Rhodium-Catalyzed Addition of Arylboronic Acids to Nitriles: Application in the Synthesis of Unsymmetrical Polysubstituted Pyridines

Home , Heterocyclic compound

Chan Tong Lau

A thesis submitted in conformity with the requirements for the degree of Master of Science Graduate Department of Chemistry University of Toronto

Rhodium-Catalyzed Addition of Arylboronic Acids to Nitriles: Application in the Synthesis of Unsymmetrical Polysubstituted Pyridines

Chan Tong Lau

Master of Science

Graduate Department of Chemistry University of Toronto

2011

Abstract

Investigations pertaining to the rhodium(I)-catalyzed addition of arylboronic acids to

(arylsulfonyl)acetonitriles were undertaken. The resulting carbon-carbon bond forming reaction has led to the efficient synthesis of novel stereoselective (Z)-β-sulfonylvinylamines, which upon acidic hydrolysis, afford useful β-keto sulfones possessing a diverse range of aryl and sulfonyl substituents. The synthetic utility of these (Z)-β-sulfonylvinylamines was subsequently explored by generating the corresponding 1-aza-allyl anion equivalents under basic conditions. This interesting anionic intermediate was then introduced to various ,-unsaturated systems to produce a diverse array of functionalized pyridine derivatives including unsymmetrical polysubstituted pyridines.

Acknowledgments

Being given the opportunity to formally include an acknowledgments section has allowed me to fully appreciate the significant impact that numerous individuals have made on my development both in and outside the lab. Firstly, I would like to extend a gesture of thanks and gratitude to Mark for accepting me into his group and creating an environment that makes it easy for his students to grow as researchers.

I would like to thank Gavin for all of his help and support spanning both major projects that I have been involved with during my time in Toronto. It was a pleasure to be part of team “Rhodium Catalysis” which then branched out to team “Pyridine Synthesis”. We may have been a small team, but we had a lot of heart.

It has been a pleasure to have met Norman and Patrick, whose sense of humour and easygoing natures were the catalysts (haha) that led to the formation of a good friendship. I would also like to thank my fellow first year graduate students Momo, Jackie, Jenny, and Jenn. We had some really good conversations and I could not have asked for a better group of people to have started graduate studies with. Thank you for your friendships.

I would also like to take this time to thank Shabnam, Richard, and Dennis for keeping me company in the form of being my desk-mate and bench-mate. It was really fun to work beside you each day and I consider myself lucky to have sat and worked next to you. Finally, I would like to express my appreciation towards all of the Lautens group members both past and present for making my experience this past year a wonderful one.

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Table of Contents

Acknowledgments ...... iii Table of Contents ...... iv List of Abbreviations ...... vi List of Tables ...... viii List of Schemes...... ix List of Appendices ...... xiii

Chapter 1 : General Introduction ...... 1 Chapter 2 : Rh(I)-Catalyzed Additions to Carbon-Heteroatom Multiple Bonds ...... 3 2.1 Additions to Aldehydes ...... 3 2.2 Additions to Imines ...... 5 2.3 Additions to Anhydrides ...... 7 2.4 Transition Metal-Catalyzed Additions to Nitriles ...... 8 2.4-1 Palladium Catalysis ...... 8 2.4-2 Nickel Catalysis ...... 10 2.4-3 Rhodium Catalysis ...... 10 2.5 Rh-Catalyzed Additions to (Arylsulfonyl)acetonitriles ...... 12 2.5-1 Project Target ...... 12 2.5-2 Preliminary Discoveries and Optimization Process ...... 13 2.5-3 Scope of β-Keto Sulfones ...... 16 2.5-4 Synthesis of α-Arylated β-Sulfonylvinylamines...... 17 2.5-5 Synthesis of α-Arylated (Phenylsulfonyl)acetonitriles ...... 17 2.5-6 Scope of α-Arylated β-Sulfonylvinylamines ...... 18 2.5-7 Proposed Mechanism ...... 20 2.5-8 Conclusions ...... 21 Chapter 3 : 1-Aza-allylic Anions in the Synthesis of Heterocycles ...... 22 3.1 Approaches in Heterocycle Syntheses Derived from 1-Aza-Allyl Anions ...... 23 3.1-1 Piperidine Synthesis ...... 24 3.1-2 Pyrrole Synthesis ...... 24 3.1-3 Tetrahydrofuran Synthesis ...... 25

3.1-4 Pyridine Synthesis ...... 26 3.2 Heterocycle Syntheses Derived from β-Sulfonyl- vinylamines as 1-Aza-Allyl Anion Equivalents ...... 26 3.3 Synthesis of 2,4,6-Trisubstituted Pyridines from β-Sulfonylvinylamines via 1-Aza-Allyl Anion Equivalents ...... 27 3.3-1 Targeting the Synthesis of 2,4,6-Triaryl Pyridines ...... 28 3.3-2 Syntheses of Symmetrical 2,4,6-Triaryl Pyridines ...... 28 3.3-2a Chichibabin Pyridine Synthesis ...... 29 3.3-2b Kröhnke Pyridine Synthesis ...... 29 3.3-2c N-Phosphinylethanimine-Based Pyridine Synthesis ...... 30 3.3-2d Pyridine Synthesis Under Solvent-Free and Microwave Conditions ...... 31 3.3-3 Syntheses of Unsymmetrical 2,4,6-Triaryl Pyridines ...... 32 3.3-3a Kröhnke Unsymmetrical Pyridine Synthesis ...... 32 3.3-3b Lithiated-Phosphonate-Based Unsymmetrical Pyridine Synthesis ...... 33 3.3-3c Unsymmetrical Pyridine Synthesis Under Microwave and Lewis Acidic Conditions ...... 34 3.3-4 Preliminary Discoveries and Optimization Process ...... 34 3.3-5 Proposed Mechanism ...... 36 3.3-6 Scope of Unsymmetrical 2,4,6-Triarylsubstituted Pyridines ...... 37 3.3-7 Scope of Chalcones and β-Sulfonylvinylamines ...... 38 3.3-8 Scope of Heteroaryl-Containing Pyridines ...... 39 3.3-9 Synthesis of Polycyclic Pyridines ...... 40 3.3-10 Synthesis of Di-aryl-mono-alkyl Trisubstiuted Pyridines ...... 41 3.3-11 Synthesis of Di-aryl Disubstituted Pyridines ...... 42 3.3-12 Conclusions ...... 45 Appendix A: Supporting Information for Rhodium-Catalyzed Addition of Arylboronic Acids to (Arylsulfonyl)acetonitriles ...... 46 Appendix B: Supporting Information for Synthesis of Unsymmetrical Polysubstituted Pyridines ...... 53

List of Abbreviations

% percent 9-BBN 9-Borabicyclo[3.3.1]nonane Ac acetyl acac acetylacetonate aq. aqueous Ar aryl B: base BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BIPHEP 2,2'-bis(diphenylphosphino)-1,1'-biphenyl Bn benzyl bpy 2,2'-bipyridine br broad cat. catalyst cod 1,5-cyclooctadiene coe cyclooctene d doublet dba dibenzylideneacetone DCE 1,2-dichloroethane DCM dichloromethane dd doublet of doublets DME dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppb 1,4-bis(diphenylphosphino)butane dppbenz 1,2-bis(diphenylphosphino)benzene dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1'-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane E entgegen equiv. equivalent ESI electrospray ionization h hour HRMS high resolution mass spectrometry iPr isopropyl IR infrared J coupling constant LDA lithium diisopropylamide LG leaving group m meta M molar m multiplet

m.p. melting point mCPBA meta-chloroperbenzoic acid mg milligram MHz megahertz mL milliliter mmol millimoles 2-(diphenylphosphino)-2′-methoxy-1,1′- MOP binaphthyl MW microwave N normal NMR nuclear magnetic resonance Nu nucleophile o ortho oC degrees Celsius p para Ph phenyl ppm parts per million q quartet rt room temperature s singlet sat. saturated t triplet tBu tert-butyl tert tertiary TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TPPDS disodium triphenylphosphine-3,3'-disulfonate Ts tosyl UV ultraviolet Z zusammen α alpha β beta δ chemical shift or delta π pi σ sigma

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List of Tables

Table 2-1. Catalyst Screening for the Addition of Phenylboronic Acid to (Phenylsulfonyl)- acetonitrile 1a...... 13

Table 2-2. Solvent Screening for the Addition of Phenylboronic Acid to (Phenylsulfonyl)- acetonitrile 1a...... 14

Table 2-3. Scope of Arylboronic Acid and the Sulfonyl Substituent Group of Nitrile 1 in the Synthesis of β-Aryl Keto Sulfones 3...... 16

Table 2-4. Scope of α-Arylated (Phenylsulfonyl)acetonitrile Derivatives...... 18

Table 3-1. Optimization for the Formation of Pyridine 13...... 35

Table 3-2. Scope of Unsymmetrical Pyridines 18...... 37

Table 3-3. Scope of Chalcones...... 38

Table 3-4. Scope of -Sulfonylvinylamines...... 39

Table 3-5. Scope of Di-aryl-mono-alkyl Substituted Pyridines...... 42

Table 3-6. Optimization for Diphenyl Pyridine Isomers 26 and 27...... 44

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List of Schemes

Scheme 1-1. Common Carbon-Carbon Bond Forming Reactions using Rhodium...... 1

Scheme 1-2. Rh(I)-Catalyzed Synthesis of (Z)-β-Sulfonylvinylamines and β-Keto Sulfones...... 2

Scheme 1-3. Synthesis of Polysubstituted Pyridines from (Z)-β-Sulfonylvinylamines...... 2

Scheme 2-1. Arylation of Aldehydes with Arylstannanes...... 4

Scheme 2-2. Arylation of Aldehydes with Arylboron Reagents...... 4

Scheme 2-3. Electronic effects in the Arylation of Aldehydes...... 4

Scheme 2-4. Asymmetric Arylative Cyclization of Alkynals...... 5

Scheme 2-5. Arylation of Imines with Arylstannanes...... 5

Scheme 2-6. Asymmetric Arylation of Imines with Arylstannanes...... 6

Scheme 2-7. Asymmetric Arylation of Imines using C2-symmetric Diene Ligands...... 6

Scheme 2-8. Diastereoselective Arylation of Imines...... 6

Scheme 2-9. Acylation of Boronic Acids...... 7

Scheme 2-10. Rhodium-catalyzed Route to Unsymmetrical Diketones...... 7

Scheme 2-11. Palladium-catalyzed Intramolecular Addition to Nitriles...... 8

Scheme 2-12. Palladium-catalyzed Intermolecular Addition to Nitriles...... 8

Scheme 2-13. Acetoxypalladation of Alkynes and Intramolecular Nitrile Cyclization...... 9

Scheme 2-14. Cationic Palladium(II)-Catalyzed Addition to Nitriles...... 9

Scheme 2-15. Nickel-Catalyzed Addition to Nitriles...... 10

Scheme 2-16. Rhodium-Catalyzed Addition to Nitriles to Form Indenones...... 10

Scheme 2-17. Rhodium-Catalyzed Addition to Nitriles to Form Cyclic Ketones...... 11

Scheme 2-18. (oxa-π-allyl)Rhodium(I) Addition to Nitriles...... 11

Scheme 2-19. Intermolecular Rhodium-Catalyzed Addition to Nitriles...... 11

Scheme 2-20. Selective Rhodium-Catalyzed Addition to Nitriles from Ethyl Cyanoformate....12

Scheme 2-21. General Strategy of Project...... 12

Scheme 2-22. Scope of β-sulfonylvinylamines 2a-2d...... 15

Scheme 2-23. X-ray Crystal Structure of 2b Showing 30% Displacement Ellipsoids...... 15

Scheme 2-24. Proposed Synthesis of α-Arylated β-Sulfonylvinylamines...... 17

Scheme 2-25. Scope of Arylboronic Acid and α-Arylated (Phenylsulfonyl)acetonitriles 4 in the Synthesis of β-Sulfonylvinylamines 5...... 18

Scheme 2-26. X-ray Crystal Structure of 5c Showing 30% Displacement Ellipsoids...... 19

Scheme 2-27. Proposed Mechanism of Rh(I)-Catalyzed Addition of Arylboronic Acids to Nitrile 1...... 20

Scheme 2-28. Substrate Variants 7-10...... 21

Scheme 3-1. Synthesis of 1,2,3,4-Tetrahydropyridines using 1-Aza-allyl Anions...... 22

Scheme 3-2. Incorporating Biselectrophiles in 1-Aza-allyl Anion-Based Heterocyclic Synthesis...... 23

Scheme 3-3. Incorporating Bifunctional Substrates in 1-Aza-allyl Anion-Based Heterocyclic Synthesis...... 24

Scheme 3-4. Piperidine Synthesis...... 24

Scheme 3-5. Pyrrole Synthesis...... 25

Scheme 3-6. Tetrahydrofuran Synthesis...... 25

Scheme 3-7. Pyridine Synthesis...... 26

Scheme 3-8. Thiol-Containing Heterocycle Synthesis...... 27

Scheme 3-9. Sulfone-Containing Dihydropyridine Synthesis...... 27

Scheme 3-10. Proposed Synthesis of 2,4,6-Trisubstituted Pyridines...... 28

Scheme 3-11. Chichibabin Synthesis of 2,4,6-Triphenylpyridine...... 29

Scheme 3-12. Kröhnke Synthesis of 2,6-diphenyl-4-(p-chlorophenyl)pyridine...... 30

Scheme 3-13. N-Phosphinylethanimine-Based Synthesis of 2,6-diphenyl-4-(2- thienyl)pyridine...... 31

Scheme 3-14. Solvent-Free Synthesis of 2,6-bis(4-iodophenyl)-4-phenylpyridine...... 31

Scheme 3-15. Microwave Synthesis of 2,6-diphenyl-4-(2-thienyl)pyridine...... 31

Scheme 3-16. Lee Synthesis of 4-(furan-3-yl)-6-(thiophen-2-yl)-2,4'-bipyridine...... 32

Scheme 3-17. Malik Synthesis of 2-(4-chlorophenyl)-4-(3-nitrophenyl)-6-(thiophen-2- yl)pyridine...... 33

Scheme 3-18. Yan Synthesis of 4-(4-chlorophenyl)-2-phenyl-6-(p-tolyl)pyridine...... 33

Scheme 3-19. β-enaminophosphonate Ylid-Based Synthesis of 4-(4-methoxyphenyl)-6- (naphthalen-2-yl)-2,4'-bipyridine...... 34

Scheme 3-20. Kröhnke-Based Microwave and Lewis-Acidic Synthesis of 2-(4-chlorophenyl)-6- phenyl-4-(p-tolyl)pyridine...... 34

Scheme 3-21. Proposed Mechanism for the Synthesis of 2,4,6-Triphenylpyridine 17...... 36

Scheme 3-22. Scope of Heteroaryl-Containing Pyridines 21...... 39

Scheme 3-23. Proposed Synthesis of Polycyclic Pyridines...... 40

Scheme 3-24. Synthesis of Polycyclic Pyridines 23 and 24...... 41

Scheme 3-25. Synthesis of Unsymmetrical Di-aryl-mono-alkyl Substituted Pyridine 25...... 42

Scheme 3-26. Isomeric 2,6- and 2,4-Diphenylpyridine Formed...... 43

Scheme 3-27. Proposed Mechanism for Formation of 2,6-Diphenylpyridine 27...... 43

xii

List of Appendices

Appendix A: Supporting Information for Rhodium-Catalyzed Addition of Arylboronic Acids to (Arylsulfonyl)acetonitriles………………………………………………………………46 Appendix B: Supporting Information for Synthesis of Unsymmetrical Polysubstituted Pyridines……………………………………………...…………………………………53

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Chapter 1 : General Introduction

The incorporation of transition metals in synthetic organic chemistry has become more prevalent over the past thirty years. Applications of transition metal catalysts and reagents have allowed for transformations that are not possible by any other method and have also served vital roles in generating more efficient approaches in the total syntheses of complex molecules.

In recent years, transition metal-catalysis involving rhodium has emerged as a powerful tool for many important carbon-carbon bond forming reactions. As outlined in Scheme 1-1, notable rhodium(I)-catalyzed transformations of this kind include: (i) conjugate addition to activated alkenes1, (ii) addition to unactivated alkenes2 and alkynes3, (iii) hydroformylations4, (iv) cycloisomerizations5, and (v) allylic substitutions6.

Scheme 1-1. Common Carbon-Carbon Bond Forming Reactions using Rhodium

It is evident that carbon-rhodium nucleophilic additions to carbon-carbon multiple bonds has been thoroughly investigated7, and so as part of an ongoing effort in developing novel

1 Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. 2 Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001, 123, 5358. 3 Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. J. Am. Chem. Soc. 2001, 123, 9918. 4 Breit, B.; Zahn, S. K. Tetrahedron Lett. 1998, 39, 1901. 5 Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1998, 44, 4967. 6 Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. 7 (a) Knochel, P. Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, United Kingdom, 1991; Vol. 9. (b) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169. (c) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.

2 rhodium-catalyzed reactions, the first half of this thesis will focus on the less explored carbon- carbon bond forming reactions derived from additions to carbon-heteroatom multiple bonds. More specifically, advances to the rhodium-catalyzed addition of arylboronic acids to nitriles will be illustrated in the synthesis of (Z)-β-sulfonylvinylamines and β-keto sulfones (Scheme 1- 2).

Scheme 1-2. Rh(I)-Catalyzed Synthesis of (Z)-β-Sulfonylvinylamines and β-Keto Sulfones

The latter section of this thesis will present a novel synthesis of highly substituted pyridines utilizing the unique (Z)-β-sulfonylvinylamines compounds synthesized from the aforementioned rhodium-catalyzed reaction. This remarkable cascade reaction involves the generation of a 1-aza-allyl anion species from the corresponding β-sulfonylvinylamine followed by reaction with ,-unsaturated systems to produce a large array of complex pyridine derivatives ranging from highly differentiated substitution patterns to polycyclic heterocycles (Scheme 1-3).

