Development of Catalytic C–CN, C–O, and N–CN Sigma-Bonds Activation and Alkene Addition Reactions

A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY

Zhongda Pan

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

Advisor: Christopher J. Douglas

November 2016

Acknowledgements

I would like to thank my advisor, Prof. Chris Douglas and the entire Douglas group for creating a supportive atmosphere through my doctoral study. I thank Chris for supporting my research and giving me much freedom to experiment new research ideas. I would like to thank my lab mates in the Douglas group, in particular, Dr. Giang Hoang, Dr. Ashley Dreis, and Dr. Jodi Ogilve for their valuable mentorship, discussion, and encouragement. I also thank my co-workers, Dylan Walsh, Dr. Sarah Pound, Dr. Naveen Rondla, Shengyang Wang, and Jason Brethorst for their important contribution to my research projects. I am greatly indebted to my parents for their unconditional love and support, which have helped me push through the tough times.

Dedication

To my parents

Abstract

This Thesis describes the development of transition-metal-catalyzed alkene additions reactions through the activation of C–C and C–heteroatom σ-bonds. In these transformations, a C–C or C–heteroatom σ-bond is activated, cleaved, and added across an alkene double bond without inducing fragmentation, allowing addition of an alkene with vicinal functional groups and rapid construction of carbo- and heterocycles in an atom-economical manner. Chapter 1 provides an overview of catalytic alkene addition reactions and C–C σ-bond activation reactions. Chapters 2, 3, and 5 describe alkene addition reactions by catalytic activation of C–CN, C–O, and N–CN σ-bonds, respectively. An unprecedented metal-free N–CN bond cleavage process is discussed in Chapter 4.

iii

Table of Contents

List of Schemes viii List of Tables xii List of Abbreviations xiii

Chapter 1 Catalytic Alkene Difunctionalization Reactions by C–C and C– Heteroatom Bonds Activation 1

1.1 Overview of catalytic alkene difunctionalization reactions 1 1.2 Overview of catalytic C–C bond activation reactions 4 1.3 Topic and organization of this Thesis 10

Chapter 2 Palladium-Catalyzed Intramolecular Asymmetric Cyanoamidation of Alkenes by C–CN Bond Activation of Cyanoformamides 12

2.1 Introduction: transition-metal-catalyzed C–CN bond activation reactions 12 2.2 Overview of carbocyanation reactions 15 2.2.1 Mechanistic considerations 15 2.2.2 General patterns of carbocyanation reactions 20 2.3 Survey of carbocyanation reactions 22 2.3.1 Carbocyanation of alkynes 22 2.3.2 Acylcyanation of alkynes 32 2.3.3 Carbocyanation of alkenes 37 2.3.4 Acylcyanation of alkenes 41 2.4 Research proposal: asymmetric intramolecular cyanoamidation of alkenes 45 2.5 Results and discussion 46

2.5.1 Initial investigations with BPh3 and identification of irreproducible results 46 2.5.2 Cyanoamidation reaction of 2.92a: ligand screening 48 2.5.3 Cyanoamidation reaction of 2.92a: further screening 51 2.5.4 Cyanoamidation reaction of 2.92b 53

2.6 Conclusion and future work 55 2.7 Experimental section 56 2.7.1 General details 56 2.7.2 Synthesis of substrates 2.92a and 2.92b 57 2.7.3 General procedure for cyanoamidation reactions 60

Chapter 3 Iridium-Catalyzed Intramolecular Oxyacylation of Alkenes by C–O Bond Activation of Salicylate Esters 62

3.1 Introduction: transition-metal-catalyzed C–O bond activation reactions 62 3.2 Survey of acyl C–O bond activation reactions 63 3.2.1 Stoichiometric acyl C–O bond activation reactions 63 3.2.2 Catalytic, decarbonylative acyl C–O bond activation reactions 68 3.2.3 Catalytic, non-decarbonylative acyl C–O bond activation reactions 76 3.3 Research proposal: alkene oxyacylation reaction by acyl C–O bond activation 80 3.4 Results and discussion 84 3.4.1 Early investigations and discovery of a hydroxyl directing group 84 3.4.2 Screening of conditions with salicylate ester 3.103 87 3.4.3 Substrate scope study and transformations of oxyacylation product 89 3.4.4 Mechanistic investigations 91 3.5 Conclusions and future work 94 3.6 Experimental section 95 3.6.1 General details 95 3.6.2 Synthesis of substrates 96 3.6.3 General procedure for oxyacylation reactions 108 3.6.4 Derivatizations of 3.104a 116

Chapter 4 Metal-Free, Lewis Acid-Promoted Intramolecular Aminocyanation of Alkenes by N–CN Bond Cleavage of Cyanamides 120

4.1 Introduction: transition-metal-catalyzed cyanofunctionalization reactions 120 4.2 A brief survey of catalytic cyanofunctionalization reactions 123 v

4.3 Oxycyanation and aminocyanation reactions 131 4.4 Discovery of a metal-free intramolecular aminocyanation reaction 135 4.5 Scope and limitations of aminocyanation reaction 141 4.6 Mechanistic considerations 143 4.7 Conclusion and future work 150 4.8 Experimental Section 150 4.8.1 General details 150 4.8.2 Optimization of aminocyanation conditions 152 4.8.3 Overview of substrate synthesis 152 4.8.4 Preparation of aniline intermediates 154 4.8.5 Preparation of sulfonamide intermediates 163 4.8.6 Synthesis of cyanamide substrates 170 4.8.7 Intramolecular aminocyanation of cyanamides 175 4.8.8 Crossover experiments 180

Chapter 5 Progress in Developing a Palladium/Lewis Acid-Catalyzed Aminocyanation Reaction for the Construction of Nitrogen Heterocycles 182

5.1 Formal aminocyanation reactions not involving N–CN bond cleavage 182 5.2 Aminocyanation reactions involving N–CN bond cleavage 185 5.3 Research proposal: intramolecular aminocyanation of alkenes towards a broader scope of nitrogen heterocycles 191 5.4 Results and discussion 193 5.4.1 Aminocyanation of N-sulfonyl cyanamide 5.33 193 5.4.2 Aminocyanation of N-acyl cyanamide 5.36 195 5.4.3 Substrate scope and limitations 200 5.4.4 Mechanistic considerations 206 5.5 Conclusion and future work 207 5.6 Experimental section 207 5.6.1 General details 207 5.6.2 Optimization of conditions for aminocyanation of 5.36a 209 5.6.3 Overview of substrate synthesis 214 vi

5.6.4 Synthesis of cyanamides 5.42 (Step 1) 214 5.6.5 Synthesis of carboxylic acids 5.44 (Step 2) 219 5.6.6 Synthesis of substrates 5.36 (Step 3) 227 5.6.7 Synthesis of N-sulfonyl cyanamides 5.33 240 5.6.8 Palladium–Lewis acid-catalyzed aminocyanation reactions 243

Bibliography 261

vii

List of Schemes

Chapter 1

Scheme 1-1 Catalytic alkene addition reactions 2 Scheme 1-2 Palladium-catalyzed asymmetric alkene carboamination reaction 3 Scheme 1-3 Direct addition of alkenes via C–C and C–heteroatom bond activation 4 Scheme 1-4 Enantioselective C–C bond activation of benzocyclobutanones 6 Scheme 1-5 C–C bond activation of cyclobutanones by enantioselective β-carbon elimination 7 Scheme 1-6 Rhodium-catalyzed intramolecular carboacylation of alkenes 8

Scheme 1-7 Proposed catalytic cycle of carbocyclation reaction with RhCl(PPh3)3 9 Scheme 1-8 Overview of research projects 10

Chapter 2

Scheme 2-1 C–CN bond activation by transition-metal complexes 13 Scheme 2-2 Nickel-catalyzed C–CN bond activation in DuPont's adiponitrile process 14 Scheme 2-3 Transformations of metal–cyanide complexes 15 Scheme 2-4 General mechanism for carbocyanation of alkynes and alkenes 16 Scheme 2-5 Lewis acid-accelerated oxidative addition of C–CN bond 17 Scheme 2-6 Migratory insertion of alkynes and alkenes 18 Scheme 2-7 Reductive elimination of metal–cyanide complexes 20 Scheme 2-8 Nickel-catalyzed arylcyanation of alkynes 23 Scheme 2-9 Nickel–Lewis acid-catalyzed carbocyanation of alkynes 24 Scheme 2-10 Chelation-assisted alkylcyanation of alkynes 26 Scheme 2-11 Nickel-catalyzed allylcyanation of alkynes 28 Scheme 2-12 Substrate scope and synthetic application of allylcyanation reaction 29 Scheme 2-13 Nickel–Lewis acid-catalyzed alkynylcyanation of alkynes and 1,2-dienes 31 Scheme 2-14 Palladium-catalyzed formal cyanoacylation of terminal alkynes 32 Scheme 2-15 Nickel-catalyzed cyanoesterification of 1,2-dienes 34

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Scheme 2-16 Palladium-catalyzed intramolecular cyanoamidation of alkynyl cyanoformamides 35 Scheme 2-17 Palladium-catalyzed intramolecular cyanoesterification of alkynes 36 Scheme 2-18 Nickel-catalyzed arylcyanation of norbornene and norbornadiene 38 Scheme 2-19 Nickel–Lewis acid-catalyzed asymmetric intramolecular arylcyanation of alkenes 39 Scheme 2-20 Nickel–Lewis acid-catalyzed arylcyanation of alkenes 40 Scheme 2-21 Synthesis of (–)-esermethole and (–)-eptazocine through asymmetric arylcyanation of alkenes 41 Scheme 2-22 Palladium-catalyzed cyanoesterification of strained alkenes 42 Scheme 2-23 Palladium-catalyzed intramolecular cyanoamidation of alkenes 43 Scheme 2-24 Palladium-catalyzed intramolecular acylcyanation of alkenes using α- iminonitriles 45 Scheme 2-25 Proposed intramolecular asymmetric alkene cyanoamidation reactions 46 Scheme 2-26 Cyanoamidation reaction of 2.93a 47

Chapter 3

Scheme 3-1 C–O bond activation of esters by transition-metal complexes 63 Scheme 3-2 Oxidative addition of phenyl propionate with Ni(0) complexes 64 Scheme 3-3 Oxidative addition of a quinolin-8-ol-derived ester to a Rh(I) complex 66 Scheme 3-4 Chelation-assisted C–O bond activation of N-acyl amino acid ester 67 Scheme 3-5 Oxidative addition of aryl trifluoroacetates to a Pd(0) complex 68 Scheme 3-6 Ruthenium-catalyzed decarbonylative reduction of esters 69 Scheme 3-7 Chelation-assisted decarbonylative arylation of proline ester amidine 70 Scheme 3-8 Decarbonylative Heck-type coupling of electron-deficient esters 72 Scheme 3-9 Nickel-catalyzed decarbonylative cross-coupling of (hetero)aryl esters 73 Scheme 3-10 C–O/C–H coupling by acyl C–O bond activation and C–H activation 74 Scheme 3-11 Decarbonylative C–O/C–H coupling of azoles and heteroaryl esters 76 Scheme 3-12 Catalytic Suzuki-type coupling reactions of phenyl trifluoroacetates 77 Scheme 3-13 Pyridine-directed non-decarbonylative cross-coupling reactions 78 Scheme 3-14 Nickel-catalyzed formal cycloaddition of salicylic acid ketals to alkynes 79 ix

Scheme 3-15 Conception of oxyacylation reaction 80 Scheme 3-16 Intramolecular oxyacylation reaction of nitriles 82 Scheme 3-17 Rhodium-catalyzed intramolecular oxyacylation reaction of alkenes 83 Scheme 3-18 Preliminary screening with esters 3.97a–d 85 Scheme 3-19 Screening of conditions with salicylate ester 3.101 87 Scheme 3-20 Formation of methyl salicylate 3.107 89 Scheme 3-21 Transformations of the hydroxyl directing group 91 Scheme 3-22 Proposed catalytic cycle 92 Scheme 3-23 Mechanistic experiments 93 Scheme 3-24 Possible mechanism for the thermal racemization of enantioriched product 94

Chapter 4

Scheme 4-1 Metal-catalyzed cyanofunctionalization reaction 120 Scheme 4-2 Generic catalytic cycle for cyanofunctionalization of alkynes and alkenes 121 Scheme 4-3 O–CN bond cleavage of isopropyl cyanate by a molybdenum complex 123 Scheme 4-4 Palladium- and nickel-catalyzed intramolecular borylcyanation of alkynes 124 Scheme 4-5 Palladium-catalyzed intermolecular borylcyanation of alkynes 126 Scheme 4-6 Mechanistic experiments for borylcyanation reaction 127 Scheme 4-7 Palladium-catalyzed thiocyanation of terminal alkynes 128 Scheme 4-8 Palladium-catalyzed thiocyanation of arynes 129 Scheme 4-9 Palladium-catalyzed germylcyanation of alkynes 130 Scheme 4-10 Palladium–Lewis acid-catalyzed intramolecular oxycyanation of alkenes 132 Scheme 4-11 Proposed aminocyanation reaction by N–CN bond cleavage 134 Scheme 4-12 Cleavage of N–CN bond of cyanamides by a silyl–iron complex 135 Scheme 4-13 Synthesis of N-tosyl cyanamide 4.40 136 Scheme 4-14 Identification of aminocyanation product 4.46 with metal complexes 138 Scheme 4-15 Cyanation of indoles using N-cyano-N-phenyl-p-toluenesulfonamide 143 Scheme 4-16 Proposed mechanism 144 Scheme 4-17 Double-crossover experiments 145 Scheme 4-18 Selective formation of alkenyl nitrile 4.46n 146 Scheme 4-19 C–H cyanation of α-methyl styrenes by N–CN bond cleavage 147 x

Scheme 4-20 Theoretical study of aminocyanation reaction 148 Scheme 4-21 Synthesis of substrates 4.40a–f 152 Scheme 4-22 Synthesis of substrates 4.40g and 4.40h 153 Scheme 4-23 Synthesis of substrates 4.40i–l, 4.40n, 4.40o, and 4.40r 154

Chapter 5

Scheme 5-1 Formal aminocyanation of α,β-unsaturated cyclic enones 183 Scheme 5-2 Palladium-catalyzed aminoamidation and aminocyanation of alkenes 185 Scheme 5-3 Aminocyanation of arynes by N–CN bond cleavage 187 Scheme 5-4 Palladium–Lewis acid-catalyzed intramolecular aminocyanation of alkenes 188 Scheme 5-5 Proposed mechanism for aminocyanation reaction 190 Scheme 5-6 Coincidence of substrate design and reaction discovery 191 Scheme 5-7 Synthesis of nitrogen heterocycles in a direct addition approach 192 Scheme 5-8 Current focus of alkene aminocyanation reactions 193 Scheme 5-9 Preliminary substrate scope for aminocyanation of 5.33 195 Scheme 5-10 Aminocyanation of N-acyl cyanamide 5.36 196 Scheme 5-11 Optimized conditions for aminocyanation of 5.36 200 Scheme 5-12 Proposed mechanism for aminocyanation 207

List of Tables

Chapter 2

Table 2-1 General patterns of carbocyanation reaction 21 Table 2-2 Initial study of cyanoamidation reaction of 2.92a 47 Table 2-3 Ligand screening of asymmetric cyanoamidation reaction of 2.92a 50 Table 2-4 Further screening of asymmetric cyanoamidation reaction of 2.92a 51 Table 2-5 Cyanoamidation of 2.92a with added DMPU 53 Table 2-6 Cyanoamidation reaction of 2.92b 54

Chapter 3

Table 3-1 Optimization of oxyacylation conditions with salicylate ester 3.103 87 Table 3-2 Substrate scope for oxyacylation of salicylate esters 90

Chapter 4

Table 4-1 Selected element–cyano σ bonds dissociation energies 122 Table 4-2 Aminocyanation of 4.40 under palladium catalysis 136 Table 4-3 Optimization of aminocyanation conditions 139 Table 4-4 Metal-free aminocyanation — Lewis acids screening 140 Table 4-5 Scope and limitations of aminocyanation reaction 142 Table 4-6 Correlation of strength of Lewis acids with their performance 149

Chapter 5

Table 5-1 Screening of conditions for aminocyanation of 5.33 194 Table 5-2 OFAT Screening for aminocyanation of 5.36 196 Table 5-3 Representative optimization results for aminocyanation of 5.36 197 Table 5-4 Substrate scope for aminocyanation reaction 202 Table 5-5 Incompatible substrates 206 Table 5-6 Complete reaction screening for aminocyanation of 5.36a 210 xii

List of Abbreviations

Ac acetyl acac acetylacetonyl Ar aryl BDE bond dissociation energy (S,S)-BDPP ((2R,4R)-pentane-2,4-diyl)bis(diphenylphosphane) BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINOL 1,1'-bi-2-naphthol Bn benzyl Boc tert-butoxycarbonyl tBu tert-butyl tBuXphos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl bpy 2,2'-bipyridine (R,R)-ChiraPhos (2R,3R)-(+)-2,3-bis(diphenylphosphino)butane cod 1,5-cyclooctadiene coe cyclooctene conv. conversion Cp cyclopentadienyl Cy cyclohexyl dba dibenzylideneacetone DCC dicyclohexylcarbodiimide 1,2-DCE 1,2-dichloroethane dcype 2-bis(dicyclohexylphosphino)ethane decalin decahydronaphthalene DFT density functional theory DIOP 4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMPU N,N′-dimethylpropylene urea DPEphos bis[(2-diphenylphosphino)phenyl] ether

xiii dppb 1,4-bis(diphenylphosphino)butane dppdmp 1,3-bis-(diphenylphosphino)-2,2-dimethylpropane dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1′-ferrocenediyl-bis(diphenylphosphine) dppp 1,3-bis(diphenylphosphino)propane dr diastereomeric ratio (R)-DTBM-SEGPHOS (R)-(–)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3- benzodioxole + E electrophile ee enantiomeric excess Et ethyl EtOAc ethyl acetate FG functional group GC gas chromatography

H8-BINOL (R)-(+)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-2-naphthol Hex hexanes HPLC high performance liquid chromatography IPA isopropanol IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (R,R)-i-Pr-Foxap (R)-1-(diphenylphosphino)-2-[(R)-4-isopropyloxazolin-2-yl]ferrocene LA Lewis acid Me methyl Me-Phos 2-dicyclohexylphosphino-2′-methylbiphenyl (R)-MonoPhos (R)-(–)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a′]dinaphthalen-4- yl)dimethylamine MOP 2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl nbd norbornadiene NCTS N-cyano-N-phenyl-p-toluenesulfonamide Nixantphos 4,6-bis(diphenylphosphino)-10H-phenoxazine NMDPP neomenthyldiphenylphosphine NMP N-methyl-2-pyrrolidinone

xiv

Ns para-nitrobenzenesulfonyl Nu or Nu– nucleophile OFAT one-factor-at-a-time PEG polyethylene glycol PEPPSI™-IPr [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II) dichloride Ph phenyl PhMe toluene (R)-Phanephos (R)-(–)-4,12-bis(diphenylphosphino)-[2.2]-paracyclophane pin pinacolato PMP para-methoxyphenyl PPG polypropylene glycol ppm part per million iPr isopropyl pyr. pyridine rac. racemic rt room temperature Ru-Phos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (R,R)-SIPHOS-PE N-di[(R)-1-phenylethyl]-[(R)-1,1′-spirobiindane-7,7′-diyl]-phosphoramidite S-Phos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl TADDOL 2,2-dimethyl-α,α,α′,α′-tetraphenyldioxolane-4,5-dimethanol (S,S,R,R)-TangPhos (1S,1S',2R,2R')-1,1'-di-tert-butyl-(2,2')-diphospholane TBS tert-butyldimethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid or trifluoroacetate THF tetrahydrofuran TMS trimethylsilyl o-Tol ortho-tolyl p-Tol para-tolyl (R)-Tol-BINAP (R)-(+)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (R,R,R)-(+)-Tol-SKP (+)-1,13-bis[di(4-methylphenyl)phosphino]-(5aR,8aR,14aR)-5a,6,7,8,8a,9-

hexahydro-5H-[1]benzopyrano[3,2-d]xanthene TrixiePhos rac-2-(di-tert-butylphosphino)-1,1′-binaphthyl Ts para-toluenesulfonyl Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

xvi Chapter 1 | 1 Chapter 1 Catalytic Alkene Difunctionalization Reactions by C–C and C–Heteroatom Bond Activation

1.1 Overview of catalytic alkene difunctionalization reactions

Transition-metal-catalyzed alkene addition reactions are powerful tools in chemical synthesis, representative examples including hydrogenation, the Wacker oxidation, hydroformylation, hydrocyanation, and other alkene hydrofunctionalization reactions. 1 Over the past decade, palladium-catalyzed alkene difunctionalization reactions have emerged as a new strategy for rapid construction of molecular complexity from ubiquitous alkenes, where vicinal functional groups are introduced simultaneously onto the alkene double bonds to form two or more new bonds and/or stereocenters (Scheme 1- 1).2 The difunctionalization reaction is typically initiated by the nucleophilic attack to the alkene–palladium coordination complex, a process known as nucleopalladation, to generate the alkylpalladium (II) intermediate 1.1. The success of the second functionalization greatly relies upon transforming the alkyl–palladium bond of 1.1 into a new C–C or C–heteroatom bond while outcompeting the often facile β-hydride elimination process. Successful strategies for completing the second functionalization include (1) formation of a π-allyl complex using conjugated dienes,3 (2) insertion of a second alkene into the palladium–alkyl bond,4 (3) insertion of carbon monoxide into the palladium–alkyl bond,5 (4) oxidation of Pd(II) to Pd(IV), followed by a rapid reductive 6 elimination or SN2-type substitution, and (5) formation of 1.1 through an unusual, intramolecular syn-oxypalladation or syn-aminopalladation process, followed by rapid reductive elimination.7

Chapter 1 | 2

Scheme 1-1 Catalytic alkene addition reactions

Although class alkene difunctionalization reactions, such as the Sharpless asymmetric dihydroxylation has been extensively studied since the 1980's, recent successes in this field include forming C–O/C–N bonds in conjunction with vicinal C–C or C–heteroatom bonds to access a large variety of oxygen- and nitrogen-containing 8 – 11 heterocycles in a regio- and stereocontrolled manner. For example, Wolfe et al. developed an asymmetric alkene carboamination reaction and applied the method to the enantioselective synthesis of natural product (–)-tylophorine (Scheme 1-2). 12 In the presence of a base, catalytic Pd2dba3, and a chiral phosphoramidite ligand (R)-Siphos-PE, N-Boc-pent-4-enylamine 1.3 was coupled with aryl bromide 1.4 via palladium amido complex 1.5. Subsequent alkene insertion into the Pd–N bond proceeded through a syn- aminopalladation pathway to generate alkylpalladium complex 1.6,13 which underwent C–C bond-forming reductive elimination to provide 2-(arylmethyl)-pyrrolidine 1.7 in an enantiomerically enriched form. Pyrrolidine 1.7 was readily converted to (–)-tylophorine

Chapter 1 | 3 in two steps. Additionally, an enantioselective alkene carboalkoxylation reaction was developed for the synthesis of chiral 2-(arylmethyl)-tetrahydrofuran derivatives.14

Scheme 1-2 Palladium-catalyzed asymmetric alkene carboamination reaction

Despite significant advances, the established methods typically rely upon an exogenous electrophile (e.g., aryl halides) or nucleophile (e.g., halides, amines, carboxylates) to accomplish C–C or C–heteroatom bond formation vicinal to the heteroatom. Therefore, stoichiometric, or excess, addition of bases, oxidants or metal salts is often required, leading to inevitable waste formation (Scheme 1-3, A). In this context, our goal is to develop a direct addition approach that simultaneously introduces both a carbon or heteroatom group along with a synthetically useful functional group onto an alkene to generate the desired carbo- and/or heterocycles in a regioselective manner, thereby obviating the need for exogenous reagents (Scheme 1-3, B).

Chapter 1 | 4

Scheme 1-3 Direct addition of alkenes via C–C and C–heteroatom bond activation

To this end, we directed our attention to transition-metal-catalyzed σ bond activation, an emerging area in catalysis.15 Oxidative addition of C–C or “inert” C–heteroatom σ bonds to a transition metal generates an activated organometallic intermediate, which can deliver both fragments onto the C–C π bond of an alkene/alkyne upon migratory insertion and subsequent reductive elimination (Scheme 1-3, C). Accordingly, one new C–C bond and one C–heteroatom (or C–C) bond, along with one or two stereocenters are formed at the expense of breaking one bond, thus offering a highly atom economical approach16 to functionalized carbo- and heterocycles.

1.2 Overview of catalytic C–C bond activation reactions

Over the past three decades, catalytic C–C bond activation has attracted considerable attention from the synthetic community, yet significant challenges remain unsolved.17 C– C bond activation dates back to 1955, when Tipper serendipitously discovered the oxidative addition of the C–C bond of cyclopropane to a Pt(II) center.18 Since 1985, systematic studies employing two classes of strained molecules, cyclopropyl derivatives

Chapter 1 | 5 and biphenylenes have established the concept of C–C bond activation and set stage for the extensive developments in catalytic activation reactions.19 These efforts have enabled the transition of C–C bond activation from an exotic reaction to part of the synthetic chemist's repertoire for constructing complex molecules. Reports of C–C bond activation predominately focus on the activation of small strained rings because the expansion of such molecules via oxidative addition releases strain energy alongside the formation of stable metallacycles, thereby compensating the generally unfavorable C–C bond activation process.20 Notable advances along this line include enantioselective C–C bond activation reactions. For instance, following early success with C–C bond activation of benzocyclobutanones,21 the Dong group reported an enantioselective variant by cleaving the acyl C–C bond of 1.8 in the presence of catalytic

[Rh(cod)Cl]2 and a chiral bidentate phosphine ligand, (R)-DTBM-SEGPhos (Scheme 1- 4). 22 The resulting five-membered rhodacycle 1.9 added across the tethered alkene, followed by C–C bond-forming reductive elimination to provide the tricyclic-ring product 1.10 in a highly enantiomerically enriched form. A similar strategy was highlighted in constructing the tricyclic core of the natural product cycloinumakiol 1.13 by C–C bond activation and intramolecular insertion of trisubstituted alkene 1.11. 23 Further elaboration of 1.12 to the proposed cycloinumakiol 1.13 resulted in disagreement with the isolated sample regarding the NMR spectroscopic data. X-ray crystallography analysis led to an unambiguous structural revision of cycloinumakiol to structure 1.14., thus highlighting the power of strain-ring C–C bond activation in the synthesis of biologically relavent molecules. Shortly thereafter, enantioselective C–C bond activation of cyclobutanones was developed by Cramer et al.24

Chapter 1 | 6

Scheme 1-4 Enantioselective C–C bond activation of benzocyclobutanones

In addition to direct oxidative addition of C–C bonds, β-carbon elimination is another common strategy to activate C–C bonds.25 There are now several enantioselective variants as well. 26 As a representative example, Murakami et al. demonstrated the activation of cyclobutanone equipped with a boronic ester group (1.15) towards an asymmetric synthesis of sesquiterpene, (–)-α-herbertenol (Scheme 1-5).26a Initial boron– rhodium transmetallation of 1.15 with a rhodium complex afforded arylrhodium complex 1.16 and further triggered an intramolecular addition to form symmetric bicycle[2.1.1]- hexane skeleton 1.17. Chiral ligand-controlled enantioselective β-carbon elimination selectively cleaved one enantiotopic C–C bond, leading to an alkylrhodium complex bearing a quaternary carbon center (1.18), which was converted to chiral ketone 1.19 though protonolysis and further allowed a formal synthesis of (–)-α-herbertenol.

Chapter 1 | 7

Scheme 1-5 C–C bond activation of cyclobutanones by enantioselective β-carbon elimination

The absence of strain-release renders the activation of unstrained C–C bonds particularly challenging in the context of C–C bond activation, requiring alternative strategies to overcome the kinetic and thermodynamic barriers of cleaving C–C bonds. Stoichiometric bond activation reactions driven by aromatization and chelation-assistance formed early pioneering work. 27 – 29 Selective C–C bond activation of pincer-type compounds under exceptionally mild conditions represents another milestone, as demonstrated by Milstein and co-workers.30 Nevertheless, catalytic activation reactions of unstrained C–C bonds, especially those resulting in increased molecular complexity rather than fragmentations (e.g., hydrogenolysis, decarbonylation, and skeletal rearrangement) remained underdeveloped.31 More than 20 years after Suggs and Jun's studies of stoichiometric C–C bond activation of quinolinyl ketones, our group demonstrated that a catalytic, quinoline- directed C–C bond activation could be readily coupled with subsequent intramolecular alkene insertion to accomplish the carboacylation reaction of alkenes (Scheme 1-6).32 The coordination of quinoline nitrogen to a rhodium complex assists the acyl C–C bond

Chapter 1 | 8 activation and stabilizes the presumptive five-membered acyl–rhodium complex 1.21. Subsequent insertion of a 1,1-disubstituted alkene, followed by reductive elimination provides the cyclized product 1.22 while avoiding a potential β-hydride elimination pathway. By virtue of resulting all-carbon quaternary center, both an aryl and a carbonyl group are simultaneously introduced onto the alkene double bond in an atom-economical fashion.

Scheme 1-6 Rhodium-catalyzed intramolecular carboacylation of alkenes

Under optimized conditions, dihydrobenzofurans bearing a methyl-, ethyl-, or phenyl-substituted quaternary carbon center could be synthesized in excellent yields (1.22a–c). A mono-substituted alkene was also examined, albeit in 25% yield (1.22d); cleavage of the allyl ether instead of competing β-hydride elimination was the predominant decomposition pathway. Furthermore, the carboacylation reaction was also

Chapter 1 | 9 useful in constructing other heterocyclic frameworks, including benzofuranone (1.22e), chromane (1.22f), and indoline (1.22g). Analogously, dihydroindene (1.22h) and a dihydro-1H-pyrrolizine (1.22i) were also successfully obtained. In addition, quinoline- directed C–C bond activation was also successfully coupled with an intermolecular alkene insertion33 and a Suzuki-type cross-coupling reaction.34

Scheme 1-7 Proposed catalytic cycle of carbocyclation reaction with RhCl(PPh3)3

Johnson and Rathbun performed mechanistic studies on the carboacylation reaction under RhCl(PPh3)3 catalysis, including determination of the rate law, the catalytic resting state, the activation parameters, and the rate-limiting step by studying the 12C/13C kinetic isotope effects (Scheme 1-7).35 Under standard conditions, the reaction rate showed zero-

Chapter 1 | 10 order dependence upon substrate 1.20 (saturation kinetics) and first-order dependence upon RhCl(PPh3)3. In contrast, reactions performed in the presence of added product 1.22 or exogenous PPh3 resulted in a change from zero- to first-order dependence upon substrate, indicating product inhibition and disrupted ligand dissociation from

RhCl(PPh3)3, respectively. These results suggested a substrate–rhodium complex 1.23 as the resting state of catalysis. Measurement of 12C/13C kinetic isotope effects revealed significant isotope effects at the ketone carbon (1.027 ± 0.005) and the α-aromatic carbon (1.028 ± 0.004), while negligible isotope effects at the alkene carbons (all less than 1.003 ± 0.005). Thus, the oxidative addition of C–C bond (1.23 → 1.24) was likely the rate-determining step, which was also consistent with a relatively small activation entropy (ΔS‡ = –4.3 ± 2.4 eu) since minimal change of molecular organization was expected during the C–C bond activation step. Shortly after, Johnson et al. further extended their mechanistic investigations to the carboacylation reactions catalyzed by [Rh(C2H4)2Cl]2, including the examination of additional substrates bearing substituents on the aromatic ring, quinoline ring, and alkene.36

1.3 Topic and organization of this Thesis

Following our group's success of alkene carboacylation reactions by C–C bond activation, this Thesis describes the author's efforts towards developing novel alkene difunctionalization reactions by incorporating the strategy of C–C and C–heteroatom σ bonds activation, as briefly summarized in Scheme 1-8.

Scheme 1-8 Overview of research projects

Chapter 1 | 11 As a subfield of C–C bond activation reactions, catalytic C–CN bond activation does not require the use of strained substrates or embedded directing groups, which, in conjunction with the synthetic versatility of cyano groups, has drawn great attention from the synthetic community. Chapter 2 summaries the basic concepts and recent advances of C–CN bond activation, followed by our attempts to develop an asymmetric alkene cyanoamidation reaction to access chiral pyrrolidinone and piperidinone heterocycles. In addition to directing the C–C bond activation, a quinoline group has also proven effective in directing the activation of the C–O bond of an ester, namely the oxyacylation reaction, to affect the difunctionalization of an alkene with an alkoxy and an acyl group in an unconventional fashion. Along this line, chapter 3 describes the discovery of an intramolecular alkene oxyacylation reaction with salicylate esters, featuring a more versatile hydroxyl directing group. Chapters 4 and 5 discuss the advances in activating the N–CN σ bond of a cyanamide and subsequent alkene addition process. In both transformations, namely aminocyanation reactions, the N–CN bond of a cyanamide substrate is activated, cleaved, and formally added across an alkene in an intramolecular fashion, allowing access to nitrogen-containing heterocycles bearing a nitrile functional group. Notably, the aminocyanation reactions can proceed under either metal-free, Lewis acid-promoted conditions (chapter 4), or palladium–Lewis acid cooperative catalysis (chapter 5).

Chapter 2 | 12 Chapter 2 Palladium-Catalyzed Intramolecular Asymmetric Cyanoamidation of Alkenes by C–CN Bond Activation of Cyanoformamides

2.1 Introduction: transition-metal-catalyzed C–CN bond activation reactions

The development of methods for activating and functionalizing C–CN bonds is important in organic synthesis. 37 Nitriles exist commonly in agrochemicals, pharmaceuticals, and organic materials. Moreover, they serve as highly versatile precursors for various functional groups, such as aldehydes, carboxylic acids, amides, amines, and tetrazoles, among others.38 Recently, the versatility of cyano groups was highlighted by the Yu group in palladium-catalyzed meta-selective C–H activation reactions.39 Despite having high bond dissociation energies (>100 kcal/mol), 40 C–CN bonds have proven cleavable by several transition-metal complexes without using strained molecules and/or embedded directing groups. The cyano group is known to coordinate to metal centers in either η1- or η2- fashion with high binding affinity, 41 which can kinetically facilitate the bond activation (Scheme 2-1). The η2-coordination sets the stage for subsequent oxidative addition of C–CN bonds to transition metals (Scheme 2-1, path A). Alternatively, the cyano group can insert into the M–Si bond of a silyl-iron or silyl- rhodium complex to afford an η2-iminoacyl intermediate, followed by C–CN bond cleavage to give the silyl-isonitrile complex (Scheme 2-1, path B).42 In both pathways, the formation of stronger M–CN bonds provides the thermodynamic driving force for the overall transformation.

