.90, 128.06, 128.60, 128.76, 129.02, 129.55, 129.80, 130.22, 130.48, 130.59, 130.86, 133.31, 136.47, 136.51, 140.73, 141.25, 141.31, 160.99, 166.40. MS (70 eV, EI) m/z (%): 417 (29), 416 (100), 316 (4), 272 (10), 257 (5), 149 (9), 55 (10), 40 (4). IR ATR ν (cm-1): 2966, 2926, 1716, 1664, 1606, 1512, 1460, 1365, 1288, 1256, 1236, 1159, 1125, 1104, 1034, 960, 840, 802, 755, 696. HRMS (EI) for C26H23FNO3 (416.1662) [M-H]+: 416.1656.

6.3 Preparation of Arylated Products Using TP7

Synthesis of 4'-(dimethylamino)-3-(trimethylsilyl)-[1,1'-biphenyl]-2-carbaldehyde (34aa and 34ba):

According to TP7, a solution of 2n in THF (2 mmol, 4 equiv, 1.1 M) was added dropwise to a mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and

2-(4-

methoxystyryl)phenyl)trimethylsilane (32) (141.2 mg, 0.5 mmol, 1 equiv) or N-(2(trimethylsilyl)benzylidene)butan-1-amine (33) (116.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 16 h (34aa) or 3 h (34ba), before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was washed with brine and dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 34aa or 34ba as a redish oil.

185

Isolated yield of 34aa: 76 % 34ba: 73 % Solvent for purification: i-hexane/ethyl acetate 95:5. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.35 (s, 9 H), 3.04 (s, 6 H), 6.85 (d, J=7.74 Hz, 2 H),

7.24 - 7.29 (m, 2 H), 7.42 - 7.47 (m, 1 H), 7.55 (t, J=7.46 Hz, 1 H), 7.70 (d, J=7.19 Hz, 1 H), 9.99 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.33, 40.70, 112.35, 131.17, 131.79, 131.86, 132.08,

134.19, 138.32, 142.20, 147.32, 149.82, 194.47. MS (70 eV, EI) m/z (%): 297 (26), 283 (23), 282 (100), 266 (8), 237 (11), 208 (12), 165 (8), 141 (10), 140 (18). IR ATR ν (cm-1): 2946, 2923, 2851, 1680, 1607, 1571, 1523, 1453, 1445, 1381, 1353, 1244, 1195, 1179, 1143, 1049, 946, 860, 837, 820, 795, 763, 671. HRMS (EI) for C18H23NOSi (297.1549) [M]+: 297.1549.

Synthesis of 4'-fluoro-3-(trimethylsilyl)-[1,1'-biphenyl]-2-carbaldehyde (34ab and 34bb):

According to TP7, a solution of 2g in THF (2 mmol, 4 equiv., 1.02 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv.)

and 2-(4-

methoxystyryl)phenyl)trimethylsilane (32) (141.2 mg, 0.5 mmol, 1 equiv.) or N-(2(trimethylsilyl)benzylidene)butan-1-amine (33) (116.7 mg, 0.5 mmol, 1 equiv.) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv.) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 16 h (34ab) or 2 h (34bb), before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 34ab or 34bb as white crystals.

Isolated yield of 34ab: 61 %. 34ab: 88 %. Solvent for purification: i-hexane/ethyl acetate 95:5. m.p.: 65.3 – 66.9 °C.

186

C.Experimental Section 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 7.15 (t, J=8.57 Hz, 2 H), 7.30 - 7.43 (m, 3

H), 7.58 (t, J=7.60 Hz, 1 H), 7.77 (d, J=7.46 Hz, 1 H), 9.95 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.23, 115.18, 115.46, 131.60, 131.71, 132.01, 134.98,

135.19, 138.37, 142.62, 145.99, 161.00, 164.28, 193.65. MS (70 eV, EI) m/z (%): 258 (23), 257 (100), 196 (3), 183 (22), 165 (4). IR ATR ν (cm-1): 2950, 2860, 1686, 1599, 1503, 1379, 1245, 1228, 848, 839, 800, 763. HRMS (EI) for C15H14OFSi (257.0798) [M-CH3]+: 257.0786.