Scheme 1-3. Synthesis of Polysubstituted Pyridines from (Z)-β-Sulfonylvinylamines

The overall objective for this study is two-fold. Initially, the goal was to expand the scope of rhodium-catalyzed reactions, and upon the unexpected discovery of novel vinylamine products, investigations were undertaken to explore the synthetic utility of this interesting class of amine in the construction of complex pyridine derivatives.

Chapter 2 : Rh(I)-Catalyzed Additions to Carbon-Heteroatom Multiple Bonds

The insertion of carbon-heteroatom multiple bonds into organotransition metal bonds is an important carbon-carbon bond forming process. Nucleophilic additions involving main group organometallics such as organolithium and organomagnesium compounds to carbon-heteroatom multiple bonds represent useful approaches in forming carbon-carbon bonds. However, analogous additions involving organometallic compounds of late transition metals such as organorhodium compounds have not been as prevalent by comparison. This discrepancy can be explained by the reduced nucleophilicity generally associated with late transition metals, which diminishes its compatibility with polarized carbon-heteroatom multiple bonds. Insertions of this type are further discouraged due to the observation that electrophilic metals tend to favour σ complexes with carbon-heteroatom multiple bonds rather than π complexes since the latter coordination model is crucial at least in the transition state to carry out the desired 2+2 addition.8 As well, stronger π bonds are generally associated with carbon-heteroatom bonds relative to carbon-carbon bonds9.

On the other hand, the advantage of incorporating less nucleophilic reagents into reaction models provides greater chemoselective control when dealing with multifunctional molecules. Recent reports have illustrated that rhodium(I) catalysts can facilitate 1,2-additions to aldehydes, imines, anhydrides, and nitriles. In the subsequent sections, selected examples involving each of these unsaturated heteroatom groups will be examined in an effort to emphasize advances in organorhodium chemistry.

2.1 Additions to Aldehydes The first report involving an organorhodium species adding to aldehydes was illustrated in 1997 by Oi10 using arylstannanes (Scheme 2-1). Quickly following this initial discovery were reports

8 (a) Shambayati, S.; Schreiber, S. L. Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Schreiber, S. L., Eds.; Pergamon Press: Oxford, United Kingdom, 1991; Vol. 1. (b) Noyori, R.; Yamakawa, S.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931. 9 For instance, a C=C π bond has a bond dissociation energy of approx. 65 kcal/mol whereas the BDE is 85 kcal/mol for a C=O π bond: Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Synthesis; Harper and Row: New York, New York, 1987; p. 162. 10 Inoue, I; Moro, M.; Oi, S. Chem. Commun. 1997, 1621.

4 from Miyaura11 and Batey12, who incorporated organoboron reagents which provided an air/moisture stable and less toxic alternative (Scheme 2-2).

Scheme 2-1. Arylation of Aldehydes with Arylstannanes

Scheme 2-2. Arylation of Aldehydes with Arylboron Reagents

Li studied the electronic effects of Rh(I)-catalyzed additions to aldehydes using phenyltin derivatives where it was shown that there was indeed a correlation between reactivity and the presence of electron-donating groups (Scheme 2-3).

Scheme 2-3. Electronic effects in the Arylation of Aldehydes

In the case of R = Me, the reactivity of the Ph-Sn bond is enhanced due to an alkyl group’s ability to inductively donate electrons. Similarly, reactions were able to proceed when R = OH due to a more influential electron donating resonance effect to the empty d-orbital of tin in comparison to the associated electron-withdrawing inductive effect. However, when R = Cl, electron-withdrawing induction may be stronger than the corresponding resonance effect, which results in no reaction.

Recently, Hayashi13 has illustrated an efficient asymmetric cyclization of alkynals (Scheme 2-4). This reaction presumably involves the Rh(I)-catalyzed addition of arylboron

11 Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998, 37, 3279. 12 Smil, D. V.; Thadani, A. N.; Batey, R. A. Org. Lett. 1999, 1, 1683.

5 nucleophiles to the alkyne functionality followed by generation of a chiral stereocenter from the ensuing cyclization to form chiral products containing allylic alcohols and tetrasubstituted olefins.

Scheme 2-4. Asymmetric Arylative Cyclization of Alkynals

2.2 Additions to Imines Oi14 was among the first to investigate additions to imines using organorhodium nucleophiles (Scheme 2-5). It was found that due to the low degree of electrophilicity of imines, electron- withdrawing activators such as tosyl groups were required in order for reaction to take place.

Scheme 2-5. Arylation of Imines with Arylstannanes

Hayashi15 proceeded to build upon this work by introducing the corresponding asymmetric imine addition (Scheme 2-6). This report marked the first catalytic asymmetric synthesis of diarymethylamines, which constitutes as a building block for many biologically biologically important compounds16. Hayashi17 later developed an alternative approach to

13 Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54. 14 Inoue, Y.; Kawanishi, T.; Fukuhara, H.; Oi, S. Tetrahedron Lett. 1999, 40, 9259. 15 Ishigedani, M.; Hayashi, T. J. Am. Chem. Soc. 2000, 122, 976. 16 (a) Bishop, M. J.; McNutt, R. W. Bioorg. Med. Chem. Lett. 1995, 5, 1311. (b) Spencer, C. M.; Foulds, D.; Peters, D. H. Drugs 1993, 46, 1055. (c) Sakurai, S.; Ogawa, N.; Suzuki, T.; Kato, K.; Ohashi, T.; Yasuda, S.; Kato, H.; Ito, Y. Chem. Pharm. Bull. 1996, 44, 765. 17 Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

6 accessing chiral diarylmethylamines through the use of novel C2-symmetric bicyclo[2.2.2]octadiene ligands (Scheme 2-7).

Scheme 2-6. Asymmetric Arylation of Imines with Arylstannanes

Scheme 2-7. Asymmetric Arylation of Imines using C2-symmetric Diene Ligands

In 2005, Ellman18 was able to illustrate a highly diastereoselective addition of arylboronic acids to both aromatic and aliphatic N-tert-butanesulfinyl imines (Scheme 2-8).

Scheme 2-8. Diastereoselective Arylation of Imines

From these examples, it is evident that rhodium-catalyzed additions to imines have made significant contributions in the asymmetric synthesis of -branched amines.

18 Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092.

2.3 Additions to Anhydrides Frost19 reported an efficient rhodium-catalyzed addition reaction which allowed for the synthesis of ketones from boronic acids (Scheme 2-9). The mechanism is described as a transmetalation to form the arylrhodium nucleophile followed by addition to the anhydride and finally, hydrolysis of the resulting rhodium alkoxide or enolate to afford the desired ketone products.

Scheme 2-9. Acylation of Boronic Acids

Traditional acylation reactions may require harsh Lewis-acidic conditions and lead to problems related to regiospecificity, and so this acylation equivalent methodology serves as a milder and efficient alternative.

Narasaka20 reported a rhodium-catalyzed acylation of vinylsilanes to furnish - benzoyloxy ketones (Scheme 2-10). Upon subsequent ester cleavage and acidic workup, this rhodium protocol afforded a novel route to the synthesis of unsymmetrical diketones. Generation of a Rh(III) complex is proposed to be an intermediate leading to the formation of the desired ketone product.

Scheme 2-10. Rhodium-catalyzed Route to Unsymmetrical Diketones

19 Wadsworth, K. J.; Frost, C. G. Chem. Commun. 2001, 2316. 20 Yamane, M.; Uera, K.; Narasaka, K. Chem. Lett. 2004, 33, 424.

2.4 Transition Metal-Catalyzed Additions to Nitriles

Developments in late transition metal-catalyzed additions to nitriles have led to discoveries that palladium, nickel, and rhodium complexes are capable of facilitating such reactions.

2.4-1 Palladium Catalysis The first efficient carbopalladation of nitriles was illustrated by Larock21 in the synthesis of carbocycles (Scheme 2-11). The mechanistic pathway can be described by an initial alkyne insertion followed by subsequent palladium addition to the nitrile group in intramolecular fashion.

Scheme 2-11. Palladium-catalyzed Intramolecular Addition to Nitriles

Larock22 later reported intermolecular approaches involving palladium(II) catalyzed C-H and boronic acid additions to nitriles (Scheme 2-12). In the case of the C-H activation strategy, it was proposed that electrophilic palladation of the arene by the active catalyst,

(DMSO)2Pd(O2CCF3)2, was taking place.

Scheme 2-12. Palladium-catalyzed Intermolecular Addition to Nitriles

21 Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem. Soc. 1999, 121, 3238. 22 Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302.

Using a tethered system, Lu23 was able to demonstrate an acetoxypalladation of alkynes followed by cyclization of the resulting vinyl palladium species to nitriles (Scheme 2-13). The final products were hypothesized to be formed following isomerisation and intermolecular aminolysis processes.

Scheme 2-13. Acetoxypalladation of Alkynes and Intramolecular Nitrile Cyclization

Recently, Lu24 also reported a cationic Pd(II)-catalyzed addition of aryl boronic acids to nitriles in the synthesis of benzofurans (Scheme 2-14). It was believed that the use of cationic palladium species would be appropriate due to the presence of vacant co-ordination sites and high Lewis acidic properties to allow for a more facile insertion of the C-N triple bond.

Scheme 2-14. Cationic Palladium(II)-Catalyzed Addition to Nitriles

23 Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343. 24 Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987.

2.4-2 Nickel Catalysis Nickel-catalyzed additions to nitriles were not known processes until very recently. Cheng25 was able to show an efficient method for synthesizing arylketones using a Ni(II) catalyst (see Scheme 2-15). A working hypothesis for this reaction describes its initiation by a (dppe)Ni(II)(OH)(Cl) species, which is formed via a ligand substitution of water with the assistance of Lewis acid ZnCl2. After transmetallation with phenylboronic acid, the ZnCl2 likely removes chloride from the resulting Ni(II) species providing a coordination site for the nitrile substrate. ZnCl2 may also activate the nitrile group so as to promote the insertion step.

Scheme 2-15. Nickel-Catalyzed Addition to Nitriles

2.4-3 Rhodium Catalysis Although insertions of nitrile groups to form carbon-carbon bonds are more prevalent from palladium sources, the scope of the corresponding rhodium-based reactions have been steadily increasing in the past few years.

Work by Murakami has illustrated that annulation reactions involving carbon-carbon multiple bonds and nitrile groups can be carried out. A common strategy employed for this transformation begins with transmetalation of an organoboron reagent followed by alkyne or alkene insertion, and finally nucleophilic addition to the cyano group to close the ring.

As shown in Scheme 2-16, the synthesis of indenones was realized using 2- cyanophenylboronic acid and alkynes.26

Scheme 2-16. Rhodium-Catalyzed Addition to Nitriles to Form Indenones

25 Wong, Y.-C.; Parthasarathy, K.; Cheng, C.-H. Org. Lett. 2010, 12, 1736. 26 Miura, T.; Murakami, M. Org. Lett. 2005, 7, 3339.

Through the use of nitrile-substituted alkynes, intramolecular cyclisation reactions leading to the formation of cyclic ketones were developed (Scheme 2-17).27

Scheme 2-17. Rhodium-Catalyzed Addition to Nitriles to Form Cyclic Ketones

Murakami also discovered that generating an (oxa-π-allyl)rhodium(I) species from an unsaturated ester functionality could be trapped by the electophilic nitrile group to form five- and six-membered β-enamino esters (Scheme 2-18).28

Scheme 2-18. (oxa-π-allyl)Rhodium(I) Addition to Nitriles

Rhodium-catalyzed additions to nitriles are not limited to intramolecular processes, but there are, however, fewer reported examples depicting successful intermolecular approaches. Using aromatic nitriles, Miura29 was able to demonstrate the desired additions to afford the corresponding ketones (Scheme 2-19).

Scheme 2-19. Intermolecular Rhodium-Catalyzed Addition to Nitriles

27 Miura, T.; Nakazawa, H.; Murakami, M. Chem. Commun. 2005, 2855. 28 Miura, T.; Harumashi, T.; Murakami, M. Org. Lett. 2007, 9, 741. 29 Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229.

Scheme 2-20. Selective Rhodium-Catalyzed Addition to Nitriles from Ethyl Cyanoformate

In 2007, Murakami30 was able to illustrate nitrile addition using arylrhodium(I) species to ethyl cyanoformate in the synthesis of -keto esters. This selective reactivity in the presence of an ester functionality rarely occurs with organometallic reagents due to strongly competing side reactions involving nucleophilic attack to the ester followed by elimination of the nitrile (Scheme 2-20).

2.5 Rh-Catalyzed Additions to (Arylsulfonyl)acetonitriles In an effort to continue the development of rhodium-catalyzed additions to unsaturated carbon- heteroatom bonds, we proposed to investigate insertion reactions pertaining to the nitrile group. As seen in many of the previously illustrated examples, such insertions typically involve the use of organoboron nucleophiles, and as a general trend, the incorporation of rhodium(I) catalysts with organoboron reagents have emerged as effective synthetic methods in carbon-carbon bond forming reactions.31 With this in mind, we set out to explore rhodium-catalyzed additions of arylboronic acids to (arylsulfonyl)acetonitriles (Scheme 2-21).

Scheme 2-21. General Strategy of Project

2.5-1 Project Target In addition to extending the scope of rhodium-catalyzed reactions to nitriles, we were also interested in synthesizing important compounds. As a result, the type of products being targeted from this addition reaction were β-keto sulfones, which have shown a broad range of synthetic

30 Shimizu, H.; Murakami, M. Chem. Commun. 2007, 2855. 31 Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005. (d) Miura, T.; Murakami, M. Chem. Commun. 2007, 217. (e) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (f) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. Also see refs. 7b,c.

13 utility in the syntheses of acetylenes32, olefins33, allenes34, vinyl sulfones35, and optically active β-hydroxy sulfones36. β-keto sulfone derivatives have also been reported to exhibit fungicidal activity37 and have shown some therapeutic potential for metabolic syndrome and type II diabetes.38 Furthermore, based on previous studies39 in our laboratories on the rhodium- catalyzed addition of arylboronic acids to allylic sulfones, we envisioned that the sulfone moiety could also play a role in activating the nitrile towards addition as a potential directing group.

2.5-2 Preliminary Discoveries and Optimization Process40 Commercially available (phenylsulfonyl)acetonitrile was identified as a suitable candidate and with a substrate in hand, catalyst screening for the addition reaction was subsequently carried out (Table 2-1).

Table 2-1. Catalyst Screening for the Addition of Phenylboronic Acid to (Phenylsulfonyl)acetonitrile 1a

Entry Catalyst Yield of 2a and 3a (%)a 1 0 2 [Rh(PPh3)OH]2 0 3 [Rh(cod)OH]2 5 4 [Rh(binap)Cl]2 6 5 [Rh(dppp)Cl]2 31 6 [Rh(dppb)Cl]2 38 7 [Rh(dppf)Cl]2 50 8 [Rh(biphep)Cl]2 72 b 9 [Rh(binap)OH]2 90 a Unless specified otherwise, the yield was measured by 1H-NMR (400 MHz) of the crude material using mesitylene as an internal standard. b Isolated yield of 2a and 3a in a 7:1 ratio.

32 Bartlett, P. A.; Green, F. R., III; Rose, E. H. J. Am. Chem. Soc. 1978, 100, 4852. 33 Ihara, M.; Suzuki, S.; Taniguchi, T.; Tokunaga, Y.; Fukumoto, K. Tetrahedron 1995, 51, 9873. 34 Baldwin, J. E.; Adlington, R. M.; Crouch, N. P.; Hill, R. L.; Laffey, T. G. Tetrahedron Lett. 1995, 36, 7925. 35 Sengupta, S.; Sarma, D. S.; Mondal, S. Tetrahedron: Asymmetry 1998, 9, 2311. 36 Svatos, A.; Hunkova, Z.; Kren, V.; Hoskovec, M.; Saman, D.; Valterova, I.; Vrkoc, J.; Koutek, B. Tetrahedron: Asymmetry 1996, 7, 1285. 37 Wolf, W. M. J. Mol. Struct. 1999, 474, 113. 38 Xiang, J.; Ipek, M.; Suri, V.; Tam, M.; Xing, Y.; Huang, N.; Zhang, Y.; Tobin, J.; Mansour, T. S.; McKew, J. Bioorg. Med. Chem. 2007, 15, 4396. 39 Tsui, G. C.; Lautens, M. Angew. Chem., Int. Ed. 2010, 49, 8938. 40 Performed by Gavin C. Tsui, University of Toronto, PhD candidate.

During the catalyst screening process, it was discovered that catalyst free conditions

(entry 1) and monodentate phosphine ligand PPh3 (entry 2) gave no desired product. Using

[Rh(cod)OH]2 without any added ligands gave very low yields. However, incorporating bidentate ligands into the reaction generally afforded much better yields and, [Rh(binap)OH]2 appeared to give the highest yields. However, upon isolation, it was determined that products 2a and 3a were obtained as an inseparable mixture in a 7:1 ratio. Surprisingly, the expected β-keto sulfone product 3a was found to be the minor product whereas the major product was identified to be an unusual β-sulfonylvinylamine 2a. This product is produced via tautomerization of the imine intermediate formed once the desired addition reaction initially takes place.

In an attempt to improve the ratios obtained, a solvent screen was carried out, but unfortunately, none of the solvents tested were found to give better results (Table 2-2).