Chapter 2 | 13

Scheme 2-1 C–CN bond activation by transition-metal complexes

The cleavage of C–CN bonds by transition metals has been known for decades. In 1969, Blum et al. observed the rhodium-catalyzed decarbonylation of aroyl cyanides.43a In 1971, Burmeister and Edwards studied the oxidative addition of C–CN bond of 1,1,1- tricyanoethane with tetrakis(triphenylphosphine)platinum(0). 44 A notable industrial application of C–CN bond activation is illustrated in DuPont's synthesis of adiponitrile (ADN), an important precursor to nylon 6-6 (Scheme 2-2).45 A key component of this process is a nickel-catalyzed isomerization of 2-methyl-3-butenenitrile (2M3BN) to 3- pentenenitrile (3PN), both of which form as kinetic mixtures from the hydrocyanation of butadiene with hydrogen cyanide. The 2M3BN–3PN isomerization proceeds through Lewis acid-assisted C–CN bond cleavage and formation of a Ni(II) π-allyl cyanide intermediate. Subsequent olefin isomerization of 3PN, followed by another Ni-catalyzed hydrocyanation generates ADN. Detailed mechanistic study of the ADN process, particularly the roles of Lewis acid additives, have been documented by DuPont researchers and Jones et al.46

Chapter 2 | 14

Scheme 2-2 Nickel-catalyzed C–CN bond activation in DuPont's adiponitrile process

Despite extensive study of the elementary steps in C–CN bond activation, catalytic activation of C–CN bonds towards organic synthesis has not been widely investigated until the early 2000s. The development of such methods relies on identifying a suitable downstream transformation of the metal–cyanide intermediates (R–M–CN) to achieve the turnover of catalyst (Scheme 2-3). Thus, three types of transformations are commonly encountered: cross-coupling reactions (type A), cyanation reactions (type B), and carbocyanation reactions (type C). In cross-coupling reactions, aryl and aliphatic cyanides serve as the pseudohalides, which are coupled with organometallic reactants to form new C–C,47 C–N,48 C–P,49 C–Si,50 and C–B51 bonds. In addition, C–CN bonds are reduced, upon coupling with hydride donors to C–H bonds under hydrodecyanation conditions, 52 thereby rendering the cyano group removable. 53 Although high catalyst loading and reaction temperature are generally required, metal-catalyzed cross-coupling reaction of nitriles provides an alternative entry to the realm of cross-coupling chemistry. In cyanation reactions, nitriles serve as the cyanating agents to form new C–CN bonds. 54 Operating by various mechanisms, 55 these reactions employ nitriles as nonmetallic cyano-group sources offers several advantages over the conventional methods (e.g., the Sandmeyer reaction and the Rosenmund–von Braun reaction): (1) toxic metal cyanides are avoided, (2) catalytic formation of the metal–cyanide species minimizes undesired catalyst deactivation by excess cyanide ions, and (3) nitriles used for cyanation reactions are low cost and convenient to handle. Compared with the aforementioned cross-coupling reaction, the cyanation reaction arguably provides an

Chapter 2 | 15 orthogonal reactivity pattern, in which the cyano group, instead of another R group, is utilized for new C–C bond formation. The carbocyanation reaction is particularly interesting because both groups within an organic nitrile are incorporated into the product.56 A metal–cyanide intermediate adds across a C–C π bond to install two new C–C bonds in one operation, representing an attractive strategy for constructing highly functionalized nitriles with minimal by-product formation. From an atom-economical viewpoint, the carbocyanation reaction employs ubiquitous alkenes and alkynes as reactants, thereby obviating the need for stoichiometric organometallic agents or prefunctionalized organohalides. The following contents of this chapter will focus on carbocyanation reactions using transition metals. Carbocyanation reactions described via alternative mechanistic scenarios will not be discussed.57

Scheme 2-3 Transformations of metal–cyanide complexes

2.2 Overview of carbocyanation reactions

2.2.1 Mechanistic considerations

Carbocyanation reactions are predominantly catalyzed by nickel(0) or palladium(0) complexes. As shown in Scheme 2-4, oxidative addition of the C–CN bond of the η2 complex 2.1 gives the metal–cyanide adduct 2.2, which coordinates to alkyne/alkene and generates the tetra- or pentacoordinated complex 2.4. Migration of the R group onto the C–C π-bond provides complex 2.5 (carbometalation), which undergoes reductive elimination to give nitrile product 2.7 and regenerate the catalyst. An alternate, yet less

Chapter 2 | 16 precedented pathway involves the migration of the cyano group, namely cyanometalation, to form the isomeric complex 2.6, which would lead to the same product (2.7) upon reductive elimination.

Scheme 2-4 General mechanism for carbocyanation of alkynes and alkenes

Oxidative addition of the C–CN bond is significantly accelerated by Lewis acids (Scheme 2-5). The coordination of a Lewis acid to the nitrogen atom of cyanide not only renders the C–CN bond more electrophilic towards metal addition, but also stabilizes the resulting oxidative adduct, thereby lowering the barrier of C–CN bond cleavage. Jones et al. quantitatively evaluated the role of triphenyl boron (BPh3) in affecting the C–CN activation of allyl cyanide to an electron rich (dippe)Ni(0) complex (dippe = 1,2- 46b bis(diisopropylphosphino)ethane). In the absence of BPh3, C–CN bond cleavage was reversible, leading to the Ni(II) π-allyl cyanide complex 2.9, which eventually converted to the more thermodynamically stable Ni(0) η2-crotonitrile complex 2.10 via a

Chapter 2 | 17 competitive allylic C–H activation pathway. In contrast, the added BPh3 drastically accelerated the C–CN activation, which outcompeted the C–H activation reaction and exclusively formed the corresponding cyanide–BPh3 adduct 2.12.

Scheme 2-5 Lewis acid-accelerated oxidative addition of C–CN bond

The migratory insertion of an alkyne/alkene π-bond generates new carbon–carbon and carbon–metal bonds. The insertion generally occurs in a syn fashion, introducing the metal and the R group onto the same face of π-bond (Scheme 2-6). An unsymmetrical alkyne would coordinate in a direction to avoid the steric repulsion between the bulkier groups, that is, the R1 group on the alkyne and the R group on the metal center (Scheme

2-6a). Occasionally, upon coordinating to a Lewis acid (e.g., BPh3 or B(C6F5)3, the cyanide becomes the bulkier substituent, yet the overall regioselectivity can be rationalized by analogous steric considerations. The insertion of an alkene into the carbon–metal bond is thermodynamically less favored than the insertion of an alkyne because more energy is needed to break the C–C

Chapter 2 | 18 π-bond of an alkyne than that of an alkene.58 Moreover, the C(sp3)–M–CN complex resulting from an alkene insertion is reluctant to undergo the C–CN bond-forming reductive elimination, which is often outcompeted by the undesired β-hydride elimination pathway whenever possible (Scheme 2-6b). Carbocyanation of strained bicyclic alkenes possessing β-hydrogens inaccessible to elimination, in particular, norbornene (2.13) and norbornadiene (2.14) has met limited success in the context of intramolecular reactions. On the other hand, substrates suitable for intramolecular carbocyanation reaction (e.g., 2.15) are designed to enhance both the rate and regioselectivity of reaction by increasing the local concentration of alkene. Intramolecular cyclizations predominately occur in a 5- exo-trig or 6-exo-trig fashion; a geminal disubstituted alkene is often critical to prevent the non-productive β-hydride elimination, although sterically demanding alkene substituents may in turn retard the insertion process.

Scheme 2-6 Migratory insertion of alkynes and alkenes

Chapter 2 | 19 Reductive elimination represents the product-forming step and allows turnover of the active catalyst (Scheme 2-7). In general, the nitrile product does not undergo further C–CN bond activation, presumably due to the increased steric hindrance of product. Analogously, a weaker coordination to the nitrile product allows Lewis acids to re-enter the catalytic cycle. Reductive elimination reactions that form C–CN bonds are less thoroughly studied than reactions that form C–H bonds and other C–C bonds. Hartwig and Klinkenberg investigated the rate of reductive elimination from a series of arylpalladium (II) cyanides complexes containing a dppdmp ligand * and various para-substituted aryl groups (2.16). 59 It was found that complexes bearing electron-donating groups underwent reductive elimination faster that those bearing electron-withdrawing groups; this trend was in contrast to the electronic effects observed from most other reductive elimination reactions of arylpalladium (II) complexes. Further computational studies suggested a migration-like transition state 2.17, where the aryl group served as a nucleophile attacking the electrophilic cyanide. In accordance with the proposed pathway, reactions with added Lewis acid proceeded faster than those without Lewis acids, as a result of increased electrophilicity of the cyanide group.60

* dppdmp = 1,3-bis-(diphenylphosphino)-2,2-dimethylpropane

Chapter 2 | 20

Scheme 2-7 Reductive elimination of metal–cyanide complexes

2.2.2 General patterns of carbocyanation reactions

A broad array of nitriles have been employed in carbocyanation reactions and the general patterns are summarized in Table 2-1. Early developments using aryl- and alkenyl cyanides, namely arylcyanation and alkenylcyanation reactions, revealed most of the key features of such transformations, including the necessity of electron-rich metal complexes, control of regioselectivity associated with unsymmetrical alkynes, and the critical role of Lewis acid additives. Further investigations have enabled allyl-, alkynyl-, and alkyl cyanides in conjunction with 1,2-dienes and alkenes as viable reactants, significantly expanding the synthetic utility of carbocyanation reactions. Meanwhile, the activation of acyl–cyanide bonds (RCO–CN) have met success with mostly palladium catalysis. These transformations, namely cyanoacylation, cyanoesterification, and cyanoamidation reactions, introduce two carbonyl equivalents onto the unsaturated C–C bonds to allow rapid construction of carbocyclic and heterocyclic compounds that were challenging to access by conventional methods.

Chapter 2 | 21

Table 2-1 General patterns of carbocyanation reaction

π-bond reactants cyanides carbocyanation subtype catalyst

arylcyanation aryl cyanides

alkenylcyanation

alkenyl cyanides

mostly Ni(0) alkynes allylcyanation

allyl cyanides

alkynylcyanation alkynyl cyanides

1,2-dienes alkylcyanation alkyl cyanides

cyanoacylation

aroyl cyanides

cyanoesterification alkenes cyanoformate esters mostly Pd(0)

cyanoamidation

cyanoformamides or carbamoyl cyanides

Chapter 2 | 22 A survey of carbocyanation reactions can be divided into four subsections: (1) carbocyanation * of alkynes † (Chapter 2.3.1), (2) acylcyanation of alkynes† (Chapter 2.3.2), (3) carbocyanation of alkenes (Chapter 2.3.3), and (4) acylcyanation of alkenes (Chapter 2.3.4).

2.3 Survey of carbocyanation reactions

2.3.1 Carbocyanation of alkynes

In 2004, Nakao and Hiyama reported a nickel-catalyzed arylcyanation of alkynes to generate β-aryl alkenenitriles (Scheme 2-8), representing the first carbocyanation 61 methodology. Ni(cod)2 and PMe3 were identified as the optimal catalytic combination, 3 whereas other metal complexes (e.g., Pt(cod)2, CpPd(η -allyl), and [RhCl(cod)]2) or bidentate ligands (e.g., dppe and 2,2'-bipyridyl) were ineffective. Substrates bearing electron-withdrawing substituents reacted faster (2.21a–e, 19–30 h) than those bearing electron-neutral and electron-donating substituents (2.21f–h, 40–111 h), indicating that the oxidative addition of C–CN bond is rate-determining. Functional groups including trifluoromethyl, keto, ester, and more notably, formyl, cyano, and boryl groups were well tolerated (2.21a–e, and 2.21i). Additionally, substrates with metal- and ortho-substituents (2.21j–l) worked equally well. The substrate scope was further extended to heteroaryl nitriles and an intramolecular variant.62 Reactions with unsymmetrical alkynes yielded a mixture of regioisomers, favoring the one with the aryl group attached to the less hindered alkyne carbon. Thus, 4-methyl- 2-pentyne was converted to a mixture of 2.21m and 2.21m' in a 62:38 ratio, whereas complete regioselectivity was obtained with 4,4-dimethyl-2-pentyne, yielding 2.21n as essentially the only product.

* Conventionally, carbocyanation reactions include aryl-, alkenyl-, allyl-, alkynyl-, and alkylcyanation, whereas acylcyanation reactions indicate cyanoacylation, cyanoesterification, and cyanoamidation. † Including reactions with 1,2-dienes.

Chapter 2 | 23 The observed regioselectivity was ascribed to the steric repulsion between the nickel center and the bulkier group on the alkyne, both of which are present in the alkenyl nickel (II) complex 2.22A as the product of migratory insertion of the Ni–CN bond (cyanonickelation). Subsequent computational study revised the original mechanistic model and suggested the arylnickelation product 2.22B was more feasible.63

Scheme 2-8 Nickel-catalyzed arylcyanation of alkynes

Lewis acids dramatically improve the efficiency of carbocyanation reactions and allow the activation of challenging substrates that are inert under previous conditions.64 For example, aryl nitriles bearing electron-donating groups (2.25a–c) and halogen groups (2.25d and 2.25e) smoothly afforded the corresponding arylcyanation products in

Chapter 2 | 24 excellent yield, with as low as 1 mol% of Ni(cod)2 (Scheme 2-9a). Aluminum-based

Lewis acids, AlMe3 and AlMe2Cl, proved optimal, yet extensive screening of conditions revealed that other Lewis acids, such as AlCl3, AlPh3∙Et2O, BEt3, BPh3, B(C6F3)3, ZnCl2, and Zn(OTf)2, were also effective. Under a higher catalyst loading, sterically demanding 2,6-dimethylbenzonitrile afforded product 2.25f in 78% yield.

Scheme 2-9 Nickel–Lewis acid-catalyzed carbocyanation of alkynes

Chapter 2 | 25 The scope of the nickel–Lewis acid system was successfully extended to alkenyl cyanides (Scheme 2-9b). Reactions using BPh3 as the cocatalyst converted di- and trisubstituted alkenenitriles to the corresponding products 2.25g and 2.25h in excellent yields. Regioselective C–CN bond activation of benzylidenemalononitrile was also feasible (2.25i). Activation of alkyl cyanides including acetonitrile, propionitrile, and (trimethylsilyl)acetonitrile has met with preliminary success, providing product 2.25j, 2.25k, and 2.25l, respectively. The low yields of 2.25k and 2.25l were attributed to a competitive β-hydride elimination from the oxidative adduct of C–CN bond, followed by hydrocyanation of alkyne 2.24. Analogous nickel–Lewis acid catalysis was applied to the 65 carbocyanation of arylacetonitriles (ArCH2CN) with alkynes. The high yields (80–95%) for most substrates likely benefited from the lack of β-hydrogens in the corresponding organometallic intermediates. To address the challenges associated with β-hydrogen-containing alkyl nitriles, Nakao and Hiyama introduced chelating heteroatoms onto the γ-position of nitriles.66 The heteroatom group coordinated to the metal center to generate a five-membered, kinetically favored metallacycle, thereby suppressing the undesired β-hydride elimination pathway. Subsequent reaction of the metallacycle with alkynes provided the acrylonitrile products analogously to previous report (Scheme 2-10a). Various alkyl nitriles bearing a γ-heteroatom group were evaluated under the nickel– Lewis acid catalysis (Scheme 2-10b). Products with acyclic, cyclic amino groups, and even the strained aziridine group were obtained in excellent yields (2.28a, 2.28b, and 2.28c, respectively). α-Ethyl, phenyl, and silyloxy nitriles gave high yields of products (2.28d–f). Pyridyl sp2-nitrogen, and moreover, ether, thioether, and acetal moieties were able to direct the alkylcyanation with moderate to good yields (2.28g–k). Several problematic substrates were identified during the study. Nitriles bearing arylamine, amide, or imidazole groups failed to produce desired products (2.29a–c), whereas substrates with ester, thioacetal or epoxide groups resulted in substrate decomposition or apparent nickel catalyst decomposition (2.30d–f).

Chapter 2 | 26

Scheme 2-10 Chelation-assisted alkylcyanation of alkynes

As shown in Chapter 2.1, allyl cyanides were known to undergo facile C–CN bond activation with nickel catalysis.45,46 It is therefore unsurprising that extensive efforts have been directed towards carbocyanation reactions with allyl cyanides. Nakao and Hiyama reported the allylcyanation reaction of alkynes using substituted allyl cyanides in the 67 presence of Ni(cod)2. In contrast to other carbocyanation reactions, which typically

Chapter 2 | 27 required electron-rich nickel centers, this study identified an electron-deficient phosphine,

P(4-CF3–C6H4)3 as the optimal ligand, indicating the oxidative addition of allyl C–CN bond might not be rate-determining. Additionally, acetonitrile was the optimal solvent instead of the commonly used toluene, providing 78% yield of nitrile 2.32a from allyl cyanide 2.31a (Scheme 2-11a). 3-pentenenitrile (2.31b) and its regioisomer 2-methyl-3- butenenitrile (2.31c) gave the same product 2.32b as a mixture of E- and Z-isomers. This result suggested π-allylnickel complex 2.33 as the common intermediate, which subsequently underwent a selective migration of the less congested carbon to generate alkenylnickel complex 2.34 (Scheme 2-11b). Allyl cyanide bearing a bulky tBu terminal afforded product 2.32d in a stereochemically pure form (> 99:1 selectivity). Allylcyanation with α-siloxylallyl cyanide (2.35) gave silyl enol ether 2.36, which was hydrolyzed to aldehyde 2.37 in 81% overall yield. The convenient preparation of starting siloxyl cyanides, the high regioselectivity through nickel–allyl migration, and the versatility of the resulting aldehydes or ketones rendered the allylcyanation reaction synthetically useful.

Chapter 2 | 28

Scheme 2-11 Nickel-catalyzed allylcyanation of alkynes

Scheme 2-12 summarizes the substrate scope of allylcyanation reaction. Tetrasubstituted α-siloxylallyl cyanides afforded the corresponding ketone products in good yields (2.37a and 2.37b). β-methallyl cyanide gave branched aldehyde 2.37c in 69% yield. Sterically less biased alkynes such as 2-pentyne resulted in a mixture of isomers with low regioselectivity (2.37d and 2.27d', 61:39 ratio). Fortunately, allylcyanation of

Chapter 2 | 29 terminal alkynes proceeded with good yields and excellent regioselectivities, favoring products with the terminal alkyne substituent attached to the cyano-substituted carbon (2.37e–h).

Scheme 2-12 Substrate scope and synthetic application of allylcyanation reaction

The allylcyanation method was highlighted in the total synthesis of plaunotol, an antibacterial natural product active against Helicobacter pylori (Scheme 2-12b). Employing nickel–Lewis acid catalysis, gram-scale allylcyanation of terminal alkyne

Chapter 2 | 30 2.38 with α-siloxylallyl cyanide 2.35, followed by hydrolysis of the resulting silyl enol ether (not shown) afforded aldehyde 2.39 in 64% yield with 94:4 regioselectivity. Aldehyde 2.39 was subsequently elaborated into plaunotol in six steps. The activation of a C(sp)–CN bond followed by subsequent insertion of alkyne π- bond, namely the alkynylcyanation reaction, enables direct access to conjugated enynes. Nakao and Hiyama first reported this transformation by employing nickel-Lewis acid catalysis (Scheme 2-13a).68 The bidentate phosphine, Xantphos was found critical to promote the desired reaction, whereas a number of monodentate phosphines were completely ineffective. Lewis acid cocatalysts such as BPh3 and B(C6F5)3 promoted the desired C–CN bond activation, thus minimizing the competitive homo-cyclotrimerization of starting alkynes. Internal alkynyl cyanides bearing silyl, phenyl, alkyl, and alkenyl substituent underwent alkynylcyanation with 4-octyne to give the corresponding product in good to excellent yields (2.42a–e). Terminal alkynes participated in the reaction with tert- butyldimethylsilyl-substituted alkynyl cyanide (2.43) to generate trisubstituted enynes in excellect yields and expected regioselectivity, favoring the regioisomer with the alkynyl group attached to the terminal alkyne carbon (2.42f–h). Alkynylcyanation of 1,2-dienes (2.44) was also feasible under similar conditions, providing conjugated enyne 2.45 and regioisomer 2.45' in good yields and high selectivity (2.45a–c, Scheme 2-13b). Mechanistically, the 1,2-diene coordinated to the oxidative addition adduct of C(sp)–CN bond in a manner that avoided the steric repulsion between the bulkier R substituent on

1,2-diene and the BPh3-coordinated cyanide group (2.46). Subsequent migration of the alkynyl group onto the cumulative carbon of 1,2-diene led to π-allylnickel complex 2.48 and the less stable isomer 2.48'. C–CN bond-forming reductive elimination of 2.48 and 2.48' gave rise to products 2.45 and 2.45', respectively.

Chapter 2 | 31

Scheme 2-13 Nickel–Lewis acid-catalyzed alkynylcyanation of alkynes and 1,2-dienes

Chapter 2 | 32 2.3.2 Acylcyanation of alkynes

Takaya and co-workers reported an early example of palladium-catalyzed alkyne cyanoacylation reaction (Scheme 2-14).69 Reaction of benzoyl cyanide 2.49 with terminal alkyne 2.50 provided keto nitrile 2.51 as the main product along with trace, but detectable amount of regio isomer 2.52 and acetylenic ketone 2.53. Control experiments suggested a mechanism different from those encountered in most other carbocyanation reactions. Thus, the acyl C–CN bond underwent oxidative addition to palladium(0) to generate acylpalladium(II) cyanide complex 2.54. Instead of a direct insertion of the alkyne π- bond, coupling of the terminal alkyne with 2.54 gave arylacetylene 2.53. Subsequent hydrocyanation of 2.53 followed by reductive elimination of the resulting intermediate 2.55 generated product 2.52, which isomerized to the more stable 2.51.

Scheme 2-14 Palladium-catalyzed formal cyanoacylation of terminal alkynes

Chapter 2 | 33 In 2006, Nakao and Hiyama reported a nickel-catalyzed cyanoesterication of 1,2- dienes (Scheme 2-15a). 70 The acyl C–CN bond of ethyl cyanoformate (2.56) was activated and added across the internal π-bond of 1,2-diene (2.57), giving conjugated esters 2.58 and 2.59 as a mixture of regioisomers. 1,2-Dienes bearing n-hexyl, cyclohexyl, tert-butyl, silyloxyalkyl, and cyanoalkyl groups provided good combined yields and selectivities of the corresponding products (2.58a–e). Similar to the mechanistic scenario in the alkynylcyanation of 1,2-dienes,68 migration of the ester group in complex 2.60 onto the cumulative carbon of 1,2-diene led to isomeric π-allylnickel complexes 2.62 and 2.62', which accounted for the formation of product 2.58 and 2.59, respectively. Mechanistic experiments revealed the interconversion between the two π-allylnickel complexes, and the reactivation of product by the same catalysis, allowing a thermodynamic equilibrium between 2.58 and 2.59. A three-component coupling of chloroformate ester (2.60), trimethylsilyl cyanide (2.61), and 1,2-dienes (2.57) was also developed, providing an indirect, yet practical method for the cyanoesterification of 1,2-dienes. Shortly after, by employing nickel– Lewis acid catalysis, the same group reported an acylcyanation of alkynes with cyanoformate esters or cyanoformamides (R1R2N–CO–CN), enabling the synthesis of β- cyano-substituted acrylates and acrylamides, respectively (not shown).71

Chapter 2 | 34

Scheme 2-15 Nickel-catalyzed cyanoesterification of 1,2-dienes

Takemoto and co-workers developed an intramolecular variant of alkyne acylcyanation reaction.72 Simply heating alkynyl cyanoformamides 2.63 in the presence of catalytic Pd(PPh3)4 in xylene afforded a series of α-alkylidene lactams as a mixture of Z- and E-isomers (Scheme 2-16). Control experiments indicated that the cyanoamidation reaction proceeded stereoselectively to affored (Z)-2.64 as the initial product, which subsequently isomerized to the E-isomer presumably catalyzed by palladium.

Chapter 2 | 35 Aniline-derived cyanoformamides with a n-butyl, tert-butyl, phenyl, and siloxylmethyl substituent at the terminal alkyne proceeded to the corresponding oxindoles in good to excellent yields and selectivities (2.64a–d). Cyclization of L-valine- and L- proline-derived substrates afforded enantiopure lactams 2.64f and 2.64g, respectively. Five- and six-membered, and more impressively, seven- and four-membered lactams were synthesized in a stereoselective manner under the same conditions (2.64e–h).

Scheme 2-16 Palladium-catalyzed intramolecular cyanoamidation of alkynyl cyanoformamides

Douglas et al. described a palladium-catalyzed intramolecular cyanoesterification of alkynes (Scheme 2-17).73 Cleavage of the acyl C–CN bond of cyanoformate ester 2.65 gave oxidative adduct 2.66, followed by alkyne insertion and reductive elimination to afford α-alkylidene lactone 2.67. Thermo- and/or palladium-induced isomerization of 2.67 resulted in lactone 2.68 as the isolated product. On the other hand, due to the inherent instability of cyanoformate esters, several decomposition pathways were

Chapter 2 | 36 identified. Decarbonylation of 2.66 led to alkoxy palladium complex 2.69, which either formed alcohol 2.71 upon protonation or underwent disproportionation with another molecule of 2.65 to generate carbonate 2.70. Optimal yield of product 2.68a was obtained using a microwave reactor and briefly heating the reaction mixture in a polar solvent (DMF) at 200 °C for 5 minutes. In this manner, substrates bearing various para- substituents on the aromatic ring gave the corresponding products in moderate to good yields (2.68b–g). Ortho- and meta-substituents, as well as a naphthalene group were well tolerated (2.68h–j). Replacing the terminal aryl group with an alkyl group allowed the isolation of a lactone product prior to isomerization (2.67k). The reaction could not be extended to the formation of 6-membered rings.

Scheme 2-17 Palladium-catalyzed intramolecular cyanoesterification of alkynes

Chapter 2 | 37 2.3.3 Carbocyanation of alkenes

As discussed in Chapter 2.2.1, carbocyanation of alkenes is more challenging than carbocyanation of alkynes due to the inherent reluctance of alkenes towards migratory insertion and C(sp3)–CN bond-forming reductive elimination, as well as the presence of a highly competitive β-hydride elimination pathway. Nakao and Hiyama described a nickel-catalyzed intermolecular arylcyanation of norbornene (2.13) and norbornadiene (2.14).74 Syn-addition of aryl and cyanide groups across the less hindered face of alkenes furnished bicyclic nitriles with complete exo-selectivity (Scheme 2-18). In the case of reactions with norbornadiene, only monocyanated products were obtained, suggesting the inertness of 2.74 towards further addition. Aryl cyanides bearing para-substituents including methyl, trifluoromethyl, fluoro, keto, ester, formyl, and methoxy groups proceeded to give the corresponding products in good to excellent yields (2.73a–g). With slightly increased catalyst loading and extended reaction time, ortho- and meta-substituted aryl cyanides, and heteroaryl cyanides reacted efficiently as well (2.73h–l). However, strained alkenes such as N-Boc-7- azabicyclo[2.2.1]heptene and bicycle[2.2.2]octane as well as simple alkenes, such as styrene, 1-hexene, and cyclopentene were completely inert, indicating a limitation of alkene reactants.

Chapter 2 | 38

Scheme 2-18 Nickel-catalyzed arylcyanation of norbornene and norbornadiene

Despite the challenges of developing carbocyanation reaction of alkenes, this field was significantly advanced by Jacobsen 75 and Hiyama 76 with two simultaneous discoveries of nickel–Lewis acid-catalyzed asymmetric intramolecular arylcyanation reactions. Jacobsen and Watson studied the asymmetric arylcyanation of aryl cyanides tethered to an olefin moiety (2.75) in the presence of a nickel complex and a chiral ligand (Scheme 2-19).75 Screening of a wide spectrum of chiral phosphorus ligands including chiral mono- and bidentate phosphines, as well as chiral P,N-ligands and phosphoramidite ligands revealed (S,S,R,R)-TangPHOS as the optimal choice regarding the reactant's enantioselectivity. Employing NiCl2∙DME as the Ni(0) source and Zn as the terminal reductant effectively suppressed a competitive pathway of olefin isomerization, which was observed with Ni(cod)2. This catalyst combination, in conjunction with BPh3 as the Lewis acid co-catalyst, effectively delivered the indane product 2.76a bearing an all-carbon quaternary center in 85% yield and 93% ee.

Chapter 2 | 39 Substrates bearing a fluoro or a methoxy group on the aromatic backbone afforded the corresponding chiral indane products in excellent yields and ee's (2.76b and 2.76c, respectively). Cyclization of alkenes substituted with bulkier groups including n-propyl, i-butyl, phenyl, p-methoxyphenyl, and p-trifluoromethylphenyl required higher catalyst loading and extended reaction times, resulting in slightly diminished yields yet consistently excellent ee's (2.76d–h). Additionally, fused pyrole 2.76i and benzopyran 2.76j were obtained analogously, allowing an extended scope to heterocyclic frameworks.

Scheme 2-19 Nickel–Lewis acid-catalyzed asymmetric intramolecular arylcyanation of alkenes

Hiyama and Nakao concurrently reported a similar intramolecular arylcyanation reaction of alkenes.76 The substrate scope was first examined in a racemic manifold employing Ni(cod)2 as catalyst, AlMe2Cl as cocatalyst, and a suitable phosphine ligand. Alkyl-, silyl-, and amino-tethered substrates, as well as chloro- and methoxy-substituted ones reacted in good to excellent yields (2.78a–f). Phenyl- and sterically demanding dimethylphenylsilyl-substituted alkenes cyclized smoothly into the corresponding indolines (2.78g and 2.78h). Six- and seven-membered-ring products (2.78i and 2.78j),

Chapter 2 | 40 and furthermore, oxindole 2.78k resulting from a conjugated double bond were successfully constructed in the presence of suitable phosphine ligands. More impressively, trisubstituted alkene 2.77l participated in the reaction to give indoline product 2.78l in 88% yield and in an essentially stereochemically pure form (dr = 98:2). The relative stereochemistry of product was determined by X-ray crystallography, showing a syn- relationship between the aryl group and the cyanide group, which suggested a syn- addition mechanistic pathway.

Scheme 2-20 Nickel–Lewis acid-catalyzed arylcyanation of alkenes

The asymmetric version of arylcyanation reaction was exemplified in the syntheses of natural products (–)-esermethole and (–)-eptazocine (Scheme 2-21). Arylcyanation of nitrile 2.77f in the presence of Ni(cod)2, AlMe2Cl, and a chiral phosphino-oxazoline ligand (R,R)-i-Pr-Foxap afforded indoline (S)-2.78f in 88% yield and 96% ee. In three steps, (S)-2.78f was converted to (–)-esermethole, a synthetic precursor of several acetylcholinesterase inhibitors. Likewise, cyclization of 2.77m using (R,R)-ChiraPhos as

Chapter 2 | 41 the chiral ligand delivered 98% yield and 92% ee of nitrile (R)-2.78m, which was elaborated into (–)-eptazocine, a commercially available opioid analgesic.

Scheme 2-21 Synthesis of (–)-esermethole and (–)-eptazocine through asymmetric arylcyanation of alkenes

2.3.4 Acylcyanation of alkenes

Takagi and co-workers reported an intermolecular cyanoesterification of strained 77 alkenes (Scheme 2-22). In the presence of catalytic Pd(PPh3)4, the acyl C–CN bond of alkyl cyanoformates 2.79 was activated and added across the π-bond of strained alkenes including norbornene (2.13), norbonadiene (2.14), and benzonorbornadiene (2.82).

Ni(cod)2/PMe3, the optimal catalyst for arylcyanation of norbornene (Scheme 2-18) was ineffective in this reaction.74 In terms of the stereochemistry of alkene addition, both the ester and cyanide groups were introduced exclusively onto the exo-face of alkene, providing a range of bicyclic nitriles in moderate to good yields (2.80, 2.81, and 2.83).

Chapter 2 | 42

Scheme 2-22 Palladium-catalyzed cyanoesterification of strained alkenes

Substrates suitable for alkene acylcyanation in an intramolecular context have been rationally designed to enable novel synthesis of classic heterocyclic scaffolds. Takemoto and co-workers achieved a palladium-catalyzed intramolecular cyanoamidation reaction to access a series of 3,3-disubstituted oxindoles, which are common synthetic precursors to many biologically active natural products (Scheme 2-23).78 Heating cyanoformamide 2.84a (R1 = Me, R2 = Bn, R3 = H) in the presence of 2 mol% of Pd(PPh3)4 in xylene at 130 °C provided oxindole 2.85a in quantitative yield after 6 h, while the reaction catalyzed by Pd(dba)2 (2 mol%) and P(tBu)3 (8 mol%) completed after 15 min, providing 2.85a in 98% yield. Such rate enhancement was likely owing to the formation of a more reactive Pd(0) species. In the same manner, oxindoles bearing various substituents at the quaternary center (2.85a–g) and on the aryl backbone

(2.85h–j) were obtained in excellent yields. Employing Pd(PPh3)4 as catalyst expanded the scope of cyanoamidation reaction to oxindole with an unprotected N–H group (2.85k), azaoxindole (2.86l), alkyl lactams (2.86m and 2.86n), and seven-membered biaryl lactam (2.86o) in good to excellent yields.

Chapter 2 | 43

Scheme 2-23 Palladium-catalyzed intramolecular cyanoamidation of alkenes

In 2008, the same group developed an asymmetric version of cyanoamidation reaction (Scheme 2-23b).78a A broad screening of chiral phosphorous ligands revealed that BINOL-derived phosphoramidites afforded promising results, whereas other diphenol-, spirobiindane diol-, and TADDOL-derived phosphoramidites, as well as

Chapter 2 | 44 monodentate phosphines (e.g., NMDPP and MOP) and bidentate phosphines (e.g., BINAP and DIOP) were completely ineffective in terms of enantioselectivity.* Upon further tuning of ligand structure, phosphoramidite 2.86 was found optimal which, in conjunction with 2 mol% of Pd(dba)2 and one equivalent of DMPU promoted the formation of oxindole 2.85a in quantitative yield and 81% ee. The combination of nonpolar decalin as solvent with a polar, Lewis basic additive DMPU appeared to be necessary for a high ee. The role of DMPU was not studied in detail and also somewhat surprisingly, Lewis acids were not evaluated at all. A reasonably broad scope of substrates was examined, affording the corresponding chiral oxindoles in consistently high yields and up to 86% ee. Oxindole 2.85f was further transformed into esermethole in a racemic form (not shown), thus representing a potential application of this method. A racemic synthesis of the pyroloindole core of an alkaloid vincorine using cyanoamidation reaction was also attempted.78b Direct acylcyanation using acyl cyanides (RCO–CN) is challenging because acyl cyanides are generally unstable towards routine purification methods, such as column chromatography, and also because the acyl–metal–cyanide (RCO–M–CN) oxidative adduct suffers facile de-carbonylation prior to alkene insertion. To address these issues, Douglas et al. utilized α-iminonitriles (2.87) as acyl cyanide surrogates to participate in a palladium–Lewis acid-catalyzed intramolecular cyclization, namely the iminocyanation reaction, to provide imines 2.88 as the initial products (Scheme 2-24). 79 A one-pot hydrolysis of 2.88 gave indanones 2.89, achieving a formal acylcyanation product from the masked acyl cyanides. Indanones bearing aryl substituents para to the ketone including hydrogen, methyl, tert-butyl, fluoro, chloro, trifluoromethyl, and methoxy groups were obtained in good to excellent yields (2.89a–g). Ortho- and meta-fluoro substituents, a trimethylsilyl group, and an ethyl-substituted alkene were well tolerated (2.89h–k).