Synthesis of 3'-chloro-4'-(trifluoromethyl)-3-(trimethylsilyl)-[1,1'-biphenyl]-2carbaldehyde (34ac):

According to TP7, a solution of 10e in THF (2 mmol, 4 equiv, 1.01 M) was added dropwise to a mixture of anhydrous CrCl2 (6.1 mg, 0.05 mmol, 0.1 equiv) and 2-(4methoxystyryl)phenyl)trimethylsilane (32) (141.2 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 25 h, before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 34ac as a yellow oil.

Isolated yield: 75 %. Solvent for purification: i-hexane/ethyl acetate 95:5. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.35 (s, 9 H), 7.38 (d, J=7.74 Hz, 1 H), 7.47 (dd,

J=8.16, 1.80 Hz, 1 H), 7.57 - 7.66 (m, 2 H), 7.71 (d, J=1.94 Hz, 1 H), 7.82 (d, J=7.46 Hz, 1 H), 9.96 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.19, 122.59 (q, J=273.58 Hz), 128.32, 128.61 (q,

J=5.41 Hz), 131.36, 131.53, 132.21 (q, J=1.99 Hz), 132.25, 134.21, 135.70, 135.95, 138.22, 143.34, 144.11, 192.71. MS (70 eV, EI) m/z (%): 343 (35), 342 (21), 341 (100), 307 (5), 170 (4). IR ATR ν (cm-1): 2946, 2853, 1696, 1571, 1482, 1402, 1379, 1323, 1285, 1245, 1175, 1136, 1130, 1110, 1035, 906, 872, 835, 798, 764, 703, 672, 662. 187

HRMS (EI) for C16H13OClF3Si (341.0376) [M-CH3]+: 341.0382.

Synthesis of 2-(benzo[d][1,3]dioxol-5-yl)-6-(trimethylsilyl)benzaldehyde (34ad): TMS O H O O

According to TP7, a solution of 2k in THF (2 mmol, 4 equiv, 1.10 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and 2-(4-

methoxystyryl)phenyl)trimethylsilane (32) (141.2 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 16 h, before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 34ad as a yellow viscous oil.

Isolated yield: 67 %. Solvent for purification: i-hexane/ethyl acetate 95:5. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 6.04 (s, 2 H), 6.71 - 7.04 (m, 3 H), 7.36 -

7.45 (m, 1 H), 7.56 (t, J=7.46 Hz, 1 H), 7.73 (d, J=7.46 Hz, 1 H), 9.97 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.25, 101.36, 108.09, 110.34, 124.08, 131.67, 131.90,

132.82, 134.87, 138.52, 142.40, 146.69, 147.58, 147.73, 193.93. MS (70 eV, EI) m/z (%): 284 (24), 283 (100), 253 (12), 242 (11), 209 (10), 165 (7), 141 (10). IR ATR ν (cm-1): 2949, 2894, 1693, 1680, 1502, 1488, 1455, 1437, 1386, 1336, 1243, 1222, 1180, 1105, 1038, 1031, 936, 907, 838, 795, 763, 673. HRMS (EI) for C17H18O3Si (298.1025) [M]+: 298.1019.

Synthesis of 4'-(trifluoromethoxy)-3-(trimethylsilyl)-[1,1'-biphenyl]-2-carbaldehyde (34bc):

188

C.Experimental Section According to TP7, a solution of 2z in THF (2 mmol, 4 equiv, 1.10 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and N-(2-

(trimethylsilyl)benzylidene)butan-1-amine (33) (116.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 3 h, before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 34bc as white crystals. Isolated yield: 75 %. Solvent for purification: i-hexane/ethyl acetate 100:1, then 30:1. m.p.: 65.8 – 67.6 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 7.27 - 7.33 (m, 2 H), 7.39 (d, J=8.29 Hz,

3 H), 7.59 (t, J=7.46 Hz, 1 H), 7.78 (d, J=7.46 Hz, 1 H), 9.95 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.19, 120.45 (J=157.50 Hz), 120.70, 131.40, 131.60,

132.05, 135.44, 137.73, 138.30, 142.77, 145.54, 149.05, 193.40. MS (70 eV, EI) m/z (%): 324 (18), 323 (100), 249 (11), 165 (10), 82 (10), 69 (16), 44 (21). IR ATR ν (cm-1): 2949, 2894, 1693, 1680, 1502, 1488, 1455, 1437, 1386, 1336, 1243, 1222, 1180, 1105, 1038, 936, 907, 838, 795, 763, 673. HRMS (EI) for C16H14F3O2Si (323.0715) [M-CH3]+: 323.0710.