Table 2-2. Solvent Screening for the Addition of Phenylboronic Acid to (Phenylsulfonyl)acetonitrile 1a

Entry Solvent Conversion (%)a 2a:3aa 1 dioxane >99 (90b) 7:1 2 DME >99 7:1

3 DCE >99 5:1 4 toluene >99 5:1 5 THF 63 10:1 6 MeOH 33 7:1 7 MeCN 0 - a Unless specified otherwise, the yield was measured by 1H-NMR (400 MHz) of the crude material using mesitylene as an internal standard. b Isolated yield of 2a and 3a in a 7:1 ratio.

On the other hand, adding 1 equiv of Cs2CO3 significantly changed the product ratios and resulted in the exclusive formation of β-sulfonylvinylamine 2a. Presumably, the introduction of base facilitates deprotonation of the imine initially formed from the reaction, which promotes enamine formation. As shown in Scheme 2-22, the optimized reaction conditions tolerated both electron-donating and electron-withdrawing groups to afford products 2b and 2c in good yields. However, due to incomplete conversion (30% starting material), 4- cyanophenylboronic acid gave product 2d in 56% yield. Despite the presence of an aromatic

15 nitrile group in the product, a second addition was not observed, which is interesting as most of the literature examples41 involve additions to aromatic nitriles.

Scheme 2-22. Scope of β-sulfonylvinylamines 2a-2d

X-ray crystallographic analysis of 2b confirmed the identity of the β-sulfonylvinylamine being formed, and also denoted that the enamine possessed a Z-alkene geometry (Scheme 2-23). We propose that a stabilizing intramolecular hydrogen bonding interaction is present between the amine and sulfone groups, which contributes to the observation of this favoured double bond geometry.

Scheme 2-23. X-ray Crystal Structure of 2b Showing 30% Displacement Ellipsoids

Previously, the synthesis of β-sulfonylvinylamines has only been demonstrated via 42 reduction of the nitrile group with LiAlH4. This rhodium-catalyzed methodology represents the first transition metal-catalyzed stereoselective synthesis of β-sulfonylvinylamines.

41 Ueura, K.; Miyamura, S.; Satoh, T.; Miura, M. J. Organomet. Chem. 2006, 691, 2821. Also see refs. 29, 30.

2.5-3 Scope of β-Keto Sulfones43 Tsui next investigated the scope of the reaction in a one-pot, two-step sequence by which the catalytic nitrile addition would be carried out first followed by hydrolysis to the desired β- keto sulfone products (Table 2-3). When reacting (phenylsulfonyl)acetonitrile 1a with various arylboronic acids, a diverse variety of functionality can be tolerated. Products containing electron-donating/-withdrawing groups (entries 2-3, 6-7), sterically hindered groups (entry 8), heteroaryl groups (entry 11), chloride and sulfide substituents (entries 4-5) were all afforded in good yields. However, it is important to note that when reacting 1a with 2-formyl or 2- acetylphenylboronic acids resulted in recovery of starting material.

Table 2-3. Scope of Arylboronic Acid and the Sulfonyl Substituent Group of Nitrile 1 in the Synthesis of β-Aryl Keto Sulfones 3

Entry R Ar Yield (%)a Product

1 C6H5 1a C6H5 97 3a 2 C6H5 1a 4-AcC6H4 97 3b

3 C6H5 1a 4-OMeC6H4 95 3c b 4 C6H5 1a 4-ClC6H4 92 3d b 5 C6H5 1a 4-SMeC6H4 86 3e b 6 C6H5 1a 3-AcC6H4 92 3f b 7 C6H5 1a 3-OMeC6H4 98 3g b,c 8 C6H5 1a 2-MeC6H4 89 3h b 9 C6H5 1a 1-naphthyl 94 3i d 10 C6H5 1a 3-thienyl 83 3j 11 4-CF3C6H4 1b C6H5 91 3k 12 4-OMeC6H4 1c C6H5 99 3l 13 4-FC6H4 C6H5 96 3m 14 3-OMeC6H4 1e C6H5 93 3n e 15 2-MeC6H4 1f C6H5 97 3o 16 1-naphthyl 1g C6H5 98 3p 17 Bn 1h C6H5 98 3q a Isolated yields. b The catalytic reactions were run for 2.5h. c 2-Formyl and 2-acetylphenylboronic acids were unreactive. d The product and starting material were isolated as an inseparable mixture in a ratio of 6.7:1. No desired products were obtained when R = 2-BrC6H4 and 2-ClC6H4.

42 Feringa, B. L. J. Chem. Soc., Chem. Commun. 1985, 466. 43 Performed by Gavin C. Tsui, University of Toronto, PhD candidate.

In order to investigate the scope of the R group from the sulfonyl moiety, substrates 1b-h were synthesized44 from the corresponding thiols. Electron-rich/-poor and sterically hindered groups all resulted in excellent yields of products 3k-q. However, o-halo-substitutents appeared to severely hinder the reaction. The reaction model also tolerated non-aromatic substituents such as a benzyl group to afford 3q in excellent yield.

2.5-4 Synthesis of α-Arylated β-Sulfonylvinylamines In an effort to expand the scope of this reaction, we envisioned that starting from α-substituted (phenylsulfonyl)acetonnitrile derivatives would provide access to the corresponding tetrasubstituted alkene products (Scheme 2-24).

Scheme 2-24. Proposed Synthesis of α-Arylated β-Sulfonylvinylamines

2.5-5 Synthesis of α-Arylated (Phenylsulfonyl)acetonitriles

The synthesis of the starting α-arylated (phenylsulfonyl)acetonitrile substrates was carried out in accordance to a protocol established by Yamanaka (Table 2-4).45 The reaction can be described as a condensation of aryl halides with the sodium salt of (phenylsulfonyl)acetonitrile in the presence of a tetrakis(triphenylphosphine)palladium catalyst.

As expected, the yields obtained for 4a-c corresponded to literature values. In our attempts to extend this methodology to the synthesis of additional α-arylated (phenylsulfonyl)acetonitrile substrates, we discovered that ortho-substituted groups significantly affected reactivity resulting in low yields of 4d and recovery of starting material when R = 2- OH. The reaction model tolerated an electron-poor para-substituted acetyl group to afford 4e in good yield.

44 Tsui, G. C.; Glenadel, Q.; Lau, C.; Lautens, M. Org. Lett. 2011, 13, 208. 45 Sakamoto, T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1990, 38, 1513.

Table 2-4. Scope of α-Arylated (Phenylsulfonyl)acetonitrile Derivatives

Entry R Yield (%)a Product 1 H 90 4a 2 4-OMe 83 4b 3 4-CN 67 4c 4 2-Clb 30 4d 5 4-Ac 73c 4e 6 2-OH 0d - a Isolated yields. b Utilized 1-bromo-2- chlorobenzene. c Recovered a complex mixture of products when using 1-(4-bromophenyl)ethanone. d Recovered starting material.

2.5-6 Scope of α-Arylated β-Sulfonylvinylamines We next investigated the scope by reacting α-arylated (phenylsulfonyl)acetonitriles 4a-e with various arylboronic acids (Scheme 2-25).

Scheme 2-25. Scope of Arylboronic Acid and α-Arylated (Phenylsulfonyl)acetonitriles 4 in the Synthesis of β-Sulfonylvinylamines 5

With phenylboronic acid as a reaction partner, these studies illustrated that (phenylsulfonyl)acetontriles possessing α-substituted phenyl and anisole groups (5a-b) can afford the desired products in good yields. However, electron-withdrawing groups such as 4- cyano and 4-acetyl substituents (4c, 4e) were not tolerated as it resulted in either a complex mixture of products or the recovery of starting material in the latter example. Substrate 4c contains an aromatic nitrile group and presumably introduces an additional site of reaction which could explain the complex mixture of products observed. The o-chloro-substituent on 4d hindered the reaction and resulted in recovery of an inseparable mixture of product and starting material in a ratio of 1:0.73 by 1H-NMR.

Investigating the scope of arylboronic acids with (phenylsulfonyl)acetontrile 1a showed that the reaction tolerated electron-rich and -poor groups to afford products 5c-d in moderate to good yields. However, reaction with 2-chlorophenylboronic acid resulted in the recovery of starting material.

Attempts to create functionality on both aromatic groups in the resulting 1,2-diaryl alkene products led to the recovery of inseparable mixtures of starting material and product when utilizing 4-acetylphenylboronic acid. Fortunately, product 5e was afforded in a moderate yield when using o-chlorophenyl substituted (phenylsulfonyl)acetontrile 4d and 4- methoxyphenyl boronic acid.

X-ray crystallographic analysis of 5c confirmed the identity of the tetrasubstituted β- sulfonylvinylamine being formed, and proved that the enamine also possessed (Z)-selectivity (Scheme 2-26).

Scheme 2-26. X-ray Crystal Structure of 5c Showing 30% Displacement Ellipsoids

2.5-7 Proposed Mechanism Based on the insight provided by previously reported examples of rhodium-catalyzed additions to nitriles, we propose that the rhodium-aryl nucleophile 6 is initially generated via transmetalation between the rhodium hydroxide catalyst and arylboronic acid (Scheme 2-27). Once formed, insertion of the nitrile group takes place resulting in the formation of a metallated imine species 7a. It is possible that the rhodium co-ordinates to the oxygen of the neighbouring sulfone group, which would then give rise to a rhodacycle. At this point, two possible pathways are possible: tautomerization of the rhodacycle to form metallated enamine species 7b followed by protonolysis and hydrolysis to afford β-keto sulfone 3. Alternatively, immediate protonlysis of 7a could also occur to form imine 8. At this point, base assists in promoting tautomerization to produce the favoured enamine product 2. If acid is introduced, hydrolysis of 5 takes place resulting in the formation of β-keto sulfone 3.

Scheme 2-27. Proposed Mechanism of Rh(I)-Catalyzed Addition of Arylboronic Acids to Nitrile 1

In order to explain the observed (Z)-selectivity, we believe that a stabilizing intramolecular hydrogen bonding interaction between the amine and sulfone group forming a six-membered ring is a major contributing factor. This interaction could also explain the favoured enamine formation even in the absence of base. The (Z)-selectivity observed in the 1,2- diaryl alkene product 5c provide evidence that sterics do not dictate the alkene geometry alone because the less hindered (E)-alkene should be the preferred product if that was the case.

Scheme 2-28. Substrate Variants 7-1046

Additional substrates with distinct structural variations were next examined by Tsui in order to further elucidate the role of the sulfone group (See Scheme 2-28). Sulfide 9 resulted in the recovery of starting material, and despite possessing potential co-ordinating groups as well as electron-withdrawing character, sulfoxide 10 and benzoylacetonitrile 11 exhibited no reactivity. Homologated sulfone 12 also did not produce the desired product. These observations support our hypothesis of a hydrogen bonded six-membered ring playing a key role in the reaction.

2.5-8 Conclusions In order to contribute to the developing field of rhodium-catalyzed insertions to carbon- heteroatom multiple bonds, we have developed an efficient methodology involving the rhodium(I)-catalyzed addition of arylboronic acids to (arylsulfonyl)acetonitriles. This methodology proceeds in stereoselective fashion allowing access to (Z)-β-sulfonylvinylamines in generally good yields (up to 97%) including examples possessing aryl substituents in the α position. The reaction can then be subsequently subjected to acidic conditions in the same pot to afford a diverse variety of useful β-keto sulfone products with a broad scope of aryl and sulfonyl substituent groups in excellent yields. To the best of our knowledge, this constitutes the first report of transition metal-catalyzed stereoselective synthesis of β-sulfonylvinylamines and the synthetic utility of these interesting enamine products will be discussed in the following sections.

46 Performed by Gavin C. Tsui, University of Toronto, PhD candidate.

Chapter 3 : 1-Aza-allylic Anions in the Synthesis of Heterocycles

The widespread use of 1-aza-allyl anions in organic syntheses is attributable to their versatility47 in carbon-carbon bond reactions. In particular, these anion synthons have been successfully applied in the syntheses of heterocyclic systems ranging from tetrahydrofurans and pyrroles to higher functionalized polycyclic structures.48 Scheme 3-1 depicts a typical synthesis of tetrahydropyridines utilizing 1-aza-allyl anions as building blocks. In this example, a 1-aza-allyl intermediate is formed after deprotonation with LDA which following an SN2 reaction furnishes the observed terthered imine product. Subsequent regeneration of the 1-aza-allyl species and iterative SN2 reaction to close the ring affords the desired pyridine product.

Scheme 3-1. Synthesis of 1,2,3,4-Tetrahydropyridines using 1-Aza-allyl Anions49

Advantages derived from this methodology of synthesizing heterocycles include a broad scope of synthetic utility as 1-aza-allyl anions react with many electrophiles (alkyl halides, carbonyls, imines, epoxides and nitriles) almost exclusively at the β-carbon. In addtion, these anionic synthons do not generally undergo reaction with themselves, their neutral parent compound or the final product which minimizes the possibility of undesirable side product

47 (a) Enamines: their Synthesis, Structure and Reactions; Cook, A. G., Ed.; Marcel Dekker: New York, New York, 1969. (b) Modern Synthetic Reactions, 2nd ed.; House, H. O., Ed.; W. A. Benjamin, Inc.: Menlo Park, California, 1972. 48 (a) Mangelinckx, S.; Giubellina, N.; Kimpe, N. D. Chem. Rev. 2004, 104, 2353. (b) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253. (c) Caro, C. F.; Lappert, M. F.; Merle, P. G. Coord. Chem. Rev. 2001, 605, 219. (d) Semmelhack, M. F. Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: Oxford, United Kingdom, 1991; Vol. 2. (e) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517. 49 Stevens, C.; De Kimpe, N. Synlett 1994, 351.

23 formation.48a The ambident nature of 1-aza-allyl anions further complements these synthons in the construction of heterocycles as it offers a “built-in” handle for ring closing processes.

3.1 Approaches in Heterocycle Syntheses Derived from 1-Aza-Allyl Anions There are numerous approaches that can be undertaken when synthesizing heterocycles via a 1- aza-allyl anion pathway.48a These variants can generally be categorized according to the type of functionalized tether appended to the starting imine. When reacting 1-aza-allyl anions with biselectrophiles, one can envision an initial C-alkylation at the β-carbon to install the tether followed by subsequent N-alkylation and cyclization to form the N-heterocyclic compound (Scheme 3-2). A nucleophilic function can also be introduced to the imine through the use of bifunctional substrates containing a nucleophile and electrophile at either termini. This variation allows for cyclization across the imino group (Scheme 3-3).

Scheme 3-2. Incorporating Biselectrophiles in 1-Aza-allyl Anion-Based Heterocyclic Synthesis

Scheme 3-3. Incorporating Bifunctional Substrates in 1-Aza-allyl Anion-Based Heterocyclic Synthesis

3.1-1 Piperidine Synthesis In the synthesis of piperidines, De Kimpe50 was able to synthesize 3-vinylpiperidines from 1- azapentadienyl anions (Scheme 3-4). This was accomplished by forming δ-chloroimine substrates and in accordance to strategy (e), the ring closing step was carried out via reductive cyclization.

Scheme 3-4. Piperidine Synthesis

3.1-2 Pyrrole Synthesis One of the first reported syntheses of heterocyclic compounds derived from 1-aza-allyl precursors is the formation of pyrrole derivatives. Based on synthetic strategy (c), Fischer51

50 Aelterman, W.; De Kimpe, N. Tetrahedron 1998, 54, 2563. 51 Wittig, G.; Röderer, R.; Fischer, S. Tetrahedron Lett. 1973, 3517.

25 illustrated successful condensation reactions between lithioazaenolates and α-halogenated ketones to afford pyrroles (Scheme 3-5). The proposed mechanism explains an initial SN2 reaction between the metalated imine and the halomethyl group followed by subsequent cyclization and dehydration.

Scheme 3-5. Pyrrole Synthesis

3.1-3 Tetrahydrofuran Synthesis

As alluded to earlier, 1-aza-allyl anions have also been implemented as building blocks in the formation of oxygen-containing heterocycles. Based on strategy (h), De Kimpe52 introduced a methodology for the synthesis of tetrahydrofurans from α,α-dichloroketimines involving the instalment of an alcohol protected tether, which upon aqueous acidic conditions enables the free alcohol to undergo nucleophilic cyclization to the resulting carbonyl group (Scheme 3-6).

Scheme 3-6. Tetrahydrofuran Synthesis

52 De Kimpe, N.; Coppens, W.; Welch, J.; De Corte, B. Synthesis 1990, 675.

3.1-4 Pyridine Synthesis In a synthesis of alkylpyridines, Tanaka53 illustrated that 1-aza-allyl anions originating from α,β- unsaturated ketimines could readily reduce nitriles to produce a viable nucleophile for intramolecular cyclization, and following aromatization lead to the desired pyridine product (Scheme 3-7). This methodology closely resembles strategy (f) prior to elimination of the amine group.

Scheme 3-7. Pyridine Synthesis

3.2 Heterocycle Syntheses Derived from β-Sulfonyl- vinylamines as 1-Aza-Allyl Anion Equivalents Despite the widespread use of 1-aza-allyl anions in heterocycle syntheses, there have surprisingly been very few reports illustrating synthetic applications involving β- sulfonylvinylamines as 1-aza-allyl anion equivalents. Muraoka54 reacted 1-aza-allyl anions derived from β-imino sulphones with carbon disulphide as the electrophilic partner in order to generate sulfur-containing heterocycles. However, difficulties in controlling the reactivity of the anion resulted in low yields and formation of additional products (Scheme 3-8).

53 Takabe, K.; Fujiwara, H.; Katagirl, T.; Tanaka, J. Tetrahedron Lett. 1975, 4375. 54 Muraoka, M.; Yamamoto, T.; Ebisawa, T.; Kobayashi, W.; Takeshima, T. J. Chem. Soc., Perkin Trans. I 1978, 1017.