* BINOL = 1,1'-bi-2-naphthol; TADDOL = 2,2-dimethyl-α,α,α′,α′-tetraphenyldioxolane-4,5-dimethanol; NMDPP = neomenthyldiphenylphosphine; MOP = 2-(diphenylphosphino)-2'-methoxy-1,1'-binaphthyl; BINAP = 2,2'- bis(diphenylphosphino)-1,1'-binaphthyl; DIOP = 4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane.

Chapter 2 | 45

Scheme 2-24 Palladium-catalyzed intramolecular acylcyanation of alkenes using α- iminonitriles

2.4 Research proposal: Asymmetric intramolecular cyanoamidation of alkenes

Takemoto group's cyanoamidation method for constructing chiral oxindole frameworks is pioneering,78a yet somewhat limited with respect to the rigid aromatic backbones and five-membered ring formation. In this regard, we envisioned that the cyanoamidation reactions of cyanoformamides bearing an alkyl-tethered, more flexible alkene 2.90 would generate the acyl–Pd–CN intermediate 2.91 (Scheme 2-25a). Subsequent alkene migratory insertion and reductive elimination would generate 3,3- disubstituted pyrrolidinones (2.92) and piperidinones (2.93) bearing an all-carbon quaternary stereocenter. Enantiopure 3,3-disubstituted lactams are challenging to prepare by conventional methods, yet they are found embedded in the core of many indole alkaloids, such as (–)-quebrachamine, (–)-aspidospermidine, and (–)-epieburnamonine, among others (Scheme 2-25b). The proposed cyanoamidation reaction would allow direct construction of lactams with a synthetically useful cyano group for further manipulation, thus enabling concise access to the abovementioned natural products.

Chapter 2 | 46

Scheme 2-25 Proposed intramolecular asymmetric alkene cyanoamidation reactions

To create enantioselectivity during the stereocenter-forming alkene insertion step, a suitable chiral ligand or additive needs to be identified. Takemoto group's success in using chiral phosphoramidite ligands suggested a starting entry to the ligand screening process. In addition, Lewis basic additives such as DMPU and NMP were critical in enhancing the reaction rate, but mechanistic insight of their role was still unclear. Moreover, Lewis acids were not studied in Takemoto's work, which was rather surprising when realizing the prevalent application of Lewis acids in carbocyanation reactions. Thus, we not only sought to explore the role of Lewis acids in our system, but also initiated an in-depth mechanistic study of the reported alkene cyanoamidation conditions, which is currently ongoing in our laboratory.*

2.5 Results and discussion

2.5.1 Initial investigations with BPh3 and identification of irreproducible results

Previous study of the cyanoamidation of cyanoformamides 2.93a with an ethyl- substituted alkene provided the six-membered piperidinone 2.94a with low conversion

* Unpublished results by Dr. Jodi Ogilve.

Chapter 2 | 47 (Scheme 2-26).* In contrast to Takemoto's result, added DMPU failed to improve the conversion, whereas BPh3 significantly accelerated the reaction and resulted in excellent conversion and good yield of product.

Scheme 2-26 Cyanoamidation reaction of 2.93a

In this study, cyanoformamides 2.92a, which was readily prepared from aniline in 3 steps, was heated in toluene at 130 °C in the presence of Pd2dba3, a chiral phosphoramidite ligand, and BPh3 (Table 2-2). The expected five-membered pyrrolidinone 2.95a was isolated in good yield using ligand L1 and L3 (entries 1 and 2). However, the enantioselectivity of product was irreproducible when a different batch of

BPh3 was employed (entries 3 and 4), likely as a result of inconsistent batch quality from different vendors. Control experiments without BPh3 gave lower, yet consistent ee's.

Interestingly, 2.95a was isolated in excellent yields, which suggested that BPh3 was not required to promote the presumably more facile five-membered ring formation (entries 5 and 6).

Table 2-2 Initial study of cyanoamidation reaction of 2.92a

* Unpublished results by Dr. Ashley Dreis. For details, see: Dreis, A. M. Ph.D. Dissertation, University of Minnesota–Twin Cities, 2014.

Chapter 2 | 48 [a] [b] Entry Ligand BPh3 (mol%) Source of BPh3 Yield (%) ee (%) 1 L1 50 Strem Chemicals 84 56 2 L3 50 Strem Chemicals 75 9 3 L1 50 Sigma-Aldrich 84 46 4 L3 50 Sigma-Aldrich 84 72 5 L1 0 – 89 24, 22[c] 6 L3 0 – 98 58, 60[c] [a] Isolated yields. [b] Measured by chiral HPLC. The absolute stereochemistry was not determined. [c] Two independent runs.

2.5.2 Cyanoamidation reaction of 2.92a: ligand screening

With these preliminary results, a variety of chiral phosphoramidite ligands derived from BINOL, H8-BINOL, TADDOL, and other backbones were screened without BPh3 (Figure 2-1). The results are summarized in Table 2-3.

Chapter 2 | 49

Figure 2-1 Screened chiral phosphoramidite ligands

At 130 °C, ligands derived from BINOL (L3 and L6), TADDOL (L10), and a spirobiindane backbone (L9) resulted in equally efficient conversion (Table 2-3, entries 1–4), whereas L3 and L6 gave higher enantioselectivities (60% and 58%, respectively). Lowering the temperature to 90 °C with L3 retained excellent conversion, yet the ee's were not significantly improved (entries 5–7). Next, a broader scope of ligands were screened at this temperature (entries 7–20). Ligand L3, containing achiral isopropyl- substituted amine gave the highest ee of 65% (entry 7) compared to its chiral counterparts (entries 8 and 9, L1 and L2), as well as the achiral, methyl-, and ethyl-substituted ligands (entries 10 and 11, L12 and L37, respectively). Compared to L3, ligand derived from 3,3'-dimethyl BINOL backbone (L32) and a partially hydrogenated BINOL backbone (L4) did not improve the selectivity (entries 12 and 13). Introducing cyclic amines onto the ligand structure (L8 and L17) had negative impact on both the conversion and ee

Chapter 2 | 50 (entries 14 and 15). Ligands derived from TADDOL (L10, L11, and L21) and other backbones (L20 and L29) were also examined, resulting in incomplete or no reaction and decreased selectivity (entries 16–20). Overall, L3 was found optimal at this stage of screening, affording the cyanoamidation product with excellent yield and up to 65% ee.

Table 2-3 Ligand screening of asymmetric cyanoamidation reaction of 2.92a

Entry Ligand T (°C) Conv.[a] (Yield)[b] ee (%) 1 L3 130 quant. (98%) 60 2 L6 130 quant. (89%) 58 3 L10 130 quant. (88%) 33 4 L9 130 93% (88%) 20 5 L3 120 quant. 60 6 L3 110 quant. 65 7 L3 90 quant. 65 8 L1 90 quant. (99%) 51 9 L2 90 –[c] 58 10 L12 90 83% (82%) 50 11 L37 90 (64%) 58 12 L32 90 – 55 13 L4 90 – 61 14 L18 90 50% (46%) 47 15 L7 90 – 34 16 L10 90 47% (46%) 42 17 L11 90 – 42 18 L21 90 68% (66%) 47

Chapter 2 | 51 Entry Ligand T (°C) Conv.[a] (Yield)[b] ee (%) 19 L20 90 trace – 20 L29 90 trace – [a] Calculated based on the 1H NMR spectra of crude reaction mixture. [b] Isolated yields. [c] Not measured.

2.5.3 Cyanoamidation reaction of 2.92a: further screening

A brief screening of solvents, including THF, trifluorotoluene, m-xylene, and 1,4- dioxane showed negligible impact on product ee (Table 2-4, entries 1–4), whereas polar DMF led to incomplete reaction and much lower selectivity (entry 5). A number of ligands were screened in THF at 90 °C. In general, the resulting ee's were either comparative or lower than those obtained from reactions in toluene (entries 6–13).

Table 2-4 Further screening of asymmetric cyanoamidation reaction of 2.92a

Entry Ligand Solvent T (°C) ee (%) ee in PhMe (%)[a] 1 L3 THF 90 62 65

2 L3 PhCF3 80 64 – 3 L3 m-xylene 80 66 – 4 L3 1,4-dioxane 80 67 – 5 L3 DMF 80 28 – 6 L4 THF 90 63 61 7 L6 THF 90 52 58[b] 8 L10 THF 90 44 42 9 L11 THF 90 46 42 10 L12 THF 90 36 55

Chapter 2 | 52 Entry Ligand Solvent T (°C) ee (%) ee in PhMe (%)[a] 11 L18 THF 90 34 47 12 L21 THF 90 46 47 13 L32 THF 90 52 55 14[c] (S,S)-BDPP PhMe 90 no reaction – 15[c] (R)-Tol-BINAP PhMe 90 no reaction – 16[c] (R)-Phanephos PhMe 90 2[d] – 17[c] (R,R,R)-(+)-Tol-SKP PhMe 90 0[d] – 18[c] IPr carbene PhMe 90 –[d] –

[a] See Table 2-3. [b] At 130 °C. [c] η5-cyclopentadienyl-η3-1-phenylallyl-palladium

[CpPd(1-phenylallyl)] was used instead of Pd2dba3. [d] Full conversion.

Chiral bidentate phosphine ligands such as (S,S)-BDPP and (R)-Tol-BINAP failed to promoted the reaction (entries 14 and 15), which seemed to be consistent with Takemoto's report.78c Interestingly, (R)-Phanephos and (R,R,R)-(+)-Tol-SKP, which were known bidentate ligands with a wide bite angle gave full conversion (entries 16 and 17). However, the product was isolated in essentially racemic form (2% and 0% ee, respectively). It was currently unclear why these ligands failed to induce any enantioselectivity. Cyanoamidation reaction with an N-heterocyclic carbene (IPr) also proceeded smoothly to give the racemic product in quantitative conversion (entry 18). Based on this result, future development of the asymmetric variants using chiral N- heterocyclic carbenes would be feasible. Takemoto found that reactions performed in non-polar solvent (decalin) with added DMPU gave improved selectivities. Thus, DMPU was examined in the cyanoamidation of 2.92a (Table 2-5). Under racemic conditions with CpPd(1-phenylallyl) as the catalyst,

Chapter 2 | 53

PPh3 as the ligand, reactions performed in methylcyclohexane or cyclohexane showed reasonable conversion, whereas decalin was ineffective. A brief examination of chiral phosphoramidite ligands and bidentate ligands, however, did not afford improved selectivities (entries 4–8).

Table 2-5 Cyanoamidation of 2.92a with added DMPU

Entry Ligand Solvent Conv. (%) ee (%) [a] 1 PPh3 methylcyclohexane 56 – [a] 2 PPh3 cyclohexane 77 – [a] 3 PPh3 decalin trace – 4 ent-L2 methylcyclohexane 77 –35 5 L3 methylcyclohexane 40 50 6 L37 methylcyclohexane quant. 43 7 (R)-Phanephos methylcyclohexane 16 –6 8 (R,R,R)-(+)-Tol-SKP methylcyclohexane 14 –4

[a] 5 mol% CpPd(1-phenylallyl) and 10 mol% PPh3.

2.5.4 Cyanoamidation reaction of 2.92b

A new cyanoformamide substrate 2.92b bearing a conjugated, styrene-type alkene was also prepared and subjected to extensive optimizations (Table 2-6). The resulting 3,3-disubstituted pyrrolidinone 2.95b would potentially serve as an advanced intermediate to the synthesis of neoselaginellic acid, which was isolated from the plant of Selaginella moellendorfii.

Heating 2.92b with Pd(PPh3)4 in toluene at 130 °C resulted in sluggish reaction.

Added Lewis acids, such as BPh3 and ZnCl2 promoted the transformation, whereas

Chapter 2 | 54 DMPU completely shut down the reaction (entries 1–4). Increasing the ligand/palladium ratio from 1:1 to 2:1 enabled a complete conversion and a slight increase in selectivity (entries 5–7). Trifluorotoluene, 1,4-dioxane, and 1,2-DCE were equally effective in terms of conversion, and toluene gave the best ee (42%, entries 8–10). Screening of phosphoramidite ligands was performed in toluene at 100 °C (entries 11–25), and up to 65% ee was obtained using the 3,3'-dimethyl-BINOL-derived ligand L32 (entry 23), although the conversion was only moderate. L3, the optimal ligand for the cyanoamidation of 2.92a, gave a comparative 50% ee (entry 11).

Table 2-6 Cyanoamidation reaction of 2.92b

Additive Entry Ligand Solvent T (°C) Conv. (Yield) ee (%) (equiv.) 1[a] – – PhMe 130 40% – [a] 2 – BPh3 (1.0) PhMe 130 87% – [a] 3 – ZnCl2 (1.0) PhMe 130 quant. – 4[a] – DMPU (1.0) PhMe 130 trace – 5 L2[b] – PhMe 100 50% 34 6 L2[c] – PhMe 100 quant. 38 7 L2 – PhMe 100 quant. 42

8 L2 – PhCF3 100 74% 26 9 L2 – 1,4-dioxane 100 quant. 40 10 L2 – 1,2-DCE 100 80% 21 11 L3 – PhMe 100 50% 50 12 L4 – PhMe 100 53% 30

Chapter 2 | 55 Additive Entry Ligand Solvent T (°C) Conv. (Yield) ee (%) (equiv.) 13 L5 – PhMe 100 quant. 25 14 L6 – PhMe 100 22% 50 15 L7 – PhMe 100 74% 26 16 L9 – PhMe 100 40% 0 17 L10 – PhMe 100 trace – 18 L11 – PhMe 100 23% 29 19 L12 – PhMe 100 trace – 20 L16 – PhMe 100 30% 39 21 L18 – PhMe 100 trace – 22 L30 – PhMe 100 82% 46 23 L32 – PhMe 100 54% 65 24 L33 – PhMe 100 50% 40 25 L34 – PhMe 100 13% 54

[a] 8 mol% Pd(PPh3)4 was used instead of Pd2dba3. [b] 8 mol% L2. DMPU = N,N'- dimethylpropylene urea. 1,2-DCE = 1,2-dichloroethane.

2.6 Conclusion and future work

In conclusion, we achieved success in developing asymmetric intramolecular cyanoamidation reactions of two alkyl-tethered cyanoformamides 2.92a and 2.92b to synthesize the 3,3-disubstituted pyrrolidinones 2.95a and 2.95b, respectively, with up to 65% ee. Lewis acid additives generally accelerated the rate of reaction, but their roles in affecting the enantioselectivity, as well as a detailed understanding of the enantiodetermining step are yet to be studied in depth. Future work will be directed towards examining ligands with a broad scope of chiral scaffolds (e.g., chiral phosphites and N-heterocyclic carbenes) in order further optimize the enantioselectivity, which would eventually allow one to highlight this method in natural product synthesis.

Chapter 2 | 56 2.7 Experimental section

2.7.1 General details

All reactions were carried out using oven-dried glassware under a nitrogen atmosphere unless otherwise noted. Dichloromethane (CH2Cl2), toluene, and trifluorotoluene were distilled from CaH2 prior to use. Tetrahydrofuran (THF) was distilled from Na/benzophenone prior to use. Dichloromethane, toluene, THF, and trifluorotoluene were further degassed by bubbling a stream of argon through the liquid in a Strauss flask and then stored in a nitrogen-filled glove box. Anhydrous N,N- dimethylformamide (DMF), anhydrous diethyl ether (Et2O), and acetone were purchased from Sigma-Aldrich and used without further purification. Unless otherwise noted, all chemicals were purchased from commercial sources and used as received. Pd(PPh3)4 and

Pd2dba3 were purchased from Sigma-Aldrich or Strem and used as received.

Triphenylborane (BPh3) was purchased from Strem and Sigma-Aldrich and recrystallized from anhydrous heptane under nitrogen.* CpPd(1-phenylallyl) was synthesized following a known procedure.† Palladium-catalyzed cyanoamidation reactions were carried out in a Vacuum Atmospheres nitrogen-filled glove box in 1 dram vials (Chemglass) with PTFE lined caps and heating was applied by aluminum block heaters. Analytical thin-layer chromatography (TLC) and preparative thin-layer chromatography were carried out using 250 μm and 1000 μm silica plates (SiliCycle), respectively. Eluted plates were visualized first with a UV lamp (254 nm) and then stained with potassium permanganate or p-anisaldehyde, followed by heating. Flash column chromatography was performed using 230 – 400 mesh (particle size 40 – 63 μm) silica gel purchased from SiliCycle. 1H NMR (300 and 500 MHz) and 13C NMR (75 and 125 MHz) spectra were obtained on Varian Inova and Bruker Avance instruments. 1H NMR spectra data were

* BPh3 was recrystallized from anhydrous heptane under nitrogen after the irreproducibility issue was identified. For a detailed procedure, see: Köster, R.; Binger, P.; Fenzl, W. Inorg. Synth. 1974, 15, 134. † Fraser, A. W.; Besaw, J. E.; Hull, L. E.; Baird, M. C. Organometallics 2012, 31, 2470.

Chapter 2 | 57 13 reported as δ values in ppm relative to chloroform (δ 7.26) if collected in CDCl3. C NMR spectra data were reported as δ values in ppm relative to chloroform (δ 77.00) 1 when collected in CDCl3. H NMR coupling constants were reported in Hz, and multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); quint (quintet); m (multiplet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dddd (doublet of doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); ddt (doublet of doublet of triplets); dq (doublet of quartets); app (apparent); br (broad). Infrared (IR) spectra were obtained on a MIDAC FT-IR spectrometer. A thin- film of sample was prepared by evaporating solvent (CH2Cl2 or CDCl3) on NaCl plates. Low-resolution mass spectra (LRMS) in chemical ionization (CI) experiments were performed on a Varian Saturn 2200 GC-MS system. High-resolution mass spectra (HRMS) in electrospray ionization (ESI) experiments were performed on a Bruker BioTOF II (Time-of-flight) instrument using PEG-300, PEG-400 or PPG-400 as an internal standard. All ee’s were determined by Agilent HPLC equipped with CHIRALCEL® OD-H columns using a mixture of hexanes (Hex) and isopropanol (IPA) as the mobile phase.

2.7.2 Synthesis of substrates 2.92a and 2.92b

Chapter 2 | 58 Synthesis of 2.96:* Aniline (0.1 mol, 9.31 g) and methyl vinyl ketone (0.12 mol, 9.7 mL) were vigorously stirred in water (100 mL) at room temperature for 16 h. The resulting mixture was extracted with CH2Cl2 (50 mL×3) and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford the aza- Michael adduct as an oil, which was used without further purification. Next, to a suspension of methyltriphenylphosphonium bromide (0.2 mol, 71.4 g) in THF (400 mL) was added potassium tert-butoxide in portions (0.2 mol, 22.4 g) at room temperature. The resulting yellow suspension was stirred for 1 h and cooled to 0 °C . A solution of the crude product (ca. 0.1 mol) in Et2O (50 mL) was slowly added at 0 °C . The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was then acidified with sat. NH4Cl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc/hexanes) to give aniline 2.96 as a yellow oil (9.2 g, 57.1 mmol, 57% yield over two steps). Rf = 1 0.37 (2:8 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.23 – 7.13 (m, 2H), 6.70 (tt, J = 7.4, 1.1 Hz, 1H), 6.65 – 6.57 (m, 2H), 4.86 (tt, J = 2.2, 1.1 Hz, 1H), 4.80 (dq, J = 2.0, 1.0 Hz, 1H), 3.64 (br s, 1H), 3.22 (t, J = 6.7 Hz, 2H), 2.35 (ddd, J = 7.4, 6.6, 1.0 Hz, 2H), 13 1.76 (t, J = 1.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ 148.1, 142.9, 129.2, 117.4, 112.9, 112.4, 41.2, 37.3, 21.9; IR (thin film) 3432, 3071, 3046, 1611; LRMS (EI) m/z 162 [M+H]+.

Synthesis of 2.92a: To a solution of 2.96a (2.8 mmol, 451 mg) in Et2O (10 mL) was † added a stock solution of carbonyl cyanide in Et2O (1.0 M, 4.2 mmol, 4.2 mL) at room temperature. The mixture was stirred overnight, diluted with more Et2O, filtered over Celite, and concentrated in vacuo. The residue was purified by flash column chromatography (15:85 EtOAc/hexanes) to give 2.92a as a pale yellow waxy solid (540

* Adjusted from a known procedure: De, K.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. J. Org. Chem. 2009, 74, 6260. † Prepared following a known procedure: Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto. Y. Org. Lett. 2006, 8, 2711. Caution: carbonyl cyanide is highly toxic. All reactions must be performed in a well-vented fume hood.

Chapter 2 | 59 mg, 2.52 mmol, 90% yield). Mixture of rotamers: 92:8; Rf = 0.41 (1:4 EtOAc/hexanes); 1 H NMR (500 MHz, CDCl3) δ 7.56 – 7.46 (m, 3H), 7.36 – 7.28 (m, 2H), 4.83 (s, 1H), 4.71 (s, 1H), 3.92 (t, J = 7.4 Hz, 2H), 2.24 (t, J = 7.4 Hz, 2H), 1.71 (s, 3H); 13C NMR

(126 MHz, CDCl3) δ 144.5, 141.3, 138.2, 130.1, 129.9, 128.1, 112.9, 110.6, 47.4, 34.9, + 22.2; IR (thin film) 3078, 2234, 1679, 1595; HRMS (ESI) calcd for [C13H14N2O + Na] 237.0998, found 237.0990. * Synthesis of 2.97: Trifluoromethanesulfonic acid (4.5 mmol, 0.40 mL) in CH2Cl2 (2 mL) was added dropwise to a solution of benzyl azide† (4.1 mmol, 545 mg) and acetophenone (4.1 mmol, 493 mg) in CH2Cl2 (8 mL) at 0 °C . After N2 evolution subsided (ca. 30 min), the solution was allowed to warm to room temperature and stirred overnight.

The reaction was quenched with sat. NaHCO3 (Caution: CO2 generation) and extracted with CH2Cl2 (20 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (4:96 acetone/hexanes) to give 2.97 as a bright yellow oil (519 1 mg, 2.3 mmol, 56% yield). Rf = 0.35 (1:9 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 8.05 – 7.89 (m, 2H), 7.63 – 7.53 (m, 1H), 7.46 (ddd, J = 8.1, 6.4, 1.2 Hz, 2H), 7.22 – 7.13 (m, 2H), 6.76 – 6.58 (m, 3H), 4.12 (br s, 1H), 3.62 (t, J = 6.1 Hz, 2H), 3.29 (t, J = 6.1 Hz, 2H). 1H NMR data was consistent with literature.* Synthesis of 2.92b: 2.92b was synthesized in the same manner as 2.92a in 86% yield as a pale yellow solid. Mixture of rotamers: 93:7; Rf = 0.55 (1:4 EtOAc/hexanes); 1 H NMR (500 MHz, CDCl3) δ 7.50 – 7.42 (m, 3H), 7.29 – 7.19 (m, 7H), 5.35 (d, J = 1.0 Hz, 1H), 5.09 (d, J = 1.3 Hz, 1H), 3.94 – 3.83 (m, 2H), 2.76 (td, J = 7.5, 1.1 Hz, 2H); 13C

NMR (126 MHz, CDCl3) δ 144.4, 144.0, 139.55, 138.2, 130.0, 129.7, 128.4, 127.9, 127.7, + 125.7, 114.6, 110.5, 48.4, 32.5; HRMS (ESI) calcd for [C18H16N2O + Na] 299.1155, found 299.1155.

* Adjusted from a known procedure: Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan, G. L.; Aubé, J. J. Am. Chem. Soc. 2000, 122, 7226. † Prepared following a known procedure: Campbell-Cerduyn, L. S.; Mirfeizi, L.; Dierckx, R. A.; Elsinga, P. H.; Feringa, B. L. Chem. Commun. 2009, 2139.

Chapter 2 | 60 2.7.3 General procedure for cyanoamidation reactions

A representative example (Table 2-3, entry 1): In a nitrogen-filled glove box, a 1 dram vial was charged with a magnetic stirring bar, cyanoformamides 2.92a (0.1 mmol,

21.4 mg), Pd2dba3 (4 mol%, 0.004 mmol, 3.7 mg), L3 (8 mol%, 0.008 mmol, 4.6 mg), and toluene (0.5 mL). The reaction mixture was sealed with a PTFE lined cap, removed from the glove box, and heated in an aluminum heating block at 130 °C for 24 h. The reaction mixture was concentrated in vacuo and the conversion was estimated by 1H NMR analysis. The isolated yield of 2.95a was obtained by concentrating the crude mixture onto Celite (dry loading method) followed by flash column chromatography (1:9 → 1:4 EtOAc/hexanes). The ee was analyzed by HPLC.

2.95a (Table 2-3, entry 1): Prepared from 2.92a on 0.1 mmol scale and isolated as a 1 colorless oil. Rf = 0.20 (1:4 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.66 – 7.61 (m, 2H), 7.47 – 7.32 (m, 2H), 7.22 – 7.12 (m, 1H), 4.01 – 3.79 (m, 2H), 2.71 (d, J = 16.8 Hz, 1H), 2.63 (d, J = 17.2 Hz, 1H), 2.30 (dt, J = 12.9, 8.3 Hz, 1H), 2.17 (dddd, J = 12.9, 13 6.7, 4.2, 0.7 Hz, 1H), 1.39 (s, 3H); C NMR (75 MHz, CDCl3) δ 174.6, 138.8, 128.9, 125.0, 120.6, 118.1, 45.6, 44.7, 31.4, 27.3, 23.0; IR (thin film) 3063, 2249, 1694, 1598; + HRMS (ESI) calcd for [C13H14N2O + Na] 237.0998, found 237.1003; HPLC [Chiralcel

OD-H Hex:IPA = 80:20, 1.0 mL/min, λ= 254.4 nm], TR (major) 16.3 min, TR (minor) 20.1 min, ee 60%.

Chapter 2 | 61

2.95b (Table 2-6, entry 23): Prepared from 2.92b on 0.1 mmol scale and isolated as 1 a colorless oil. Rf = 0.18 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.68 – 7.60 (m, 2H), 7.55 – 7.47 (m, 2H), 7.43 – 7.36 (m, 4H), 7.36 – 7.30 (m, 1H), 7.21 – 7.16 (m, 1H), 3.83 (ddd, J = 9.7, 8.3, 1.4 Hz, 1H), 3.73 (td, J = 9.9, 6.1 Hz, 1H), 3.05 (d, J = 16.9 Hz, 1H), 2.99 (d, J = 16.9 Hz, 1H), 2.86 (ddd, J = 12.9, 6.0, 1.4 Hz, 1H), 2.60 (ddd, 13 J = 12.9, 10.1, 8.4 Hz, 1H); C NMR (126 MHz, CDCl3) δ 172.5, 138.9, 137.6, 129.2, 129.0, 128.4, 126.1, 125.2, 119.9, 117.3, 51.7, 45.2, 31.0, 28.1; HRMS (ESI) calcd for + [C18H16N2O + Na] 299.1155, found 299.1159; HPLC [Chiralcel OD-H Hex:IPA =

75:25, 1.0 mL/min, λ= 254.4 nm], TR (major) 19.5 min, TR (minor) 26.5 min, ee 65%.

Chapter 3 | 62

Chapter 3 Iridium-Catalyzed Intramolecular Oxyacylation of Alkenes by C–O Bond Activation of Salicylate Esters

3.1 Introduction: transition-metal-catalyzed C–O bond activation reactions

Carboxylic esters are among the most abundant functional groups in organic chemistry. Traditional chemical transformations of esters, such as basic hydrolysis, addition of organometallic reagents, and hydride reduction, occur with the fragmentation of esters. Other classic, non-fragmenting manipulations of esters, such as the Claisen– Ireland rearrangement and the Petasis–Tebbe olefination, require either strong basic conditions and/or moisture-sensitive reagents, exhibiting limited functional group tolerance. The development new modes of ester activation, notably the emerging transition-metal-catalyzed activation of ester C–O bonds, would greatly expand the synthetic utility of esters and offer unconventional approaches to access other valuable functional groups.80 The C–O bond activation (oxidative addition) of esters by low-valent transition- metal centers generally proceeds by two paths (Scheme 3-1). Cleavage of the alkyl carbon–oxygen bond generates an alkyl–metal–carboxylate intermediate (path A), which has been intensively studied regarding the Tsuji–Trost reaction of allyl esters and the preparation of π-allyl metal complexes.81 Recent advances along this line include two seminal reports on nickel-catalyzed, Suzuki-type cross-coupling reactions of phenolic esters with boronic acids, featuring a facile cleavage of the aryl C–O bond of esters.82 These reactions represent appealing methods to construct C–C bonds by using readily available esters. Moreover, the esters are inert under palladium-catalyzed coupling conditions, rendering them orthogonal groups to aryl halides in terms of selective cross- coupling reactions.

Chapter 3 | 63

Scheme 3-1 C–O bond activation of esters by transition-metal complexes

In path B, activation of the acyl carbon–oxygen bond gives rise to an acyl–metal– alkoxide complex. 83 Similar acyl–metal complexes are important intermediates in organometallic catalysis, and they are commonly generated from either the carbonylation of alkyl/aryl–metal complexes (R–M + CO → R–CO–M) or the oxidative addition of activated carboxylic acid derivatives (e.g., acid chlorides and anhydrides).84 Compared with the established routes for accessing such acyl–metal complexes, the acyl C–O bond activation is more challenging because (1) esters are less electrophilic towards metal addition, (2) acyl C–O bond cleavage is reversible, and (3) the resulting acyl–metal complex may undergo decarbonylation, resulting in catalyst deactivation and/or competitive side reactions (e.g., β-hydride elimination and disproportionation). In this regard, the development of new catalytic methods for acyl C–O bond activation, particularly those enabling non-decarbonylative manipulation of esters, remains highly desirable.

3.2 Survey of acyl C–O bond activation reactions

3.2.1 Stoichiometric acyl C–O bond activation reactions

In 1980, Yamamoto and co-workers first observed that treating phenyl propinoate

3.1 (neat) with Ni(cod)2 and PPh3 at 54 °C generated ethylene (C2H4), phenol, and

Ni(CO)(PPh3)3 in approximately a 1:1:1 ratio, suggesting the facile cleavage of acyl C–O bond under mild conditions (Scheme 3-2, A).85 In their proposed pathway, the initial oxidative addition adduct, acyl(phenoxo)nickel complex 3.2, underwent decarbonylation

Chapter 3 | 64 to form ethyl(phenoxo)nickel complex 3.3. Subsequent β-hydride elimination and reductive elimination produced ethylene and phenol. Carbon monoxide, which was either released during the decarbonylation step or trapped by other Ni(0) species, was found coordinated within a stable nickel carbonyl complex, Ni(CO)(PPh)3.

Switching to a more basic triethylphosphine (PEt3) altered the reaction pathway of the analogous ethyl(phenoxo)nickel complex 3.5 (Scheme 3-2, B). Instead of undergoing β-elimination, 3.5 decomposed through a disproportionation process to release a 1:1 mixture of ethylene and ethane, along with the formation of two nickel complexes,

Ni(CO)2(PEt3)2 and Ni(OPh)2.

Scheme 3-2 Oxidative addition of phenyl propionate with Ni(0) complexes

Chapter 3 | 65 Treating alkyl(p-cyanophenoxo)(2,2'-bipyridine)Ni(II) complex 3.6 with stoichiometric CO at –78 °C readily yielded acyl(phenoxo)nickel(II) complex 3.7 (Scheme 3-2, C). Addition of excess CO or π acids such as maleic anhydride (MAH) further triggered the reductive elimination of 3.7 to give the starting ester. These results clearly demonstrated that the C–O bond cleavage was reversible. In accordance with the experimental observation that the oxidative addition was accelerated by electron- withdrawing phenyl substituents and electron-rich phosphine ligands, subsequent kinetic studies suggested that the C–O bond cleavage proceeded through a nucleophilic attack of the Ni(0) center at the ester carbonyl group. This process was also likely assisted by initial coordination of the metal to the π electrons of the benzene ring of the phenyl ester, since esters lacking this π system, such as ethyl acetate, were inert towards activation. Oxidative addition of carboxylates to rhodium, 86 cobalt, 87 and ruthenium hydride complexes88 were also reported in similar scenarios, yet the fate of the oxidative addition adducts varied based on the nature of metal centers and ligands. Grotjahn and Joubran devised a quinolin-8-ol-derived acetate bearing a phosphino substituent at the C-2 position (3.8) and examined its reactivity towards acyl C–O bond 89 cleavage by a [Rh(coe)2Cl]2 complex (coe = cyclooctene). It was envisioned that the N,P-bidentate coordination by 3.8 would bring the metal center in close proximity to the ester group, thereby facilitating the oxidative addition of C–O bond and forming complex 3.9 (Scheme 3-3). Subsequent decarbonylation would lead to the hexacoordinate complex

3.10. However, treating 3.8 with [Rh(coe)2Cl]2 in C6D6 readily afforded the unanticipated yet thermally stable complex 3.11 (and its enantiomer) as the only products, as confirmed by extensive 1D and 2D NMR experiments. The formation of 3.11 clearly demonstrated the cleavage of the C–O bond, yet the decarbonylation event did not occur. Instead, another molecule of 3.8 completed the coordination sphere of rhodium center. Interestingly, among the three possible diastereomers, 3.11 was produced in a highly selective manner (83% isolated yield), although the mechanism accounting for such selectivity was unclear.

Chapter 3 | 66

Scheme 3-3 Oxidative addition of a quinolin-8-ol-derived ester to a Rh(I) complex

The effectiveness of chelation in assisting C–O bond cleavage and preventing decarbonylation of the oxidative adduct was demonstrated in a follow-up study by the same group by employing the N-acyl amino acid ester 3.12 (Scheme 3-4). 90 Under conditions similar to the previous study, five-coordinate oxidative adduct 3.13 was formed in quantitative yield (determined by 1H NMR). 1H and 31P NMR spectra suggested a cis-relationship between the phosphino group and the acyl group, although the exact stereochemistries of 3.13 was difficult to assign. Decarbonylation of 3.13, leading to complexes such as 3.15, was not observed. Treating 3.13 with PMe3 displaced the coordinated amide and resulted in a more stable complex 3.14, in which the acyl group was cis to both phosphino groups.

Chapter 3 | 67

Scheme 3-4 Chelation-assisted C–O bond activation of N-acyl amino acid ester

Compared to the oxidative addition of esters to Ni(0) centers, oxidative addition of esters to the less electron-rich Pd(0) centers is sluggish, yet still feasible, provided an electron-deficient ester substrate is employed.91 The Yamamoto group found that heating

PdEt2(PMe3)2 (3.16) in the presence of styrene generated a Pd(0) complex

Pd(styrene)(PMe3)2 (3.17) in situ. This complex readily activated the acyl C–O bond of substituted aryl trifluoroacetates (3.18) under mild conditions to yield the corresponding oxidative addition adduct 3.19, which slowly decomposed in solution at –20 °C . 1H, 13C, and 31P NMR experiments supported a trans-configuration of the phosphine groups in 3.19. On the other hand, reaction of 3.17 with the para-nitro-substituted ester 3.18d yielded the cis-bis(nitrophenoxo)palladium(II) complex 3.20, presumably through a disproportionation reaction of the initial adduct 3.19d. These experiments demonstrated that the oxidative addition of acyl C–O bond was feasible as an elementary step and set the stage for the successful development of catalytic methods for a broader utility of acyl C–O bond activation of esters.