Synthesis of 4'-(trifluoromethoxy)-3-(trimethylsilyl)-[1,1'-biphenyl]-2-carbaldehyde (34bd):

According to TP7, a solution of 10f in THF (2 mmol, 4 equiv, 0.94 M) was added dropwise to a

mixture

of

anhydrous

CrCl2

(6.1

mg,

0.05

mmol,

0.1

equiv)

and N-(2-

(trimethylsilyl)benzylidene)butan-1-amine (33) (116.7 mg, 0.5 mmol, 1 equiv) at 23 °C. Then, 2,3-dichlorobutane (9.5 mg, 0.75 mmol, 1.5 equiv) was added dropwise at 23 °C. The reaction mixture was stirred at 23 °C for 1.5 h, before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 34bd as white crystals. 189

Isolated yield: 74 %. Solvent for purification: i-hexane/ethyl acetate 200:1. m.p.: 76.3 - 78.3 °C. 1H

NMR (300 MHz, DMSO) δ/ppm: 0.34 (s, 9 H), 1.38 (s, 9 H), 7.30 (d, J=8.29 Hz, 2 H),

7.39 - 7.51 (m, 3 H), 7.57 (t, J=7.46 Hz, 1 H), 7.74 (d, J=7.19 Hz, 1 H), 9.97 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 0.27, 31.34, 34.63, 125.21, 129.87, 131.76, 131.89,

134.81, 135.95, 138.38, 142.23, 147.20, 150.95, 194.20. MS (70 eV, EI) m/z (%): 296 (25), 295 (100), 239 (5), 221 (4), 179 (3), 165 (6), 126 (14), 57 (11). IR ATR ν (cm-1): 2962, 2886, 1669, 1569, 1456, 1406, 1246, 1182, 1113, 1082, 1016, 859, 836, 796, 748, 669, 668. HRMS (EI) for C19H23OSi (295.1518) [M-CH3]+: 295.1525.

Synthesis of 4'-(trifluoromethoxy)-3-(trimethylsilyl)-[1,1'-biphenyl]-2-carbaldehyde (37):

A solution of 2i in THF (2 mmol, 4 equiv, 1.0 M) was added dropwise to a mixture of anhydrous CrCl2 (3.7 mg, 0.03 mmol, 0.03 equiv) and 35 (116.7 mg, 0.5 mmol, 1 equiv) at 23 °C. The suspension was stirred at 23 °C for 2 h. Then anhydrous CrCl2 (12.2 mg, 0.1 mmol, 0.1 equiv) and a solution of 2g were added followed by the dropwise addition of 2,3dichlorobutane (190 mg, 1.5 mmol, 1.5 equiv). The reaction mixture was stirred at 23 °C for addtional 1 h, before being quenched with an aq. solution of HCl (2M) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude compound, which was purified by column chromatography to yield 37 as light yellow crystals.

Isolated yield: 65 %. Solvent for purification: i-hexane/ethyl acetate 100:1, then 10:1 m.p.: 83.0 – 84.8 °C.

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C.Experimental Section 1H

NMR (300 MHz, DMSO) δ/ppm: 3.86 (s, 3 H), 6.97 (d, J=8.57 Hz, 2 H), 7.10 (t, J=8.71

Hz, 2 H), 7.23 - 7.34 (m, 5 H), 7.40 (d, J=7.74 Hz, 1 H), 7.56 (t, J=7.60 Hz, 1 H), 9.93 (s, 1 H). 13C

NMR (75 MHz, DMSO) δ/ppm: 55.31, 113.77, 114.85, 115.14, 130.16, 130.42, 130.94,

131.01, 131.12, 131.31, 131.54, 133.14, 135.91, 135.96, 142.71, 144.54, 159.46, 160.73, 164.00, 193.54. MS (70 eV, EI) m/z (%): 306 (100), 275 (27), 263 (11), 233 (20), 207 (5), 170 (7), 139 (4). IR ATR ν (cm-1): 2923, 2845, 1699, 1604, 1507, 1456, 1292, 1253, 1213, 1172, 1038, 1017, 835, 805, 744, 677. HRMS (EI) for C20H15FO2 (306.1056) [M]+: 306.1050.

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