Scheme 3-8. Thiol-Containing Heterocycle Synthesis

In the synthesis of sulfone-containing dihydropyridines, Feringa55 illustrated an expedient method involving the use of β-(p-toluenesulphonyl)vinylamine as a source of 1-aza- allyl anion (Scheme 3-9). The proposed mechanism is explained by an initial conjugate addition at the β-carbon of the anion followed by nucleophilic cyclization at the N-terminus upon regeneration of the 1-aza-allyl anion, and finally dehydration takes place to furnish the desired dyhydropyridines.

Scheme 3-9. Sulfone-Containing Dihydropyridine Synthesis

3.3 Synthesis of 2,4,6-Trisubstituted Pyridines from β- Sulfonylvinylamines via 1-Aza-Allyl Anion Equivalents Inspired by Feringa’s dihydropyridine synthesis55, we envisioned the use of our β- sulfonylvinylamines as a source of 1-aza-allyl anions in heterocyclic synthesis. We proposed that subjecting these amines under the appropriate reaction conditions would allow for elimination of sulfinic acid and lead to the formation of 2,4,6-trisubstituted pyridines (Scheme 3-10).

55 Feringa, B. L. J. Chem. Soc. Chem. Commun. 1985, 466.

Scheme 3-10. Proposed Synthesis of 2,4,6-Trisubstituted Pyridines

3.3-1 Targeting the Synthesis of 2,4,6-Triaryl Pyridines Pyridines possessing a 2,4,6-triaryl substitution pattern are of immense interest owing to their diverse roles in homogeneous catalysis56, biology57,58, and materials science59,60. As a result of the wide applications of pyridine derivatives, we targeted our studies towards the synthesis of these desirable pyridines. Furthermore, while an extensive variety of synthetic methods have been developed for the construction of symmetrical pyridines possessing 2,4,6-triaryl substitution patterns, the synthesis of unsymmetrical pyridines is significantly less developed. In the subsequent sections, existing methods to the formation of both types of pyridines will be discussed.

3.3-2 Syntheses of Symmetrical 2,4,6-Triaryl Pyridines In the case of symmetrical 2,4,6-trisubstituted pyridines, there exists a plane of symmetry as a result of the pyridyl ring system containing identical substituents at the 2 and 6 positions. Numerous methodologies have been reported in the syntheses of such pyridine derivatives and they will be briefly outlined below.

56 (a) Pàmies, O.; Bäckvall, J. E. Chem.--Eur. J. 2001, 7, 5052. (b) Yang, H.; Gao, H.; Angelici, R. J. Organometallics. 2000, 19, 622. 57 Applications as anti-cancer agents: (a) Basnet, A.;Thapa, P.; Karki, R.; Na, Y.; Jahng, Y.; Jeong, B. S.; Jeong, T. C.; Lee, C. S.; Lee, E. S. Bioorg. Med. Chem. 2007, 15, 4351. (b) Zhao, L. X.; Moon, Y. S.; Basnet, A.; Kim, E. K.; Cho, W. J.; Jahng, Y.; Park, J. G.; Jeong, T. C.; Cho, W. J.; Choi, S. U.; Lee, C. O.; Lee, S. Y.; Lee, C. S.; Lee, E. S. Bioorg. Med. Chem. Lett. 2004, 14, 1333. (c) Zhao, L. X.; Kim, T. S.; Ahn, S. H.; Kim, T. H.; Kim, E. K.; Cho, W. J.; Choi, H.; Lee, C. S.; Kim, J. A.; Jeong, T. C.; Chang, C. J.; Lee, E. S. Bioorg. Med. Chem. Lett. 2001, 11, 2659; d) Carter, P. J.; Cheng, C. C.; Thorp, H. H. J. Am. Chem. Soc. 1998, 120, 632. 58 Applications as chemosensors: (a) Yang, Q. Z.; Wu, L. Z.; Zhang, H.; Chen, B.; Wu, Z. X.; Zhang, L. P.; Tung, C. H. Inorg. Chem. 2004, 43, 5195. (b) Siu, P. K. M.; Lai, S. W.; Lu, W.; Zhu, N.; Che, C. M. Eur. J. Inorg. Chem. 2003, 2749. (c) Wong, K. H.; Chan, M. C. W.; Che, C. M. Chem. Eur. J. 1999, 5, 2845. 59 Applications as optoelectronic devices: (a) Liu, R.; Chang, J.; Xiao, Q.; Li, Y.; Chen, H.; Zhu, H. Dyes and Pigments 2011, 88, 88; b) Chen, J. L.; Chang, S. Y.; Chi, Y.; Chen, K.; Cheng, Y. M.; Lin, C. W.; Lee, G. H.; Chou, P. T.; Wu, C. H.; Shih, P. I.; Shu, C. F. Chem.--Asian J. 2008, 3, 2112; c) Williams, J. A. G. Top. Curr. Chem. 2007, 281, 205; d) Chou, P. T.; Chi, Y. Chem.--Eur J. 2007, 13, 380; e) Yan, B. P.; Cheung, C. C. C.; Kui, S. C. F.; Xiang, H. F.; Roy, V. A. L.; Xu, S. J.; Che, C. M. Adv. Mater. 2007, 19, 3599; f) Yan, B. P.; Cheung, C. C. C.; Kui, S. C. F.; Roy, V. A. L.; Che, C. M.; Xu, S. J. Appl. Phys. Lett. 2007, 91, 63508; g) Chou, P. T.; Chi, Y. Eur. J. Inorg. Chem. 2006, 3319; h) Sun, W.; Zhu, H.; Barron, P. M. Chem. Mater. 2006, 18, 2602. 60 Applications as semi-conductors: (a) Lu, W.; Roy, V. A. L.; Che, C. M. Chem. Commun. 2006, 3972. (b) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.

3.3-2a Chichibabin Pyridine Synthesis The Chichibabin61 pyridine synthesis is carried out by condensation reactions between combinations of ketones, aldehydes, α,β-unsaturated compounds and ammonia. In the synthesis of triphenylpyridine, Scheme 3-11 shows formation of a chalcone via an aldol condensation followed by conjugate addition from an additional equivalent of the enolate source to form a 1,5-diketone species. Condensation with ammonia facilitates ring closing to form the corresponding dihydropyridine and following dehydrogenation, results in the formation of the desired pyridine.

It is important to note that ammonia acts as both the base for the aldol condensation and also represents the nitrogen source appearing in the final product. General detriments to this methodology include the high probability of side product formation stemming from mixed aldol condensations if unsymmetrical ketones are utilized as well as undesirable reactions occurring between the various electrophilic and nucleophilic sources (e.g., enolates and nitrogen based nucleophiles) present in the reaction.

Scheme 3-11. Chichibabin Synthesis of 2,4,6-Triphenylpyridine62

3.3-2b Kröhnke Pyridine Synthesis The Kröhnke63 pyridine synthesis involves condensation of α-pyridinium ketone salts with enones to generate pyridines via a 2,3-ene-1,5-dione intermediate (Scheme 3-12). The desired pyridyl ring is obtained from elimination of the pyridinium salt followed by imine tautomerization prior to a condensation reaction.

61 Seven, R. P.; Frank, R. L. J. Am. Chem. Soc. 1953, 75, 6042. 62 Weiss, M. J. Am. Chem. Soc. 1952, 74, 200. 63 Kröhnke, F.; Zecher, W. Angew. Chem. Int. Ed. 1962, 1, 626.

Scheme 3-12. Kröhnke Synthesis of 2,6-diphenyl-4-(p-chlorophenyl)pyridine

3.3-2c N-Phosphinylethanimine-Based Pyridine Synthesis Interestingly, 1-aza-allyl anions derived from N-phosphinylethanimines64 can be reacted with aldehydes to form 2,4,6-trisubstituted pyridines (Scheme 3-13). As shown, once formed from KOtBu, the N-phosphinyl-1-aza-allyl anion undergoes condensation at the β-carbon with 2- furaldehyde leading to the generation of a proposed 1-azadiene intermediate. This intermediate proceeds to react with an additional equivalent of the 1-aza-allyl anion species resulting in the formation of a dihydropyridine derivative after elimination of the phosphinic amide. From this point, aromatization to the desired pyridine compound occurs either through direct elimination of diphenylphosphine oxide or release of diphenylphosphinic acid followed by dehydrogenation.

64 Kobayashi, T.; Kakiuchi, H.; Kato, H. Bull. Chem. Soc. Jpn. 1991, 64, 392.

Scheme 3-13. N-Phosphinylethanimine-Based Synthesis of 2,6-diphenyl-4-(2-thienyl)pyridine

3.3-2d Pyridine Synthesis Under Solvent-Free and Microwave Conditions Recently, Raston65 and Tu66 have respectively demonstrated that Chichibabin-type pyridine syntheses can be carried out under solvent-free and microwave conditions (Schemes 3-14 and 3- 15).

Scheme 3-14. Solvent-Free Synthesis of 2,6-bis(4-iodophenyl)-4-phenylpyridine

Scheme 3-15. Microwave Synthesis of 2,6-diphenyl-4-(2-thienyl)pyridine

65 Cave, G. W. V.; Raston, C. L. Chem. Commun. 2000, 2199. 66 Tu, S.; Li, T.; Shi, F.; Fang, F.; Zhu, S.; Wei, X.; Zong, Z. Chem. Lett. 2005, 34, 732.

3.3-3 Syntheses of Unsymmetrical 2,4,6-Triaryl Pyridines Unsymmetrical 2,4,6-trisubstituted pyridines do not possess a plane of symmetry, which essentially excludes variants whereby identical substituents are situated at the 2 and 6 positions of the pyridyl ring system. For this section, reports pertaining to the syntheses of unsymmetrical pyridines possessing differentiated substituents at each position will be examined. It is important to note that despite showing promise in this underdeveloped field of pyridine syntheses, existing methods typically suffer from low yields and limited scope.

3.3-3a Kröhnke Unsymmetrical Pyridine Synthesis Based on Kröhnke’s symmetrical pyridine synthesis, Lee67 and Malik68 have demonstrated the construction of unsymmetrical 2,4,6-triaryl substituted pyridines using α-pyridinium ketone iodide salts with appropriate enone substrates. However, the yields associated with Lee’s methodology are low whereas in Malik’s approach, the products are limited to having 2-thienyl substituents in the 2 position (Schemes 3-16 and 3-17). Yan69 illustrated a microwave-assisted one-pot, four-component variation of Kröhnke’s method, but once again, yields and scope appeared to be limited (Scheme 3-18).

Scheme 3-16. Lee Synthesis of 4-(furan-3-yl)-6-(thiophen-2-yl)-2,4'-bipyridine

67 (a) Basnet, A.; Thapa, P.; Karki, R.; Na, Y.; Jahng, Y.; Jeong, B. S.; Jeong, T. C.; Lee, C. S.; Lee, E. S. Bioorg. Med. Chem. 2007, 15, 4351. (b) Zhao, L. X.; Moon, Y. S.; Basnet, A.; Kim, E. K.; Cho, W. J.; Jahng, Y.; Park, J. G.; Jeong, T. C.; Cho, W. J.; Choi, S. U.; Lee, C. O.; Lee, S. Y.; Lee, C. S.; Lee, E. S. Bioorg. Med. Chem. Lett. 2004, 14, 1333. 68 Malik, S.; Pandey, K. J. Chem. Eng. Data. 1983, 28, 430. 69 Yan, C.-G.; Cai, X.-M.; Wang, Q.-F.; Wang, T.-Y.; Zheng, M. Org. Biomol. Chem. 2007, 5, 945.

Scheme 3-17. Malik Synthesis of 2-(4-chlorophenyl)-4-(3-nitrophenyl)-6-(thiophen-2-yl)pyridine

Scheme 3-18. Yan Synthesis of 4-(4-chlorophenyl)-2-phenyl-6-(p-tolyl)pyridine

3.3-3b Lithiated-Phosphonate-Based Unsymmetrical Pyridine Synthesis Bearing some resemblance to the previously discussed N-phosphinylethanimine-based synthesis of symmetrical pyridines, Kiselyov70 has demonstrated that by reacting aldehydes with the corresponding stabilized phosphorous ylid derived from β-enaminophosphonate derivatives generate α,β-unsaturated imines via a Horner-Wadsworth-Emmons reaction. This 1-azadiene intermediate undergoes further reaction as a Michael acceptor for the sodium enolate of methyl aryl ketones, which following condensation and oxidation result in the formation of the desired pyridine (Scheme 3-19). The scope appears to be limited for this methodology.

70 Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 9297.

Scheme 3-19. β-Enaminophosphonate Ylid-Based Synthesis of 4-(4-methoxyphenyl)-6-(naphthalen-2- yl)-2,4'-bipyridine

3.3-3c Unsymmetrical Pyridine Synthesis Under Microwave and Lewis Acidic Conditions Based on Kröhnke’s pyridine synthesis, and incorporating urea as a source of ammonia, Bouruah71 illustrated that the syntheses of several -aryl substituted unsymmetrical pyridines under microwave and Lewis-acidic conditions could be accomplished in good yields (Scheme 3- 20).

Scheme 3-20. Kröhnke-Based Microwave and Lewis-Acidic Synthesis of 2-(4-chlorophenyl)-6-phenyl-4- (p-tolyl)pyridine

3.3-4 Preliminary Discoveries and Optimization Process By utilizing (Z)-β-sulfonylvinylamine 2a formed from our previously discovered44 rhodium(I)- catalyzed addition of arylboronic acids to (arylsulfonyl)acetonitriles as starting substrates, we became interested in obtaining similar reactivity that was observed previously in Feringa’s

71 Borthakur, M.; Dutta, M.; Gogoi, S.; Bouruah, R. C. Synlett 2008, 20, 3125.

35 dihydropyridine synthesis55. It was hypothesized that generation of the corresponding 1-aza- allyl anion equivalent followed by reaction with chalcone would first lead to a sulfone containing dihydropyridine intermediate and under appropriate reaction conditions, we proposed that elimination of sulfinic acid could take place, affording the desired 2,4,6-triaryl substituted pyridine product.

For preliminary studies, variation in the type of base, temperature, and solvent were screened in the synthesis of 2,4,6-triphenylpyridine 13 (Table 3-1). It is important to note that excess base is necessary for complete consumption of the starting enamine substrate, otherwise yields are significantly lowered. We began our investigation by reacting β-sulfonylvinylamine 2a with chalcone under Feringa’s original reaction conditions, and rather than formation of the expected dihydropyridine product, we obtained triphenylpyridine 13 in 30% yield (entry 1).

Table 3-1. Optimization for the Formation of Pyridine 13

Entry Base Equiv Temp. (oC) Time (h) Yield of 17 (%)a 1b NaH 3.0 rt 3 30 c d 2 K2CO3 3.0 75 14 < 5 3c KOtBu 3.0 75 2.5 20 4c NaOMe 3.0 75 2.5 50 5c NaOMe 3.0 rt 14 77 6c KOH 3.0 rt 2 62 7c NaOH 3.0 rt 14 78 8c NaOH 3.0 75 2.5 81 a Isolated yields. b Used THF as solvent. c Used dioxane as solvent. d Recovery of starting material.

Weaker carbonate bases led to the recovery of starting material whereas NaH and a sterically hindered KOtBu base resulted in low yields. At room temperature, NaOMe produced 4 in 77% yield while higher temperatures proved to be detrimental to overall yields. NaOH proved to be the ideal base as higher temperatures were tolerated without a reduction in yield, which allowed for significantly shorter reaction times (entry 8).

3.3-5 Proposed Mechanism The mechanism proposed for this remarkable cascade reaction is based on the typical reactivity observed in 1-aza-allyl anion chemistry and coincides with the mechanistic pathway proposed by Feringa up until the formation of the sulfone-containing dihydropyridine intermediate 15. Subsequent steps have been described using pKa-based explanations and leaving group abilities.

A plausible mechanism can therefore be rationalized by first generating the 1-aza-allyl anion synthon 13 with base followed by Michael addition of the resulting carbanion72 to the chalcone to form imine 14. Excess base facilitates condensation of this imine to the carbonyl group leading to dihydropyridine 15. After deprotonation of 7, tautomerization places the resulting anion in a stabilized position adjacent to the electron-withdrawing sulfone moiety. Finally, aromatization of 16, via elimination of sulfinic acid, results in the formation of pyridine product 17.

Scheme 3-21. Proposed Mechanism for the Synthesis of 2,4,6-Triphenylpyridine 17

72 Initial C-alkylation at the β-carbon of 1-aza-allyl anions is typically observed over N-alkylation; see ref. 48b.

3.3-6 Scope of Unsymmetrical 2,4,6-Triarylsubstituted Pyridines With a set of optimized conditions in hand, the scope of unsymmetrical 2,4,6-triarylsubstituted pyridine synthesis was next studied (Table 3-2).

Table 3-2. Scope of Unsymmetrical Pyridines 18

Yield Yield Entry Substrate Product Entry Substrate Product (%)a (%)a

1 78 6 72

2 75b 7 72

3 73b 8 64

4 85b 9 55

5 87b 10 81b

a Isolated yields. b Reaction performed at room temperature over 14h.

We were able to illustrate that a diverse array of these desirable pyridines could be synthesized in moderate to good yields. This reaction provides access to structurally novel bipyridyl derivatives that may serve as tri- and bidentate ligands in homogeneous catalysis (18a- e). In addition, the presence of halogenated substituents provides synthetically useful handles for construction of increasingly complex pyridines and allows for further functionalization such as the introduction of chiral components for potential applications in asymmetric catalysis. This methodology also allows for the synthesis of heteroaryl-containing unsymmetrical pyridines including -pyridyl, -thienyl, as well as -furyl groups all in good yields.

3.3-7 Scope of Chalcones and β-Sulfonylvinylamines When investigating the scope of chalcone derivatives, it was found that electron-rich and chloride substituents resulted in good yields whereas electron-poor nitro substituents led to low yields (Table 3-3).