Chapter 3 | 68

Scheme 3-5 Oxidative addition of aryl trifluoroacetates to a Pd(0) complex

3.2.2 Catalytic, decarbonylative acyl C–O bond activation reactions

In 2001, Murai and Chatani reported a ruthenium-catalyzed decarbonylative reduction of esters (Scheme 3-6a).92,93 2-Naphthoate bearing a pyridine ring (3.21a) was heated in the presence of catalytic amount of Ru3(CO)12. The pendant pyridine group directed the metal to activate the ester C–O bond, providing the five-membered chelate complex 3.24. Subsequent reduction with a hydride donor, however, did not yield the expected aldehyde 3.25, but resulted in the decarbonylated naphthalene (3.22) in excellent yield, along with the formation of 2-pyridinemethanol. Control experiments indicated that aldehyde 3.25 was not involved as an intermediate, thus complex 3.24 likely underwent decarbonylation first, followed by formate-mediated reduction to give 3.22. The importance of pyridine as the directing group and the length of tether group in directing the desired bond cleavage was illustrated by using a benzyl substrate 3.26, 2- pyridinylethyl ester 3.27, 2-pyridinyl ester 3.28, and ester 3.29 bearing a sp3-nitrogen; these molecules did not give the corresponding naphthalene product (Scheme 3-6b)

Chapter 3 | 69 Despite the high reaction temperature, this reaction demonstrated a broad substrate scope and good functional group tolerance (Scheme 3-6c). Aryl esters with various electron-donating (3.30, R = Me, OMe, NMe2), electron-withdrawing (R = F, Cl, CF3), and heterocyclic substituents (R = 2-pyridyl, 2-indolyl, ferrocenyl) on the phenyl group proceeded to the corresponding arenes in good to excellent yields. Moreover, both linear and branched alkyl esters (3.31 and 3.32), as well as an oxazoline directing group (3.33) were well tolerated.

Scheme 3-6 Ruthenium-catalyzed decarbonylative reduction of esters

Chapter 3 | 70 The oxidative addition adduct of an acyl C–O bond and the corresponding complex from decarbonylation can also be employed in complexity-building cross-coupling reactions, enabling the synthetically useful C–C bond formation to occur. As exemplified by Sames and co-workers, heating proline ester-derived amidine 3.34 in the presence of catalytic Ru3(CO)12 initiated a directed C–O bond activation and led to the six-membered chelate 3.37 (Scheme 3-7).94 Subsequent decarbonylation, followed by transmetallation with phenylboronic ester 3.35 afforded, via intermediate 3.38, the more stable five- membered metallacycle 3.39. * Reductive elimination of 3.39 yielded the α-phenyl amidine product 3.36. Notably, an alternative amidine-directed C–H activation/arylation pathway was completely outcompeted by the observed C–O activation/arylation reaction, since the corresponding C–H arylation product 3.40 was not detected under the initial reaction conditions.

Scheme 3-7 Chelation-assisted decarbonylative arylation of proline ester amidine

* An alternative transmetallation/decarbonylation sequence is also possible.

Chapter 3 | 71 Gooβen and Paetzole reported that decarbonylative acyl C–O bond activation, in conjunction with Heck-type olefination, could be used to construct conjugated arenes in equally high efficiency compared to the traditional methods (Scheme 3-8).95 In this work, palladium-catalyzed acyl C–O bond cleavage of electron-deficient aryl esters (3.41), followed by decarbonylation enabled the resulting aryl–palladium complex to enter the catalytic cycle, analogous to a typical Heck reaction, and eventually furnish the corresponding cross-coupled products in good yields and high regioselectivity (3.43 versus 3.43'). A array of p-nitrophenyl carboxylates containing electron-donating and electron-deficient groups (3.43a–h), as well as heterocyclic groups (3.43i and 3.43j) were suitable substrates. Extended π-system (3.43k), electron-poor olefins (3.43l and 3.43m), and even simple non-substituted styrene (3.43n) could be readily constructed in excellent yields. Moreover, the by-product, p-nitrophenol, was successfully recycled via a

Sc(OTf)3-promoted, solvent-free esterification reaction with benzoic acid to regenerate the starting ester in good yield, thereby highlighting the waste minimization feature of this method.

Chapter 3 | 72

Scheme 3-8 Decarbonylative Heck-type coupling of electron-deficient esters

In addition to ruthenium and palladium, nickel complexes also proved to be applicable towards activating acyl C–O bonds of esters. A recent publication from the Itami group highlighted the power of nickel catalysis in constructing aryl- and heteroaryl- substituted biaryls via a decarbonylative Suzuki-type cross-coupling of esters and boronic 96 acids (Scheme 3-9). Using Ni(OAc)2 as an inexpensive Ni(0) precursor, PnBu3 as the ligand, in conjunction with Na2CO3 as the base, an impressive scope of aryl esters (3.45a–e) and heteroaryl esters bearing thiophene, benzothiophene, furan, oxazole, thiazole, pyridine, quinoline, chromone, and pyrazine rings (3.45f–p) were readily converted to the corresponding cross-coupled products. Applications towards orthogonal coupling, one-pot coupling, and the synthesis of a drug-like molecule were also well demonstrated (not shown).

Chapter 3 | 73

Scheme 3-9 Nickel-catalyzed decarbonylative cross-coupling of (hetero)aryl esters

Computational chemistry elucidated some key mechanistic insights for this transformation. First, the phenoxide group in the ester pre-coordinated to the metal center and thus assisted the acyl C–O bond activation (ethyl esters were unreactive). Second, added Na2CO3 promoted the transmetallation of the oxidative adduct 3.46 through a six- membered transition state TS1. Third, transmetallation occurred prior to decarbonylation due to a lower energy barrier (22.3 kcal/mol for transmetallation of 3.46 via TS1, versus

Chapter 3 | 74 29.2 kcal/mol for decarbonylation from 3.46). And the last, the decarbonylation step (3.47 → 3.48) was rate-determining. Metal-catalyzed direct coupling reactions between esters with aromatic and heteroaromatic C–H bonds, namely C–O/C–H coupling reactions, represent an attractive strategy for (hetero)biaryl synthesis (Scheme 3-10). Here, a vast array of arenes and hetereoarenes are cheap and commercially available, thus pre-functionalization of nucleophiles is avoided. In addition, compared with the classic C–X/C–M coupling reactions and the recently developed C–X/C–H coupling reactions, where aryl halides are used as the electrophiles,97 esters are robust, less toxic, and straightforward to prepare. Furthermore, the alcohol (or phenol) by-product from the C–O/C–H coupling can be recycled back to the starting ester (e.g., ref. 95), and orthogonal couplings have been developed (e.g., ref. 82 and 96).

Scheme 3-10 C–O/C–H coupling by acyl C–O bond activation and C–H activation

A conceptual breakthrough was achieved by the Itami group in 2012.98 Heteroaryl- derived phenol carboxylates (3.50) underwent a nickel-catalyzed decarbonylative acyl C– O bond cleavage and coupled with azoles (3.49) to allow the synthesis of heterobiaryls (3.51). A striking ligand effect was found: 1,2-bis(dicyclohexylphosphino)ethane (dcype) was essentially the only phosphine ligand to promote this reaction, whereas a large number of phosphorous and nitrogen based ligands (>20 screened) were totally

Chapter 3 | 75 ineffective. Under the optimal conditions, biaryls substituted with thiophene (3.51a and 3.51c), furan (3.51b and 3.51d), thiazole (3.51e), pyrazine (3.51f), and pyridine (3.51g and 3.51h) heterocycles were readily constructed in good to excellent yields. In addition to benzooxazole (3.49), oxazole and thiazole (not shown) were also efficient C–H coupling partners. Mechanistically, oxidative addition of the acyl C–O bond of the ester to the Ni(0) center, followed by decarbonylation of the resulting adduct 3.52 would generate the heteroaryl–nickel–phenoxide complex 3.53. Subsequent deprotonation of the azole C–H bond presumably was promoted by phenoxide or added base (K3PO4), leading to complex 3.54 along with the phenol by-product. Product-forming reductive elimination afforded the coupled product and generated a seemingly inactivate nickel–carbonyl complex such as 3.55. The required high temperature (150 °C ) suggested that a thermal extrusion of carbon monoxide was involved in the regeneration of the active Ni(0) catalyst. Indeed, a

Ni(0)–carbonyl complex Ni(dcype)(CO)2 was independently prepared as a stable solid in near quantitative yield, which proved to be a equally reactive catalyst in the C–O/C–H coupling.

Chapter 3 | 76

Scheme 3-11 Decarbonylative C–O/C–H coupling of azoles and heteroaryl esters

3.2.3 Catalytic, non-decarbonylative acyl C–O bond activation reactions

Shortly after their initial study of the oxidative addition of esters with stoichiometric palladium complexes,91 Yamamoto and co-workers developed the first catalytic variant for activating the acyl C–O bond of phenyl trifluoroacetates,99 which were subsequently coupled with phenyl boronic acids in a Suzuki-type reaction to enable a facile synthesis

Chapter 3 | 77 of trifluoromethyl ketones (Scheme 3-12). The combination of Pd(OAc)2 and monodentate phosphine ligand PnBu3 in a 1:3 ratio proved optimal in promoting the acyl C–O bond cleavage while stabilizing the resulting adduct 3.59 from decomposition. Unlike a typical Suzuki coupling where an added based was required to drive the transmetallation step, the existence of a basic phenoxide ligand in 3.59 allowed the transmetallation with boronic acid 3.57 to proceed smoothly without added base, affording the aryl–palladium complex 3.60, and eventually the cross-coupled ketones 3.58. Under similar conditions, two additional perfluoroalkyl ketones were obtained in excellent yields (3.61). Although limited to activated esters, this work represented a milestone in the field of metal-catalyzed ester activation, and a number of new and creative methods have been developed since then.

Scheme 3-12 Catalytic Suzuki-type coupling reactions of phenyl trifluoroacetates

The union of chelation-assisted C–O bond activation with the intrinsically facile transmetallation of the resulting metal–alkoxide intermediate towards organoboron species have allowed the creative development of two non-decarbonylative cross- coupling reactions under ruthenium93 and palladium catalysis,100 respectively. 2-pyridinylmethyl esters (3.62) underwent a pyridine-directed acyl C–O bond 93 cleavage with catalytic Ru3(CO)12 (Scheme 3-13, top). In contrast to the previous example, where decarbonylation occurred in the presence of a hydride donor (e.g.,

Chapter 3 | 78

HCO2NH4), 3.66 readily transmetallated with various organoboronates (3.63) to generate , upon C–C bond-forming reductive elimination, the ketone products 3.64. Likewise, the 2-pyridyl esters (3.68) were suitable substrates in a palladium- catalyzed cross-coupling reaction with aryl- and alkylboronic acids (3.69).100 Coordination of the palladium center to the pyridine triggered a nucleophilic attack to the sp2-carbon center of ester, and the resulting tetrahedral intermediate 3.71 further collapsed into the key acyl–palladium intermediate 3.72 (Scheme 3-13, bottom). Transmetallation and reductive elimination furnished the ketones 3.70 in overall good yields.

Scheme 3-13 Pyridine-directed non-decarbonylative cross-coupling reactions

The chemistry of the oxidative addition adduct from acyl C–O bond activation is not limited to cross-coupling reactions,92–100 but also has been extended to a number of C–C π bond insertion reactions by creative design of substrates. Matsubara and co-workers reported a nickel-catalyzed formal cycloaddition reaction of alkyne 3.76 with salicylic acid ketal 3.75, allowing rapid construction of substituted chromones 3.77 in a single step

Chapter 3 | 79 101 (Scheme 3-14). The use of electron-rich monodentate phosphine PCy3 and one equivalent of pyridine as additive proved to be beneficial to drive the reaction to completion. The ester substrates (3.75) were readily prepared from widely available salicylic acids and benzophenone. Upon oxidative addition to the Ni(0) center, the resulting seven- membered adduct 3.79 underwent a strain-releasing β-elimination to form the more stable five-membered oxa-nickelacycle 3.80 along with the extrusion of benzophenone (3.78). Subsequent coordination of the metal center to alkyne 3.76 adopted a direction minimizing the unfavored steric replusion between the phosphine ligand and the bulkier alkyne substituent (RL). Finally, insertion of the acyl carbon–nickel bond, via complex 3.82, followed by reductive elimination resulted in a net cycloaddition process.

Scheme 3-14 Nickel-catalyzed formal cycloaddition of salicylic acid ketals to alkynes

Chapter 3 | 80 A number of substituted chromones could be prepared using the symmetrical 4- octyne as the coupling partner (3.77a–e). Reactions with unsymmetrical, yet highly sterically-biased alkynes, such as tert-butyl- and trimethylsilyl-substituted alkynes afforded the corresponding chromones with complete regioselectivity (3.77f and 3.77g). Less sterically-biased alkynes, however, provided the product in good yield overall, but poor regiocontrol (3.77h and 3.77h'). Additionally, pyridine- and naphthalene-fused products could be prepared in a similar manner (3.77i and 3.77j). Similar strategies have been applied in activating other carbonyl molecules, including phthalic anhydrides,102 anthranilic acid derivatives, 103 isatoic anhydrides, 104 phthalimides, 105 and carbonylsalicylamides.106

3.3 Research proposal: alkene oxyacylation reaction by acyl C–O bond activation

Despite significant advances, the reported acyl C–O bond activation reactions focused predominantly on coupling reactions. To a large extent, the acylated oxygen is treated as a leaving group and inevitably fragmented through alkoxide cleavage and/or decarbonylation. Following our previous success with intra- and intermolecular alkene carboacylation reactions by C–C bond activation,32,33 we aim to combine acyl C–O bond activation with the addition of an alkene, namely the oxyacylation reaction, as a conceptually novel approach to manipulate esters (Scheme 3-15). Here, both a carbonyl and an alkoxy group are added across the alkene π bond in a highly atom-economical fashion to allow the formation of β-alkoxy ketones, which are the typical products from the aldol reaction.

Scheme 3-15 Conception of oxyacylation reaction

Chapter 3 | 81 The potential of inserting an unsaturated bond into the ester C–O bond was first demonstrated by Ohe and co-workers.107 A phenol ester with a cyanomethyl side-chain (3.83) was heated under palladium catalysis to initiate an acyl C–O bond activation process, generating a nitrile-coordinated oxidative addition adduct 3.85 (Scheme 3-16). The added zinc powder reduced the Pd(II) precursor to Pd(0). Meanwhile, the resulting Lewis acidic Zn(II) salt presumably promoted the oxidative addition by coordinating to the ester carbonyl group. Insertion of the nitrile π bond (oxypalladation) to the palladium–oxygen bond, followed by prototropic isomerization gave the amido– palladium complex 3.87. Instead of C–N bond reductive elimination to form the N-acyl- benzofuran (3.84'), further isomerization of 3.87 into the aza-allyl–palladium 3.88, C–C bond reductive elimination, and tautomerization accounted for the formation of 3-acyl-2- amino-benzofuran 3.84 and achieved an overall net addition of an ester across the nitrile. A double cross-over experiment (not shown) confirmed that the reaction occurred in an intramolecular fashion. Notably, the observed side-product 2-(cyanomethyl)phenol (3.90) was attributed to the formal hydrolysis of 3.85, thus ruling out other alternative mechanisms that did not involve a direct oxidative addition of ester C–O bond.* Under the optimized conditions, a number of aryl carboxylates proceeded to the corresponding 3-acyl-2-aminobenzofurans in good to excellent yields (3.84a–f). Interestingly, acetate, formate, and even carbonate were tolerated and smoothly converted into the corresponding acetyl-, formyl-, and ethoxycarbonyl-substituted products (3.84g, 3.84h, and 3.84i, respectively).

* For example, nucleophilic attack of the benzylic anion α to the cyano group to the ester carbonyl would initiate an intramolecular acyl transfer process and generate the same product.

Chapter 3 | 82

Scheme 3-16 Intramolecular oxyacylation reaction of nitriles

Our group contributed to the development of oxyacylation reaction with the first oxyacylation reaction using an alkene as the π bond component.108 In the presence of a * cationic rhodium (I) complex [Rh(cod)2]BF4, a bidentate phosphine dppp, and a mixture solvent system (toluene/1,2-DCE), the acyl C–O bond of 8-quinolinecarboxylic ester 3.91 was cleaved and intramolecularly added across the pendant alkene to yield the dihydrobenzofuran product bearing an oxa-quaternary center (Scheme 3-17, 3.92). The quinoline moiety was judiciously chosen to assist the C–O bond oxidative. In addition, it stabilized the resulting acyl–rhodium–alkoxide adduct from decarbonylation

* dppp = 1,3-bis(diphenylphosphino)propane

Chapter 3 | 83 through the five-membered rhodacycle 3.94. A plausible rate-determining alkene insertion occurred at high temperature (150 °C ) to generate complex 3.95, whereas a formal hydrolysis of 3.94 would account for the detection of the phenol side-product 3.96. Product forming-reductive elimination released the β-alkoxy ketone and allowed the active catalyst to re-enter the cycle.

Scheme 3-17 Rhodium-catalyzed intramolecular oxyacylation reaction of alkenes

Chapter 3 | 84 Products with electron-neutral (3.92a and 3.92b), electron-donating (3.92c), and electron-withdrawing substituents on the phenyl ring (3.92e) were obtained in good to excellent yields. Selective activation of a quinolinyl ester over an ethyl ester was possible (3.92d). Methyl group ortho to the ester center (3.92f and 3.92g) did not hamper the reaction. Ethyl- and benzyloxymethyl-substituted alkenes were also tolerated (3.92h and 3.92i), yet the allyl group failed to produce the product (3.92j), likely due to a competitive β-hydride elimination. Six-membered chromane (3.92k) and dihydrobenzodioxine (3.92l) were also successfully constructed.

3.4 Results and discussion

3.4.1 Early investigations and discovery of a hydroxyl directing group*

The development of alkene oxyacylation reaction has realized the union of C–O bond activation with alkene addition reactions, offering a complementary method to access the important β-alkoxy ketone moiety. This study also served as the basis of two associated studies.109 8-Acylquinolines appeared to be a privileged system through our efforts, yet their removal or functionalization proved to be challenging, thus limited a broader synthetic utility of the current method. Although our ultimate goal is to developed a “directing-group-free” C–O bond activation, we realized that the associated challenges, such as the chemoselectivity of bond activation, the non-productive decarbonylation process, and the turn-over of catalyst, remained significant. Thus, our next endeavor is to search for more versatile directing groups with a primary focus on intramolecular reaction. The study of new oxyacylation reaction began with esters 3.97a–d, which retained the 1,1-disubstituted alkene and the rigid aromatic backbone (Scheme 3-18). These substrates were readily prepared from o-(2-methylallyl)phenol (3.100) and the

* Experiments discussed in chapter 3.4.1 and part of chatper 3.4.2 were designed and performed by Dr. Giang Hoang. For details of optimization, substrate synthesis, and associated spectroscopic data, see Hoang, G. T. Ph.D. Dissertation, University of Minnesota – Twin Cities, 2012.

Chapter 3 | 85 corresponding carboxylic acids; 3.97a contained a pyridine ring as a potential directing group, and 3.97b–d were equipped with a heteroatom directing group (X = NH2, SMe, and PPh2, respectively). These substrates were heated in toluene or m-xylene with a Rh(I) complex (10 mol%) at 130 or 150 °C without a ligand, in order to probe the effectiveness of directing groups. Ester 3.97a decomposed upon heating at 130 °C, while 3.97b and 3.97c isomerized extensively to 3.99, likely as a result of a thermal- and/or rhodium-promoted alkene isomerization process. The cyclized products 3.98 were not detected. Interestingly, the reaction of ester 3.97d gave the starting phenol 3.100 as the main by-product, indicating that the phosphorous atom was able to direct the metal and assisted C–O bond activation. However, subsequent alkene insertion was hampered, possibly due to the sterically demanding phosphine substituent, thus rendering the decomposition pathway more favorable and generating phenol 3.100 as the detected product.

Scheme 3-18 Preliminary screening with esters 3.97a–d

Despite the failure of to detect the desired product, these preliminary results shed light on the design of subsequent experiments regarding the strength and steric bulkiness

Chapter 3 | 86 of directing groups. Further, we were inspired by the recent developments of directing group-assisted metal catalysis, in particular, the rhodium-catalyzed alkene and alkyne hydroacylation reactions of salicylaldehyde derivatives, which are directed by hydroxyl groups.110 With these advances in mind, we prepared salicylate ester 3.101 from the widely available salicylic acid and extensively examined the conditions to favor the formation the oxyacylation product 3.102 (Scheme 3-19). We envisioned that deprotonation of the hydroxyl group by added base would create an anionic, hence stronger coordination to the metal center, thereby initiating the acyl C–O bond activation through a five-membered acyl–rhodium–phenoxide chelate. Extensive screening of Rh(I) and Ir(I) complexes, phosphorus ligands, bases, solvents, and temperatures revealed the best conditions employing [Rh(cod)OH]2 as the catalyst, monodentate phosphine (R)-MOP,* and heating in m-xylene at 170 °C without a base. Under these conditions, product 3.102 was obtained in a moderate 47% yield. Other identified by-products included the alkene isomer 3.99 and phenol 3.100.

* MOP = 2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl.

Chapter 3 | 87

Scheme 3-19 Screening of conditions with salicylate ester 3.101

3.4.2 Screening of conditions with salicylate ester 3.103

Next, we directed our attention to salicylate ester 3.103 bearing an extended alkene linker. 3.103 was designed owing to its decreased tendency to undergo alkene isomerization. Conditions for the oxyacylation of 3.103 were screened analogous to 3.101: chromane 3.104 was the target product, whereas phenol 3.105 and isomerized ester 3.106 were identified as the main by-products (Table 3-1).

Table 3-1 Optimization of oxyacylation conditions with salicylate ester 3.103

Chapter 3 | 88 Entry Metal[a] Ligand[b] Solvent T (°C ) Yield of 3.104 (%)[c] [d] 1 [Rh(cod)OH]2 – m-xylene 170 3 [d] 2 [Ir(cod)OMe]2 – m-xylene 170 6 [e] 3 [Ir(cod)OMe]2 dppp m-xylene 170 0

4 [Ir(cod)OMe]2 PCy3 m-xylene 170 19

5 [Ir(cod)OMe]2 Me-Phos m-xylene 170 32

6 [Ir(cod)OMe]2 X-Phos m-xylene 170 47

7 [Ir(cod)OMe]2 MOP m-xylene 170 61

8 [Ir(cod)OMe]2 MOP m-xylene 150 49 [f] [g] 9 [Ir(cod)OMe]2 MOP mesitylene 170 78 10 Ir(cod)(acac)[f] MOP mesitylene 170 64[g] [a] 10 mol% metal unless otherwise noted. [b] 12 mol% unless otherwise noted. [c] Determined by 1H NMR spectroscopy using p-methoxyacetophenone as the intermal standard. [d] Run with 1.0 equiv. NaHCO3. [e] 6 mol% ligand. [f] 8 mol% metal. [g] Isolated yield. dppp = 1,3-bis(diphenylphosphino)propane, Cy = cyclohexyl, Me-Phos = 2-dicyclohexylphosphino-2′-methylbiphenyl, X-Phos = 2-dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl, MOP = 2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl, acac = acetylacetonate.

Trace, but detectable amounts of product was obtained using [Rh(cod)OH]2 and

[Ir(cod)OMe]2. These two complexes presumably exchanged the hydroxide/methoxide ligand with the phenoxyl group, enabling the metal to coordinate with the substrate and enter the catalytic cycle. (entries 1 and 2). Similar ligand exchange between

[M(cod)OMe]2 (M = Rh and Ir) and phenol in the presence of a phosphine ligand was reported.111 Added bidentate phosphine dppp, which was employed in the quinoline- directed oxyacylation reaction, was unreactive (entry 3). Further screening of monophosphines revealed MOP as the optimal choice, affording the product in 61% yield at 170 °C and 49% yield at 150 °C (entries 4–8). Switching from m-xylene to higher-

Chapter 3 | 89 boiling mesitylene in conjunction with 4 mol% [Ir(cod)OMe]2 and 12 mol% MOP afforded an optimal 78% isolated yield (entry 9).

Scheme 3-20 Formation of methyl salicylate 3.107

During the optimization with [Ir(cod)OMe]2 and MOP, we identified a small amount of methyl salicylate (3.107) from the crude reaction mixture. It was hypothesized that the initial ligand exchange between the metal precatalyst and the substrate released methanol, which further underwent transesterification with substrate 3.103 and led to 3.107. Methyl salicylate was seemingly inert towards further activation, yet it occasionally co-eluted with the desired product during column chromatography. To our delight, Ir(cod)(acac) also catalyzed the reaction, albeit with slightly decreased efficiency (64%, entry 10). Fortunately, methyl salicylate was not detected using Ir(cod)(acac), thus making the product purification easier in some cases.

3.4.3 Substrate scope study and transformations of oxyacylation product

With the optimal conditions in hand, we proceeded to examine the scope for oxyacylation reaction. The substrates were readily prepared from phenol 3.105 and a range of cheap and commercially available salicylic acids through routine esterification reactions. Ketone products with electron-donating substituents (R = Me, 3.104b; R = OMe, 3.104g) and halogens (R = F, 3.104c; R = Cl; 3.104d) para to the carbonyl group were obtained with good yields under conditions A or B. Notably, a carbon–bromine bond was tolerated (3.104e, 35% yield; 60% yield brsm). A substrate bearing an electron- withdrawing CF3 group proceeded at lower temperature (150 °C ) and could be scaled up

Chapter 3 | 90 to a 1.3 mmol scale without diminished efficiency (3.104f, 72% versus 82% yield). Likewise, nitro- and chloro-substituents para to the hydroxyl group were well-tolerated (3.104h and 3.104i). Products derived from bulkier 2-hydroxy-1-naphthoic ester (3.104j) and ethyl-substituted alkenes (3.104k and 3.104l) were readily prepared. Other than chromane backbones, dihydrobenzofuran (3.104m) and dihydrobenzodioxine (3.104n) were also successfully constructed, albeit in modest yields.

Table 3-2 Substrate scope for oxyacylation of salicylate esters

[a] Conditions A: [Ir(cod)OMe]2 (4 mol%), MOP (12 mol%), mesitylene, 170 °C , 48 h. Conditions B: Ir(cod)(acac) (8 mol%), MOP (12 mol%), mesitylene, 170 °C , 48 h. [b] Isolated yield for all substrates. [c] Reaction performed at 150 °C . [d] 41% Recovered 3.103e, 60% yield of 3.104e based on recovered starting material. [e] 72% Isolated yield of 3.104f on a 1.35 mmol scale reaction.

The versatility of the hydroxyl directing group was demonstrated by various chemical transformations of the oxyacylation product 3.104a. Treating 3.104a with acetic anhydride and trifluoromethanesulfonic anhydride under standard conditions afforded the

Chapter 3 | 91 corresponding acetate 3.104o and aryl triflate 3.104q in 87% and 88% yield, respectively. Basic etherification with methyl iodide gave methyl ether 3.104p in nearly quantitative yield. Moreover, facile Suzuki cross-coupling of 3.104q with phenyl boronic acid provided biaryl 3.104r in excellent yield. Although the attempt to form a catechol- derived ester from 3.104a by a Baeyer–Villiger oxidation was unsuccessful (not shown), formal removal of the hydroxyl directing group was realized by palladium-catalyzed reduction of aryl triflate 3.104q, providing ketone 3.104s in 86% yield.

Scheme 3-21 Transformations of the hydroxyl directing group

3.4.4 Mechanistic investigations

Mechanistically, ligand exchange of [Ir(cod)OMe]2 with substrate 3.103, in the presence of MOP ligand, generated the iridium–alkoxide complex 3.109 and initiated the catalytic cycle (Scheme 3-22). Methanol was released as the by-product, which was eventually incorporated into methyl salicylate (3.107) via transesterification. Upon coordination, the alkoxide ligand brought the iridium center into close proximity to the ester, thereby assisting the C–O bond activation and stabilizing the resulting adduct 3.110 from decarbonylation. Migratory insertion of the alkene to the iridium–oxygen bond established the oxa-quaternary stereocenter and afforded complex 3.111. Subsequent C– C bond-forming reductive elimination established the hydroxyl ketone moiety in 3.112

Chapter 3 | 92 which, upon proton exchange with another molecule of 3.103, released the product 3.104 and regenerated the catalytic species 3.109.

Scheme 3-22 Proposed catalytic cycle

We carried out additional experiments to further probe the mechanism (Scheme 3- 23). Substrates without a directing group (Scheme 3-23a, X = H) or bearing other substituents ortho to the ester (X = OMe, NH2, NHTs, and NHCOCF3) failed to afford the corresponding oxyacylation products, clearly indicating the necessity of hydroxyl directing group. Oxyacylation of 3.103a with an optically active MOP ligand [(R)-MOP, ≥ 94% ee] returned the product in essentially racemic form (< 5% ee, Scheme 3-23b). On the other hand, heating (R)-MOP solely in mesitylene at 170 °C for 48 h did not cause

Chapter 3 | 93 detectable racemization of the ligand, indicating that the product racemization was not due to loss of optical purity of ligand.

Scheme 3-23 Mechanistic experiments

Chapter 3 | 94 To further trace the origin of racemization, enantioriched product 3.104f was re- subjected to both the standard oxyacylation conditions and simple heating in mesitylene at 170 °C (Scheme 3-23c).* In both cases, 3.104f racemized. The thermal racemization was likely due to a plausible retro-oxy-Michael reaction, as shown in Scheme 3-24. Furthermore, heating a mixture of product 3.104h and exogenous phenol 3.108 under oxyacylation conditions resulted in crossover product 3.104h' (Scheme 3-23d). Double crossover experiment using 3.103c and 3.103l generated not only the expected oxyacylation products (3.104c and 3.104l), but the two crossover products 3.104c' and 3.104f. These results suggested the reversibility of several steps in the catalytic cycle (Scheme 3-22). First, product re-entered the cycle premably by exchanging the more acidic hydroxyl group with [Ir(cod)OMe]2. Second, both the migratory insertion step and reductive elimination step were reversible. The crossover event shown in Scheme 3-23d could presumably proceed by a ligand exchange between the exogenous phenol (e.g., 3.108) with the phenoxide ligand in 3.110. The double crossover result shown in Scheme 3-23e might be explained by a phenoxide ligand exchange between the oxidative adducts generated from 3.103c and 3.103l, respectively.

Scheme 3-24 Possible mechanism for the thermal racemization of enantioriched product

3.5 Conclusions and future work

In summary, we have developed an intramolecular alkene oxyacylation using a hydroxyl directing group.112 This method expanded the synthetic utility of the chemistry

*3.104f was resolved using chiral HPLC. Experiments indicated in Scheme 3-23c were performed by Jason Brethorst.

Chapter 3 | 95 of acyl C–O bond activation by employing readily available salicylate esters as reactants, enabling the synthesis of highly substituted chromane heterocycles in an atom- economical fashion. The versatility of hydroxyl directing group was highlighted in a series of derivatization reactions of the oxyacylation product, including the removal of directing group. Preliminary mechanistic studies revealed the key ligand exchange process between the precatalyst and the directing group, and the reversible nature of the overall catalytic cycle, thus identifying the significant challenges in developing the asymmetric variant of alkene oxyacylation reactions. Future work is focused on developing other reactive catalytic systems and extending the scope of oxyacylation chemistry towards novel directing groups, other π bond reactants, and intermolecular oxyacylation reactions.

3.6 Experimental section

3.6.1 General details

All reactions were carried out using oven-dried glassware under a nitrogen atmosphere unless otherwise noted. Acetonitrile (CH3CN), toluene (PhMe), dichloromethane (CH2Cl2), 1,4-dioxane, and N,N-dimethylformamide (DMF) were distilled prior to use. Solvents for oxyacylation reactions (anhydrous m-xylene or mesitylene) were further degassed by bubbling a stream of argon through the liquid in a Strauss flask and then stored in a nitrogen-filled glove box. Rhodium and iridium complexes and phosphine ligands were purchased from commercial vendors except for

[Ir(cod)OMe]2, which was synthesized from IrCl3 in two steps following a known * procedure. We found that commercial samples of [Ir(cod)OMe]2 generally provided lower yields in the oxyacylation reactions, which was tentatively attributed to the residual water or methanol therein. Improved and reproducible yields were obtained upon drying

[Ir(cod)OMe]2 under active vacuum over P2O5. (S)-MOP was synthesized from (S)-

* (a) Herde, J. L.; Lambert, J. C.; Senoff, C. V.; Cushing, M. A. Inorg. Synth. 1974, 15, 18–20. (b) Uson R.; Oro L. A.; Cabeza J. A.; Bryndza H. E.; Stepro M. P. Inorg. Synth. 1985, 23, 126.

Chapter 3 | 96 BINOL. * All other chemicals were purchased from commercial sources and used as received. All oxyacylation reactions were carried out in a Vacuum Atmospheres nitrogen- filled glove box in 1 dram vials (Chemglass) with PTFE lined caps and heating was applied by aluminum block heaters. Analytical thin-layer chromatography (TLC) and preparative thin-layer chromatography were carried out using 250 μm and 1000 μm silica plates (SiliCycle), respectively. Eluted plates were visualized first with a UV lamp (254 nm) and then stained with potassium permanganate or p-anisaldehyde, followed by heating. Flash column chromatography was performed using 230 – 400 mesh (particle size 40 – 63 μm) silica gel purchased from SiliCycle. 1H NMR (300 and 500 MHz) and 13C NMR (75 and 125 MHz) spectra were obtained on Varian Inova instruments. 1H NMR spectra data were reported as δ values in 13 ppm relative to chloroform (δ 7.26) if collected in CDCl3. C NMR spectra data were 1 reported as δ values in ppm relative to chloroform (δ 77.00) if collected in CDCl3. H NMR coupling constants were reported in Hz, and multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); quint (quintet); m (multiplet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dddd (doublet of doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); ddt (doublet of doublet of triplets); dq (doublet of quartets); app (apparent); br (broad). Infrared (IR) spectra were obtained on a MIDAC FT-IR spectrometer. A thin-film of sample was prepared by evaporating solvent (CH2Cl2 or CDCl3) on NaCl plates. Low-resolution mass spectra (LRMS) in chemical ionization (CI) experiments were performed on a Varian Saturn 2200 GC-MS system. High-resolution mass spectra (HRMS) in electrospray ionization (ESI) experiments were performed on a Bruker BioTOF II (Time-of-flight) instrument using PEG-300, PEG-400 or PPG-400 as an internal standard.