Table 3-3. Scope of Chalcones

1 2 a Entry R R Yield (%) Product 1 4-OMe H 86 19a b 2 4-NO2 H 34 19b 3 4-Cl H 93 19c 4 H 4-OMe 85 19d

5 H 4-NO2 20 19e 6 H 4-Cl 95 19f a Isolated yields. b Obtained 57% yield with KOH.

The effects of varying the -sulfonylvinylamine substrates were also studied, and it was determined that electron-donating, electron-withdrawing, and chloride substituents were all tolerated to afford the product in good yields (Table 3-4).

Table 3-4. Scope of -Sulfonylvinylamines

a Entry R Yield (%) Product 1 4-OMe 80 20a

2 4-CF3 70 20b 6 4-Cl 90 20c a Isolated yields. b Obtained 57% yield with KOH. 3.3-8 Scope of Heteroaryl-Containing Pyridines In an effort to further expand the scope of this reaction, we next turned our attention towards the synthesis of heteroaryl-containing 2,4,6-triarylsubstituted pyridines (Scheme 3-22).

Scheme 3-22. Scope of Heteroaryl-Containing Pyridines 21

As observed from Table 4, heteroaryl containing pyridines were successfully synthesized in good yields. In addition to the incorporation of typical heteroaryl groups (-furyl, -thienyl and -pyridyl), the reaction also allows introduction of two heteroaryl substituents in the final product (21d) as well as an unprotected pyrrole group (21c).

3.3-9 Synthesis of Polycyclic Pyridines While in the process of investigating different approaches to broaden the utility of - sulfonylvinylamines, it was postulated that reaction of these species with “fused” chalcone substrates would lead to the formation of desirable pyridine containing polycyclic heterocycles (Scheme 3-23). The applications of this class of compounds span several fields including asymmetric catalysis73, material science60b,74, and biology75.

Scheme 3-23. Proposed Synthesis of Polycyclic Pyridines

For this study, we selected a tetralone-based , -unsaturated system 22 to react with - sulfonylvinylamine 2a. Under the previously optimized reaction conditions, we obtained the expected polycyclic product 23 in 55% yield (Scheme 3-24). Interestingly, at room temperature, we observed formation of sulfonylated product 24. In order to determine if the sulfonylated compound is a potential intermediate along the mechanistic pathway leading to formation of 23, pure 24 was subjected to the optimized conditions, and only starting material was recovered. This observation shows that 24 is not an intermediate of 23 and implies that 24 could possibly be a kinetic product formed from an oxidation process formally removing hydrogen leading to its aromatization. KOH afforded the highest yield of either the desired product 23 (71%) or the sulfonylated product 24 (57%) when the appropriate reaction conditions were applied.

73 Chelucci, G.; Thummel, R. Chem. Rev. 2002, 102, 3129. 74 Balzani, V.; Juris, A.; Venturi, M. Chem. Rev. 1996, 98, 759. 75 (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627; (b) Denny, W. A.; Baguley, B. C. Curr. Top. Med. Chem. 2003, 3, 339.

Scheme 3-24. Synthesis of Polycyclic Pyridines 23 and 24

3.3-10 Synthesis of Di-aryl-mono-alkyl Trisubstiuted Pyridines We were curious to determine if our reaction would be amenable towards the synthesis of diaryl-mono-alkyl trisubstituted pyridines. In order to accomplish this, we selected various enones possessing alkyl substituents to be reacted with -sulfonylvinylamine 2a.

As outlined in Table 3-5, alkyl substituents possessing α-hydrogens afforded poor yields of the desired pyridine product and in all cases, a complex mixture of possible aldol reaction side products was also recovered. Furthermore, carrying out reactions at room temperature appeared to increase the formation of these side products and introduced inseparable impurities to the alkylated pyridines. Yields significantly improved when R = tBu presumably due to the fact that enolizable protons are no longer present to potentially interfere with the desired reaction. However, experiments involving this bulky substituent were extremely sluggish at room temperature, but at higher temperatures, KOH proved to be the ideal base and produced the desired pyridine in 55% yield. It is important to note that when an α-phenylated enone possessing a tBu group in the 4 position was screened under optimized conditions, starting material was recovered. It is likely that the bulky alkyl group severely impeded the initial conjugate addition step from taking place.

Table 3-5. Scope of Di-aryl-mono-alkyl Substituted Pyridines

Entry R Base Temp. (oC) Time (h) Yield (%)a 1 Me NaOH 75 2.5 10b 2 Me NaOMe 75 2.5 16b 3 iPr NaOH 75 2.5 20b 4 iPr NaOH rt 12 - b, c i b 5 Pr NaOMe 75 2.5 26 i b, c 6 Pr KOH rt 12 - 7 tBu NaOH 75 5h 48d 8 tBu NaOMe 75 5h 20d 9 tBu KOH 75 5h 55d a Isolated yields. b Also isolated complex mixture of possible aldol side products. c Recovered an inseparable mixture of desired product and unidentifiable impurities. d The reaction proved to be extremely sluggish at room temperature as significant amount of starting substrate 2a was still present after 24h via crude 1H-NMR.

Since our initial goal described the construction of unsymmetrical 2,4,6-trisubstituted pyridines exhibiting three distinct substituents, we also targeted the synthesis of an appropriate derivative following a di-aryl-mono-alkyl substitution pattern. Using an appropriately functionalized -sulfonylvinylamine, and applying our previously optimized reaction conditions, we were able to synthesize the desired unsymmetrical pyridine 25 in good yield (Scheme 3-25).

Scheme 3-25. Synthesis of Unsymmetrical Di-aryl-mono-alkyl Substituted Pyridine 25

3.3-11 Synthesis of Di-aryl Disubstituted Pyridines An additional , -unsaturated system that we selected to examine was cinnamaldehyde, which would presumably provide access to di-aryl substituted pyridines. When -sulfonylvinylamine

2a was initially reacted under the standard optimized conditions with cinnamaldehyde, surprisingly, two isomeric products 26 and 27 were recovered in 24% and 17% yield respectively (Scheme 3-26).

Scheme 3-26. Isomeric 2,6- and 2,4-Diphenylpyridine Formed

Although formation of 26 can be explained based on the proposed mechanism (Scheme 3-21), there must also be an additional operating mechanistic pathway leading to the generation of 27. We believe that in order for the observed 2,6-substitution pattern to occur, C-alkylation is likely to take place in a 1,2-addition fashion to the carbonyl group followed by subsequent E1cB type elimination to form a dihydropyridine intermediate (Scheme 3-27). Alternatively, an aldol condensation reaction could also occur followed by a 6π electrocyclic ring-closing to furnish the dihydropyridine. From this point, base-induced tautomerization and elimination of sufinic acid as proposed before furnishes 2,6-diphenylpyridine.

Scheme 3-27. Proposed Mechanism for Formation of 2,6-Diphenylpyridine 27

Following our discovery of isomers 26 and 27, we next set out to increase the total overall yields of both disubstituted pyridine products as well as determine reaction conditions

44 that may lead to the selective formation of one isomer over the other. The screening process consisted of varying the base and reaction temperature to determine if a trend in reactivity could be discovered (Table 3-6). Through these studies, it was found that in all cases, room temperature caused a significant decline in yields of pyridine isomer 27. Furthermore, when the temperature was increased to 75 oC, a 1:1 ratio of each pyridine isomer was generally obtained. KOH afforded the highest yields of both pyridine isomers 26 and 27 at 36% and 48% respectively. We believed that incorporating bulky bases to the reaction could lead to the formation of a single isomer, and despite a very low yield of 14% for pyridine 26, KOtBu in combination with room temperature conditions was able to suppress the formation of 27. When KOtBu was utilized at higher temperatures, we observed a 2:1 ratio of 26 to 27 in comparison to the typical 1:1 ratio, which implies that the bulky base may be contributing to the preferential formation of one isomer. As an aside, when 4-methoxycinnamaldehyde was used in combination with NaOH at higher temperatures, we obtained similar results for the 2,4- diarylpyridine product but recovered the corresponding 2,6-disubstituted product with impurities as an inseparable mixture. Similarly, in the case of 4-nitrocinnamaldehyde, we observed formation of the desired 2,4-diarylpyridine as a single isomer in 7% yield.

Table 3-6. Optimization for Diphenyl Pyridine Isomers 26 and 27

o Yield of Yield of Entry Base Temp. ( C) Time (h) a a 26 (%) 27 (%) 1 NaOH 75 2.5 24 17 2 NaOH rt 12 16 8 3 NaOMe 75 2.5 30 29

4 KOH 75 2.5 36 48 t 5 KO Bu 75 2.5 14 6 t 6 KO Bu rt 12 14 0 7 NaOtBu 75 2.5 16 17 8 NaOtBu rt 12 13 8 a Isolated yields.

3.3-12 Conclusions The construction of unsymmetrical 2,4,6-triarylpyridines is significantly underdeveloped in comparison to their symmetrical counterparts. In order to address this discrepancy, we have developed a modular synthesis of unsymmetrical pyridines, which tolerates a wide variety of functionality in good yields. This has led to the synthesis of novel pyridine products which are potentially useful building blocks in the design of more complex heterocycles as well as ligands for catalysis. The scope of our methodology also extends towards the synthesis of important polycyclic pyridines as well as trisubstituted pyridine derivatives containing tert-butyl groups and a diverse array of aryl and heteroaryl substitutents. The development of this efficient pyridine synthesis methodology has also served as a basis in which to further the synthetic utility of our previously discovered -sulfonylvinylamine synthons.

Appendix A: Supporting Information for Rhodium- Catalyzed Addition of Arylboronic Acids to (Arylsulfonyl)acetonitriles

General Experimental: Unless otherwise noted, reactions were carried out under argon atmosphere, in flame-dried, single-neck, round bottom flasks fitted with a rubber septum, with magnetic stirring. Air- or water-sensitive liquids and solutions were transferred via syringe or stainless steel canula. Organic solutions were concentrated by rotary evaporation at 23–40 °C under 40 Torr (house vacuum). Analytical thin layer chromatography (TLC) was performed with Silicycle™ normal phase glass plates (0.25 mm, 60-A pore size, 230-400 mesh). Visualization was done under a 254 nm UV light source and generally by immersion in potassium permanganate (KMnO4), followed by heating using a heat gun. Purification of reaction products was generally done by flash chromatography with Silicycle™ Ultra-Pure 230- 400 mesh silica gel, as described by Still et al.76

Materials: [Rh(COD)OH]2, [Rh(COD)Cl] 2, BINAP, BIPHEP, DPPP, DPPF and DPPB were purchased from Strem Chemicals Inc. and used as received. Arylboronic acids were purchased from Combi-Blocks, Inc. and Sigma-Aldrich, Inc., and used without further purification.

Tetrahydrofuran, 1,4-dioxane and toluene were purified by distillation under N2 from Na/benzophenone immediately prior to use. Ether and dichloromethane were purified by the method of Pangborn et al.77 Hexanes used for chromatography was purified by simple distillation before use. Chloroacetonitrile, (phenylsulfonyl)acetonitrile 2a, and benzoylacetonitrile were purchased from Sigma-Aldrich, Inc., and used without further purification. Substrates 4a-e78, 979, 1080, and 1281 were synthesized according to literature procedure.

76 Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923. 77 Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518. 78 Sakamoto, T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1990, 38, 1513. 79 Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.; Wakabayashi, S. J. Am. Chem. Soc. 1984, 106, 7890. 80 Numata, T.; Itoh, O.; Yoshimura, T.; Oae, S. Bull. Chem. Soc. Jpn. 1983, 56, 257. 81 Murakami, T.; Furusawa, K. Synthesis 2002, 479.

Varian 400 (400 MHz/100 MHz) NMR spectrometer equipped with ATB8123-400 probe. Recorded shifts for protons are reported in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvents (CHCl3: δ 7.26,

CHDCl2: δ 5.29, C6HD5: δ 7.15, CD2HOD: δ 3.30). Chemical shifts for carbon resonances are reported in parts per million (δ scale) downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3: δ 77.0, CH2Cl2: δ 53.8, C6D6: δ 128.0, CD3OD: δ 49.2). Data are represented as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,, qn = quintuplet, sx = sextet, sp = septuplet, m = multiplet, br = broad), and coupling constant (J, Hz). Infrared (IR) spectra were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrometer as a neat film on a NaCl plate. Data is presented as frequency of absorption (cm–1). High resolution mass spectra were obtained from a SI2 Micromass 70S-250 mass spectrometer (EI) or an ABI/Sciex Qstar mass spectrometer (ESI). Melting points were taken on a Fisher-Johns melting point apparatus and are uncorrected.

Experimental Procedures. General procedure (A) for the synthesis of (Z)-β- sulfonylvinylamines via Rh(I)-catalyzed addition of arylboronic acids to (phenylsulfonyl)acetonitrile: To a 2-dram vial equipped with a magnetic stir bar was added

[Rh(COD)OH]2 (3.0 mg, 0.0066 mmol, 2 mol%), BINAP (12.0 mg, 0.019 mmol, 6 mol%) and

Cs2CO3 (105 mg, 0.32 mmol). The vial was capped with a septum and flushed with argon. Dioxane (1.0 mL) was added and the solution was stirred for 10 min in a 50 oC oil bath (slowly turned orange/reddish) then cooled to room temperature. (Phenylsulfonyl)acetonitrile 1a (0.32 mmol, 1.0 eq.) and arylboronic acid (0.80 mmol, 2.5 eq.) were added as a solution in o dioxane/H2O (1.5 mL/0.25 mL). The vial was sealed and heated in a 75 C oil bath for 14 hrs. The solvent was removed in vacuo and the crude was purified by flash column chromatography

(EtOAc/hexanes/1% Et3N) on silica gel.

General procedure (B) for the synthesis of β-keto sulfones via Rh(I)-catalyzed addition of arylboronic acids to (benzyl-/arylsulfonyl)acetonitriles followed by hydrolysis: To a 2-dram vial equipped with a magnetic stir bar was added [Rh(COD)OH]2 (3.0 mg, 0.0066 mmol, 2 mol%) and BINAP (12.0 mg, 0.019 mmol, 6 mol%). The vial was capped with a septum and flushed with argon. Dioxane (1.0 mL) was added and the solution was stirred for 10 min in a 50 oC oil bath (slowly turned orange/reddish) then cooled to room temperature. (Benzyl- /arylsulfonyl)acetonitrile 1 (0.32 mmol, 1.0 eq.) and arylboronic acid (0.80 mmol, 2.5 eq.) were

48 added as a solution in dioxane/H2O (1.5 mL/0.25 mL). The vial was sealed and heated in a 75 oC oil bath for 14 or 2.5 hrs. Upon completion of the catalytic reaction, 1M aqueous HCl (1 mL) was added (turned yellow) and the mixture was heated at 75 oC for 3 hrs. The reaction crude was concentrated in vacuo and purified by flash column chromatography (EtOAc/hexanes) on silica gel.

General procedure (C) for the synthesis of (benzyl-/arylsulfonyl)acetonitriles 1b-h: Sulfide synthesis. To a 50-mL flask were added the thiol (3.6 mmol), Na2CO3 (0.59g, 5.6 mmol), acetone (20 mL) and chloroacetonitrile (0.23 mL, 3.6 mmol). The mixture was heated at 50 oC for 5 to 12 hrs until all starting materials were consumed. The mixture was then filtered through a funnel to remove insolubles and the filtrate was concentrated in vacuo. The corresponding crude sulfide product was obtained in quantitative yield and used in the next step without further purification. Oxidation of sulfide to sulfone. To a 100-mL flask was dissolved the sulfide (3.2 mmol) in dichloromethane (40 mL), added MCPBA (77%) (1.6 g, 7.1 mmol) as a solid portion- wise at 0 oC. The mixture was stirred at r.t. for 12 hrs then quenched with aq. sat. Na2S2O3 solution (20 mL). The aqueous layer was extracted with dichloromethane (20 mL x 3).

The combined organic layer was washed with aq. sat. NaHCO3 solution, water then brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (EtOAc/hexanes).

Characterization Data:

Refer to our previous report for characterization of (benzyl-/arylsulfonyl)acetonitriles 1b-h and β-keto sulfones 3a-q synthesized by Tsui.44

(phenylsulfonyl)acetonitrile 1a. Purchased from Sigma-Aldrich, Inc. and used without further purification. 1H NMR (400 MHz, CDCl3): δ 8.07-8.03 (2H, m), 7.82-7.77 (1H, m), 7.70-7.65 (2H, m), 4.07 (2H, m) ppm. 13C NMR (100 MHz, CDCl3): δ 136.6, 135.4, 129.8, 128.8, 110.4, 45.7 ppm.

(Z)-1,2-diphenyl-2-(phenylsulfonyl)ethenamine 5a. Prepared according to general procedure A without Cs2CO3. The reaction was run for 6 hrs. The product was obtained as a yellow solid in 91% yield (61 mg, 0.20 mmol scale). 1H NMR (400 MHz, CDCl3): δ 7.68-7.65 (2H, m), 7.50-7.45 (1H, m), 7.41-7.34 (2H, m), 7.16-7.07 (5H, m), 7.02-6.92 (3H, m), 6.90-6.86 (2H, m), 5.90 (2H, br s) ppm. 13C NMR (100 MHz, CDCl3): δ 155.3, 142.4, 137.8, 133.9, 133.5, 132.3, 128.9, 128.4, 128.3, 128.0, 127.4, 127.0, 126.8, 105.4 ppm. IR (NaCl, neat film): 3453, 3349, 3059, 3024, 2924, 1613, 1543, 1493, 1447, 1385, 1281, 1150, 1126, 1076, 934, 725 cm-1. HRMS m/z (ESI): calcd. for C20H18NO2S [MH+]: 336.1052; found: 336.1063. M.p. 108-110 oC.

(Z)-1-(4-methoxyphenyl)-2-phenyl-2-(phenylsulfonyl)ethenamine 5c. Prepared according to general procedure A without Cs2CO3. The reaction was run for 6 hrs. The product was obtained as a yellow solid in 80% yield (93 mg, 0.32 mmol scale). 1H NMR (400 MHz, CDCl3): δ 7.69- 7.65 (2H, m), 7.49-7.45 (1H, m), 7.39-7.34 (2H, m), 7.11-7.06 (2H, m), 7.03-6.96 (3H, m), 6.92-6.88 (2H, m), 6.64-6.59 (2H, m), 3.68 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 159.9, 155.1, 142.5, 133.9 (2), 132.2, 130.1, 129.8, 128.4, 127.5, 126.9 (2), 113.4, 105.1, 55.1 ppm. IR (NaCl, neat film): 3457, 3349, 1609, 1547, 1508, 1443, 1385, 1281, 1250, 1126, 1076, 837 cm-1. o HRMS m/z (EI): calcd. for C21H19NO3S [M+]: 365.1086; found: 365.1084. M.p. 152-155 C.

(Z)-2-(2-chlorophenyl)-1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethenamine 5e. Prepared according to general procedure A without Cs2CO3. The reaction was run for 6 hrs. The product was obtained as a white solid in 63% yield (161 mg, 0.64 mmol scale). 1H NMR (400 MHz, CDCl3): δ 7.64 (2H, m), 7.42-7.54 (2H, m), 7.32-7.40 (2H, m), 7.14 (2H, m), 7.07-7.13 (1H, m), 6.99-7.06 (1H, m), 6.93 (1H, m), 6.61 (1H, m), 3.68 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 160.2, 156.5, 142.1, 137.7, 136.6, 132.5, 132.4, 129.8, 129.7, 129.2, 128.5, 127.2, 126.0, 113.2, 101.5, 55.2 ppm. IR (NaCl, neat film): 3450, 3351, 3064, 3004, 2960, 2936, 2838, -1 1582, 1539, 1469, 1387, 1153, 1031, 913 cm . HRMS m/z (EI): calcd. for C21H18ClNO3S [MH+]: 400.0696; found: 400.0765. M.p. 134-135 oC.

Spectra:

Appendix B: Supporting Information for Synthesis of Unsymmetrical Polysubstituted Pyridines

General Experimental: Unless otherwise noted, reactions were carried out in single-neck, round bottom flasks fitted with a rubber septum, with magnetic stirring. Water-sensitive liquids and solutions were transferred via syringe or stainless steel canula. Organic solutions were concentrated by rotary evaporation at 23–40 °C under 40 Torr (house vacuum). Analytical thin layer chromatography (TLC) was performed with Silicycle™ normal phase glass plates (0.25 mm, 60-A pore size, 230-400 mesh). Visualization was done under a 254 nm UV light source. Purification of reaction products was generally done by flash chromatography with Silicycle™ Ultra-Pure 230-400 mesh silica gel, as described by Still et al.82

Materials: [Rh(COD)OH]2 and BINAP were purchased from Strem Chemicals Inc. and used as received. Arylboronic acids were purchased from Combi-Blocks, and used without further purification. (Phenylsulfonyl)acetonitrile was purchased from Sigma-Aldrich, Inc., and used without further purification. Sodium hydroxide, potassium hydroxide, sodium methoxide, and cesium carbonate were purchased from ACP Chemicals, Inc., and Sigma-Aldrich, Inc., and used as received. Commercially available chalcone derivatives (table 2, entries 1-4, 6) were purchased from Sigma-Aldrich, Inc., and Alfa Aesar, and used without further purification. All aldehydes and α-hydrogen containing compounds used to synthesize α, β-unsaturated substrates were purchased from Sigma-Aldrich, Inc., and used without further purification.

Tetrahydrofuran and 1,4-dioxane were purified by distillation under N2 from Na/benzophenone immediately prior to use.

Instrumentation: Proton nuclear magnetic resonance spectra (1H NMR) spectra and carbon nuclear magnetic resonance spectra (13C NMR) were recorded at 23 °C with a Varian Mercury 400 (400 MHz/100 MHz) NMR spectrometer equipped with a Nalorac4N-400 probe, or a Varian 400 (400 MHz/100 MHz) NMR spectrometer equipped with ATB8123-400 probe. Recorded shifts for protons are reported in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvents (CHCl3: δ 7.26,

CHDCl2: δ 5.29, C6HD5: δ 7.15, CD2HOD: δ 3.30). Chemical shifts for carbon resonances are

82 Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

54 reported in parts per million (δ scale) downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3: δ 77.0, CH2Cl2: δ 53.8, C6D6: δ 128.0, CD3OD: δ 49.2). Data are represented as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, qn = quintuplet, sx = sextet, sp = septuplet, m = multiplet, br = broad), and coupling constant (J, Hz). Infrared (IR) spectra were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrometer as a neat film on a NaCl plate. Data is presented as frequency of absorption (cm–1). High resolution mass spectra were obtained from a SI2 Micromass 70S-250 mass spectrometer (EI) or an ABI/Sciex Qstar mass spectrometer (ESI). Melting points were taken on a Fisher-Johns melting point apparatus and are uncorrected.

Experimental Procedures. General procedure for Rh(I)-catalyzed addition of arylboronic acids to (phenylsulfonyl)acetonitrile for synthesis of β-Sulfonylvinylamines: To a 25mL round bottom flask equipped with a magnetic stir bar was added [Rh(COD)OH]2 (18.2 mg, 2 mol%) and BINAP (71.8 mg, 0.12 mmol, 6 mol%). The round bottom flask was capped with a septum and flushed with argon. Dioxane (4.0 mL) was added and the solution was stirred for 10 min in a 50 oC oil bath (slowly turned orange/reddish) then cooled to room temperature. To a 20mL scintillation vial was added (phenylsulfonyl)acetonitrile (364 mg, 2.00 mmol) followed by the appropriate boronic acid (600 mg, 5.00 mmol), and Cs2CO3 (650 mg, 2.00 mmol). To this vial was added dioxane (8.0 mL) and water (1.2 mL), and the mixture was swirled until it became homogeneous. Addition of this homogeneous solution to the round bottome flask was accomplished using a syringe, and the reaction was heated in a 75 °C oil bath for 12 hrs. The solvent was removed in vacuo and the crude was purified by flash column chromatography

(EtOAc/hexanes) with 1% Et3N on silica gel.

General procedure for addition of β-Sulfonylvinylamines to α, β-unsaturated ketones for synthesis of polysubstituted pyridine derivatives: To a 2-dram vial equipped with a magnetic stir bar was added the β-Sulfonylvinylamine (0.20 mmol) followed by the α,β-unsaturated substrate (0.30 mmol) and dioxane (1.8 mL). Allowed the reaction to stir for five minutes before adding the appropriate base (0.60 mmol) as a solid and heated in a 75 °C oil bath for 2.5 hrs. The solvent was removed in vacuo and the crude was purified by flash column chromatography (EtOAc/hexanes) on silica gel.

Characterization Data:

(E)-1-(4-nitrophenyl)-3-phenylprop-2-en-1-one (table 3-3, entry 5). Prepared according to the literature procedure.83 The product was obtained as an orange solid in 82% yield (415 mg). 1H NMR (400 MHz, CDCl3): δ 8.36 (2H, d, J = 8.0 Hz), 8.15 (2H, d, J = 8.0 Hz), 7.85 (1H, d, J = 13 15.6 Hz), 7.67 (2H, m), 7.51–7.45 (4H, m) ppm. C NMR (100 MHz, CDCl3): δ 189.1, 150.1, 146.9, 143.1, 134.3, 131.3, 129.4, 129.2, 128.7, 123.9, 121.3 ppm. M.p. 145-146 oC. The characterization data are fully concordant with the literature report.84

(E)-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (table 3-5, entry 3). Prepared according to the literature procedure.85 The product was obtained as a yellowish-orange solid in 50% yield 1 (110 mg). H NMR (400 MHz, CDCl3): δ 9.19 (1H, br. s), 8.01–7.97 (2H, m), 7.75–7.81 (1H, d, J = 15.6 Hz), 7.45–7.60 (3H, m), 7.16–7.22 (1H, d, J = 15.6 Hz), 7.01 (1H, s), 6.73 (1H, s), 13 6.33–6.36 (1H, m) ppm. C NMR (100 MHz, CDCl3): δ 190.9, 135.1, 132.6, 128.8, 128.5, 123.5, 116.0, 115.6, 111.7 ppm. M.p. 136-137 oC. The characterization data are fully concordant with the literature report.86

(E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one (table 3-5, entry 2). Prepared according to the literature procedure.87 The product was obtained as a brown solid in 45% yield (108 mg). 1H NMR (400 MHz, CDCl3): δ 7.82 (2H, d, J = 7.32 Hz), 7.76 (1H, d, J = 15.3 Hz), 7.30-7.41 (m, 13 3H), 7.12-7.28 (m, 3H), 6.89 (t, J = 4.9 Hz, 1H) ppm. C NMR (100 MHz, CDCl3): δ 189.8, 140.3, 138.0, 137.1, 132.7, 132.0, 128.8, 128.6, 128.1, 120.7 ppm. M.p. 42-44 oC. The characterization data are fully concordant with the literature report.88

83 Bhagat, S., et al. Journal of Molecular Catalysis A: Chemical. 2006, 244, 20. 84 Cai, M., et al. Green Chem. 2009, 11, 1687. 85 Ferlin, M. G., et al. European Journal of Medicinal Chemistry. 2009, 44, 2854. 86 Robinson, T. P., et al. Bioorg. Med. Chem. 2005, 13, 4007. 87 Ferlin, M. G., et al. European Journal of Medicinal Chemistry. 2009, 44, 2854. 88 Ranu, B. C., et al. J. Org. Chem. 2005, 70, 8621.

(E)-3-(furan-2-yl)-1-phenylprop-2-en-1-one (table 3-5, entry 1). Prepared according to the literature procedure.89 The product was obtained as a yellow solid in 85% yield (842 mg). 1H NMR (400 MHz, CDCl3): δ 7.95-8.15 (2H, m), 7.42-7.65 (6H, m), 6.72 (1H, d, J = 3.4 Hz), 13 6.52 (1H, dd, J = 3.4, 1.8 Hz) ppm. C NMR (100 MHz, CDCl3): δ 189.2, 151.3, 144.6, 137.8, 132.4, 130.2, 128.2, 128.0, 118.9, 115.9, 112.4 ppm. The characterization data are fully concordant with the literature report.8

(E)-1,3-di(furan-2-yl)prop-2-en-1-one (table 3-5, entry 4). Prepared according to the literature procedure.90 The product was obtained as a yellow solid in 78% yield (734 mg). 1H NMR (400 MHz, CDCl3): δ 7.65 (1H, s), 7.63 (1H, d, J = 15.6 Hz), 7.53 (1H, d, J = 1.6 Hz), 7.32 (1H, d, J = 15.6 Hz), 7.31 (1H, d, J = 4.0 Hz), 6.73 (1H, d, J = 3.6 Hz), 6.58 (1H, d, J = 3.4 Hz), 6.51 13 (1H, d, J = 3.4 Hz) ppm. C NMR (100 MHz, CDCl3): δ 177.7, 153.7, 151.6, 146.6, 145.0, 129.9, 118.8, 117.4, 116.4, 112.7, 112.5 ppm. M.p. 88-90 oC. The characterization data are fully concordant with the literature report.91

(E)-1-(furan-2-yl)-3-(thiophen-2-yl)prop-2-en-1-one (table 3-2, entry 9). Prepared according to the literature procedure.92 The product was obtained as a yellow solid in 87% yield (887 mg). 1 H NMR (400 MHz, CDCl3): δ 7.84 (1H, dd, J = 3.6, 1.2 Hz), 7.65 (1H, dd, J = 5.2, 1.2 Hz), 7.59 (1H, d, J =15.2 Hz), 7.52 (1H, d, J = 2.0 Hz), 7.31 (1H, d, J = 15.2 Hz), 7.16 (1H, dd, J = 5.2, 3.6 Hz), 6.71 (1H, d, J = 3.6 Hz), 6.50 (1H, dd, J = 3.6, 2.0 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 181.7, 151.4, 145.6, 145.0, 133.8, 131.7, 129.9, 128.2, 119.0, 116.4, 112.7 ppm. M.p. 69-70 oC. The characterization data are fully concordant with the literature report.11

89 Chong, J. M., et al. J. Am. Chem. Soc. 2000, 122, 1822. 90 Zohdi, H. F., et al. Syn. Commun. 2009, 39, 2789. 91 Liu, W., et al. Chem. Biol. Drug Des. 2009, 73, 661. 92 Liu, S., et al. J. Am. Chem. Soc. 2008, 130, 6918.

(E)-3-phenyl-1-(pyridin-2-yl)prop-2-en-1-one (table 3-5, entry 6). Prepared according to the literature procedure.93 The product was obtained as a light brown solid in 73% yield (558 mg). 1 H NMR (400 MHz, CDCl3): δ 8.84 (1H, m), 8.31 (1H, dd, J = 16.1, 0.5 Hz), 8.20 (1H, dd, J = 7.2, 1.2 Hz), 7.95 (1H, d, J = 16.1 Hz), 7.87 (1H, dt, J = 7.6, 1.7 Hz), 7.73 (2H, m), 7.49 (1H, 13 m), 7.42 (3H, m) ppm. C NMR (100 MHz, CDCl3): δ 189.70, 154.46, 149.08, 144.99, 137.22, 135.38, 130.77, 129.07, 129.05, 127.10, 123.14, 121.09 ppm. M.p. 70-72 oC. The characterization data are fully concordant with the literature report.12

(E)-2-benzylidene-3,4-dihydronaphthalen-1(2H)-one (22). Prepared according to the literature procedure.11 The product was obtained as an off-white solid in 88% yield (1.03 g). 1H NMR (400 MHz, CDCl3): δ 8.12 (1H, d, J = 7.8 Hz), 7.86 (1H, s), 7.46-7.49 (1H, m), 7.39-7.44 (4H, m), 7.33-7.36 (2H, m), 7.23 (1H, d, J = 5.4 Hz), 3.11-3.13 (2H, m), 2.94 (2H, t, J = 7.8 Hz) 13 ppm. C NMR (100 MHz, CDCl3): δ 187.9, 143.2, 136.6, 135.8, 135.4, 133.4, 133.3, 129.9, 128.5, 128.4, 128.20, 128.16, 127.0, 28.8, 27.2 ppm. M.p. 104-106 oC. The characterization data are fully concordant with the literature report.11

(E)-4,4-dimethyl-1-phenylpent-1-en-3-one (table 3-6, entry 7). Prepared according to the literature procedure.94 The product was obtained as a colourless oil in 82% yield (1.54 g). 1H NMR (400 MHz, CDCl3): δ 7.69 (1H, d, J = 15.6 Hz), 7.50–7.65 (2H, m), 7.34–7.50 (3H, m), 13 7.13 (1H, d, J = 15.6 Hz), 1.20 (9H, s) ppm. C NMR (100 MHz, CDCl3): δ 204.1, 142.8, 134.8, 130.1, 128.8, 128.2, 120.6, 43.2, 26.2 ppm. The characterization data are fully concordant with the literature report.95

93 Singh, P. K., et al. Org. Lett. 2008, 10, 4121. 94 Deng, J., et al. J. Org. Chem. 2010, 75, 2981. 95 Tanaka, K., et al. Org. Lett. 2005, 7, 3561.

(E)-3-(4-bromophenyl)-1-(6-bromopyridin-2-yl)prop-2-en-1-one (table 3-2, entry 3). Prepared according to the literature procedure.96 The product was obtained as a slight yellow 1 solid in 70% yield (1.41g). H NMR (400 MHz, CDCl3): δ 8.18 (1H, d, J = 15.9 Hz), 8.14 (1H, dd, J = 7.2, 0.9 Hz), 7.86 (1H, d, J = 15.9 Hz), 7.77-7.67 (m, 2H), 7.58 (2H, s), 7.57 (2H, s) 13 ppm. C NMR (100 MHz, CDCl3): δ 187.4, 154.9, 144.2, 141.1, 139.2, 133.9, 132.2, 131.7, 130.3, 125.1, 121.8, 120.9 ppm. The characterization data are fully concordant with the literature report.96

(Z)-1-phenyl-2-(phenylsulfonyl)ethenamine (2a). Prepared according to the literature procedure.97 The product was obtained as a yellow solid in 86% yield (222 mg). 1H NMR (400 13 MHz, CDCl3): δ 7.96 (2H, m), 7.35-7.60 (8H, m), 6.05 (2H, br. s), 5.11 (1H, s) ppm. C NMR (100 MHz, CDCl3): δ 156.69, 144.66, 137.15, 132.56, 131.06, 129.20, 126.53, 126.19, 92.09 ppm. The characterization data are fully concordant with the literature report.15

(Z)-1-(4-methoxyphenyl)-2-(phenylsulfonyl)ethenamine (20a). Prepared according to the literature procedure.15 The product was obtained as a yellow oil in 95% yield (275 mg). 1H NMR (400 MHz, CDCl3): δ 7.95 (2H, m), 7.46-7.57 (3H, m), 7.42 (2H, m), 6.89 (2H, m), 5.91 13 (2H, br. s), 5.07 (1H, s), 3.82 (3H, s) ppm. C NMR (100 MHz, CDCl3): δ 161.93, 156.39, 144.88, 132.43, 129.21, 129.15, 127.98, 126.14, 114.49, 91.05, 55.65 ppm. The characterization data are fully concordant with the literature report.15

96 D. G. Kurth, et al., J. Am. Chem. Soc., 2008, 130, 2073. 97 G. C. Tsui, et al. Org. Lett. 2011, 13, 208.

(Z)-2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethenamine (20b). Prepared according to general procedure. The product was obtained as a yellow solid in 64% yield (209 mg). 1H NMR (400 MHz, CDCl3): δ 7.92-7.97 (2H, m), 7.48-7.67 (7H, m), 6.01 (2H, br. s), 5.10 (1H, s) 13 ppm. C NMR (100 MHz, CDCl3): δ 155.06, 144.17, 140.61, 132.85, 129.30, 127.15, 126.27, 126.19 (q, J = 3.8 Hz), 125.12, 122.41, 93.51 ppm. IR (NaCl, neat film): 3453, 3352, 1628, 1555, 1327, 1285, 1169, 1130, 1084, 1065, 860, 826, 752, 721, 687, 660, 575, 552, 521 cm-1. + HRMS m/z (ESI): calcd. for C15H12F3NO2S [MH ]: 328.0541; found: 328.0619. M.p. 118-119 oC.