3.6.2 Synthesis of substrates

* (a) Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J. Org. Chem. 1993, 58, 1945–1948. (b) Uozumi, Y.; Kawatsura, M.; Hayashi, T. Org. Synth. 2002, 78, 1

Chapter 3 | 97

Synthesis of 3.115: To a 20 mL reaction vial with PTFE lined cap, 2-iodophenol (1.10 g, 5.0 mmol), palladium acetate (34 mg, 0.15 mmol), cesium carbonate (0.651 g, 2.0 mmol), and freshly distilled acetonitrile (7.2 mL) were added. 3-Butene-2-ol 3.113 (0.7 mL, 8.0 mmol) was added and the reaction vessel was purged with argon gas for 3-5 minutes. The cap was replaced tightly and the reaction mixture was maintained at 100 °C for 24 hours using an aluminum heating block. The reaction mixture was transferred to a

250 mL beaker and saturated aqueous NH4Cl solution (20 mL), water (50 mL) and ethyl acetate (20 mL) were added (occasionally insoluble particles remained then the mixture was filtered through Celite). The organic layer was separated, washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford 3.115 as a colorless oil (0.4578 g, 1 2.78 mmol, 56%). Rf = 0.23 (1:4 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.13–7.09 (m, 1H), 7.05 (dd, J = 8.0, 2.0 Hz, 1H), 6.90–6.88 (m, 1H), 6.85 (dt, J = 7.5, 1.5 Hz, 1H), 2.92–2.89 (m, 2H), 2.85–2.82 (m, 2H), 2.17 (s, 3H); 13C NMR (125

MHz, CDCl3) δ 211.8, 154.3, 130.4, 128.0, 127.3, 120.6, 117.4, 45.3, 29.7, 23.1; IR (thin + film) 3404, 2933, 1702, 1490, 1233; HRMS (ESI) calcd for [C10H12O2 + Na] 187.0730, found 187.0731. Note: The 1H and 13C NMR of 3.115 show an inseparable compound which disappeared after the subsequent Wittig reaction. We tentatively assign it as the hemiketal form of 3.115. Synthesis of 3.116: Prepared in the same manner as 3.115, form 2-iodophenol (1.10 g, 5.0 mmol), palladium acetate (34 mg, 0.15 mmol), cesium carbonate (0.651 g, 2.0

Chapter 3 | 98 mmol), alcohol 3.114 (0.68 ml, 6.5 mmol) and freshly distilled acetonitrile (7.2 mL), the reaction afforded 3.116 as a colorless oil (0.5064 g, 2.84 mmol, 57%) after flash 1 chromatography. Rf = 0.22 (1:9 EtOAc:Hex); 3.116 (ketone form) H NMR (500 MHz,

CDCl3) δ 8.01 (s, 1H), 7.14–7.09 (m, 1H), 7.04 (dd, J = 7.5, 1.7 Hz, 1H), 6.90 (dd, J = 8.1, 1.2 Hz, 1H), 6.84 (td, J = 7.4, 1.2 Hz, 1H), 2.92–2.81 (m, 4H), 2.44 (q, J = 7.3 Hz, 13 2H), 1.04 (t, J = 7.3, 3H); C NMR (125 MHz, CDCl3) δ 214.4, 154.1, 130.2, 127.6, 127.5, 120.4, 116.7, 43.3, 35.5, 23.5, 7.5; 3.116 (hemiketal form) 13C NMR (125 MHz,

CDCl3) δ 152.5, 128.9, 127.0, 121.8, 120.3, 116.8, 97.9, 34.0, 28.6, 21.1, 7.5; IR (thin + film) 3438, 2974, 1702, 1455, 1265; HRMS (ESI) calcd for [C11H14O2 + Na] 201.0886, found 201.0880. Note: The 1H and 13C NMR of 3.116 show an inseparable compound which disappeared after the subsequent Wittig reaction. We tentatively assign it as the hemiketal form of 3.116. Synthesis of 3.117: To a suspension of methyltriphenylphosphonium bromide (4.28 g, 12 mmol) in toluene was slowly added potassium tert-butoxide (1.34 g, 12 mmol) at 0 °C . The resulting mixture was stirred for 2 h at room temperature, followed by addition of a solution of 3.115 (0.458 g, 2.78 mmol) in toluene (5 mL) at 0 °C . The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered through a pad of Celite with excess EtOAc. The layers were separated and the aqueous phase was washed with EtOAc (2  20 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to afford phenol 3.117 1 as a yellow oil (0.450 g, 0.278 mmol, quantitative yield). Rf = 0.5 (1:9 EtOAc:Hex); H

NMR (500 MHz, CDCl3) δ 7.24 (dd, J = 7.3, 1.5 Hz, 1H), 7.17 (td, J = 7.8, 1.5 Hz, 1H), 6.98 (td, J = 7.3, 1.0 Hz, 1H), 6.83 (dd, J = 7.8, 1.0 Hz, 1H), 5.38 (br s, 1H), 4.88–4.86 (m, 2H), 2.89–2.86 (m, 2H), 2.44–2.41 (m, 2H), 1.89 (s, 3H); 13C NMR (125 MHz,

CDCl3) δ 153.2, 145.8, 130.0, 128.2, 127.1, 120.8, 115.2, 110.1, 37.6, 28.4, 22.6; IR (thin – film) 3424, 3072, 1648, 1236; HRMS (ESI) calcd for [C11H14O – H] 161.0972, found 161.0968.

Chapter 3 | 99 Synthesis of 3.118: Prepared in the same manner as 3.117. Starting with ketone 3.116 (0.534 g, 3.0 mmol), methyltriphenylphosphonium bromide (4.28 g, 12 mmol) and potassium tert-butoxide (1.34 g, 12 mmol), the reaction afford 3.118 as a colorless oil

(0.423 g, 2.4 mmol, 80%) after flash column chromatography. Rf = 0.6 (1:4 EtOAc:Hex); 1 H NMR (300 MHz, CDCl3) δ 7.18–7.02 (m, 2H), 6.88 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.84–4.81 (m, 3H), 2.76 (m, 2H), 2.40–2.26 (m, 2H), 2.09 (q, J = 7.5 Hz, 13 2H), 1.05 (t, J = 7.5 Hz, 3H); C NMR (75 MHz, CDCl3) δ 153.4, 151.4, 130.1, 128.2, 127.1, 120.8, 115.2, 108.0, 36.2, 29.0, 28.8, 12.3; IR (thin film) 3065, 2961, 2927, 1643, – 1609, 1590, 1327, 1233. HRMS (ESI) calcd for [C12H16O – H] 175.1128, found 175.1133. Synthesis of ester substrates: To a 25 mL round bottom flask was added carboxylic acid (1.2 mmol, 1.2 eq), N,N’-dicyclohexylcarbodiimine (1.8 mmol, 1.8 equiv.), 4-(dimethylamino)pyridine (0.2 mmol, 0.2 equiv.), phenol (1.0 mmol, 1 equiv.) and CH2Cl2 (4.0 mL). The mixture was heated to reflux overnight (oil bath) or stirred at room temperature for 48–72 hours as indicated below. The reaction mixture was then cooled to room temperature, diluted with CH2Cl2 (50 mL), and filtered with the aid of

Celite. The filtrate was washed with sat. NH4Cl (2  30 mL), followed by sat. NaHCO3

(30 mL). The organic portion was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting crude product was purified by flash column chromatography

(gradient, CH2Cl2:Hex or EtOAc:Hex) to afford the corresponding ester.

3.103a: Prepared under reflux conditions, from salicylic acid (0.49 g, 3.5 mmol), phenol 3.117 (0.38 g, 2.3 mmol), N,N’-dicyclohexylcarbodiimine (0.86 g, 4.2 mmol) and 4-(dimethylamino)pyridine (0.14 g, 1.2 mmol). The reacction afforded 3.103 as a colorless oil (0.441 g, 1.56 mmol, 68%) after flash column chromatography. Rf = 0.53

Chapter 3 | 100 1 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 10.54 (s, 1H), 8.10 (dd, J = 8.0, 1.7 Hz, 1H), 7.56 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 7.35–7.29 (m, 1H), 7.29–7.23 (m, 2H), 7.15 (dd, J = 7.8, 1.4 Hz, 1H), 7.06 (dd, J = 8.4, 1.0 Hz, 1H), 7.01–6.96 (m, 1H), 4.69 (s, 1H), 4.64 13 (s, 1H), 2.74–2.69 (m, 2H), 2.33–2.28 (m, 2H), 1.69 (s, 3H); C NMR (75 MHz, CDCl3) δ 168.9, 162.2, 148.3, 144.8, 136.5, 134.0, 130.4, 130.2, 127.2, 126.6, 122.2, 119.5, 117.9, 111.7, 110.7, 38.2, 28.8, 22.2; IR (thin film) 3227, 3074, 2932, 1683, 1651, 1616, 1583, + 1247; HRMS (ESI) calcd for [C18H18O3 + Na] 305.1146, found 305.1162.

3.103b: Prepared under reflux conditions, from 4-methyl salicylic acid (0.365 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.049 g, 0.4 mmol). The reaction afforded 3.103b as a colorless oil (0.320 g, 1.08 mmol, 54%) after flash column chromatography. Rf = 1 0.45 (1:1 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.53 (s, 1H), 8.00 (d, J = 7.5 Hz, 1H), 7.35–7.32 (m, 1H), 7.31–7.25 (m, 2H), 7.18 (dd, J = 8.0, 1.5 Hz, 1H), 6.89 (s, 1H), 6.82 (dd, J = 8.0, 1.0 Hz, 1H), 4.72 (app s, 1H), 4.67 app s, 1H) 2.75–2.72 (m, 2H), 2.41 13 (s, 3H), 2.34–2.31 (m, 2H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3) δ 168.9, 162.2, 148.3, 148.0, 144.8, 134.1, 130.3, 129.9, 127.1, 126.5, 122.3, 120.8, 118.0, 110.7, 109.1, 38.2, 28.9, 22.3, 21.9; IR (thin film) 3431, 3075, 2934, 1684, 1625, 1249, 1208; HRMS + (ESI) calcd for [C19H20O3 + Na] 319.1305, found 319.1309.

Chapter 3 | 101 3.103c: Prepared under reflux conditions, from 4-fluoro salicylic acid (0.375 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.049 g, 0.4 mmol). The reaction afforded 3.103c as a colorless oil (0.529 g, 1.76 mmol, 88%) after flash column chromatography. Rf = 1 0.80 (1:1 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.54 (d, J = 1 Hz, 1H), 8.13 (dd, J = 8.5, 6.5 Hz, 1H), 7.35–7.27 (m, 3H), 7.16 (dd, J = 8.0, 1.5 Hz, 1H), 6.77 (dd, J = 10.0, 2.0 Hz, 1H), 6.72 (td, J = 8.3, 2.5 Hz, 1H), 4.72 (s, 1H), 4.66 (s, 1H), 2.74–2.71 (m, 2H), 13 1 2.34–2.30 (m, 2H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3) δ 168.2, 167.7 (d, JF-C = 3 3 255.3 Hz), 164.4 (d, JF-C = 14.0 Hz), 148.1, 144.7, 134.0, 132.3 (d, JF-C = 12.0 Hz), 2 2 130.4, 127.2, 126.7, 122.1, 110.7, 108.4, 107.8 (d, JF-C = 23.1 Hz), 104.7 (d, JF-C = 24.0 Hz), 38.2, 28.8, 22.3; IR (thin film) 3427, 3080, 2937, 1688, 1622, 1258, 1209; HRMS + (ESI) calcd for [C18H17FO3 + Na] 323.1054, found 323.1064.

3.103d: Prepared under reflux conditions, from 4-chloro salicylic acid (0.414 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.049 g, 0.4 mmol). The reaction afforded 3.103d as a colorless oil (0.544 g, 1.72 mmol, 86%) after flash column chromatography. Rf = 1 0.65 (1:1 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.68 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.36–7.33 (m, 1H), 7.32–7.27 (m, 2H), 7.17 (dd, J = 8.0, 1.5 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.5, 3 Hz, 1H), 4.74 (s, 1H), 4.67 (s, 1H), 2.75–2.72 (m, 2H), 13 2.34–2.31 (m, 2H), 1.73 (s, 3H); C NMR (125 MHz, CDCl3) δ 168.3, 162.7, 148.1, 144.6, 142.3, 133.9, 131.0, 130.4, 127.2, 126.7, 122.1, 120.2, 118.0, 110.7, 110.3, 38.1, 28.8, 22.3; IR (thin film) 3425, 3076, 2935, 1693, 1614, 1281, 1201; HRMS (ESI) calcd – for [C18H17ClO3 – H] 315.0793, found 315.0794.

Chapter 3 | 102

3.103e: Prepared under reflux conditions, from 4-bromo salicylic acid (0.521 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1.0 mmol). The reaction afforded 3.103e as a colorless oil (0.592 g, 1.64 mmol, 82%) after flash column chromatography. Rf = 1 0.54 (1:1 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.64 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.35–7.26 (m, 4H), 7.17–7.14 (m, 2H), 4.72 (s, 1H), 4.66 (s, 1H), 2.74–2.70 (m, 2H), 13 2.33–2.30 (m, 2H), 1.72 (s, 3H); C NMR (75 MHz, CDCl3) δ 168.4, 162.5, 148.0, 144.6, 133.9, 131.0, 130.9, 130.4, 127.2, 126.7, 123.1, 122.1, 121.1, 110.7, 110.7, 38.2, 28.8, 22.4 ; IR (thin film) 3424, 2935, 1690, 1607, 1280, 1201; HRMS (ESI) calcd for + [C18H17BrO3 + Na] 383.0253, found 383.0248.

3.103f: Prepared under reflux conditions, from trifluoromethyl salicylic acid (0.445 g, 2.16 mmol), phenol 3.117 (0.288 g, 1.78 mmol), N,N’-dicyclohexylcarbodiimine (0.668 g, 3.24 mmol) and 4-(dimethylamino)pyridine (0.048 g, 0.4 mmol). The reaction afforded 3.103f as an colorless amorphous solid (0.4752 g, 1.35 mmol, 76%) after flash 1 column chromatography. Rf = 0.57 (4:6 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.67 (s, 1H), 8.21–8.20 (m, 1H), 7.34 (dt, J = 11.4, 3.1 Hz, 2H), 7.30 (m, 2H), 7.25–7.21 (m, 1H), 7.16 (dd, J = 7.7, 1.5 Hz, 1H), 4.70 (s, 1H), 4.64 (s, 1H), 2.74–2.68 (m, 2H), 13 2.34–2.28 (m, 2H), 1.70 (s, 3H); C NMR (75 MHz, CDCl3) δ 168.1, 162.1, 148.0, 144.6, 2 1 137.6 (q, JF-C = 33.0 Hz), 133.9, 131.0, 130.5, 127.3, 126.9, 123.0 (q, JC-F = 273 Hz),

Chapter 3 | 103 3 3 122.0, 115.8 (q, JC-F = 3.5 Hz), 115.37 (q, JC-F = 3.9 Hz), 114.4, 110.8, 38.2, 28.7, 22.4; + IR (thin film) 3082, 2941, 1645, 1573, 1322; HRMS (ESI) calcd for [C19H17F3O3 + Na] 373.1022, found 373.1023.

3.103g: Prepared under reflux conditions, from 4-methoxy salicylic acid (0.404 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1.0 mmol). The reaction afforded 3.103g as a colorless oil (0.472 g, 1.52 mmol, 76%) after flash column chromatography. 1 Rf = 0.65 (1:1 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.79 (s, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.33 (dd, J = 7.5, 1.5 Hz, 1H), 7.32–7.28 (m, 1H), 7.26 (dd, J = 7.5, 1.5 Hz, 1H), 7.16 (dd, J = 8.0, 1.5 Hz, 1H), 6.56 (dd, J = 8.5, 2.5 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 4.72 (s, 1H), 4.67 (s, 1H), 3.87 (s, 1H), 2.75–2.71 (m, 2H), 2.34–2.30 (m, 2H), 1.72 (s, 13 3H); C NMR (75 MHz, CDCl3) δ 168.7, 166.2, 164.5, 148.3, 144.8, 134.1, 131.5, 130.3, 127.1, 126.4, 122.3, 110.6, 108.1, 104.6, 100.8, 55.5, 38.2, 28.9, 22.3; IR (thin film) 3431, + 3078, 2936, 1679, 1625, 1254, 1216; HRMS (ESI) calcd for [C19H20O4 + Na] 335.1254, found 335.1250.

3.103h: Prepared by stirring at room temperature for 48 hours, from 5-nitro salicylic acid (0.543 g, 3.0 mmol), phenol 3.117 (0.243 g, 1,5 mmol), N,N’-

Chapter 3 | 104 dicyclohexylcarbodiimine (0.620 g, 3.0 mmol) and 4-(dimethylamino)pyridine (0.100 g, 0.8 mmol). The reaction afforded 3.103h as a yellow amorphous solid (0.380 g, 1.16 1 mmol, 77%) after flash column chromatography. Rf = 0.50 (1:1 CH2Cl2:Hex); H NMR

(500 MHz, CDCl3) δ 11.20 (s, 1H), 9.05 (d, J = 3.0 Hz, 1H), 8.43 (dd, J = 9.5, 3.0 Hz, 1H), 7.36 (dd, J = 6.5, 2.5 Hz, 1H), 7.34–7.29 (m, 2H), 7.18 (d, J = 9.5 Hz, 1H), 7.17 (dd, J = 7.5, 2.0 Hz, 1H), 4.72 (s, 1H), 4.67 (s, 1H), 2.74–2.71 (m, 2H), 2.34–2.31 (m, 2H), 13 1.71 (s, 3H); C NMR (125 MHz, CDCl3) δ 167.8, 166.7, 147.8, 144.5, 140.2, 133.9, 131.2, 130.6, 127.4, 127.1, 126.8, 121.9, 119.0, 111.5, 110.9, 38.2, 28.7, 22.4; IR (thin – film) 3424, 2936, 1697, 1627, 1252, 1204; HRMS (ESI) calcd for [C18H17NO5 – H] , 326.1034 found 326.1027.

3.103i: Prepared under reflux conditions, from 5-chloro salicylic acid (0.414 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1.0 mmol). The reaction afforded 3.103i as a colorless oil (0.540 g, 1.62 mmol, 81%) after flash column chromatography. Rf = 1 0.80 (1:1 CH2Cl2:Hex); H NMR (500 MHz, CDCl3) δ 10.49 (s, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 9, 2.5 Hz, 1H), 7.34 (dd, J = 7.0, 2.0 Hz, 1H), 7.32–7.26 (m, 2H), 7.15 (dd, J = 7.5, 1.5 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 4.74 (s, 1H), 4.68 (s, 1H), 2.74–2.71 13 (m, 2H), 2.34–2.31 (m, 2H), 1.73 (s, 3H); C NMR (125 MHz, CDCl3) δ 167.9, 160.7, 148.0, 144.6, 136.4, 133.9, 130.4, 129.3, 127.2, 126.8, 124.3, 122.0, 119.5, 112.6, 110.8, 38.2, 28.8, 22.4; IR (thin film) 3425, 3076, 2935, 1696, 1615, 1284, 1196; HRMS (ESI) – calcd for [C18H17ClO3 – H] 315.0793, found 315.0784.

Chapter 3 | 105

3.103j: Prepared by stirring at room temperature for 72 hours, from 2-hydroxy-1- naphthoic acid (0.452 g, 2.4 mmol), phenol 3.117 (0.324 g, 2.0 mmol), N,N’- dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1.0 mmol). The reaction afforded 3.103j as an off-white amorphous solid (0.480 g, 1.44 1 mmol, 72%) after flash column chromatography. Rf = 0.60 (1:1 CH2Cl2:Hex); H NMR

(500 MHz, CDCl3) δ 12.25 (br s, 1H), 9.03 (d, J = 9.0 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.65 (td, J = 7.5, 1.5 Hz, 1H), 7.46 (dt, J = 7.5, 1.0 Hz, 1H), 7.42 (dd, J = 7.5, 2.0 Hz, 1H), 7.40–7.37 (m, 1H), 7.36–7.33 (m, 1H), 7.28 (dd, J = 7.5, 1.5 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 4.69 (s, 1H), 4.64 (s, 1H), 2.82–2.79 (m, 2H), 2.39–2.36 (m, 13 2H), 1.65 (s, 3H); C NMR (125 MHz, CDCl3) δ 171.4, 165.6, 148.2, 144.6, 137.8, 134.1, 131.7, 130.4, 129.3, 128.8, 128.7, 127.3, 126.7, 125.3, 123.9, 122.4, 119.3, 110.7, 103.8, 38.2, 28.8, 22.2; IR (thin film) 3423, 3072, 2934, 1660, 1620, 1243, 1203; HRMS + (ESI) calcd for [C22H20O3 + Na] 355.1305, found 355.1325.

3.103k: Prepared under reflux conditions, from salicylic acid (0.166 g, 1.2 mmol), phenol 3.118 (0.176 g, 1 mmol), N,N’-dicyclohexylcarbodiimine (0.371 g, 1.8 mmol) and 4-(dimethylamino)pyridine (0.024 g, 0.2 mmol). The reaction afforded 3.103k as a colorless oil (0.122 g, 0.41 mmol, 41%) after flash column chromatography. Rf = 0.44 1 (1:2 CH2Cl2:Hex); H NMR (300 MHz, CDCl3) δ 10.56 (s, 1H), 8.11 (dd, J = 8.0, 1.7 Hz,

Chapter 3 | 106 1H), 7.63–7.50 (m, 1H), 7.38–7.21 (m, 3H), 7.16 (dd, J = 7.5, 1.6 Hz, 1H), 7.10–7.04 (m, 1H), 7.03–6.94 (m, 1H), 4.71 (s, 1H), 4.68 (s, 1H), 2.72 (dd, J = 9.6, 6.7 Hz, 2H), 2.39– 2.26 (m, 2H), 2.00 (q, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,

CDCl3) δ 168.9, 162.2, 150.4, 148.3, 136.5, 134.2, 130.4, 130.2, 127.2, 126.6, 122.2, 119.5, 117.9, 111.7, 108.4, 36.6, 29.1, 28.7, 12.2; IR (thin film) 3215, 3069, 2933, 1698, + 1644, 1582, 1488, 1129; HRMS (ESI) calcd for [C19H20O3 + Na] 319.1305, found 319.1306.

3.103l: Prepared under reflux conditions, from trifluoromethyl salicylic acid (0.495 g, 2.4 mmol), phenol 3.118 (0.352 g, 2.0 mmol), N,N’-dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1.0 mmol). The reaction afforded 3.103l as a colorless amorphous solid (0.582 g, 1.6 mmol, 80%) after flash column 1 chromatography. Rf = 0.58 (1:2 CH2Cl2:Hex); H NMR (300 MHz, CDCl3) δ 10.68 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.40–7.20 (m, 5H), 7.17–7.12 (m, 1H), 4.73 (s, 1H), 4.68 (s, 1H), 2.72 (dd, J = 9.4, 6.7 Hz, 2H), 2.39–2.24 (m, 2H), 2.01 (q, J = 7.3 Hz, 2H), 0.99 13 (t, J = 7.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ 168.1, 162.1, 150.2, 148.0, 137.6 (q, 2 1 JF-C = 33.0 Hz), 134.0, 131.0, 130.5, 127.3, 126.9, 123.1 (q, JF-C = 273.2 Hz), 122.0, 3 3 115.8 (q, JF-C = 3.5 Hz), 115.30 (q, JF-C = 3.9 Hz), 114.4, 108.5, 36.6, 29.0, 28.7, 12.2; IR (thin film) 3194, 3078, 2964, 1698, 1650, 1508, 1325; HRMS (ESI) calcd for – [C19H17F3O3 – H] 363.1214, found 363.1218.

Chapter 3 | 107

3.103m: Prepared under reflux conditions, from salicylic acid (0.166 g, 1.2 mmol), 2-(2-methylallyl)phenol* (0.148 g, 1 mmol), N,N’-dicyclohexylcarbodiimine (0.371 g, 1.8 mmol) and 4-(dimethylamino)pyridine (0.024 g, 0.2 mmol). The reaction afforded 3.103m as a colorless oil (0.2035 g, 0.76 mmol, 76%) after flash column chromatography. 1 Rf = 0.65 (1:9 EtOAc:Hex); H NMR (300 MHz, CDCl3) δ 10.54 (s, 1H), 8.07 (dd, J = 8.0, 1.7 Hz, 1H), 7.55 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.39–7.22 (m, 3H), 7.19–7.12 (m, 1H), 7.05 (dd, J = 8.4, 0.9 Hz, 1H), 6.98 (ddd, J = 8.2, 7.3, 1.1 Hz, 1H), 4.77 (app s, 1H), 4.62 (s, 1H), 3.31 (d, J = 5.4 Hz, 2H), 1.67 (d, J = 5.4 Hz, 3H); 13C NMR (75 MHz,

CDCl3) δ 168.7, 162.1, 148.6, 143.2, 136.4, 131.8, 131.1, 130.2, 127.5, 126.5, 122.4, 119.4, 117.8, 112.5, 111.8, 38.8, 22.1; IR (thin film) 3234, 3076, 3293, 1694, 1650, 1615, + 1448, 1249; HRMS (ESI) calcd for [C17H16O3 + Na] 291.0992, found 291.0981.

3.103n: Prepared under reflux conditions, from 4-trifluoromethyl salicylic acid (0.495 g, 2.4 mmol), 2-((2-methylallyl)oxy)phenol † (0.328 g, 2.0 mmol), N,N’- dicyclohexylcarbodiimine (0.743 g, 3.6 mmol) and 4-(dimethylamino)pyridine (0.122 g, 1.0 mmol). The reaction afforded 3.103n as a colorless amorphous solid (0.1080 g, 0.30 1 mmol, 15%) after flash column chromatography. Rf = 0.46 (2:3 CH2Cl2:Hex); H NMR

* Prepared via Claisen rearrangement: Bartz, Q. R.; Miller, R. F.; Adams, R. J. Am. Chem. Soc. 1935, 57, 371. † Prepared from catechol and 3-chloro-2-methyl-1-propene: Deodhar, V. B.; Dalavoy, V. S.; Nayak, U. R. Org. Prep. Proc. Int. 1993, 25, 583.

Chapter 3 | 108

(500 MHz, CDCl3) δ 10.66 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H), 7.28 (td, J = 7.5, 1.5 Hz, 1H), 7.23–7.19 (m, 2H), 7.05–7.02 (m, 2H), 4.99 (s, 1H), 4.91 (s, 1H), 4.47 13 (s, 2H), 1.72 (s, 3H); C NMR (125 MHz, CDCl3) δ 167.6, 161.9, 149.9, 140.0, 139.0, 2 1 137.3 (q, JF-C = 32.0 Hz), 131.4, 127.6, 123.1 (q, JF-C = 271.4 Hz), 122.5, 121.0, 115.8 3 3 (q, JF-C = 3.0 Hz), 115.1 (q, JF-C = 4.0 Hz), 114.5, 113.8, 112.7, 72.2, 19.1; IR (thin film) – 3431, 2932, 1702, 1671, 1320, 1280, 1111; HRMS (ESI) calcd for [C18H15F3O4 – H] 351.0850, found 351.0849.

3.6.3 General procedure for oxyacylation reactions

A representative example: In a nitrogen-filled glove box, a 1 dram vial was charged with a magnetic stirring bar, salicylic ester substrate (0.1 mmol), a freshly prepared solution of [Ir(cod)OMe]2 (2.65 mg, 0.004 mmol, condition A) or Ir(cod)(acac) (3.20 mg, 0.008 mmol, condition B) in mesitylene (0.4 mL), and a solution of MOP ligand (5.6 mg, 0.012 mmol) in mesitylene (0.6 mL). The reaction mixture was sealed with a PTFE lined cap, removed from the glove box, and heated in an aluminum heating block at 150 or 170 °C for 48 h as indicated below. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by flash column chromatography (gradient,

EtOAc:Hex or Et2O:Hex) to afford the oxyacylation product. Products 3.104a, 3.104b, 3.104d, 3.104g, 3.104i, 3.104j, 3.104k, and 3.104m were prepared at 170 °C . Products 3.104c, 3.104f, 3.104h, 3.104l, and 3.104n were prepared at 150 °C .

3.104a: Prepared under condition A, from 3.103a (28.2 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (R)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104a as a colorless oil (22.0 mg, 0.078 mmol, 78%) after flash 1 column chromatography. Rf = 0.50 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ

Chapter 3 | 109 12.41 (s, 1H), 7.77 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H), 7.13– 7.04 (m, 2H), 6.97 (dd, J = 8.4, 1.0 Hz, 1H), 6.91–6.81 (m, 2H), 6.71 (d, J = 8.1 Hz, 1H), 3.40 (d, J = 14.9 Hz, 1H), 3.20 (d, J = 14.9 Hz, 1H), 2.89–2.72 (m, 2H), 2.13 (dt, J = 13.6, 13 6.7 Hz, 1H), 2.07–1.92 (m, 1H), 1.48 (s, 3H); C NMR (75 MHz, CDCl3) δ 204.5, 162.7, 153.0, 136.5, 131.3, 129.5, 127.4, 120.7, 120.2, 120.1, 118.7, 118.3, 117.3, 75.6, 46.7, 31.1, 25.0, 21.9; IR (thin film) 2916, 2848, 1632, 1581, 1487, 1350, 1244; HRMS (ESI) + calcd for [C18H18O3 + Na] 305.1146, found 305.1161.

3.104b: Prepared under condition A, from 3.103b (29.6 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104b as a colorless oil (16.9 mg, 0.057 mmol, 57%) after flash 1 column chromatography. Rf = 0.50 (1:9 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 12.47 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.12–7.07 (m, 2H), 6.86 (td, J = 8.0, 1.5 Hz, 1H), 6.78 (app s, 1H), 6.73 (dd, J = 8.0, 1.5 Hz, 1H), 6.67 (dd, J = 8.5, 1.5 Hz, 1H), 3.37 (d, J = 14.5 Hz, 1H), 3.17 (d, J = 14.5 Hz, 1H), 2.87–2.80 (m, 2H), 2.35 (s, 3H), 2.13–2.10 (m, 13 1H), 2.03–1.98 (m, 1H), 1.47 (s, 3H); C NMR (125 MHz, CDCl3) δ 203.8, 162.8, 153.1, 148.3, 131.2, 129.5, 127.4, 120.9, 120.2, 120.0, 118.4, 118.2, 117.4, 75.7, 46.6, 31.2, 25.0, 22.0, 21.9; IR (thin film) 3040, 2978, 2933, 1635, 1581, 1488, 1353, 1247; HRMS (ESI) + calcd for [C19H20O3 + Na] 319.1305, found 319.1295.

3.104c: Prepared under condition B, from 3.103c (30.0 mg, 0.1 mmol), Ir(cod)(acac) (3.20 mg, 0.008 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 150 °C . The reaction

Chapter 3 | 110 afforded 3.104c as a colorless oil (18.9 mg, 0.063 mmol, 63%) after flash column 1 chromatography. Rf = 0.45 (1:9 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 12.77 (d, J = 1.5 Hz, 1H), 7.79 (dd, J = 8.5, 6.5 Hz, 1H), 7.12–7.08 (m, 2H), 6.87 (td, J = 8.0, 1.0 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.65 (dd, J = 10.0, 2.5 Hz, 1H), 6.57 (app td, J = 9.0, 2.5 Hz, 1H), 3.36 (d, J = 14.5 Hz, 1H), 3.13 (d, J = 14.5 Hz, 1H), 2.88–2.77 (m, 2H), 2.10– 13 2.08 (m, 1H), 2.03–1.98 (m, 1H), 1.47 (s, 3H); C NMR (125 MHz, CDCl3) δ 203.4, 1 3 3 167.4 (d, JC-F = 256.3 Hz), 165.3 (d, JC-F = 14.1 Hz), 152.9, 134.0 (d, JC-F = 14.1 Hz), 2 2 129.5, 127.5, 120.7, 120.3, 117.5, 117.3, 106.9 (d, JC-F = 22.1 Hz), 104.8 (d, JC-F = 24.0 Hz), 75.6, 47.2, 31.4, 24.9, 21.9; IR (thin film) 2978, 2933, 1637, 1582, 1488, 1356, 1251; + HRMS (ESI) calcd for [C18H17FO3 + Na] 323.1054, found 323.1051.

3.104d: Prepared under condition A, from 3.103d (31.7 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104d as a colorless oil (20.0 mg, 0.063 mmol, 63%) after flash 1 column chromatography. Rf = 0.49 (1:9 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 12.56 (d, J = 1.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.12–7.08 (m, 2H), 6.99 (d, J = 2.0 Hz, 1H), 6.87 (t, J = 2.5 Hz, 1H), 6.84 (dd, J = 9.5, 1.5 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.37 (d, J = 14.5 Hz, 1H), 3.13 (d, J = 14.5 Hz, 1H), 2.88–2.76 (m, 2H), 2.13–2.07 (m, 1H), 2.03– 13 1.98 (m, 1H), 1.47 (s, 3H); C NMR (125 MHz, CDCl3) δ 204.0, 163.4, 152.9, 142.3, 132.6, 129.5, 127.5, 120.7, 120.3, 119.3, 118.9, 118.3, 117.3, 75.6, 47.2, 31.3, 24.9, 21.9; IR (thin film) 3053, 2980, 2933, 1633, 1582, 1488, 1349, 1241; HRMS (ESI) calcd for + [C18H17ClO3 + Na] 339.0758, found 339.0748.

Chapter 3 | 111

3.104e: Prepared under condition B, from 3.103e (36.1 mg, 0.1 mmol), Ir(cod)(acac) (3.20 mg, 0.008 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104e as a colorless oil (12.6 mg, 0.035 mmol, 35%) after flash column 1 chromatography. Rf = 0.50 (1:9 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 12.52 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.12–7.08 (m, 2H), 6.99 (dd, J = 8.5, 2.0 Hz, 1H), 6.87 (app td, J = 7.5, 1.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.35 (d, J = 14.5 Hz, 1H), 3.13 (d, J = 14.5 Hz, 1H), 2.82–2.79 (m, 2H), 2.09–2.07 (m, 1H), 2.02–2.00 (m, 13 1H), 1.46 (s, 3H); C NMR (125 MHz, CDCl3) δ 204.2, 163.2, 152.9, 132.5, 131.0, 129.5, 127.5, 122.2, 121.5, 120.7, 120.3, 119.2, 117.3, 75.6, 47.2, 31.4, 24.9, 21.9; IR (thin film) 3417, 2978, 2933, 1631, 1582, 1487, 1349, 1240; HRMS (ESI) calcd for + [C18H17BrO3 + Na] 383.0253, found 383.0261.

3.104f: Prepared under condition A, from 3.103f (35.0 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 150 °C. The reaction afforded 3.104f as a colorless amorphous solid (28.7 mg, 0.082 mmol 82%) 1 after flash column chromatography. Rf = 0.40 (1:9 EtOAc:Hex); H NMR (500 MHz,

CDCl3) δ 12.42 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 1.1 Hz, 1H), 7.11–7.07 (m, 3H), 6.87 (td, J = 7.5, 1.1 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 3.43 (d, J = 14.6 Hz, 1H), 3.20 (d, J = 14.6 Hz, 1H), 2.84–2.80 (m, 2H), 2.10 (ddd, J = 13.8, 7.6, 6.2 Hz, 1H), 2.01 13 (dt, J = 13.5, 6.6 Hz, 1H), 1.47 (s, 3H); C NMR (75 MHz, CDCl3) δ 204.6, 162.5, 152.8,

Chapter 3 | 112 2 * 1 * 137.3 (app q, JC-F = 32.9 Hz), 132.3, 129.6, 127.6, 123.0 (app q, JC-F = 271 Hz), 122.2, 3 3 120.6, 120.4, 117.3, 115.8 (q, JC-F = 3.9 Hz), 114.9 (q, JC-F = 3.6 Hz), 75.6, 47.4, 31.4, 24.9, 21.9; IR (thin film) 3052, 2981, 2927, 1656, 1573, 1507, 1457, 1216; HRMS (ESI) + calcd for [C19H17F3O3 + Na] 373.1022, found 373.1028.