(Z)-1-(4-chlorophenyl)-2-(phenylsulfonyl)ethenamine (20c). Prepared according to general procedure. The product was obtained as a white solid in 92% yield (270 mg). 1H NMR (400 13 MHz, CDCl3): δ 7.95 (2H, m), 7.32-7.60 (7H, m), 5.97 (2H, br. s), 5.07 (1H, s) ppm. C NMR (100 MHz, CDCl3): δ 155.17, 144.22, 136.96, 135.38, 132.52, 129.28, 129.07, 127.73, 126.07, 92.58. IR (NaCl, neat film): 3449, 3349, 3071, 3017, 2959, 2916, 2889, 2855, 1620, 1582, 1551, 1493, 1420, 1285, 1238, 1134, 1084, 999, 849, 822, 752, 721, 690, 582, 525 cm-1. HRMS + o m/z (ESI): calcd. for C14H12ClNO2S [MH ]: 294.0277; found: 294.0356. M.p. 99-101 C.

(Z)-1-(2-methoxyphenyl)-2-(phenylsulfonyl)ethenamine (table 3-2, entry 2). Prepared according to general procedure. The product was obtained as a light yellow solid in 97% yield 1 (280 mg). H NMR (400 MHz, CDCl3): δ 7.97 (2H, m), 7.46-7.58 (3H, m), 7.27-7.39 (2H, m), 13 6.25 (2H, br. s), 4.98 (1H, s), 3.83 (3H, s) ppm. C NMR (100 MHz, CDCl3): δ 156.77, 155.82, 144.99, 132.35, 131.70, 129.72, 129.08, 126.09, 125.35, 121.19, 111.91, 92.43, 55.99 ppm. IR (NaCl, neat film): 3457, 3359, 3232, 3078, 3008, 2939, 2838, 1616, 1603, 1586, 1539, 1489, -1 + 1436, 1282, 1084, 836 cm . HRMS m/z (ESI): calcd. for C15H15NO3S [MH ]: 290.0773; found: 290.0851. M.p. 107-109 oC.

2,4,6-triphenylpyridine (17). Prepared according to general procedure. The product was 1 obtained as a white solid in 81% yield (50 mg). H NMR (400 MHz, CDCl3): δ 8.23 (4H, m), 13 7.92 (2H, s), 7.78 (2H, m), 7.40–7.60 (9H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.54, 150.24, 139.62, 139.09, 129.18, 129.12, 129.04, 128.78, 127.25, 127.21, 117.18 ppm. IR (NaCl, neat film): 3086, 3059, 3032, 2924, 1662, 1604, 1593, 1578, 1551, 1497, 1446, 1400, 760, 737, 690, 571 cm-1. M.p. 134-135 oC. The characterization data are fully concordant with the literature report.98

4-(4-methoxyphenyl)-2,6-diphenylpyridine (19a). Prepared according to general procedure. 1 The product was obtained as a white solid in 86% yield (58 mg). H NMR (400 MHz, CDCl3): δ 8.19 (4H, m), 7.84 (2H, s), 7.69 (2H, m), 7.42-7.53 (6H, m), 7.05 (2H, m), 3.87 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 160.52, 157.49, 149.67, 139.77, 131.33, 129.02, 128.73, 128. 37, 127.18, 116.65, 114.58, 55.48 ppm. IR (NaCl, neat film): 3082, 3059, 3036, 3001, 2960, 2932, 2909, 2835, 1608, 1597, 1578, 1547, 1516, 1292, 1253, 1238, 1180, 1030, 826, 775, 694, 571, -1 + 521 cm . HRMS m/z (EI): calcd. for C24H19NO [M ]: 337.1467; found: 337.1459. M.p. 96-98 oC. The characterization data are fully concordant with the literature report.99

98 Adib, M., et al. Tet. Lett. 2006, 47, 5957. 99 Zheng, M., et al. Organic & Biomolecular Chemistry. 2007, 5, 945.

2-(4-nitrophenyl)-4,6-diphenylpyridine (19e). Prepared according to general procedure. The 1 product was obtained as an off-white solid in 20% yield (14 mg). H NMR (400 MHz, CDCl3): δ 8.37 (4H, m), 8.19 (2H, m), 7.96 (2H, dd, J = 1.6, 10.8 Hz), 7.75 (2H, m), 7.46-7.58 (6H, m) 13 ppm. C NMR (100 MHz, CDCl3): δ 158.09, 154.93, 150.79, 148.23, 145.50, 139.02, 138.51, 129.50, 129.38, 129.29, 128.89, 127.89, 127.21, 127.15, 124.01, 118.48, 117.84 ppm. IR (NaCl, neat film): 3061, 2955, 2925, 2854, 1593, 1551, 1521, 1342, 859, 692 cm-1. HRMS m/z (ESI): + o calcd. for C23H16N2O2 [MH ]: 353.1212; found: 353.1284. M.p. 189-190 C.

4-(4-nitrophenyl)-2,6-diphenylpyridine (19b). Prepared according to general procedure with the use of KOH. The product was obtained as an orange solid in 57% yield (40 mg). 1H NMR (400 MHz, CDCl3): δ 8.38 (2H, m), 8.20 (4H, m), 7.88 (2H, m), 7.85 (2H, s), 7.44-7.56 (6H, m) 13 ppm. C NMR (100 MHz, CDCl3): δ 158.19, 148.39, 148.06, 145.68, 139.24, 129.66, 129.05, 128.39, 127.35, 124.59, 117.16 ppm. IR (NaCl, neat film): 3086, 3063, 3036, 2955, 2924, 2851, -1 1593, 1551, 1516, 1350, 849, 814, 775, 752, 691 cm . HRMS m/z (ESI): calcd. for C23H16N2O2 [MH+]: 353.1212; found: 353.1290. M.p. 195-197 oC. The characterization data are fully concordant with the literature report.100

100 Kato, H., et al. Bulletin of the Chemical Society of Japan. 1991, 64, 392.

4-(4-chlorophenyl)-2,6-diphenylpyridine (19c). Prepared according to general procedure. The 1 product was obtained as a white solid in 95% yield (65 mg). H NMR (400 MHz, CDCl3): δ 13 8.18 (4H, m), 7.81 (2H, s), 7.65 (2H, m), 7.41-7.53 (8H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.88, 149.14, 139.63, 137.70, 135.42, 129.55, 129.40, 128.97, 128.68, 127.35, 117.01 ppm. IR (NaCl, neat film): 3086, 3063, 3036, 2955, 2924, 2851, 1593, 1551, 1516, 1350, 849, 814, -1 + 775, 752, 691 cm . HRMS m/z (EI): calcd. for C23H16ClN [M ]: 341.0971; found: 341.0843. M.p. 126-128 oC. The characterization data are fully concordant with the literature report. 101

2-(4-chlorophenyl)-4,6-diphenylpyridine (19f). Prepared according to general procedure. The 1 product was obtained as a white solid in 93% yield (64 mg). H NMR (400 MHz, CDCl3): δ 8.15 (4H, m), 7.89 (1H, d, J = 1.6 Hz), 7.83 (1H, d, J = 1.6 Hz), 7.72 (2H, m), 7.42-7.55 (8H, m) 13 ppm. C NMR (100 MHz, CDCl3): δ 157.64, 156.26, 150.41, 139.43, 138.92, 138.02, 135.19, 129.23, 129.20, 129.14, 128.92, 128.80, 128.43, 127.22, 127.16, 117.41, 116.89 ppm. IR (NaCl, neat film): 3086, 3059, 3036, 2924, 1597, 1543, 1493, 1400, 1092, 1011, 833, 694 cm-1. HRMS + o m/z (EI): calcd. for C23H16ClN [M ]: 341.0971; found: 341.0966. M.p. 127-128 C.

101 Kato, H., et al. Bulletin of the Chemical Society of Japan. 1990, 63, 1937.

2-(4-methoxyphenyl)-4,6-diphenylpyridine (19d). Prepared according to general procedure. 1 The product was obtained as a white solid in 85% yield (57 mg). H NMR (400 MHz, CDCl3): δ 8.18 (4H, m), 7.82 (2H, m), 7.73 (2H, m), 7.40-7.55 (6H, m), 7.03 (2H, m), 3.87 (3H, s) ppm. 13 C NMR (100 MHz, CDCl3): δ 160.60, 157.38, 157.17, 150.13, 139.76, 139.27, 132.28, 129.14, 129.02, 128.95, 128.73, 128.45, 127.23, 127.17, 116.52, 116.38, 114.12 ppm. IR (NaCl, neat film): 3059, 3036, 3005, 2955, 2928, 2835, 1608, 1593, 1546, 1512, 1400, 1246, 1176, -1 + 1030, 833, 760, 694, 405 cm . HRMS m/z (EI): calcd. for C24H19NO [M ]: 337.1467; found: 337.1459. M.p. 99-101 oC. The characterization data are fully concordant with the literature report.102

2,4-diphenyl-6-(4-(trifluoromethyl)phenyl)pyridine (20b). Prepared according to general procedure. The product was obtained as a white solid in 70% yield (53 mg). 1H NMR (400 MHz, CDCl3): δ 8.30 (2H, d, J = 8.0 Hz), 8.19 (2H, m), 7.93 (1H, d, J = 1.6 Hz), 7.89 (1H, d, J 13 = 1.6 Hz), 7.70-7.80 (4H, m), 7.43-7.56 (6H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.85, 155.98, 150.57, 142.93, 139.28, 138.76, 131.04, 130.71, 129.33, 129.24, 128.83, 127.44, 127.22, 127.16, 125.68 (q, J = 3 Hz), 122.95, 117.94, 117.45 ppm. IR (NaCl, neat film): 3086, 3062, 3037, 2956, 2927, 2854, 1618, 1607, 1596, 1581, 1496, 1403, 1391, 1312, 777, 734, 682, -1 + 614 cm . HRMS m/z (ESI): calcd. for C24H16F3N [MH ]: 376.1235; found: 376.1322. M.p. 131-132 oC.

102 Katritzky, A. R., et al. Synthesis. 1999, 12, 2114.

2,6-diphenyl-4-(1H-pyrrol-2-yl)pyridine (21c). Prepared according to general procedure. The 1 product was obtained as a brown solid in 59% yield (35 mg). H NMR (400 MHz, CDCl3): δ 8.75 (1H, br. s), 8.14 (2H, m), 7.70 (2H, s), 7.40-7.52 (6H, m), 6.96 (1H, m), 6.82 (1H, m), 6.37 13 (1H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.65, 141.05, 139.66, 129.90, 129.06, 128.70, 127.09, 120.76, 113.23, 110.89, 108.84 ppm. IR (NaCl, neat film): 3432, 3061, 3034, 2922, 2854, 2366, 2335, 1704, 1607, 1600, 1564, 1452, 776, 767, 728, 693, 651, 559 cm-1. HRMS m/z + o (ESI): calcd. for C21H16N2 [MH ]: 297.1313; found: 297.1392. M.p. 145-147 C.

4,6-diphenyl-2,2'-bipyridine (21e). Prepared according to general procedure. The product was 1 obtained as a white solid in 75% yield (46 mg). H NMR (400 MHz, CDCl3): δ 8.72 (1 H, ddd, J = 4.8, 2.0, 0.8 Hz), 8.70 (1 H, ddd, J = 8.0, 1.2, 0.8 Hz), 8.66 (1 H, d, J = 1.6 Hz), 8.24-8.20 (2 H, m), 8.00 (1 H, d, J = 1.6 Hz), 7.88 (1 H, ddd, J = 8.0, 7.6, 2.0 Hz), 7.85-7.82 (2 H, m), 7.57- 7.51 (4 H, m), 7.49-7.44 (2 H, m), 7.35 (1 H, ddd, J = 7.6, 4.8, 1.2 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 157.36, 156.59, 156.51, 150.51, 149.28, 139.72, 139.02, 137.08, 129.29, 129.23, 129.21, 128.97, 127.49, 127.31, 124.02, 121.74, 118.73, 117.76 ppm. IR (NaCl, neat film): 3059, 3038, 2961, 2924, 2834, 2364, 2325, 1604, 1583, 1560, 1549, 1395, 759, 686 cm-1. + o HRMS m/z (ESI): calcd. for C22H16N2 [MH ]: 309.1313; found: 309.1386. M.p. 145-146 C. The characterization data are fully concordant with the literature report.103

103 Richard, J. K., et al. J. Org. Chem. 2005 , 70, 10086.

2-(furan-2-yl)-6-phenyl-4-(thiophen-2-yl)pyridine (18i). Prepared according to general procedure at room temperature over 20h. The product was obtained as a deep orange solid in 1 81% yield (49 mg). H NMR (400 MHz, CDCl3): δ 8.12 (2H, m), 7.84 (1H, s), 7.77 (1H, s), 7.61 (1H, d, J = 4.0 Hz), 7.56 (1H, s), 7.40-7.53 (4H, m), 7.24 (1H, m), 7.16 (1H, m), 6.56 (1H, 13 m) ppm. C NMR (100 MHz, CDCl3): δ 157.91, 154.00, 149.91, 143.31, 142.89, 141.78, 139.20, 129.23, 128.74, 128.40, 127.12, 127.03, 125.41, 115.15, 113.21, 112.15, 109.21 ppm. IR (NaCl, neat film): 3108, 3087, 3066, 3040, 3012, 2957, 2924, 2853, 1612, 1549, 1538, 1525, -1 + 1016, 742, 693 cm . HRMS m/z (ESI): calcd. for C19H13NOS [MH ]: 304.0718; found: 304.0790. M.p. 96-97 oC.

2,4-di(furan-2-yl)-6-phenylpyridine (21d). Prepared according to general procedure. The product was obtained as a deep orange solid in 88% yield (51 mg). ). 1H NMR (400 MHz, CDCl3): δ 8.13 (2H, m), 7.88 (1H, d, J = 1.6 Hz), 7.85 (1H, d, J = 1.6 Hz), 7.57 (2H, dd, J = 4.0, 1.6 Hz), 7.40-7.53 (3H, m), 7.22 (1H, d, J = 4.0 Hz), 6.97 (1H, d, J = 4.0 Hz), 6.54-6.58 (2H, m) 13 ppm. C NMR (100 MHz, CDCl3): δ 157.72, 154.10, 151.82, 149.76, 143.70, 143.25, 139.27, 138.94, 129.17, 128.71, 127.08, 112.85, 112.15, 112.11, 111.11, 109.05, 108.71 ppm. IR (NaCl, neat film): 3146, 3117, 3063, 3038, 2958, 2924, 2854, 1545, 1487, 1409, 1222, 774, 738, 694 -1 + cm . HRMS m/z (ESI): calcd. for C19H13NO2 [MH ]: 288.0946; found: 288.1019. M.p. 101- 103 oC.

2,6-diphenyl-4-(thiophen-2-yl)pyridine (21b). Prepared according to general procedure. The 1 product was obtained as a white solid in 87% yield (55 mg). H NMR (400 MHz, CDCl3): δ 8.18 (4H, m), 7.86 (2H, s), 7.60 (1H, dd, J = 4.0, 1.6 Hz), 7.41-7.54 (7H, m), 7.15 (1H, dd, J = 13 3.6, 1.2 Hz) ppm. C NMR (100 MHz, CDCl3): δ 157.76, 143.03, 142.01, 139.43, 129.18, 128.75, 128.43, 127.15, 126.95, 125.29, 115.37 ppm. IR (NaCl, neat film): 3086, 3057, 3039, 2959, 2924, 2852, 1595, 1552, 1408, 866, 773, 686, 560 cm-1. HRMS m/z (ESI): calcd. for + o C21H15NS [MH ]: 314.0925; found: 314.1003. M.p. 160-163 C.

4-(furan-2-yl)-2,6-diphenylpyridine (21a). Prepared according to general procedure. The 1 product was obtained as an orange solid in 77% yield (46 mg). H NMR (400 MHz, CDCl3): δ 8.19 (4H, d, J = 8.0 Hz), 7.93 (2H, s), 7.59 (1H, s), 7.40-7.55 (7H, m), 6.98 (1H, d, J = 4.0 Hz), 13 6.57 (1H, dd, J = 3.4, 1.6 Hz) ppm. C NMR (100 MHz, CDCl3): δ 157.54, 152.02, 143.65, 139.50, 139.09, 129.12, 128.71, 127.10, 113.04, 112.15, 108.51 ppm. IR (NaCl, neat film): 3138, 3110, 3090, 3059, 3039, 2959, 2924, 2853, 1572, 1417, 1013, 774, 726, 630, 582 cm-1. + o HRMS m/z (ESI): calcd. for C21H15NO [MH ]: 298.1154; found: 298.1232. M.p. 168-170 C. The characterization data are fully concordant with the literature report.16

6-(4-chlorophenyl)-4-phenyl-2,2'-bipyridine (18a). Prepared according to general procedure. 1 The product was obtained as a yellow solid in 78% yield (54 mg). H NMR (400 MHz, CDCl3): δ 8.71 (1H, m), 8.62-8.66 (2H, m), 8.14 (2H, d, J = 8.0 Hz), 7.93 (1H, d, J = 2.0 Hz), 7.77-7.87 13 (3H, m), 7.45-7.54 (5H, m), 7.33 (1H, m) ppm. C NMR (100 MHz, CDCl3): δ 156.60, 156.37, 156.08, 150.67, 149.33, 138.82, 138.11, 137.10, 135.39, 129.31, 129.26, 129.13, 128.55, 127.46, 124.12, 121.67, 118.43, 118.01 ppm. IR (NaCl, neat film): 3085, 3058, 3036, 2962, 2928, 1601, 1567, 1550, 1474, 1442, 1402, 1383, 1102, 1091, 1013, 824, 795, 744, 695, 671, -1 + 619, 496 cm . HRMS m/z (ESI): calcd. for C22H15ClN2 [MH ]: 343.0924; found: 343.1002. M.p. 135-136 oC.

2-(4-chlorophenyl)-4-(4-methoxyphenyl)-6-phenylpyridine (18f). Prepared according to general procedure. The product was obtained as a yellow oil in 72% yield (54 mg). 1H NMR (400 MHz, CDCl3): δ 8.10-8.20 (4H, m), 7.85 (1H, d, J = 1.6 Hz), 7.79 (1H, d, J = 1.6 Hz), 7.68 13 (2H, m), 7.41-7.54 (5H, m), 7.01-7.07 (2H, m), 3.88 (3H, s) ppm. C NMR (100 MHz, CDCl3): δ 160.77, 157.77, 156.39, 150.03, 139.74, 138.33, 135.28, 131.31, 129.31, 129.06, 128.94, 128.59, 128.54, 127.32, 117.06, 116.54, 114.79, 55.66 ppm. IR (NaCl, neat film): 3084, 3063, 3039, 3004, 2958, 2932, 2836, 1700, 1583, 1428, 1291, 1237, 1180, 1090, 1031, 1013, 776, -1 + 755, 693, 570 cm . HRMS m/z (ESI): calcd. for C24H18ClNO [MH ]: 372.1077; found: 372.1155. M.p. 164-166 oC.

2-(4-chlorophenyl)-4-(furan-2-yl)-6-phenylpyridine (18g). Prepared according to general procedure. The product was obtained as an orange solid in 72% yield (48 mg). 1H NMR (400 MHz, CDCl3): δ 8.10-8.20 (4H, m), 7.91 (1H, d, J = 1.6 Hz), 7.88 (1H, d, J = 1.6 Hz), 7.57-7.59 (1H, m), 7.42-7.54 (5H, m), 6.97 (1H, dd, J = 4.0, 1.6 Hz), 6.57 (1H, dd, J = 4.0, 2.0 Hz) ppm. 13 C NMR (100 MHz, CDCl3): δ 157.81, 156.45, 151.99, 143.93, 139.48, 139.39, 138.07, 135.40, 129.42, 129.05, 128.93, 128.53, 127.25, 113.43, 112.92, 112.38, 108.86 ppm. IR (NaCl, neat film): 3117, 3086, 3063, 3038, 2922, 2850, 1611, 1546, 1490, 1012, 832, 736, 693 cm-1. + o HRMS m/z (ESI): calcd. for C21H14ClNO [MH ]: 332.0764; found: 332.0842. M.p. 135-137 C.

2-(4-chlorophenyl)-6-phenyl-4-(thiophen-2-yl)pyridine (18h). Prepared according to general procedure. The product was obtained as a white solid in 64% yield (47 mg). 1H NMR (400 MHz, CDCl3): δ 8.06-8.16 (4H, m), 7.86 (1H, d, J = 1.6 Hz), 7.81 (1H, d, J = 1.6 Hz), 7.60 (1H, dd, J = 2.4, 1.6 Hz), 7.42-7.55 (6H, m), 7.17 (1H, dd, J = 4.0, 1.6 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 158.04, 156.65, 143.37, 141.95, 139.40, 137.99, 135.47, 129.49, 129.09, 128.97, 128.65, 128.58, 127.30, 127.29, 125.58, 115.76, 115.25 ppm. IR (NaCl, neat film): 3106, 3085, 3065, 3039, 2953, 2923, 2851, 1580, 1574, 1527, 1436, 1424, 1102, 1092, 1014 cm- 1 + . HRMS m/z (ESI): calcd. for C21H14ClNS [MH ]: 348.0535; found: 348.0608. M.p. 145-147 oC.

2-(4-chlorophenyl)-6-(furan-2-yl)-4-(thiophen-2-yl)pyridine (18i). Prepared according to general procedure. The product was obtained as a deep orange solid in 55% yield (39 mg). 1H NMR (400 MHz, CDCl3): δ 8.05 (2H, m), 7.84 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 1.6 Hz), 7.60 (1H, dd, J = 2.6, 1.2 Hz), 7.57 (1H, dd, J = 2.6, 1.0 Hz), 7.42-7.48 (3H, m), 7.22 (1H, dd, J = 2.6, 0.8 Hz), 7.16 (1H, dd, J = 3.6, 1.6 Hz), 6.57 (1H, dd, J = 2.0, 1.6 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ 156.61, 153.78, 149.94, 143.43, 143.04, 141.53, 137.57, 135.34, 128.90, 128.44, 128.37, 127.18, 125.52, 114.81, 113.40, 112.17, 109.32 ppm. IR (NaCl, neat film): 3112, 3073, 2955, 2924, 2853, 1608, 1577, 1572, 1548, 1424, 1405, 1221, 1093, 1013, 828, -1 + 754, 744, 703, 592, 556 cm . HRMS m/z (ESI): calcd. for C19H12ClNOS [MH ]: 338.0328; found: 338.0400. M.p. 122-123 oC.

6'-bromo-4-(4-bromophenyl)-6-(4-chlorophenyl)-2,2'-bipyridine (18e). Prepared according to general procedure at room temperature over 14h. The product was obtained as a white solid in 1 87% yield (87 mg). H NMR (400 MHz, CDCl3): δ 8.57 (1H, dd, J = 7.6, 0.8 Hz), 8.52 (1H, d, J = 1.2 Hz), 8.09 (2H, m), 7.86 (1H, d, J = 1.6 Hz), 7.69 (1H, t, J = 7.6 Hz), 7.64 (4H, s), 7.52 13 (1H, dd, J = 7.8, 1.2 Hz), 7.48 (2H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.34, 156.31, 155.09, 149.60, 141.79, 139.40, 137.61, 137.47, 135.68, 132.49, 129.18, 129.01, 128.50, 123.91, 120.35, 118.56, 117.96 ppm. IR (NaCl, neat film): 3099, 3054, 3020, 2991, 2943, 2915, 2888, 1654, 1635, 1623, 1616, 1604, 834, 817, 798, 729, 694, 579 cm-1. HRMS m/z (ESI): + o calcd. for C22H13Br2ClN2 [MH ]: 498.9134; found: 498.9213. M.p. 210-213 C.

6'-bromo-4-(4-bromophenyl)-6-phenyl-2,2'-bipyridine (18d). Prepared according to general procedure at room temperature over 14h. The product was obtained as a white solid in 85% 1 yield (79 mg). H NMR (400 MHz, CDCl3): δ 8.61 (1H, dd, J = 7.6, 0.4 Hz), 8.51 (1H, d, J = 1.2 Hz), 8.15 (2H, m), 7.9 (1H, d, J = 1.6 Hz), 7.69 (1H, t, J = 7.6 Hz), 7.64 (4H, s), 7.42-7.55 13 (4H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.37, 154.81, 149.22, 141.56, 139.21, 139.03, 137.47, 132.26, 129.36, 128.86, 128.83, 128.20, 127.08, 123.59, 120.23, 118.67, 117.53 ppm. IR (NaCl, neat film): 3100, 3050, 3015, 2980, 2962, 2925, 2854, 1604, 1598, 1574, 1551, 1490, 1408, 1383, 1123, 1074, 1009, 822, 799, 773, 692, 642 cm-1. HRMS m/z (ESI): calcd. for + o C22H14Br2N2 [MH ]: 464.9524; found: 464.9615. M.p. 177-180 C.

2-(tert-butyl)-6-(4-chlorophenyl)-4-phenylpyridine (25k). Prepared according to general procedure at 75 oC over 5h. The product was obtained as a colourless oil in 72% yield (46 mg). 1 H NMR (400 MHz, CDCl3): δ 8.09 (2H, m), 7.71 (1H, d, J = 1.6 Hz), 7.66 (2H, m), 7.41-7.53 13 (6H, m), 1.47 (9H, s) ppm. C NMR (100 MHz, CDCl3): δ 169.92, 155.06, 149.89, 139.73, 138.60, 135.00, 129.25, 128.97, 128.96, 128.46, 127.42, 116.29, 115.50, 38.09, 30.53 ppm. IR (NaCl, neat film): 3075, 3053, 2962, 2924, 2899, 1656, 1635, 1604, 1595, 1551, 1492, 1403, -1 + 1091, 1012, 877, 734, 697, 616, 588, 575 cm . HRMS m/z (ESI): calcd. for C21H20ClN [MH ]: 322.1284; found: 322.1354.

6-(2-methoxyphenyl)-4-phenyl-2,2'-bipyridine (18b). Prepared according to general procedure at room temperature over 14h. The product was obtained as a colourless oil in 75% 1 yield (51 mg). H NMR (400 MHz, CDCl3): δ 8.70 (1H, m), 8.62 (2H, m), 8.14 (1H, d, J = 1.6 Hz), 8.03 (1H, dd, J = 9.2, 1.6 Hz), 7.78-7.85 (3H, m), 7.36-7.55 (4H, m), 7.30 (1H, m), 7.14 (1H, dt, J = 7.2, 0.8 Hz), 7.05 (1H, d, J = 7.6 Hz), 3.89 (3H, s) ppm. 13C NMR (100 MHz, CDCl3): δ 157.51, 156.80, 156.32, 155.95, 149.23, 149.21, 139.27, 137.02, 131.73, 130.25, 129.50, 129.15, 128.98, 127.58, 123.83, 123.50, 121.73, 121.31, 117.34, 111.83, 56.00 ppm. IR (NaCl, neat film): 3059, 3032, 3008, 2960, 2936, 2835, 1603, 1584, 1550, 1492, 1394, 1246, -1 + 1119, 761, 620 cm . HRMS m/z (ESI): calcd. for C23H18N2O [MH ]: 339.1419; found: 339.1499.

6'-bromo-4-(4-bromophenyl)-6-(2-methoxyphenyl)-2,2'-bipyridine (18c). Prepared according to general procedure at room temperature over 14h. The product was obtained as a 1 white solid in 73% yield (72 mg). H NMR (400 MHz, CDCl3): δ 8.56 (1H, dd, J = 7.6, 0.8 Hz), 8.51 (1H, d, J = 1.6 Hz), 8.10 (1H, d, J = 1.6 Hz), 7.99 (1H, dd, J = 6.0, 1.6 Hz), 7.60-7.69 (5H, m), 7.49 (1H, dd, J = 8.0, 0.8 Hz), 7.38-7.45 (1H, m), 7.14 (1H, dt, J = 7.6, 0.8 Hz), 7.04 (1H, d, 13 J = 8 Hz), 3.89 (3H, s) ppm. C NMR (100 MHz, CDCl3): δ 157.81, 157.45, 156.16, 154.82, 148.16, 141.70, 139.34, 137.99, 132.37, 131.65, 130.50, 129.16, 128.96, 128.18, 123.71, 123.52, 121.32, 120.38, 117.30, 111.80, 55.98 ppm. IR (NaCl, neat film): 3050, 3006, 2960, 2935, 2909, 2856, 2834, 1649, 1635, 1604, 1575, 1553, 1543, 1492, 1407, 1383, 1245, 1125, -1 + 1073, 1010, 800, 672 cm . HRMS m/z (ESI): calcd. for C23H16Br2N2O [MH ]: 494.9629; found: 494.9717. M.p. 161-162 oC.

2,4-diphenyl-5,6-dihydrobenzo[h]quinoline (23). Prepared according to general procedure with the use of KOH. The product was obtained as a light yellow solid in 71% yield (47 mg). 1H NMR (400 MHz, CDCl3): δ 8.58 (1H, dd, J = 6.4, 1.2 Hz), 8.17 (2H, m), 7.59 (1H, s), 7.29-7.51 (10H, m), 7.21 (1H, dd, J = 6.4, 0.8 Hz), 2.89-2.96 (2H, m), 2.81-2.88 (2H, m) ppm. 13C NMR (100 MHz, CDCl3): δ 154.64, 152.81, 149.48, 139.79, 139.58, 138.40, 135.46, 129.28, 129.05, 128.94, 128.88, 128.69, 128.23, 128.14, 127.70, 127.30, 127.04, 125.99, 120.15, 28.41, 25.53 ppm. . IR (NaCl, neat film): 3059, 3031, 2933, 2889, 2837, 1606, 1589, 1572, 1542, 1496, -1 + 1417, 1375, 766, 749, 738, 693 cm . HRMS m/z (ESI): calcd. for C25H19N [MH ]: 334.1517; found: 334.1590. M.p. 122-124 oC. The characterization data are fully concordant with the literature report.104

104 Zheng, M., et al. Org. Biomol. Chem. 2007, 5, 945.

2,4-diphenyl-3-(phenylsulfonyl)-5,6-dihydrobenzo[h]quinoline (24). Prepared according to general procedure with the use of KOH at room temperature over 20h. The product was 1 obtained as a white solid in 57% yield (54 mg). H NMR (400 MHz, CDCl3): δ 8.37 (1H, m), 7.59-7.65 (2H, m), 7.26-7.42 (9H, m), 7.19 (1H, m), 7.04-7.12 (6H, m), 2.81 (2H, t, J = 6.8 Hz), 13 2.57 (2H, t, J = 6.8 Hz) ppm. C NMR (100 MHz, CDCl3): δ 158.04, 154.29, 149.85, 142.52, 141.11, 138.86, 135.95, 134.16, 133.83, 132.09, 130.69, 130.03, 129.65, 128.72, 128.39, 128.20, 127.83, 127.79, 127.48, 127.15, 126.75, 27.80, 25.43 ppm. IR (NaCl, neat film): 3058, 3025, 2942, 2893, 2838, 1527, 1493, 1447, 1394, 1314, 1307, 1148, 1133, 1083, 755, 739, 725, -1 + 716, 697, 686, 666, 646, 596, 553, 526 cm . HRMS m/z (ESI): calcd. for C31H23NO2S [MH ]: 474.1449; found: 474.1528. M.p. 175-177 oC.

2,6-diphenylpyridine (27). Prepared according to general procedure with the use of KOH. The 1 product was obtained as a yellow solid in 48% yield (22 mg). H NMR (400 MHz, CDCl3): δ 8.15 (4H, m), 7.80 (1H, dd, J = 7.2, 1.2 Hz), 7.70 (1H, s), 7.68 (1H, d, J = 0.8 Hz), 7.39-7.53 13 (6H, m) ppm. C NMR (100 MHz, CDCl3): δ 157.05, 139.72, 137.68, 129.18, 128.90, 127.20, 118.84 ppm. IR (NaCl, neat film): 3059, 2924, 2851, 1574, 1566, 1450, 1439, 748, 690 cm-1. + o HRMS m/z (EI): calcd. for C17H13N [M ]: 231.1048; found: 231.1048. M.p. 78-80 C. The characterization data are fully concordant with the literature report.105

105 Namboothiri, I. N. N., et al. Tetrahedron. 1994, 50, 8127.

2,4-diphenylpyridine (26). Prepared according to general procedure with the use of KOH. The 1 product was obtained as a yellow oil in 36% yield (17 mg). H NMR (400 MHz, CDCl3): δ 8.74 (1H, dd, J = 4.4, 0.8 Hz), 8.02-8.09 (2H, m), 7.93 (1H, m), 7.66-7.72 (2H, m), 7.40-7.55 (7H, 13 m) ppm. C NMR (100 MHz, CDCl3): δ 158.15, 150.15, 149.33, 139.56, 138.61, 129.17, 129.08, 129.06, 128.81, 127.13, 127.08, 120.30, 118.81 ppm. IR (NaCl, neat film): 3059, 3028, 2924, 2851, 1678, 1604, 1593, 1578, 1543, 1470, 1447, 1389, 760, 694 cm-1. HRMS m/z (EI): + o calcd. for C17H13N [M ]: 231.1048; found: 231.1044. M.p. 67-68 C. The characterization data are fully concordant with the literature report.106

2-(tert-butyl)-4,6-diphenylpyridine (table 3-6, entry 9). Prepared according to general procedure. The product was obtained as a white solid in 55% yield (32 mg). 1H NMR (400 MHz, CDCl3): δ 8.15 (2H, m), 7.75 (1H, d, J = 1.2 Hz), 7.68 (2H, m), 7.36-7.53 (7H, m), 1.48 13 (9H, s) ppm. C NMR (100 MHz, CDCl3): δ 169.77, 156.27, 149.67, 140.19, 139.93, 129.21, 128.94, 128.84, 128.82, 127.44, 127.21, 115.99, 115.70, 38.09, 30.56 ppm. IR (NaCl, neat film): 3086, 3062, 3033, 2956, 2930, 2901, 2865, 1594, 1552, 1400, 1219, 875, 773, 762, 693, -1 + 402 cm . HRMS m/z (ESI): calcd. for C21H21N [MH ]: 288.1674; found: 288.1752. M.p. 94-95 oC.

106 Magdalena, M., et al. Tetrahedron. 2006, 62, 11063.

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