3.104g: Prepared under condition B, from 3.103g (31.2 mg, 0.1 mmol), Ir(cod)(acac) (3.20 mg, 0.008 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104g as a colorless oil (16.8 mg, 0.054 mmol, 54%) after flash column 1 chromatography. Rf = 0.32 (1:9 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 12.97 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.11–7.07 (m, 2H), 6.85 (td, J = 7.0, 1.0 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.42–6.38 (m, 2H), 3.84 (s, 3H), 3.31 (d, J = 14.0 Hz, 1H), 3.09 (d, J = 14.0 Hz, 1H), 2.81 (app t, J = 7.0 Hz, 2H), 2.14–2.08 (m, 1H), 2.02–1.96 (m, 1H), 1.46 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 202.5, 166.2, 165.8, 153.1, 133.2, 129.5, 127.4, 120.9, 120.2, 117.4, 114.6, 107.5, 100.7, 75.7, 55.6, 46.6, 31.3, 25.0, 22.0; IR (thin film) 3427,

2975, 2935, 1625, 1582, 1488, 1363, 1252, 1209; HRMS (ESI) calcd for [C19H20O4 + Na]+ 335.1254, found 335.1252.

3.104h: Prepared under condition B, from 3.103h (32.7 mg, 0.1 mmol), Ir(cod)(acac) (3.20 mg, 0.008 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 150 °C . The reaction

* 1 2 13 Signals attributable to the outer peaks for the JC-F and JC-F quartets in the C NMR spectrum of 3.104f could not be extracted from the noise. We therefore list these as apparent quartets.

Chapter 3 | 113 afforded 3.104h as a yellow amorphous solid (20.3 mg, 0.062 mmol, 62%) after flash 1 column chromatography. Rf = 0.35 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 13.03 (s, 1H), 8.86 (d, J = 1.5 Hz, 1H), 8.33 (dd, J = 9.0, 2.0 Hz, 1H), 7.08–7.04 (m, 3H), 6.85 (td, J = 7.0, 1.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 3.41 (d, J = 14.5 Hz, 1H), 3.32 (d, J = 14.5 Hz, 1H), 2.90–2.78 (m, 2H), 2.08–1.98 (m, 2H), 1.48 (s, 3H); 13C NMR (125

MHz, CDCl3) δ 204.6, 167.4, 152.6, 139.4, 131.1, 129.5, 128.5, 127.7, 120.6, 120.3, 119.3, 119.2, 117.3, 75.4, 48.2, 31.2, 24.7, 21.9; IR (thin film) 2926, 1639, 1582, 1525, - 1487, 1342, 1294; HRMS (ESI) calcd for [C18H17NO5 – H] 326.1034, found 326.1034.

3.104i: Prepared under condition A, from 3.103i (31.7 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104i as a colorless oil (16.8 mg, 0.053 mmol, 53%) after flash 1 column chromatography. Rf = 0.49 (1:9 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 12.30 (s, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.40 (dd, J = 8.5, 2.5 Hz, 1H), 7.13–7.09 (m, 2H), 6.93 (d, J = 9.5 Hz, 1H), 6.87 (td, J = 7.5, 1.0 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 3.36 (d, J = 14.5 Hz, 1H), 3.14 (d, J = 14.5 Hz, 1H), 2.88–2.76 (m, 2H), 2.12–2.06 (m, 1H), 2.03– 13 1.98 (m, 1H), 1.47 (s, 3H); C NMR (125 MHz, CDCl3) δ 204.0, 161.2, 152.8, 136.4, 130.8, 129.5, 127.7, 123.4, 120.8, 120.6, 120.4, 119.9, 117.4, 75.5, 47.4, 31.4, 24.9, 21.9; IR (thin film) 2979, 2934, 1637, 1582, 1487, 1348, 1241; HRMS (ESI) calcd for + [C18H17ClO3 + Na] 339.0758, found 339.0762.

Chapter 3 | 114 3.104j: Prepared under condition A, from 3.103j (33.2 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (S)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104j as an off-white amorphous solid (14.9 mg, 0.045 mmol, 1 45%) after flash column chromatography. Rf = 0.32 (2:8 EtOAc:Hex); H NMR (500

MHz, CDCl3) δ 9.43 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.73 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 (td, J = 7.0, 1.5 Hz, 1H), 7.41 (td, J = 7.0, 1.0 Hz, 1H), 7.11–7.06 (m ,3H), 6.84 (td, J = 7.5, 1.0 Hz, 1H), 6.77 (dd, J = 8.0, 1.0 Hz, 1H), 5.44 (br s, 1H), 3.02 (d, J = 16.0 Hz, 1H), 2.87–2.76 (m, 3H), 2.21–2.15 (m, 1H), 2.11–2.04 (m, 1H), 1.55 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 194.0, 161.8, 153.6, 137.5, 131.2, 130.0, 129.5, 128.8, 128.3, 127.6, 127.4, 125.5, 124.6, 120.7, 119.3, 115.3, 111.6, 81.5, 48.4, 39.1, 24.4, 23.3; IR (thin film) 3147, 2975, 1649, 1596, 1458, 1437, 1376, 1240; HRMS (ESI) calcd for + [C22H20O3 + Na] 355.1305, found 355.1304.

3.104k: Prepared under condition A, from 3.103k (29.6 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (R)-MOP (5.62 mg, 0.012 mmol) at 170 °C The reaction afforded 3.103k as a colorless oil (14.8 mg, 0.050 mmol, 50%) after flash 1 column chromatography. Rf = 0.57 (1:4 Et2O:Hex); H NMR (300 MHz, CDCl3) δ 12.42 (s, 1H), 7.79 (dd, J = 8.1, 1.5 Hz, 1H), 7.48–7.45 (m, 1H), 7.10–7.06 (m, 2H), 6.96 (dd, J = 8.4, 0.9 Hz, 1H), 6.90–6.83 (m, 2H), 6.72 (d, J = 8.1 Hz, 1H), 3.34 (d, J = 15.2 Hz, 1H), 3.25 (d, J = 15.2 Hz, 1H), 2.81–2.77 (m, 2H), 2.10–2.05 (m, 2H), 1.86 (q, J = 7.4 Hz, 2H), 13 1.02–0.99 (m, 3H); C NMR (125 MHz, CDCl3) 204.8, 162.7, 153.1, 136.5, 131.3, 129.5, 127.4, 121.0, 120.4, 120.1, 118.7, 118.3, 117.4, 78.0, 43.7, 29.6, 28.5, 21.7, 7.8.; IR (thin + film) 3053, 2930, 1629, 1574, 1487, 1456, 1305. HRMS (ESI) calcd for [C19H20O3 + Na] 319.1305, found 319.1308.

Chapter 3 | 115

3.104l: Prepared under condition A, from 3.103l (38.0 mg, 0.104 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (R)-MOP (5.62 mg, 0.012 mmol) at 150 °C . The reaction afforded 3.104l as a colorless oil (28.0 mg, 0.077 mmol 74%) after flash 1 column chromatography. Rf = 0.51 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 12.43 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 1.2 Hz, 1H), 7.10–7.06 (m, 3H), 6.85 (td, J = 7.5, 1.1 Hz, 1H), 6.70–6.67 (m, 1H), 3.33 (d, J = 14.8 Hz, 1H), 3.28 (d, J = 14.8 Hz, 1H), 2.81–2.77 (m, 2H), 2.08–2.06 (m, 2H), 1.86–1.83 (m, 2H), 1.01 (t, J = 7.5 Hz, 13 2 3H); C NMR (125 MHz, CDCl3) δ 204.9, 162.5, 152.9, 137.2 (q, JC-F = 33.0 Hz), 1 3 132.3, 129.5, 127.5, 123.0 (q, JC-F = 271.3 Hz), 122.2, 120.8, 120.3, 117.3, 115.8 (q, JC- 3 F = 4.0 Hz), 114.9 (q, JC-F = 3.0 Hz), 78.1, 44.4, 29.5, 28.5, 21.6, 7.8; IR (thin film) 2970, – 1930, 1649, 1624, 1582, 1488, 1329, 1236; HRMS (ESI) calcd for [C20H19F3O3 – H] 363.1214, found 363.1216.

3.104m: Prepared under condition A, from 3.103m (26.8 mg, 0.1 mmol),

[Ir(cod)OMe]2 (2.65 mg, 0.004 mmol) and (R)-MOP (5.62 mg, 0.012 mmol) at 170 °C . The reaction afforded 3.104m as a colorless oil (11.0 mg, 0.041 mmol 41%) after flash 1 column chromatography. Rf = 0.37 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 12.25 (s, 1H), 7.74 (dd, J = 8.3, 1.5 Hz, 1H), 7.49–7.45 (m, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.10 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.89–6.83 (m, 2H), 6.70 (d, J = 7.8 Hz, 1H), 3.53 (d, J = 16.1 Hz, 1H), 3.39 (d, J = 16.1 Hz, 1H), 3.34 (d, J = 16.1 Hz, 1H), 3.17 13 (d, J = 15.6 Hz, 1H), 1.64 (s, 3H). C NMR (125 MHz, CDCl3) δ 203.8, 162.6, 158.0, 136.6, 130.6, 128.1, 126.7, 125.2, 120.5, 120.0, 118.9, 118.5, 109.6, 86.9, 48.0, 41.6, 26.6;

Chapter 3 | 116 + IR (thin film) 3054, 1642, 1598, 1447, 1242; HRMS (ESI) calcd for [C17H16O3 + Na] 291.0992, found 291.0989.

3.104n: Prepared under condition B, from 3.103n (120.0 mg, 0.34 mmol), Ir(cod)(acac) (9.60 mg, 0.024 mmol) and (S)-MOP (16.90 mg, 0.036 mmol) at 150 °C . The reaction afforded 3.104n as a colorless amorphous solid (39.5 mg, 0.112 mmol, 33%) 1 after flash column chromatography. Rf = 0.55 (1:9 EtOAc:Hex); H NMR (500 MHz,

CDCl3) δ 12.27 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 1.2 Hz, 1H), 7.04 (dd, J = 8.5, 1.0 Hz, 1H), 6.94–6.91 (m, 1H), 6.90–6.86 (m, 2H), 6.80–6.77 (m, 1H), 4.34 (d, J = 12.0 Hz, 1H), 3.99 (d, J = 11.0 Hz, 1H), 3.46 (d, J = 16.0 Hz, 1H), 3.27 (d, J = 15.5 Hz, 13 1H), 1.52 (s, 3H); C NMR (125 MHz, CDCl3) δ 203.7, 162.4, 142.1, 141.7, 137.5 (q, 2 1 JC-F = 33.0 Hz), 131.5, 122.9 (q, JC-F = 272.0 Hz), 122.3, 121.8, 121.5, 117.7, 117.2, 3 3 116.0 (q, JC-F = 4.0 Hz), 115.1 (q, JC-F = 4.0 Hz), 73.8, 70.2, 43.1, 21.8; IR (thin film)

3423, 2982, 2928, 1653, 1594, 1494, 1331, 1263; HRMS (ESI) calcd for [C18H15F3O4 + H]– 351.0850, found 351.0837.

3.6.4 Derivatizations of 3.104a

Chapter 3 | 117 3.104o:* To a solution of 3.104a (0.036 g, 0.128 mmol), pyridine (21 μL, 0.26 mmol), and 4-(dimethylamino)pyridine (0.0024 g, 0.02 mmol) in freshly distilled CH2Cl2 was added acetic anhydride (21 μL, 0.20 mmol). The reaction was stirred at room temperature until TLC indicated the complete consumption of starting material. The reaction mixture was diluted with EtOAc (20 mL), washed with 1M HCl (10 mL), H2O

(10 mL) and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude mixture was purified by flash column chromatography (5:95 EtOAc:Hex) to 1 give 3.104o as a colorless oil (0.0360 g, 87%). Rf = 0.32 (1:9 EtOAc:Hex); H NMR (500

MHz, CDCl3) δ 7.76 (dd, J = 9.8, 1.5 Hz, 1H), 7.52 (td, J = 7.3, 1.0 Hz, 1H), 7.29 (td, J = 7.8, 1.0 Hz, 1H), 7.11 (dd, J = 7.8, 1.0 Hz, 1H), 7.09–7.06 (m, 2H), 6.84 (td, J = 7.3, 1.0 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 3.28 (d, J = 15.6 Hz, 1H), 3.18 (d, J = 16.1 Hz, 1H), 2.81–2.75 (m, 2H), 2.28 (s, 3H), 2.18–2.13 (m, 1H), 2.01–1.97 (m, 1H), 1.47 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 198.2, 169.4, 153.1, 148.6, 133.1, 131.7, 130.0, 129.5, 127.3, 125.9, 123.8, 120.9, 120.1, 117.3, 75.6, 49.4, 30.7, 24.9, 22.0, 21.0; IR (thin film) 3072, 2932, 1765, 1689, 1581, 1487, 1451, 1368, 1246, 1221, 1190; HRMS (ESI) calcd for + [C20H20O4 + Na] 347.1254, found 347.1259. 3.104p: To a 1 dram vial with PTFE lined cap, 3.104a (0.0282 g, 0.1 mmol), potassium carbonate (0.041 g, 0.3 mmol) and acetone (0.5 mL, technical grade) were added. Iodomethane (25 μL, 0.4 mmol) was added via a microsyringe. The reaction was stirred at room temperature until TLC indicated the complete consumption of starting material. The solvent was evaporated under vacuum and 5 mL water was added. The mixture was stirred for 1 h and extracted with EtOAc (3  10 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 3.104p as a colorless oil (0.0298 g, >95%) after flash column chromatography. Rf = 0.28 (1:9 1 Et2O:Hex); H NMR (500 MHz, CDCl3) δ 7.55 (dd, J = 8.0, 2.0 Hz, 1H), 7.43 (td, J = 7.5, 1.5 Hz, 1H), 7.06–7.03 (m, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.82 (td, J = 7.0, 1.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 3.72 (s, 3H), 3.56 (d, J = 15.5 Hz, 1H),

* Procedure was adapted from: Nicolaou, K. C.; Simmons, N.; Chen, J. S.; Haste, N. M.; Nizet, V. Tetrahedron Lett. 2011, 52, 2041.

Chapter 3 | 118 3.20 (d, J = 15.5 Hz, 1H), 2.78–2.75 (m, 2H), 2.13–2.09 (m, 1H), 2.00–1.94 (m, 1H), 13 1.47 (s, 3H); C NMR (125 MHz, CDCl3) δ 201.4, 157.9, 153.3, 133.0, 129.9, 129.8, 129.3, 127.2, 121.1, 120.6, 119.8, 117.2, 111.4, 75.8, 55.2, 51.0, 31.0, 25.4, 22.1; IR (thin film) 3432 (br), 3037, 2972, 2934, 1675, 1597, 1581, 1487, 1454, 1350, 1246; HRMS + (ESI) calcd for [C19H20O3 + Na] 319.1305, found 319.1308. 3.104q:* To a solution of 3.104a (0.0565 g, 0.2 mmol) and pyridine (32 μL, 0.4 mmol) in freshly distilled CH2Cl2 (2.0 mL) was added trifluoromethanesulfonic anhydride (40 μL, 0.24 mmol) via a microsyringe at 0 °C . The mixture was warmed to room temperature and stirred for 24 h. The mixture was then diluted with CH2Cl2 (30 mL) and washed with 1M HCl, sat. NaHCO3 and brine. After drying over Na2SO4 and concentration in vacuo, the crude product was purified by flash column chromatography

(1:99 EtOAc:Hex) to give compound 3.104q as a light brown oil (0.0730 g, 88%). Rf = 1 0.35 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.58 (td, J = 7.8, 1.5 Hz, 1H), 7.43 (td, J = 8.0, 2.0 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.07–7.03 (m, 2H), 6.84 (td, J = 7.5, 1.0 Hz, 1H), 6.56 (dd, J = 7.5, 1.0 Hz, 1H), 3.39 (d, J = 15.5 Hz, 1H), 3.18 (d, J = 15.0 Hz, 1H), 2.82–2.77 (m, 2H), 2.16–2.12 (m, 1H), 2.03– 13 1.98 (m, 1H), 1.49 (s, 3H); C NMR (125 MHz, CDCl3) δ 197.6, 152.8, 146.3, 133.2, 1 130.6, 129.5, 128.4, 127.3, 122.6, 120.8, 120.2, 118.5 (q, JC-F = 318 Hz), 117.1, 75.6, 50.0, 31.9, 24.7, 21.9 (one carbon signal is not resolved in the aromatic region); IR (thin film) 3425, 2979, 2934, 1697, 1582, 1487, 1425, 1248, 1213; HRMS (ESI) calcd for + [C19H17F3O5S + Na] 437.0641, found 437.0649. 3.104r:† To a 1 dram vial with PTFE lined cap, 3.104q (0.0414 g, 0.1 mmol), tetrakis(triphenylphosphine)palladium (0.0058 g, 0.005 mmol), potassium phosphate (0.0255 g, 0.12 mmol), phenylboronic acid (0.0146 g, 0.12 mmol) and degassed 1,4- dioxane (0.5 mL) were added under N2 atmosphere. The reaction was maintained at 110 °C for 14 h. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and filtrated to remove any insoluble materials. After concentrated in vacuo, the

* Gooen, L. J.; Linder, C.; Rodriguez, N.; Lange, P. P. Chem. Eur. J. 2009, 15, 9336. † Procedure was modified from: Nawaz, M.; Adeel, M.; Ibad, M. F.; Langer, P. Synlett 2009, 13, 2154.

Chapter 3 | 119 crude mixture was purified by flash column chromatography (1:99 EtOAc:Hex) to give compound 3.104r as a white amorphous solid (0.0276 g, 0.081 mmol, 81%). Rf = 0.52 1 (1:9 EtOAc:Hex); H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 7.5, 1.0 Hz, 1H), 7.45–7.42 (m, 1H), 7.35–7.33 (m, 3H), 7.27 (d, J = 7.5 Hz, 1H), 7.08– 7.06 (m, 2H), 6.98–6.95 (m, 2H), 6.81 (t, J = 7.0 Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 2.64 (d, J = 14.5 Hz, 1H), 2.62–2.57 (m, 1H), 2.43–2.36 (m, 1H), 2.37 (d, J = 14.5 Hz, 1H), 13 1.83–1.74 (m, 2H), 1.30 (s, 3H); C NMR (125 MHz, CDCl3) δ 206.0, 152.9, 141.9, 140.4, 140.0, 130.3, 129.9, 129.2, 128.9, 128.5, 127.8, 127.7, 127.4, 127.1, 120.6, 120.0, 117.1, 75.3, 50.2, 31.4, 25.3, 21.7; IR (thin film) 3059, 2932, 1679, 1581, 1487, 1454, + 1376, 1306, 1243; HRMS (ESI) calcd for [C24H22O2 + Na] 365.1512, found 365.1530. 3.104s:* To a 1 dram vial with PTFE lined cap, 3.104q (0.1242 g, 0.3 mmol), palladium acetate (0.0015 g, 0.006 mmol), triethylamine (125.5μL, 0.9 mmol), triphenylphosphine (0.003 g, 0.012 mmol) and freshly distilled DMF (0.6 mL) were added. Formic acid (88% aqueous solution, 26.0 μL, 0.6 mmol) was added. The reaction was stirred at 60 °C for 4 h under nitrogen. After cooling to room temperature, the mixture was diluted with Et2O (20 mL) and washed with 2M LiCl (20 mL). The aqueous phase was extracted with Et2O (2  10 mL) and the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (3:97 EtOAc:Hex) to give compound 3.104s as a 1 colorless oil (0.0690 g, 0.259 mmol, 86%). Rf = 0.56 (1:9 EtOAc:Hex); H NMR (500

MHz, CDCl3) δ 7.97 (dd, J = 8.5, 1.0 Hz, 2H), 7.57 (tt, J = 7.0, 1.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.12–7.08 (m, 2H), 6.88 (td, J = 7.0, 1.0 Hz, 1H), 6.75 (dd, J = 8.5, 1.0 Hz, 1H), 3.41 (d, J = 15.5 Hz, 1H), 3.26 (d, J = 16.0 Hz, 1H), 2.82–2.79 (m, 2H), 2.22–2.16 13 (m, 1H), 2.07–2.02 (m, 1H), 1.51 (s, 3H); C NMR (125 MHz, CDCl3) δ 198.2, 153.1, 137.7, 133.0, 129.5, 128.4, 128.36, 127.3, 121.0, 120.0, 117.3, 75.7, 46.7, 30.8, 25.0, 22.0; IR (thin film) 3060, 2931, 1686, 1582, 1487, 1449, 1350, 1306, 1249; HRMS (ESI) calcd + for [C18H18O2 + Na] 289.1199 found 289.1191.

* Procedure was modified from: Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1986, 27, 55414.

Chapter 4 | 120 Chapter 4 Metal-Free, Lewis Acid-Promoted Intramolecular Aminocyanation of Alkenes by N–CN Bond Cleavage of Cyanamides

4.1 Introduction: transition-metal-catalyzed cyanofunctionalization reactions

Transition-metal-catalyzed cyanofunctionalization reaction involves the cleavage of an element–cyano σ bond (FG–CN, Scheme 4-1) and subsequent addition across an unsaturated carbon–carbon bond to construct functionalized nitriles in an atom- economical fashion. As a conceptual extension of the well-developed carbocyanation reaction (Chapter 2), the cyanofunctionalization reaction simultaneously installs a cyano and an additional functional group, both of which can serve as convenient handles for further transformations. Cyano groups are useful synthetic precursors to various carbonyl-containing and heterocyclic moieties. Moreover, vicinal boryl-, silyl-, and stannyl-groups introduced by the activation of the corresponding FG–CN σ bond (FG = B, Si, Sn, respectively) can further engage in cross-coupling reactions to establish new carbon–carbon and carbon–heteroatom bonds, thereby allowing a rapid construction of molecular complexity.

Scheme 4-1 Metal-catalyzed cyanofunctionalization reaction

Chapter 4 | 121 Similar to carbocyanation, cyanofunctionalization reaction generally proceeds through oxidative addition of the FG–CN bond to a low-valent transition-metal complex to form the adduct 4.1 (Scheme 4-2). Coordination of C–C π bond, subsequent migratory insertion into the FG–metal bond through complex 4.2, followed by C–CN bond-forming reductive elimination releases the nitrile product (4.4) and regenerates the active catalyst.

Scheme 4-2 Generic catalytic cycle for cyanofunctionalization of alkynes and alkenes

Oxidative addition of a heteroatom–cyano σ bond is arguably more facile than that of a typical C–CN bond of a nitrile (e.g., acetonitrile), as indicated by the bond dissociation energies (BDE) shown in Table 4-1. In addition, the extended length of Si– CN, Ge–CN, and Sn–CN bonds presumably renders the bond cleavage more readily than the nitrile counterparts. Furthermore, it is well established that C–CN bond activation is promoted by added Lewis acids, which are often not required in many cyanofunctionalization reactions.

Chapter 4 | 122 Table 4-1 Selected element–cyano σ bonds dissociation energies Bond Bond Dissociation Energy (kcal/mol)[a]

H3C–CN 124 Cl–CN 101 Br–CN 87 I–CN 76

CH3S–CN 97

H2N–CN 119 [a] Extracted from: Luo, Y. -R.; Comprehensive Handbook of Chemical Bond Energies; CRC Press: BocaRaton, FL, 2007 and references cited therein.

Nevertheless, certain heteroatom–cyano bonds, such as the O–CN bonds of cyanates (RO–CN) can be challenging to activate due to their double bond character. The O–CN bond length of 2-chloro-5-cyanato-1,3-dimethylbenzene is 1.27 Å, 113 which lies in between a typical O–C single bond (ethers, 1.42–1.44 Å) and an O=C double bond (aldehydes and ketones, 1.19–1.22 Å).114 Nakazawa and co-workers demonstrated the cleavage of the O–CN bond of isopropyl cyanate using a molybdenum methyl complex (4.5) in conjunction with triethylsilane.115 Density functional theory (DFT) calculations suggested that the key step involved the migration of silyl group from the Mo center to the nitrogen of cyanate, via η2-complex 4.8, generating an N-silyl η2-imidato complex 4.9. Subsequent rearrangement afforded 4.10 and realized a formal oxidative addition of the

O–CN bond. Triethylsilyl isocyanide (Et3Si–NC) was released and isomerized to the silyl nitrile 4.6. O–CN cleavage by an iron-silyl complex was also described shortly after.116

Chapter 4 | 123

Scheme 4-3 O–CN bond cleavage of isopropyl cyanate by a molybdenum complex

The following chapter briefly reviews catalytic cyanofunctionalization reactions involving the direct oxidative addition of a FG–CN σ bond to a transition metal center. Palladium-catalyzed silylcyanation 117 and dicyanation 118 reactions, and a Lewis acid- catalyzed formal bromocyanation reaction, 119 which operated under alternative mechanisms will not be discussed.

4.2 A brief survey of catalytic cyanofunctionalization reactions

In 2003, Murakami and Suginome reported the first intramolecular borylcyanation reaction of alkynes using homopropargylic cyanoboryl ethers 4.11 (Scheme 4-4). 120

Several palladium(0) complexes and Ni(cod)2 effectively catalyzed the B–CN bond cleavage and subsequent alkyne addition without exogenous ligands, generating the cyclic β-boryl nitriles 4.12 in a regio- and stereoselective fashion. The substrates were prepared by a direct condensation of a homopropargylic tertiary alcohol with diaminocyanoborane (4.11a) or by an alternative, two-step route (4.11c). Due to the sensitivity of B–N bond towards hydrolysis, the nitrile products were isolated

Chapter 4 | 124 by distillation instead of by silica gel chromatogarphy. Substrates derived from tertiary and secondary homopropargylic alcohols smoothly cyclized onto terminal alkynes to afford the corresponding β-boryl nitriles in good to excellent yields (4.12a–c). Internal alkynes substituted with methyl, ethyl, phenyl, and alkenyl groups also proceeded to the corresponding tetrasubstituted products with consistently high yields and selectivity, favoring the syn addition products (4.12d–h).

Scheme 4-4 Palladium- and nickel-catalyzed intramolecular borylcyanation of alkynes

Chapter 4 | 125 The installed boryl groups were highly versatile synthetic handles. For example, treating product 4.12d with pinacol and acetic anhydride gave stable pinacolborane derivative 4.13a in 89% yield. Rhodium-catalyzed protodeboration and 1,4-addition, as well as palladium-catalyzed Suzuki–Miyaura coupling delivered densely substituted nitriles in excellent yields (4.13b, 4.13d, and 4.13c, respectively). Shortly after, an intermolecular variant of alkyne borylcyanation reaction was developed under palladium catalysis (Scheme 4-5). 121 The acyclic dialkylamino cyanoboranes 4.14a and 4.14b failed to react with 4-octyne in a intermolecular context. In contrast, a number of 1,2-diamine-derived cyclic cyanoboranes (4.14c–f) proved effective yielding the corresponding tetrasubstituted β-boryl nitriles in an exclusive syn addition fashion. The reactivity of cyanoboranes seemed to correlate with the rigidity of diamine backbone, with the highest yield obtained using a phenylenediamine-derived cyanoborane 4.14f (97%). Borylcyanation of unsymmetrical alkynes bearing aryl and alkyl terminal substituents selectively afforded nitrile 4.16 as the major isomer. The regioselectivity was primarily affected by the steric bulkiness of cyanoborane. Thus, reaction of 1- phenylpropyne resulted in 94% yield and 95:5 regioselectivity with 4.14d. Excellent yields were obtained with other cyanoboranes, albeit with decreased selectivity. Borylcyanation of allenes was also described under similar conditions.122 The intermolecular borylcyanation was highlighted in the facile and stereoselective synthesis of P-3622, a potential squalene synthetase inhibitor (4.19). Straightforward borylcyanation of alkyne 4.17 with cyanoborane 4.14d, followed by exchange of the diamine ligand with a pinacol ligand afforded β-boryl nitrile 4.18 in excellent yield and regioselectivity. Subsequent manipulations readily converted 4.18 to 4.19 in 3 steps.

Chapter 4 | 126

Scheme 4-5 Palladium-catalyzed intermolecular borylcyanation of alkynes

Mechanistic experiments were performed to probe the details of reaction process, particularly the proposed B–CN bond cleavage event (Scheme 4-6). 123 Mixing 13C- labeled cyanoborane 4.14f-13C with stoichiometric palladium complex and phosphine ligand generated the trans-borylpalladium(II) cyanide complex 4.20-13C, whose unlabeled counterpart 4.20 was independently prepared and observed by reacting borylpalladium(II) chloride complex 4.21 with trimethylsilyl cyanide (Scheme 4-6a and b). 4.20 gradually reductive eliminated to cyanoborane 4.14f at room temperature,

Chapter 4 | 127 suggesting that the oxidative addition of B–CN bond was reversible. Moreover, stoichiometric borylcyanation of substrate 4.11d yielded an alkenylpalladium(II) cyanide complex 4.22, whose structure was confirmed by X-ray analysis. The reductive elimination of 4.22 was promoted by heat and added dimethyl maleate. 4.22 also served as an effective catalyst for the borylcyanation of 4.11 (Scheme 4-6c and d). These results were consistent with the general mechanism depicted in Scheme 4-2.

Scheme 4-6 Mechanistic experiments for borylcyanation reaction

Ogawa and co-workers described a Pd(PPh3)4-catalyzed intermolecular thiocyanation of terminal alkynes by the S–CN bond cleavage of phenyl thiocyanate (Scheme 4-7). 124 Trisubstituted β-phenylthio nitriles were obtained in a regio- and stereoselective fashion, favoring the syn addition products with the cyano group attached to the less substituted alkyne carbon (4.23). The reaction tolerated both aliphatic and aromatic alkynes (4.23a–g), yet moderate Z/E selectivity was observed with certain substrates (4.23d–g), presumably as a result of thermal isomerization under extended

Chapter 4 | 128 heating. Unfortunately, aliphatic thiocyanates such as n-butyl thiocyanate were much less reactive towards thiocyanation (4.25h). Mixing phenyl thiocyanate with stoichiometric palladium allowed the isolation of trans-phenylthiopalladium(II) cyanide complex 4.24, clearly indicating the oxidative addition of the S–CN bond instead of the Ph–SCN bond. Addition of the Se–CN bond to alkynes was also attempted, but with limited success.124 Chung et al. modified the thiocyanation conditions by applying microwave irradiation, resulting in a lower catalyst loading (from 10 mol% to 5 mol%), a significant reduction of reaction time (from 66 h to 1 h), and improved yields and Z/E selectivity.125

Scheme 4-7 Palladium-catalyzed thiocyanation of terminal alkynes

Recently, insertion of an aryne into the S–CN bond of aryl thiocyanates was described by Werz et al. Heating aryl thiocyanate 4.25 with aryne precursor 4.26 in the presence of CsF and palladium catalyst afforded diphenylthioether 4.26, whereas no

Chapter 4 | 129 126 product was observed in the absence of palladium (Scheme 4-8). An O2 atmosphere was necessary; a much lower yield was obtained when performing the reaction under Ar or air (10–40%). A number of biarylthioethers with electron-donating and electron- withdrawing substituents could be constructed from the corresponding aryl thiocyanates in moderate to good yields (4.26a–j). Other aryne backbones were also examined (4.26k– m). The proposed mechanism involved fluoride-induced aryne formation and palladium- promoted S–CN bond cleavage, merging into putative coordinating complex 4.27. Subsequent insertion of aryne followed by reductive elimination released the product.

Scheme 4-8 Palladium-catalyzed thiocyanation of arynes

Chapter 4 | 130 A facile germylcyanation reaction of alkynes was developed that uses rather simple 127 conditions (Scheme 4-9). Heating trimethylgermyl cyanide (Me3GeCN) and terminal acetylenes in toluene with a catalytic amount of PdCl2 allowed a convenient synthesis of the corresponding (Z)-vinylgermanes in high yields. Unlike the observed regioselectivity from the thiocyanation reactions (Scheme 4-7), the trimethylgermyl group in this reaction was added to the terminal alkyne carbon. A variety of electron-neutral and electron- withdrawing functional groups were compatible with the reaction conditions, resulting in excellent yields and Z/E selectivity of products (4.28b–f), whereas electron-rich alkynes gave decreased selectivity (4.28a and 4.28g). Aliphatic alkynes bearing silylether, cyclohexyl, and ketoester groups were well-tolerated towards the addition reaction (4.28h–j).

Scheme 4-9 Palladium-catalyzed germylcyanation of alkynes

The addition across 1,6-enynes were also examined. Germylcyanation of enyne 4.29a occurred selectively at the alkyne moiety, affording the direct addition product

Chapter 4 | 131 4.30a and a cyclized product 4.31a in 21% and 79% yield, respectively. 4.31a was formed by intercepting the alkenylpalladium cyanide complex (generated from alkyne insertion) with alkene insertion, followed by reductive elimination. Reaction of 4.29b bearing a more substituted alkene resulted in a slower intramolecular insertion, returning 4.31b in 21% yield. The formation of 4.31a and 4.31b also indicated that the alkyne inserted into the Ge–Pd bond (germylpalladation) instead of the NC–Pd bond (cyanopalladation).

4.3 Oxycyanation and aminocyanation reactions

Despite significant progress towards the activation and transformation of various element–cyano σ bonds, the aforementioned cyanofunctionalization reactions exclusively focus on the addition of alkynes, leading to a rather limited scope and diversity of products, particularly when compared with the remarkable advances in carbocyanation reactions. Several explanations appear reasonable: (1) Carbonitriles are stable and widely available, whereas many heteroatom-substituted nitriles require multi-step preparation and/or special precautions to handle. (2) Much less attention has been paid in designing substrates suitable for intramolecular cyclization, although heteroatoms such as silicon, boron, nitrogen, and sulfur can serve as potential handles in tethering the reacting centers. (3) A highly reactive catalytic system remained elusive, and the role of Lewis acid promoters had never been examined. A breakthrough in this field was achieved in 2012 by the Nakao group, who developed an intramolecular alkene oxycyanation reaction under palladium/Lewis acid cooperative catalysis (Scheme 4-10). 128 The O–CN bond of aryl cyanates 4.32 was activated, cleaved, and added across a tethered alkene to generate various substituted dihydrobenzofurans bearing an oxy-quaternary stereocenter and a cyano group (4.33). The use of bidentate phosphine ligands with a large bite angle, specifically Xantphos* and

* Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Nixantphos = 4,6-bis(diphenylphosphino)-10H- phenoxazine; dppf = 1,1'-bis(diphenylphosphino)ferrocene; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; DPEphos = bis[(2-diphenylphosphino)phenyl] ether.

Chapter 4 | 132 Nixantphos, were critical in promoting the reaction, whereas other screened bidentate ligands such as dppf, BINAP, and DPEphos were completely ineffective. Consistent with their extensive application in affecting carbocyanation reactions, Lewis acid co-catalysts proved to be necessary promoters in the oxycyanation reaction, with BPh3 as the optimal choice.

Scheme 4-10 Palladium–Lewis acid-catalyzed intramolecular oxycyanation of alkenes

Various substituents para to the cyanate group, including OMe, tBu, F, Cl, and

CO2Et, were compatible with the oxycyanation conditions, affording the corresponding products with moderate to excellent yields (4.33b–f). Selective activation of the O–CN bond over an Ar–Br bond was noteworthy (4.33g). Substituents ortho to the cyanate or

Chapter 4 | 133 the alkene tether were tolerated as well (4.33h–j). Alkyl substituents other than methyl, such as ethyl and benzyloxymethyl groups also reacted smoothly (4.33k and 4.33l), yet monosubstituted alkene resulted in only trace product. Six-membered chromane synthesis was also successful (4.33m). Mechanistically, Lewis acid-promoted oxidative addition of the O–CN bond to a Pd(0) center generated complex 4.34. Subsequent alkene insertion occurred in a 5-exo- trig fashion, leading to the alkylpalladium(II) cyanide complex 4.35, which reductively eliminated product 4.33 and regenerated the active catalyst. The reductive elimination and alkene insertion were presumably accelerated by Xantphos, owing to its large bite angle. Decomposition of complex 4.34 led to phenol 4.36 as a formal decyanated side- product, although a detailed mechanism remains elucidated. Shortly after its publication, Nakao group's oxycyanation reaction, together with our previous work on quinoline-directed oxyacylation reaction108 were highlighted by Angewandte Chemie as “new types of alkene difunctionalizations for the construction of oxygen heterocycles.”129 Both methods feature the activation of carbon–oxygen bonds that are conventionally considered inert, followed by vicinal addition of alkoxy and cyano/carbonyl groups across an alkene to enable a rapid construction of dihydrobenzofuran and chromane frameworks. Inspired by Nakao's work, the author of this Thesis proposed an analogous transformation, in which the N–CN bond activation of a cyanamide130 and subsequent addition across an alkene, namely an aminocyanation reaction, would generate valuable nitrogen-heterocycles such as indoline and tetrahydroquinoline in a straightforward manner (Scheme 4-11). Potential challenges associated with the aminocyanation reaction were quickly identified. First, the cyanates employed in oxycyanation reaction were readily prepared by cyanation of the corresponding phenols, which were routinely synthesized by the Claisen rearrangement. Accordingly, an aniline precursor such as 2- methylallylaniline should be a viable precursor. However, the corresponding aza-Claisen reactions to access such anilines are not well developed. Furthermore, analogous to an O– CN bond, an N–CN bond can be challenging to cleave due to its double bond character.

Chapter 4 | 134

As shown in Table 4-1, the bond strength of an N–CN bond of a cyanamide (H2N–CN) is comparable to the C–CN bond strength of acetonitrile. The X-ray structure of a cyanamide, N-(4-chlorophenyl)-N-methylcyanamide indicated that the N–CN bond length was 1.33 Å,131 which is even shorter than an N=C double bond (imines, 1.35 Å).114 From the viewpoint of steric hindrance, the extra nitrogen substituent (R1, Scheme 4-11) would further increase the difficulty of N–CN bond cleavage.

Scheme 4-11 Proposed aminocyanation reaction by N–CN bond cleavage

Cleavage of an N–CN bond was reported using silyl–iron complex 4.37 (Scheme 4- 12), operating under a mechanism similar to Scheme 4-3.132 A silyl migration-induced addition of the nitrile gave an N-silyl η2-amidino complex 4.38, which rearranged to complex 4.39 and resulted in the cleavage of N–CN bond. Silyl isocyanide (Et3Si–NC) was dissociated from the metal center and isomerized into the silyl nitrile product. Nevertheless, aminocyanation of alkenes was unprecedented, except for one report of a copper-catalyzed intermolecular aminocyanation through radical addition, which did not involve a direct N–CN bond cleavage.133

Chapter 4 | 135

Scheme 4-12 Cleavage of N–CN bond of cyanamides by a silyl–iron complex

4.4 Discovery of a metal-free intramolecular aminocyanation reaction

With these challenges in mind, we embarked to explore the aminocyanation reaction, first by devising the cyanamide substrate 4.40 bearing an electron-withdrawing N-tosyl group (tosyl = p-toluenesulfonyl) in order to weaken the N–CN bond. The synthesis of 4.40 is depicted in Scheme 4-13, staring with diallylation of 2- iodoaniline 4.41 to give 4.42, followed by a Grignard-exchange reaction of the C–I bond and subsequent allylation with methylallyl chloride to generate aniline 4.33 in excellent yield. Deallylation of 4.33 with catalytic Pd(PPh3)4 released 2-methylallyl aniline 4.44 which, without purification, underwent sequential N-tosylation and N-cyanation to furnish the target cyanamide 4.40 as a bench-stable, crystalline solid.

Chapter 4 | 136

Scheme 4-13 Synthesis of N-tosyl cyanamide 4.40

With 4.40 in hand, we examined the aminocyanation conditions by heating 4.40 in toluene under palladium catalysis with added Lewis acid as a promoter (Table 4-2). In all experiments, the indoline product 4.46 was not detected from the crude reaction mixture, the sulfonamide 4.47, however, was identified in various amounts alongside unconsumed starting material, which implied the cleavage of N–CN bond, presumably via intermediate 4.48.

Table 4-2 Aminocyanation of 4.40 under palladium catalysis

Pd(0) Ligand Lewis acid Entry T (°C ) (10 mol% Pd) (20 mol%) (1.0 equiv)

1 Pd2dba3 XPhos BPh3 100

Chapter 4 | 137 Pd(0) Ligand Lewis acid Entry T (°C ) (10 mol% Pd) (20 mol%) (1.0 equiv)

2 Pd2dba3 tBuXPhos BPh3 100

3 Pd2dba3 MOP BPh3 100

4 Pd2dba3 PCy3 BPh3 100 [a] 5 Pd2dba3 dppp BPh3 100 [a] 6 Pd2dba3 p-Tol-BINAP BPh3 100

7 Pd(PPh3)4 – BPh3 130

8 Pd(PPh3)4 – BPh3 150

9 Pd(PPh3)4 – Zn(OTf)2 130

10 Pd(PPh3)4 – Zn(OTf)2 150 [a] 10 mol% ligand was used.

We decided to screen more metal complexes to further probe the reactivity. 4.40 was heated in toluene at 150 °C with 1.0 equivalent of BPh3 and 10 mol% of Rh, Ir, Pd, Ni, and Ru complexes. To our delight, 4.46 was readily identified from reactions using * [Rh(C2H4)2Cl]2, [Rh(coe)2Cl]2, [Ir(coe)2Cl]2, and Ir(acac)(CO)2, owing to the diagnostic splitting pattern of its diastereotopic protons. Product 4.46 was further isolated in approximately 30% yield and its structure was confirmed by spectroscopic analysis.

* coe = cyclooctene; acac = acetylacetonate.

Chapter 4 | 138

Scheme 4-14 Identification of aminocyanation product 4.46 with metal complexes

Encouraged by these results, we carried out extensive optimization of the reaction parameters, including temperature, catalyst loading, and screening of Lewis acids (

Table 4-3). A reaction employing 5 mol% of [Rh(C2H4)2Cl]2 in conjunction with 1.0 equivalent of BPh3 gave the indoline product 4.46 in 40% yield, whereas 0.5 equivalent of BPh3 gave lower but comparable yield (entries 1 and 2). Further reduction of BPh3 to 0.2 equivalent resulted in low reaction conversion (entriy 3). Notably, in the absence of

BPh3 or metal, 4.46 was not observed (entries 3 and 4). The yield of 4.46 was improved to 49% by slightly increasing the equivalents of BPh3 and lowering the reaction temperature from 150 to 110 °C (entries 6–9). Other zinc- or lithium-based Lewis acids were ineffective (entries 10–14). Pleasingly, a significant increase in yield was obtained

Chapter 4 | 139 when a stronger Lewis acid, B(C6F5)3, was employed, affording 4.46 in 72% isolated yield (entry 15).

Table 4-3 Optimization of aminocyanation conditions

Entry Metal (mol%) LA (equiv.) T (°C ) Conv. (%)[a] Yield of 4.46 (%)[b]

1 [Rh(C2H4)2Cl]2 (5) BPh3 (1.0) 150 >95 40

2 [Rh(C2H4)2Cl]2 (5) BPh3 (0.5) 150 81 36

3 [Rh(C2H4)2Cl]2 (5) BPh3 (0.2) 150 15 <5

4 [Rh(C2H4)2Cl]2 (5) – 150 17 <5

5 – BPh3 (1.0) 150 9 <5

6 [Rh(C2H4)2Cl]2 (2) BPh3 (1.0) 150 76 34

7 [Rh(C2H4)2Cl]2 (5) BPh3 (1.0) 130 92 48

8 [Rh(C2H4)2Cl]2 (5) BPh3 (1.0) 110 86 47

9 [Rh(C2H4)2Cl]2 (5) BPh3 (1.2) 110 >95 49

10 [Rh(C2H4)2Cl]2 (5) ZnCl2 (1.0) 110 16 <5

11 [Rh(C2H4)2Cl]2 (5) ZnBr2 (1.0) 110 22 <5

12 [Rh(C2H4)2Cl]2 (5) Zn(OTf)2 (1.0) 110 8 <5

13 [Rh(C2H4)2Cl]2 (5) LiBF4 (1.0) 110 8 <5

14 [Rh(C2H4)2Cl]2 (5) LiCl (1.0) 110 8 <5 [c] 15 [Rh(C2H4)2Cl]2 (5) B(C6F5)3 (1.0) 110 >95 72 [c] 16 [Rh(C2H4)2Cl]2 (5) B(C6F5)3 (1.0) 90 >95 89

17 [Rh(C2H4)2Cl]2 (5) B(C6F5)3 (0.5) 90 >95 71 [c] 18 [Rh(C2H4)2Cl]2 (5) B(C6F5)3 (1.0) 80 >95 71 [c] 19 – B(C6F5)3 (1.0) 90 >95 90

Chapter 4 | 140 [a] Estimated by 1H NMR analysis of the crude product mixture. [b] Determined by 1H NMR analysis using p-methoxyacetophenone as the internal standard. [c] Yields after column chromatography.

After further optimization, 4.46 was obtained in 89% isolated yield using 1.0 equivalent of B(C6F5)3 at 90 °C (entries 16–18). Dramatically, reaction employing B(C6F5)3 in the absence of added rhodium still afforded 4.46 in a reproducible 90% yield (entry 19)!* Intrigued by this observation, we examined other Lewis acids under the metal-free conditions (Table 4-4). Indeed, isoelectronic Lewis acids such as BF3•OEt2, AlCl3, and

Me2AlCl promoted the cyclization, yet less effectively than B(C6F5)3 (entries 1–3).

Reaction with AgOTf and Cu(OTf)2 led to decomposed reaction mixture (entries 4 and 5), whereas Zn(OTf)2 and Sc(OTf)3 resulted in unconsumed starting material (entries 6 and

7). Strong Lewis acids like SnCl4 also proved effective, providing 4.46 in 49% yield along with other unidentified byproducts (entry 8). Notably, a substoichiometric amount of B(C6F5)3 (0.2 equivalent) could be employed with comparable efficacy upon extended heating (48 h), demonstrating its potential as a catalyst (entry 9). In contrast, reaction heated with BPh3 alone was nonproductive, even at 150 °C (entry 10).

Table 4-4 Metal-free aminocyanation — Lewis acids screening

Entry Lewis acid (equiv.) T (°C ) Conv. (%)[a] Yield of 4.46 (%)[b] [c] 1 BF3•OEt2 (1.0) 90 >95 31 [c] 2 AlCl3 (1.0) 90 >95 52

3 Me2AlCl (1.0) 90 57 11 [d] 4 Ag(OSO2CF3) (1.0) 90 – <5

* B(C6F5)3 was purchased from Sigma-Aldrich and Strem Chemicals and used without further purification.

Chapter 4 | 141 Entry Lewis acid (equiv.) T (°C ) Conv. (%)[a] Yield of 4.46 (%)[b] [d] 5 Cu(OSO2CF3)2 (1.0) 90 – <5 [e] 6 Zn(OSO2CF3)2 (1.0) 90 – <5 [e] 7 Sc(OSO2CF3)3 (1.0) 90 – <5

8 SnCl4 (1.0) 90 >95 49 [f] 9 B(C6F5)2 (0.2) 90 >95 91 [e] 10 BPh3 (1.0) 150 – <5 [a] Estimated by 1H NMR analysis of the crude product mixture. [b] Determined by 1H NMR analysis using p-methoxyacetophenone as the internal standard. [c] Yields after column chromatography. [d] No 4.46 detected by NMR, complex mixture formed. [e] No 4.46 detected by NMR, only 4.40 was detected. [f] Heated for 48 hours.

4.5 Scope and limitations of aminocyanation reaction*

A number of N-tosyl cyanamides were prepared and examined under the metal-free aminocyanation conditions using 1.0 equivalent of B(C6F5)3 (Table 4-5). Indolines bearing alkyl (R = Me, 4.46b; R = tBu, 4.46c) and halogen (R = F, Cl, Br; 4.46d–f) substituents on the phenyl ring were obtained in excellent yields. Notably, a carbon– bromine bond was well-tolerated, offering a convenient handle for further functionalization (4.46f). The reaction appeared to be insensitive to the electronic effects of substituents para to the cyanamide moiety, providing indolines 4.46g (R = CF3) and 4.46h (R = OMe) in consistently excellent yields. Ethyl- and phenyl-substituted alkenes proceeded smoothly to the corresponding product in quantitative yields (4.46i and 4.46j) Extending the alkene tether afforded tetrahydroquinoline 4.46k in 93% yield. A p-nosyl- protected indoline was obtained in near quantitative yield (4.46l). The relatively mild conditions for removing nosyl groups should allow convenient further functionalizations on the nitrogen atom. In addition, a methyl-substituent ortho to the cyanamide moiety was tolerated, affording 4.46m in 90% yield. On a large scale, the reaction could be

* A portion of experiments discussed in this chapter were performed by Dr. Sarah Pound and Dr. Naveen Rondla.

Chapter 4 | 142 performed under air using 20 mol% B(C6F5)3 to afford 4.46c in 94% yield, indicating the robustness of this method. Interestingly, instead of giving the corresponding four- membered benzazetidine, the reaction of o-isopropenyl-substituted cyanamide 4.40n gave alkenyl nitrile 4.46 in quantitative yield.

Table 4-5 Scope and limitations of aminocyanation reaction

[a] Conditions: substrate (0.1 mmol), B(C6F5)3 (0.1 mmol), PhMe (0.5 mL), 90 °C, 24 h. Isolated yields after column chromatography. [b] Ran for 28 h. [c] Unconsumed starting

Chapter 4 | 143 material. [d] Complex reaction mixture. Ns = p-nitrobenzenesulfonyl.

The aminocyanation reaction appeared to be highly sensitive to the substitution pattern of the alkene moiety. Mono- and trisubstituted alkenes 4.40o and 4.40p were unreactive, whereas 4.40q resulted in complex mixture without detectable amount of product. Introducing an oxygen substituent, such as a benzyloxy (4.40r) and phenoxy group (4.40s and 4.40t) to the α position of alkene completely shut down the reaction, which was tentatively attributed to the inductive effect of C–O bonds. In addition, the cyanamide derived from aliphatic amine such as 4.40u was inert towards activation, likely due to the increased strength of N–CN bond.

4.6 Mechanistic considerations

As this reaction proceeds without an added metal catalyst, we sought an alternative mechanism to account for the observed metal-free aminocyanation. Notably, Wang et al. reported a Lewis acid-promoted cyanation reaction of indoles and pyrroles using N- cyano-N-phenyl-p-toluenesulfonamide (NCTS) as an electrophilic cyanide source, 134 representing a precedence for the cleavage of N–CN bonds under Lewis acidic conditions (Scheme 4-15).135 In our system, however, both the sulfonamide and cyano groups were added across the alkene.

Scheme 4-15 Cyanation of indoles using N-cyano-N-phenyl-p-toluenesulfonamide

We proposed that the cyanamide moiety of 1a was initially coordinated to B(C6F5)3 to afford adduct I-1, setting the stage for an intramolecular nucleophilic attack of the alkene (Scheme 4-16). Subsequent formation of aziridinium ion I-2 with the dissociation

Chapter 4 | 144 of N–CN bond was owing to the known anion abstracting properties of B(C6F5)3 (path A).136 Alternatively, attack of the central cyanamide carbon, which is the typical site of nucleophilic attack on cyanamides, would generate a seven-membered, benzazepin-type intermediate I-3 bearing a tertiary carbocation, which then collapsed to 4.46 (path B). Notably, our success with substrates 4.46i and 4.46j bearing more nucleophilic alkenes, and the failure of substrates 4.40o and 4.40q–t whose alkenes were less nucleophilic was consistent with intermediate I-3 in path B.

Scheme 4-16 Proposed mechanism

A double-crossover experiment was performed by heating a mixture of 4.40d and 13C-labeled cyanamide 4.40a-13CN under the optimal conditions, affording only the non- crossover products 4.46d and 4.46a-13CN in excellent yields (Scheme 4-17). This result indicated that the dissociation of cyanide did not occur. Likewise, mixture of 4.40l and 4.40d afforded consistently high yields of only the non-crossover products. Thus, the lack of crossover ruled out the path A in our mechanistic hypothesis.

Chapter 4 | 145

Scheme 4-17 Double-crossover experiments

As previously mentioned, aminocyanation of cyanamide 4.40n bearing a styrenyl double bond did not afford the corresponding four-membered product, but led to (Z)- alkenyl nitrile 4.46n in quantitative yield. Applying path B to substrate 4.40n would involve the corresponding six-membered intermediate I-4, which subsequently collapsed to the strained benzazetidine intermediate I-5 (Scheme 4-18, bottom). I-5 could be converted to product 4.46n through a plausible elimination which, however, could not account for the selectivity for the (Z)-alkene product. An alternative path C appeared to be operative since the elimination of I-4 would generate intermediate I-6 with a fixed alkene geometry (Scheme 4-18, top). Nevertheless, it was unclear why analogous elimination of the seven-membered intermediate (I-3, Scheme 4-16) was not observed.

Chapter 4 | 146

Scheme 4-18 Selective formation of alkenyl nitrile 4.46n

While we were working on the substrate study, Falck and Wang disclosed a rhodium-catalyzed cyanation of α-methyl styrenes by N–CN bond cleavage of N-tosyl cyanamide 4.48 and subsequent cyano-group transfer to the alkene double bond (Scheme 4-19).137 The alkenyl nitrile products 4.49 were obtained exclusively as Z-alkenes, as indicated by COSY and NOESY experiments. This work immediately caught our attention because the N–CN bond cleavage was conceptually in accordance with our early mechanistic proposal of alkene aminocyanation. Interestingly, we later discovered the metal-free, Lewis acid-promoted aminocyanation, particularly the quantitative transformation of alkenyl cyanamide 4.40n to nitrile 4.46n. 4.40n was one of the substrates (4.48a, R = Me) studied by Falck and Wang to generate product 4.49a (R = Me), which was identical to 4.46n. We therefore demonstrated that the cyano-transfer developed by Falck and Wang did not required added rhodium.

Chapter 4 | 147

Scheme 4-19 C–H cyanation of α-methyl styrenes by N–CN bond cleavage

In their study, control experiments performed in the absence of rhodium (Scheme 4- 19, Table, entry 1) or phosphine ligand (entry 2) resulted in unconsumed starting material.

On the other hand, the working catalysts were not limited to [Rh(cod)Cl]2: other rhodium and palladium complexes catalyzed the reaction in the presence of a phosphine ligand (entries 3–6) or without added phosphines (entries 7 and 8). As a indication of N–CN bond cleavage, sulfonamide 4.50 was isolated in small quantity through all experiments.

Chapter 4 | 148

An deuterium labeling experiment using [D2]-4.48h resulted in the corresponding [D2]- 4.49h with slightly decreased deuterium incorporation, suggesting that the reaction proceeded in an intramolecular fashion. Nevertheless, detailed mechanism regarding the N–CN bond cleavage and the cyano-transfer process remained elusive. Considering the generality of metal complexes in promoting the reaction in conjunction with our observation with 4.40n, we could not rule out the possibility that the metal was not involved in the direct oxidative addition of N–CN bond, but acting as a Lewis acid promoter as depicted in Scheme 4-18.

Scheme 4-20 Theoretical study of aminocyanation reaction

Shortly after our publication,138 Li el al. applied DFT calculations to our system and 139 offered new insights into the mechanism (Scheme 4-20). In the absence of B(C6F5)3, alkene addition of substrate 4.40 occurred through a cyclic transition state TS-1 with a formidable free energy (51.2 kcal/mol) in order to generate 4.46. In contrast, coordination of B(C6F5)3 to the cyano group led to stable adduct 4.51, which proceeded through

Chapter 4 | 149 transition state TS-2, similar to TS-1, to give 4.52. 4.52 was then converted to 4.46 upon dissociation of Lewis acid. The free energy barrier for the B(C6F5)3-promoted addition was significantly lower than that of the uncatalyzed pathway (29.1 kcal/mol versus 46.6 kcal/mol), clearly indicating the critical role of Lewis acid.

Table 4-6 Correlation of strength of Lewis acids with their performance

Calculated free energy Experimental Lewis acid Lewis acidity[a] barrier (kcal/mol) yield of product

B(C6F5)3 strongest 29.1 90%

SnCl4 32.7 49%

BPh3 weakest 36.8 0%

[a] Calculated based on the corresponding hydride affinity. B(C6F5)3: –91.6 kcal/mol;

SnCl4: –123.3 kcal/mol; BPh3: –130 kcal/mol.

Interestingly, attempts to locate the seven-membered intermediate I-3 were unsuccessful, but instead, Li et al. suggested a concerted and asynchronous event during the addition step. Specifically, formation of the C2–C4 bond and rupture of the N3–C4 bond occurred simultaneously, yet prior to the formation of the C1–N3 bond. Concerted electrophilic alkene additions are known and proceed in a synchronous fashion, one classic example being the hydroboration of alkenes. However, a concerted asynchronous alkene addition, as indicated in this work, was unprecedented. In addition, Li group's calculations qualitatively correlated the strength of Lewis acid with the corresponding free energy barrier regarding the cyclization event. As indicated in

Table 4-6, reactions using Lewis acids weaker than B(C6F5)3, such as SnCl4 and

BPh3 were associated with higher free energy barriers and correspondingly lower yields.

Chapter 4 | 150 4.7 Conclusion and future work

In conclusion, we developed a Lewis acid-promoted alkene aminocyanation reaction under metal-free conditions. Herein, the N–CN bond of a cyanamide substrate was activated, cleaved, and formally added across an alkene to enable a rapid construction of nitrogen heterocycles, indolines and tetrahydroquinolines in excellent yields. Preliminary mechanistic experiments suggested an intramolecular cyclization pattern, featuring a non- degradative rupture at the N–CN bond. Recent DFT calculations identified a novel concerted asynchronous pattern for the alkene addition step. Future work will be directed towards expanding the substrate scope, developing intermolecular aminocyanation reactions, and devising a catalytic variant presumably by employing chiral Lewis acids. Our recent efforts towards a metal-based aminocyanation reaction are discussed in Chapter 5.

4.8 Experimental Section

4.8.1 General details

Unless otherwise noted, all reactions were carried out using oven-dried glassware under a nitrogen atmosphere. Dichloromethane (CH2Cl2) and toluene were distilled from

CaH2 prior to use. Tetrahydrofuran (THF) was distilled from Na/benzophenone prior to use. Dichloromethane and toluene were further degassed by bubbling a stream of argon through the liquid in a Strauss flask and then stored in a nitrogen-filled glove box.

Acetonitrile (CH3CN), glacial acetic acid (AcOH), benzene, pyridine, anhydrous N,N- dimethylformamide (DMF) and anhydrous diethyl ether (Et2O) were purchased from Sigma-Aldrich and used without further purification. Unless otherwise noted, all chemicals were purchased from commercial sources and used as received. All palladium and rhodium complexes were purchased from Sigma-Aldrich or Strem and used as received. Triphenylborane (BPh3) was purchased from Sigma-Aldrich and recrystallized

Chapter 4 | 151 * from anhydrous heptanes under nitrogen. Tris(pentafluorophenyl)borane (B(C6F5)3) was purchased from Alfa Aesar or Strem and used as received. All B(C6F5)3-promoted aminocyanation reactions were carried out in a Vacuum Atmospheres nitrogen-filled glove box in 1 dram vials (Chemglass) with PTFE lined caps and heating was applied by aluminum block heaters. Analytical thin-layer chromatography (TLC) and preparative thin-layer chromatography were carried out using 250 μm and 1000 μm silica plates (SiliCycle), respectively. Eluted plates were visualized first with a UV lamp (254 nm) and then stained with potassium permanganate or p-anisaldehyde, followed by heating. Flash column chromatography was performed using 230 – 400 mesh (particle size 40 – 63 μm) silica gel purchased from SiliCycle. 1H NMR (300 and 500 MHz) and 13C NMR (75 and 125 MHz) spectra were obtained on Varian Inova and Bruker Avance instruments. 1H NMR spectra data were reported as δ values in ppm relative to chloroform (δ 7.26) if collected in CDCl3, or 13 methylene chloride (δ 5.32) if collected in CD2Cl2. C NMR spectra data were reported as δ values in ppm relative to chloroform (δ 77.00) if collected in CDCl3 or methylene 1 chloride (δ 53.41) if collected in CD2Cl2. H NMR coupling constants were reported in Hz, and multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); quint (quintet); m (multiplet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dddd (doublet of doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); ddt (doublet of doublet of triplets); dq (doublet of quartets); app (apparent); br (broad). Infrared (IR) spectra were obtained on a MIDAC FT-IR spectrometer. A thin-film of sample was prepared by evaporating solvent (CH2Cl2 or

CDCl3) on NaCl plates. Low-resolution mass spectra (LRMS) in chemical ionization (CI) experiments were performed on a Varian Saturn 2200 GC-MS system. High-resolution mass spectra (HRMS) in electrospray ionization (ESI) experiments were performed on a

* Köster, R.; Binger, P.; Fenzl, W. Inorg. Synth. 1974, 15, 134.

Chapter 4 | 152 Bruker BioTOF II (Time-of-flight) instrument using PEG-300, PEG-400 or PPG-400 as an internal standard.

4.8.2 Optimization of aminocyanation conditions

A general procedure: In a nitrogen-filled glove box, a 1 dram vial was charged with a magnetic stirring bar, cyanamide 4.40a (32.6 mg, 0.1 mmol, 1.0 equiv), metal complex (10 mol% of metal, unless otherwise noted), Lewis acid (1.0 equiv, unless otherwise noted) and Toluene (0.5 mL). The reaction mixture was sealed with a PTFE lined cap, removed from the glove box, and heated in an aluminum heating block for 24 h. The resulting mixture was allowed to cool to room temperature and a stock solution of p- methoxyacetophenone (0.1 M in Toluene, 0.3 mL, 0.03 mmol) was added as the internal NMR-standard. The resulting mixture was concentrated in vacuo and the yield of 4.46a was determined by 1H NMR analysis. The isolated yield of 4.46a was obtained by concentrating the crude mixture onto Celite (dry loading method) followed by flash column chromatography (1:9 → 1:4 EtOAc/hexanes).

4.8.3 Overview of substrate synthesis

Scheme 4-21 Synthesis of substrates 4.40a–f

Chapter 4 | 153

Scheme 4-22 Synthesis of substrates 4.40g and 4.40h

Chapter 4 | 154

Scheme 4-23 Synthesis of substrates 4.40i–l, 4.40n, 4.40o, and 4.40r

4.8.4 Preparation of aniline intermediates

Preparation of anilines 4.43a–f, 4.43i, 4.43j, 4.43r, and 4.43o

Chapter 4 | 155

Anilines 4.41b, 4.41c and 4.41f were prepared following known procedures.* The THF solution of iPrMgCl·LiCl was prepared following a known procedure.† ‡ Synthesis of 4.42a : To a N2-flushed flask was added 4.41a (1.10 g, 5.0 mmol, 1.0 equiv), potassium carbonate (2.76 g, 20.0 mmol, 4.0 equiv), allyl bromide (1.73 mL, 20.0 mmol, 4.0 equiv), and CH3CN (10.0 mL). The resulting suspension was vigorously stirred at 80 °C for 24 h at which point TLC analysis (5 : 95 EtOAc/hexanes, followed by

KMnO4 stain and heating) indicated complete consumption of starting material. The reaction mixture was diluted with CH2Cl2 (60 mL) and filtered through a short (4 – 5 cm) silica gel column. The resulting solution was concentrated in vacuo to give crude 4.42a as an orange oil. 4.42a was diluted with benzene (2.0 mL), concentrated again, and used for next step without further purification. 4.42b–d were prepared in the same manner as 4.42a. 4.42e and 4.42f were prepared in the same manner as 4.42a, except that additional allyl bromide (1.0 equiv) was added after 24 h. The reaction was completed after additional 24 h, which was indicated by TLC analysis. Synthesis of 4.43a:§ A flame-dried flask was charged with i-PrMgCl·LiCl (0.76 M in THF, 7.9 mL, 6.0 mmol, 1.2 equiv) and cooled to –12 °C under N2. Crude 4.42a (neat, ~ 5.0 mmol, 1.0 equiv) was slowly added via syringe. The resulting orange solution was stirred at –10 °C for 30 min at which point 3-chloro-2-methyl-1-propene (0.76 mL, 7.0

* 4.41b: Xiao, W. J.; Alper, H. J. Org. Chem. 1999, 64, 9646. 4.41c and 4.41f: Shirtcliff, L. D.; Weakley, T. J. R.; Haley, M. M. J. Org. Chem. 2004, 69, 6979. † Krasovkiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333. ‡ Procedure was modified from: Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934. § Procedure was modified from: Yip, K. T.; Yang, M.; Law, K. L.; Zhu, N. Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130.

Chapter 4 | 156 mmol, 1.4 equiv) and CuCN·2LiCl (1.0 M in THF, 0.5 mL, 0.5 mmol, 0.1 equiv) were sequentially added at –10 °C. The reaction was allowed to warm to room temperature over the course of 2 h and continue stirring overnight. The reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and extracted with Et2O (2 × 30 mL). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4 and concentrated. The resulting mixture was purified by flash column chromatography (1 : 9

CH2Cl2/hexanes) to give 4.43a as a colorless oil (568 mg, 2.5 mmol, 50% yield over two steps). 4.43b–f were prepared in the same manner as 4.43a, except that 3-bromo-2-methyl- 1-propene was used in all cases. 4.43i, 4.43j, 4.43r, and 4.43o were prepared in the same manner as 4.43a, except that (1) the starting aniline 4.42a was pre-purified by column chromatography (5:95 EtOAc/hexanes), and (2) the corresponding bromide was used instead of 3-chloro-2-methyl-1-propene. 2-(Bromomethyl)-1-butene was prepared from 2-ethylacrolein.* 1-Bromo-2-phenyl-2-propene was prepared from 2-phenylpropene.† (2- Bromomethylallyloxymethyl)benzene was prepared from methyl 2- (hydroxymethyl)acrylate.‡ 1 4.43a: Rf = 0.65 (5:95 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.18 (dd, J = 7.3, 1.5 Hz, 1H), 7.13 (td, J = 7.3, 1.5 Hz, 1H), 7.05 (dd, J = 8.3, 1.5 Hz, 1H), 7.00 (td, J = 7.3, 1.0 Hz, 1H), 5.77 (ddt, J = 16.4, 10.2, 6.2 Hz, 2H), 5.13 (ddd, J = 17.6, 3.4, 1.9 Hz, 2H), 5.06 (ddd, J = 10.2, 3.4, 1.5 Hz, 2H), 4.82 – 4.81 (m, 1H), 4.65 – 4.64 (m, 1H), 3.54 13 (dt, J = 6.4, 2.4 Hz, 4H), 3.45 (s, 2H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3) δ 150.0, 145.5, 135.5, 135.3, 130.4, 126.2, 123.5, 122.6, 117.0, 111.6, 56.3, 38.7, 22.7; HRMS + (ESI) calcd for [C16H21N + H] 228.1747, found 228.1752.

* Cheng, B.; Sunderhaus, J. D.; Martin, S. F. Org. Lett. 2010, 12, 3622. † Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2012, 77, 17. ‡ (a) Borrel, J. I.; Teixido, J.; Martinez-Teipel, B.; Matallana, J. L.; Copete, M. T.; Llimargas, A.; Garcia, E.; J. Med. Chem. 1998, 41, 3539. (b) Sagot, E.; Pickering, D. S.; Pu, X.; Umberti, M.; Stensbol, T. B.; Neilsen, B.; Chapelet, M.; Bolte, J.; Gefflaut, T.; Bunch, L. J. Med. Chem. 2008, 51, 4093.

Chapter 4 | 157

4.43b: Prepared from 5.0 mmol of 4.41b, 69% yield over two steps; colorless oil; Rf 1 = 0.29 (2:98 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 6.99 (s, 1H), 6.96 – 6.95 (m, 2H), 5.78 (ddt, J = 16.6, 10.3, 6.4 Hz, 2H), 5.14 (ddd, J = 17.1, 3.4, 1.5 Hz, 2H), 5.07 (ddd, J = 10.3, 3.4, 1.5 Hz, 2H), 4.82 (m, 1H), 4.65 (m, 1H), 3.51 (dt, J = 6.2, 1.5 Hz, 4H), 13 3.43 (s, 2H), 2.28 (s, 3H), 1.71 (s, 3H); C NMR (125 MHz, CDCl3) δ 147.4, 145.7, 135.6, 135.5, 132.9, 131.0, 126.9, 122.6, 116.9, 111.5, 56.7, 38.6, 22.7, 20.9; HRMS + (ESI) calcd for [C17H23N + H] 242.1903, found 242.1912.

4.43c: Prepared from 5.0 mmol of 4.41c, 59% yield over two steps; colorless oil: Rf 1 = 0.22 (2:98 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 8.3, 2.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 5.78 (ddt, J = 16.5, 10.2, 6.1 Hz, 2H), 5.15 (ddd, J = 17.6, 3.4, 1.5 Hz, 2H), 5.08 (ddd, J = 10.3, 3.4, 1.5 Hz, 2H), 4.81 (m, 1H), 4.62 (m, 1H), 3.52 (d, J = 5.8 Hz, 4H), 3.44 (s, 2H), 1.72 (s, 3H), 1.28 (s, 9H); 13C

NMR (125 MHz, CD2Cl2) δ 147.4, 145.9, 145.87, 135.8, 134.7, 127.6, 122.9, 121.9, + 116.4, 111.1, 56.5, 38.7, 34.0, 31.1, 22.5; HRMS (ESI) calcd for [C20H29N + H] 284.2373, found 284.2364.

4.43d: Prepared from 3.0 mmol of 4.41d, 60% yield over two steps; colorless oil; Rf 1 = 0.80 (5:95 EtOAc/hexanes); H NMR* (500 MHz, CDCl3) δ 7.03 (dd, J = 8.8, 5.4 Hz, 1H), 6.91 (dd, J = 9.3, 2.9 Hz, 1H), 6.85 (td, J = 8.3, 3.4 Hz, 1H), 5.77 (ddt, J = 16.5, 10.2, 6.2 Hz, 2H), 5.13 (ddd, J = 17.1, 3.4, 1.5 Hz, 2H), 5.08 (ddd, J = 10.3, 2.9, 1.5 Hz, 2H), 4.81 (m, 1H), 4.69 (m, 1H), 3.54 (dt, J = 6.4, 1.5 Hz, 4H), 3.46 (s, 2H), 1.70 (s, 3H); 13 1 4 C NMR (125 MHz, CDCl3) δ 159.3 (d, JF–C = 241.6 Hz), 145.7 (d, JF–C = 3.0 Hz), 3 3 2 144.8, 138.4 (d, JF–C = 7.1 Hz), 135.1, 124.3 (d, JF–C = 8.1 Hz), 117.2, 116.4 (d, JF–C = 2 22.2 Hz), 112.8 (d, JF–C = 22.2 Hz), 112.3, 56.9, 38.6, 22.5; HRMS (ESI) calcd for + [C16H20FN + H] 246.1653, found 246.1654. *Note: Coupling constants reported as observed. No attempt was made to distinguish

JH–H vs. JF–H.

4.43e: Prepared from 3.0 mmol of 4.41e, 49% yield over 2 steps; colorless oil; Rf = 1 0.68 (5:95 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.17 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.8, 2.9 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.76 (ddt, J = 16.5, 10.2, 6.2 Hz, 2H),

Chapter 4 | 158 5.15 (ddd, J = 17.6, 2.9, 1.5 Hz, 2H), 5.09 (dd, J = 10.2, 1.5 Hz, 2H), 4.87 (app s, 1H), 13 4.69 (m, 1H), 3.53 (m, 4H), 3.43 (s, 2H), 1.71 (s, 3H); C NMR (125 MHz, CDCl3) δ 148.4, 144.7, 137.7, 134.9, 130.1, 128.8, 126.3, 124.0, 117.4, 112.4, 56.4, 38.5, 22.6; + HRMS (ESI) calcd for [C16H20ClN + H] 262.1357, found 262.1344.

4.43f: Prepared from 5.0 mmol of 4.41f, 62% yield over 2 steps; colorless oil; Rf = 1 0.51 (hexanes); H NMR (500 MHz, CDCl3) δ 7.30 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 8.8, 2.4 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 5.74 (ddt, J = 16.5, 10.2, 6.2 Hz, 2H), 5.13 (m, 2H), 5.09 (m, 2H), 4.87 (app s, 1H), 4.68 (m, 1H), 3.52 (d, J = 5.9 Hz, 4H), 3.42 (s, 2H), 1.70 13 (s, 3H); C NMR (125 MHz, CDCl3) δ 149.0, 144.6, 138.0, 134.8, 133.1, 129.2, 124.4, + 117.4, 116.7, 112.4, 56.3, 38.5, 22.6; HRMS (ESI) calcd for [C16H20BrN + H] 306.0852, found 306.0867.

4.43i: Prepared from 2.5 mmol of 4.41a, 66% yield; colorless oil; Rf = 0.78 (5:95 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.21 (dd, J = 7.3, 1.5 Hz, 1H), 7.17 (td, J = 7.8, 1.5 Hz, 1H), 7.08 (dd, J = 7.8, 1.0 Hz, 1H), 7.04 (td, J = 7.8, 1.5 Hz, 1H), 5.81 (ddt, J = 16.4, 10.2, 6.2 Hz, 2H), 5.17 (ddd, J = 17.6, 3.4, 2.0 Hz, 2H), 5.11 (ddd, J = 10.2, 3.4, 1.5 Hz, 2H), 4.87 (m, 1H), 4.67 (m, 1H), 3.58 (dt, J = 6.4, 1.5 Hz, 4H), 3.51 (s, 2H), 13 2.04 (q, J = 7.3, 2H), 1.07 (t, J = 7.3 Hz, 3H); C NMR (125 MHz, CDCl3) δ 151.1, 150.0, 135.7, 135.3, 130.6, 126.2, 123.4, 122.6, 117.0, 109.5, 56.3, 37.2, 28.9, 12.4; + HRMS (ESI) calcd for [C17H23N + H] 242.1903, found 242.1902.

4.43j: Prepared from 3.0 mmol of 4.41a, 24% yield; colorless oil; Rf = 0.50 (1:4 1 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 7.45 (dt, J = 6.8, 1.5 Hz, 2H), 7.29 – 7.25 (m, 2H), 7.23 – 7.20 (m, 2H), 7.14 (td, J = 7.8, 1.0 Hz, 1H), 7.07 (dd, J = 7.8, 1.5 Hz, 1H), 6.98 (td, J = 7.3, 1.5 Hz, 1H), 5.81 (ddt, J = 16.5, 10.2, 6.3 Hz, 2H), 5.52 (m, 1H), 5.17 (ddd, J = 17.1, 3.4, 2.0 Hz, 2H), 5.09 (ddd, J = 10.3, 3.0, 1.5 Hz, 2H), 4.99 (app q, J 13 = 1.5 Hz, 1H), 3.95 (s, 2H), 3.59 (dt, J = 5.8, 1.0 Hz, 4H); C NMR (125 MHz, CDCl3) δ 149.6, 147.2, 140.9, 135.4, 135.2, 130.3, 128.1, 127.3, 126.3, 126.0, 123.6, 122.6, 117.2, + 114.0, 56.3, 36.0; HRMS (ESI) calcd for [C21H23N + H] 290.1903, found 290.1903.

4.43r: Prepared from 2.5 mmol of 4.41a, 57% yield; light yellow oil; Rf = 0.51 (5:95 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.37 – 7.33 (m, 4H), 7.32 – 7.27 (m,

Chapter 4 | 159 1H), 7.22 (dd, J = 7.8, 1.5 Hz, 1H), 7.18 (td, J = 7.8, 1.5 Hz, 1H), 7.08 (dd, J = 7.8, 1.0 Hz, 1H), 7.04 (td, J = 7.3, 1.5 Hz, 1H), 5.77 (ddt, J = 16.5, 10.2, 6.2 Hz, 2H), 5.19 (m, 1H), 5.14 (m, 2H), 5.07 (m, 2H), 4.86 (m, 1H), 4.52 (s, 2H), 3.99 (s, 2H), 3.56 (d, J = 1.0 13 Hz, 4H), 3.54 (s, 2H); C NMR (125 MHz, CDCl3) δ 150.1, 145.8, 138.4, 135.3, 135.0, 130.7, 128.3, 127.6, 127.5, 126.4, 123.6, 122.9, 117.1, 113.0, 73.0, 71.9, 56.4, 34.4; + HRMS (ESI) calcd for [C23H27NO + H] 334.2165, found 334.2161.

4.43o: Prepared from 4.2 mmol of 4.41a, 66% yield; colorless oil; Rf = 0.57 (1:9 1 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 7.23 (dd, J = 7.8, 1.5 Hz, 1H), 7.17 (td, J = 7.8, 2.0 Hz, 1H), 7.08 (dd, J = 8.3, 1.0 Hz, 1H), 7.05 (td, J = 7.8, 1.5 Hz, 1H), 6.01 (ddt, J = 16.7, 10.2, 6.5 Hz, 1H), 5.81 (ddt, J = 16.4, 10.2, 6.2 Hz, 2H), 5.18 (ddd, J = 17.6, 3.0, 1.5 Hz, 2H), 5.13 – 5.07 (m, 4H), 3.58 (dt, J = 5.8, 1.5 Hz, 4H), 3.54 (d, J = 6.8 13 Hz, 2H); C NMR (125 MHz, CDCl3) δ 149.6, 137.8, 136.1, 135.2, 130.1, 126.3, 123.7, + 122.7, 117.1, 115.5, 56.4, 35.0; HRMS (ESI) calcd for [C15H19N + H] 214.1590, found 214.1597.

Preparation of 4.43g, 4.43h, and 4.43k

Scheme 4.24. Synthesis of substrates 4.43g, 4.43h, and 4.43k

Chapter 4 | 160 Synthesis of 4.42g:* To a stirred solution of aniline 4.41g (1.72 g, 6.0 mmol, 1.0 equiv) in Toluene (12.0 mL) was added N,N-dimethylformamide dimethyl acetal (4.78 mL, 36.0 mmol, 6.0 equiv). The reaction was heated to reflux for 40 h, at which point TLC analysis (1:4 EtOAc/hexanes) indicated complete consumption of 4.41g. The reaction mixture was concentrated in vacuo, and the resulting brownish oil was purified by flash column chromatography (15:85 EtOAc/hexanes) to give amidine 4.42g as a yellow oil (1.93 g, 5.65 mmol, 94% yield). 1 4.42g: Rf = 0.29 (15:85 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 1.5 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.11 (s, 13 3 3H), 3.07 (s, 3H); C NMR (125 MHz, CDCl3) δ 155.6, 153.1, 135.7 (app q, JC–F = 2.0 3 2 1 Hz), 126.1 (q, JC–F = 4.0 Hz), 125.1 (q, JC–F = 33.2 Hz), 123.7 (q, JC–F = 271.8 Hz), + 117.9, 96.1, 40.2, 34.6; HRMS (ESI) calcd for [C10H10F3IN2 + H] 342.9914, found 342.9908. Synthesis of 4.43g: In a flame-dried flask, a stirred solution of amidine 4.42g (1.71 g, 5.0 mmol, 1.0 equiv) in THF (5.0 mL) was cooled to –20 °C under N2. i-PrMgCl·LiCl (1.3 M in THF, 4.2 mL, 5.5 mmol, 1.1 equiv) was slowly added via syringe. The resulting brownish solution was allowed to stir at –20 °C for 30 min at which point it was further cooled to –30 °C, and CuCN·2LiCl (1.0 M in THF, 6.0 mL, 6.0 mmol, 1.2 equiv) was slowly added while maintaining the internal temperature below –20 °C. Upon completion of addition, the resulting reddish solution was stirred at –20 °C for an additional 30 min then 3-bromo-2-methyl-1-propene (1.0 mL, 10.0 mmol, 2.0 equiv) was added dropwise at the same temperature. The reaction was allowed to stir at –20 °C for 1 h then was quenched by addition of saturated aqueous NH4Cl (10 mL). To the resulting suspension was added NH4OH solution (28.0 – 30.0% NH3 basis, 4.0 mL), and the reaction mixture was extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give amidine 4.43g as a yellow oil (1.36 g, 5.0 mmol, 100% yield). No further purification of 4.43g was needed.

* Procedure was modified from: Lindsay, D. M.; Dohle, W.; Jensen, A. E.; Kopp, F.; Knochel, P. Org. Lett. 2002, 4, 1819.

Chapter 4 | 161 1 4.43g: Rf = 0.36 (20:80:1 EtOAc/hexanes:Et3N); H NMR (500 MHz, CDCl3) δ 7.40 – 7.35 (m, 3H), 6.81 (d, J = 7.8 Hz ,1H), 4.79 (m, 1H), 4.64 (m, 1H), 3.45 (s, 2H), 13 3.02 (s, 6H), 1.70 (s, 3H); C NMR (125 MHz, CDCl3) δ 153.8, 152.6, 145.0, 133.5, 3 1 3 126.4 (q, JC–F = 4.0 Hz), 124.8 (q, JC–F = 271.8 Hz), 124.0 (q, JC–F = 4.0 Hz), 123.9 (q, 2 4 JC–F = 32.2 Hz), 118.9, 111.7 (app t, JC–F = 2.0 Hz), 40.0 (br s), 39.3, 34.2 (br, s), 22.4; + HRMS (ESI) calcd for [C14H17F3N2 + H] 271.1417, found 271.1419. 2-Iodo-4-methoxy-1-nitrobenzene (4.42h) was prepared from 5-methoxy-2- nitroaniline (4.41h) following a known procedure.* 4.42h: Prepared from 9.5 mmol of 1 4.41h, 48% yield; yellow solid; Rf = 0.31 (1:9 EtOAc/hexanes); H NMR (500 MHz,

CDCl3) δ 8.00 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.8, 2.4 Hz, 1H), 3.88 (s, 3H); matched a known report.* Synthesis of 4.43h:† In a flame-dried flask, a stirred solution of 4.42h (1.12 g, 4.0 mmol, 1.0 equiv) in THF (16.0 mL) was cooled to –40 °C under N2. PhMgCl (2.0 M in THF, 2.2 mL, 4.4 mmol, 1.1 equiv) was added dropwise via syringe. Upon completion of addition, the reaction was stirred at –40 °C for additional 5 min at which point CuCN·2LiCl (1.0 M in THF, 4.4 mL, 4.4 mmol, 1.1 equiv) was slowly added and the resulting reddish solution was stirred at –40 °C for 30 min. 3-Bromo-2-methyl-1-propene (0.48 mL, 4.8 mmol, 1.2 equiv) was added dropwise and the resulting solution was allowed to stir at –40 °C for 1 h, then quenched by addition of saturated aqueous NH4Cl

(10 mL). To the resulting suspension was added NH4OH solution (28.0 – 30.0% NH3 basis, 4.0 mL) and extracted with Et2O (3 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (15:85 CH2Cl2/hexanes) to give 4.43h as a yellow solid (353 mg, 1.7 mmol, 43%). 1 4.43h: Rf = 0.47 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 9.3 Hz, 1H), 6.82 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (d, J = 2.4 Hz, 1H), 4.82 (m, 1H), 4.49

* Dantale, S. W.; Soderberg, B. C. G. Tetrahedron 2003, 59, 5507. † Procedure was modified from: (a) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 1610. (b) Li, C.; Li. X.; Hong, R. Org. Lett. 2009, 11, 4036.

Chapter 4 | 162 13 (m, 1H), 3.87 (s, 3H), 3.67 (s, 2H), 1.76 (s, 3H); C NMR (125 MHz, CDCl3) δ 162.9, 143.2, 142.4, 137.8, 127.6, 117.2, 112.3, 112.0, 55.7 (d), 41.2, 22.9; LRMS (CI) + [C11H13NO3 + H] found 208.1. Sulfonamide 4.42k was prepared from 2-iodoaniline (4.41a) following a known procedure.* 4.42k: Prepared from 10.0 mmol of 4.41a, 96% yield; yellow solid; 1H NMR

(300 MHz, CDCl3) δ 7.67 – 7.61 (m, 4H), 7.31 (td, J = 8.4, 1.5 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 6.83 (td, J = 7.3, 1.5 Hz, 1H), 6.79 (br s, 1H), 2.38 (s, 3H); matched that previously reported.† Synthesis of 4.43k:‡ A 20 mL reaction vial was charged with a magnetic stirring bar, sulfonamide 4.42k (2.24 g, 6.0 mmol, 1.0 equiv), (±)-3-buten-2-ol (1.6 mL, 18.0 mmol, 3.0 equiv), palladium(II) acetate (26 mg, 0.12 mmol, 0.02 equiv), tetrabutylammonium chloride (1.67 g, 6.0 mmol, 1.0 equiv), sodium carbonate (1.59 g, 15.0 mmol, 2.5 equiv) and DMF (reagent grade, 12.0 mL). The reaction mixture was degassed for 5 min by bubbling a stream of N2 through the liquid, and subsequently sealed with a PTFE lined cap. The reaction was vigorously stirred at 80 °C for 48 h at which point TLC analysis (1:1 EtOAc/hexanes, followed by 2,4-dinitrophenylhydrazine stain and heating) indicated the complete consumption of starting material. The resulting mixture was diluted with water (40 mL) and extracted with CH2Cl2 (2 × 40 mL). The combined organic extracts were washed with 2 M aqueous LiCl (20 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc/hexanes) to give ketone 4.43k as a colorless solid (1.07 g, 3.4 mmol, 56% yield). 1 4.43k: Rf = 0.63 (1:1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.38 (br s, 1H), 7.63 (dt, J = 8.3, 2.0 Hz, 2H), 7.37 (dd, J = 8.3, 1.5 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 7.14 (td, J = 7.8, 2.0 Hz, 1H), 7.09 (td, J = 7.3, 1.5 Hz, 1H), 7.01 (dd, J = 7.3, 2.0 Hz, 1H), 2.72 (t, J = 6.4 Hz, 2H), 2.40 (t, J = 6.4 Hz, 2H), 2.38 (s, 3H), 2.08 (s, 3H); 13C

* Bressy, C.; Alberico D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. † Zenner, J. M.; Larock, R. C. J. Org. Chem. 1999, 64, 7312. ‡ Procedure was adopted from an analogous allylic alcohol Heck reaction using Jeffrey's conditions: Thompson, M. D.; Torabi, H. S. Synthesis 1994, 9, 965.

Chapter 4 | 163

NMR (125 MHz, CDCl3) δ 209.8, 143.2, 137.3, 134.9, 134.7, 130.0, 129.4, 127.2, 127.0, + 126.2, 125.4, 45.0, 29.7, 23.4, 21.5; HRMS (ESI) calcd for [C17H19NO3S + Na] 340.0978, found 340.0958.

4.8.5 Preparation of sulfonamide intermediates

Preparation of sulfonamide intermediates 4.45a–f, 4.45i, 4.45j, 4.45l, 4.45n, 4.45o, and 4.40r

Synthesis of 4.44a:* In a nitrogen-filled glove box, a reaction flask was charged with tetrakis(triphenylphosphine)palladium(0) (69.3 mg, 0.06 mmol. 0.02 equiv), amine 4.43a (682 mg, 3.0 mmol, 1.0 equiv), 1,3-dimethylbarbituric acid (2.81 g, 18.0 mmol, 6.0 equiv), and degassed CH2Cl2 (7.5 mL). The reaction mixture was sealed with a rubber septum, removed from the glove box and stirred at 35 °C for 16 h under N2. After cooling, the reaction mixture was diluted with CH2Cl2 (80 mL) and vigorously washed with 2 M aqueous NaOH (2 × 20 mL). The organic layer was separated, washed

with brine (20 mL), dried over Na2SO4, and concentrated in vacuo to give an orange oil, which is an inseparable mixture of the aniline product and 5,5-diallyl-1,3-dimethyl-pyrimidine-2,4,6-trione (4.53).† The crude product was used without additional purification. Synthesis of 4.55a: To a stirred solution of crude aniline product (~ 3.0 mmol, 1.0 equiv) and pyridine (0.49 mL, 6.0 mmol. 2.0 equiv) in CH2Cl2 (6.0 mL) was added p-

* Procedure was modified from: Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993, 58, 6109. † Identified by 1H NMR of the crude mixture. Also see: Kumarassamy, E.; Sivaguru, J. Chem. Commun. 2013, 49, 4346.

Chapter 4 | 164 toluenesulfonyl chloride (686 mg, 3.6 mmol, 1.2 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 h, and then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with CH2Cl2 (40 mL), washed with 1 M aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The resulting mixture was carefully purified by flash column chromatography (1:99 → 5:95 EtOAc/hexanes) to give sulfonamide 4.55a as a viscous, colorless oil (769 mg, 2.6 mmol, 85% yield over two steps). 4.45b–f, 4.45i, 4.45j, 4.45o, and 4.45r were prepared in the same manner as 4.45a. 4.45l was prepared in the same manner as 4.45a, except that p-nitrobenzenesulfonyl chloride (NsCl) was used instead of TsCl.* 4.45n was prepared from tosylation of 2- isopropenylaniline (4.41n)† in the same manner as 4.45a. 1 4.45a: Rf = 0.50 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.59 (dt, J = 8.3, 2.0 Hz, 2H), 7.46 (dd, J = 8.3, 1.0 Hz, 1H), 7.23 – 7.20 (m, 3H), 7.09 (td, J = 7.3, 1.5 Hz, 1H), 7.03 (dd, J = 7.8, 1.5 Hz, 1H), 6.68 (br s, 1H), 4.89 (app s, 1H), 4.61 (app s, 1H), 13 2.91 (s, 2H), 2.39 (s, 3H), 1.57 (s, 3H); C NMR (75 MHz, CDCl3) δ 143.8, 143.6, 136.8, 135.4, 131.2, 131.0, 129.6, 127.8, 127.0, 125.9, 124.1, 112.9, 41.0, 22.1, 21.6; HRMS + (ESI) calcd for [C17H19NO2S + Na] 324.1029, found 324.1033. 4.45b: Prepared from 3.4 mmol of 4.43b, 67% yield over two steps; viscous yellow 1 oil; Rf = 0.18 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.59 (dt, J = 8.5, 1.9 Hz, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 6.98 (dd, J = 8.2, 1.8 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 6.72 (s, 1H), 4.83 (app s, 1H), 4.56 (m, 1H), 2.86 (s, 2H), 2.36 (s, 13 3H), 2.24 (s, 3H), 1.55 (s, 3H); C NMR (125 MHz, CDCl3) δ 143.8, 143.6, 136.9, 135.9, 132.6, 131.7, 131.5, 129.5, 128.3, 127.0, 124.8, 112.6, 40.8, 22.2, 21.5, 20.9; + HRMS (ESI) calcd for [C18H21NO2S + Na] 338.1191, found 338.1187.

* 4.45l was contaminated with minor amount of 4.53. † Preparation of 4.41n: Bowman, W. R.; Fletcher, A. J.; Pedersen, J. M.; Lovell, P. J.; Elsegood, M. R. J.; Lopez, E. H.; McKee, V.; Potts, G. B. S. Tetrahedron 2007, 63, 191.

Chapter 4 | 165

4.45c: Prepared from 3.0 mmol of 4.43c, 28% yield over two steps; white solid; Rf = 1 0.13 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.61 (dt, J = 8.6, 2.0 Hz, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.23 – 7.19 (m, 3H), 7.03 (d, J = 2.4 Hz, 1H), 6.63 (s, 1H), 4.85 (m, 1H), 4.58 – 4.57 (m, 1H), 2.92 (s, 2H), 2.39 (s, 3H), 1.58 (s, 3H), 1.26 (s, 9H); 13C

NMR (125 MHz, CDCl3) δ 148.9, 143.8, 143.5, 137.1, 132.5, 131.0, 129.5, 127.9, 127.0,

124.5, 124.0, 112.5, 41.1, 34.3, 31.2, 22.1, 21.5; HRMS (ESI) calcd for [C21H27NO2S + Na]+ 380.1660, found 380.1660.

4.45d: Prepared from 3.0 mmol of 4.43d, 75% yield over two steps; yellow oil; Rf = 1 0.23 (1:9 EtOAc/hexanes); H NMR* (500 MHz, CDCl3) δ 7.56 (d, J = 8.3 Hz, 2H), 7.38 (dd, J = 8.8, 5.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 6.91 (td, J = 8.4, 2.9 Hz, 1H), 6.77 (dd, J = 8.8, 2.9 Hz, 1H), 6.55 (s, 1H), 4.88 (app s, 1H), 4.57 (app s, 1H), 2.84 (s, 2H), 2.40 (s, 13 1 3H), 1.56 (s, 3H); C NMR (125 MHz, CDCl3) δ 160.1 (d, JF-C = 245.7 Hz), 143.9, 3 4 3 142.8, 136.6, 135.1 (d, JF-C = 8.1 Hz), 131.1 (d, JF-C = 3.0 Hz), 129.6, 127.3 (d, JF-C = 2 2 9.1 Hz), 127.0, 117.3 (d, JF-C = 22.2 Hz), 114.3 (d, JF-C = 22.2 Hz), 113.2, 40.5, 22.1, + 21.5; HRMS (ESI) calcd for [C17H18FNO2S + Na] 342.0934, found 342.0935. *Note: Coupling constants reported as observed. No attempt was made to distinguish

JH–H vs. JF–H.

4.45e: Prepared from 2.7 mmol of 4.43e, 88% yield over two steps; white solid; Rf = 1 0.26 (1:9 EtOAc/hexanes); H NMR (300 MHz, CDCl3) δ 7.59 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.16 (dd, J = 8.4, 2.2 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.77 (s, 1H), 4.89 (app s, 1H), 4.60 (app s, 1H), 2.89 (s, 2H), 2.39 (s, 3H), 13 1.56 (s, 3H); C NMR (75 MHz, CDCl3) δ 144.0, 142.7, 136.4, 133.9, 133.3, 131.3, 130.6, 129.6, 127.6, 126.9, 125.6, 113.4, 40.4, 22.0, 21.5; HRMS (ESI) calcd for + [C17H18ClNO2S + Na] 358.0639, found 358.0640.

4.45f: Prepared from 1.0 mmol of 4.43f, 93% yield over two steps; white solid; Rf = 1 0.26 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 7.8 Hz, 2H), 7.36 – 7.31 (m, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.18 (s, 1H), 6.68 (app s, 1H), 4.90 (app s, 1H), 13 4.60 (s, 1H), 2.87 (s, 2H), 2.39 (s, 3H), 1.56 (s, 3H); C NMR (125 MHz, CDCl3) δ

Chapter 4 | 166 144.1, 142.8, 136.5, 134.6, 133.6, 133.4, 130.7, 129.7, 127.0, 125.7, 119.2, 113.5, 40.5, + 22.1, 21.5; HRMS (ESI) calcd for [C17H18BrNO2S + Na] 402.0134, found 402.0137. 4.45i: Prepared from 1.6 mmol of 4.43i, 88% yield over two steps; viscous colorless 1 oil; Rf = 0.29 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.23 – 7.20 (m, 3H), 7.09 (t, J = 7.3 Hz, 1H), 7.03 (dd, J = 7.8, 1.5 Hz, 1H), 6.68 (s, 1H), 4.89 (app s, 1H), 4.59 (app s, 1H), 2.93 (s, 2H), 2.39 (s, 13 3H), 1.86 (q, J = 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H); C NMR (125 MHz, CDCl3) δ 149.1, 143.7, 136.8, 135.4, 131.3, 131.0, 129.5, 127.7, 127.0, 125.9, 124.1, 110.7, 39.6, + 28.4, 21.5, 12.1; HRMS (ESI) calcd for [C18H21NO2S + Na] 338.1185, found 338.1178. 4.45j: Prepared from 0.73 mmol of 4.43j, 85% yield over two steps; light pink solid; 1 Rf = 0.23 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 1H), 7.32 – 7.28 (m, 5H), 7.22 – 7.19 (m, 3H), 7.13 – 7.09 (m, 2H), 6.51 (s, 1H), 5.44 (app s, 1H), 4.73 (app s, 1H), 3.40 (s, 2H), 2.40 (s, 3H); 13C NMR (125

MHz, CDCl3) δ 145.4, 143.8, 139.9, 136.8, 134.9, 132.2, 131.0, 129.6, 128.4, 128.0,

127.7, 127.0, 126.4, 125.8, 124.9, 114.5, 37.5, 21.6; HRMS (ESI) calcd for [C22H21NO2S + Na]+ 386.1185, found 386.1177.

4.45l: Prepared from 2.0 mmol of 4.43a, 89% yield over two steps; yellow solid; Rf 1 = 0.50 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.26 (dt, J = 8.8, 2.0 Hz, 2H), 7.90 (dt, J = 8.8, 2.0 Hz, 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.20 (td, J = 7.8, 1.5 Hz, 1H), 7.13 (td, J = 7.3, 1.0 Hz, 1H), 7.07 (dd, J = 7.3, 1.5 Hz, 1H), 7.04 (s, 1H), 4.82 (app s, 13 1H), 4.54 (app s, 1H), 2.97 (s, 2H), 1.54 (s, 3H); C NMR (125 MHz, CDCl3) δ 150.0, 145.1, 143.4, 134.1, 131.9, 131.1, 128.2, 127.8, 126.7, 124.2, 124.1, 112.8, 40.5, 22.0; – HRMS (ESI) calcd for [C16H16N2O4S – H] 331.0758, found 331.0800.

4.45n: Prepared from 10.0 mmol of 4.41n, 92% yield; light yellow oil; Rf = 0.59 1 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.3, 1.0 Hz, 1H), 7.62 (dt, J = 8.3, 2.0 Hz, 2H), 7.22 – 7.19 (m, 3H), 7.06 – 7.00 (m, 3H), 5.26 – 5.25 (m, 1H), 13 4.67 (m, 1H), 2.35 (s, 3H), 1.69 (t, J = 1.5 Hz, 3H); C NMR (125 MHz, CDCl3) δ 143.8, 141.9, 136.1, 134.6, 132.7, 129.5, 127.9, 127.88, 127.1, 124.3, 120.5, 117.1, 24.4, 21.4; + HRMS (ESI) calcd for [C16H17NO2S + Na] 310.0872, found 310.0880.

Chapter 4 | 167 4.45o: Prepared from 2.8 mmol of 4.43o, 84% yield over two steps; viscous 1 colorless oil; Rf = 0.37 (15:85 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.60 (dt, J = 8.3, 1.5 Hz, 2H), 7.40 (dd, J = 8.3, 1.5 Hz, 1H), 7.22 – 7.18 (m, 3H), 7.11 (td, J = 7.3, 1.5 Hz, 1H), 7.06 (dd, J = 7.8, 2.0 Hz, 1H), 6.59 (s, 1H), 5.77 (ddt, J = 17.1, 10.1, 6.1 Hz, 1H), 5.10 (ddd, J = 10.3, 3.4, 1.5 Hz, 1H), 4.93 (ddd, J = 17.1, 3.4, 1.5 Hz, 1H), 3.01 (app 13 dt, J = 5.9, 1.5 Hz, 2H), 2.39 (s, 3H); C NMR (125 MHz, CDCl3) δ 143.8, 136.7, 135.5, 134.9, 132.0, 130.4, 129.6, 127.6, 127.0, 126.2, 124.5, 117.0, 36.1, 21.5; HRMS (ESI) + calcd for [C16H17NO2S + Na] 310.0872, found 310.0877. 4.45r: Prepared from 1.4 mmol of 4.43r; 68% yield over two steps; viscous yellow 1 oil; Rf = 0.38 (15:85 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.55 – 7.52 (m, 3H), 7.41 – 7.37 (m, 4H), 7.36 -7.32 (m, 1H), 7.21 (ddd, J = 8.8, 6.8, 2.4 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.10 – 7.05 (m, 2H), 5.01 (m, 1H), 4.81 (m, 1H), 4.60 (s, 13 2H), 3.79 (s, 2H), 2.98 (s, 2H), 2.37 (s, 3H); C NMR (125 MHz, CDCl3) δ 144.1, 143.3, 137.2, 137.0, 135.1, 131.5, 130.8, 129.4, 128.5, 128.2, 127.9, 127.6, 126.9, 125.5, 124.0, + 115.4, 72.3, 72.2, 34.9, 21.5; HRMS (ESI) calcd for [C24H25NO3S + Na] 430.1447, found 430.1439.

Preparation of sulfonamides 4.45g, 4.45h and 4.45k

Scheme 4.25. Synthesis of sulfonamides 4.45g, 4.45h and 4.45k

Chapter 4 | 168 Synthesis of 4.45g:* A 20 mL reaction vial was charged with a magnetic stir bar, amidine 4.43g (867 mg, 3.2 mmol, 1.0 equiv), ethylenediamine (2.1 mL, 32 mmol, 10.0 equiv) and ethanol (6.0 mL). The reaction mixture was sealed with a PTFE lined cap and stirred at 90 °C for 5 h at which point TLC analysis (1:9 EtOAc/hexanes, followed by

KMnO4 stain and heating) indicated the complete consumption of starting material. The reaction mixture was allowed to cool to room temperature, concentrated in vacuo, diluted with water (40 mL) and extracted with Et2O (3 × 40 mL). The combined organic extracts were washed with water (20 mL) and brine (40 mL), dried over Na2SO4 and concentrated in vacuo to give the crude aniline product as a yellow oil. Without further purification, this product was converted to the tosyl sulfonamide as an off-white solid (852 mg, 2.3 mmol, 72% yield over two steps after column chromatography using 5:95 EtOAc/hexanes as eluents). 1 4.45g: Rf = 0.29 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.65 (dt, J = 8.3, 1.5 Hz, 2H), 7.60 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 8.8, 2.0 Hz, 1H), 7.30 (d, J = 1.5 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 4.96 (app s, 1H), 4.67 (app s, 1H), 3.06 (s, 13 2H), 2.40 (s, 3H), 1.60 (s, 3H); C NMR (125 MHz, CDCl3) δ 144.3, 142.6, 138.9, 3 2 136.3, 130.1, 129.8, 127.9 (q, JC–F = 3.0 Hz), 127.0 (q, JC–F = 33.2 Hz),* 127.0,* 124.8 3 1 4 (q, JC–F = 4.0 Hz), 124.8 (q, JC–F = 271.8 Hz), 121.9, 113.7 (app t, JC–F = 3.0 Hz), 40.8, + 22.0, 21.5; HRMS (ESI) calcd for [C18H18F3NO2S + Na] 392.0903, found 392.0916. *Note: overlapped peaks discernable due to C-F coupling. Synthesis of 4.45h: To a stirred suspension of 4.43h (347 mg, 1.7 mmol, 1.0 equiv) and zinc dust (1.64 g, 25.0 mmol) in ethanol (reagent grade, 12.0 mL) was slowly added glacial acetic acid (1.4 mL, 25.0 mmol) at room temperature. After gas evolution ceased, the reaction was stirred for 1 h at which point TLC analysis indicated the complete consumption of starting material. The resulting mixture was diluted with EtOAc (40 mL), filtered through a pad of Celite, and concentrated to a small volume. The residue was dissolved in EtOAc (40 mL) and carefully washed with saturated aqueous NaHCO3 (20

* Procedure was modified from: Zhichkin, P. E.; Peterson, L. H.; Beer, C. M.; Rennells, W. M. J. Org. Chem. 2008, 73, 8954.

Chapter 4 | 169 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give the crude aniline product as a dark brown oil. Without further purification, the crude product was converted to the tosyl sulfonamide as a colorless oil (292 mg, 0.88 mmol, 53% yield over two steps after column chromatography using 1:4 Et2O:hexanes as eluent). 1 4.45h: Rf = 0.39 (7:3 CH2Cl2/hexanes); H NMR (300 MHz, CDCl3) δ 7.55 (dt, J = 8.4, 1.8 Hz, 2H), 7.30 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.74 (dd, J = 8.8, 2.9 Hz, 1H), 6.58 (d, J = 2.9 Hz, 1H), 6.41 (s, 1H), 4.84 (app s, 1H), 4.55 (app s, 1H), 3.76 (s, 13 3H), 2.78 (s, 2H), 2.39 (s, 3H), 1.56 (s, 3H); C NMR (75 MHz, CDCl3) δ 158.0, 143.6, 143.5, 136.9, 135.0, 129.5, 127.8, 127.0, 116.3, 112.7, 112.2, 55.3, 40.8, 22.2, 21.5; + HRMS (ESI) calcd for [C18H21NO3S + Na] 354.1134, found 354.1126. Synthesis of 4.45k: To a suspension of methyltriphenylphosphonium bromide (2.14 g, 6.0 mmol, 3.0 equiv) in THF (5.0 mL) was slowly added potassium tert-butoxide (1 M in THF, 6.0 mL, 6.0 mmol, 3.0 equiv) at room temperature. The resulting yellow suspension was stirred for 2 h and ketone 4.43k (635 mg, 2.0 mmol, 1.0 equiv) in THF (2.0 mL) was slowly added. The resulting mixture was stirred overnight, then acidified with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:9 → 1:4 EtOAc/hexanes) to give sulfonamide 4.45k as a colorless solid (463 mg, 1.5 mmol, 74% yield). 1 4.45k: Rf = 0.31 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.61 (dt, J = 8.3, 2.0 Hz, 2H), 7.32 (dd, J = 6.8, 2.0 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.16 – 7.09 (m, 3H), 6.47 (s, 1H), 4.73 (app s, 1H), 4.58 (app s, 1H), 2.47 – 2.43 (m, 2H), 2.39 (s, 3H), 13 2.05 – 2.02 (m, 2H), 1.68 (s, 3H); C NMR (125 MHz, CDCl3) δ 144.8, 143.8, 136.6, 135.6, 133.9, 129.6, 129.58, 127.1, 126.9, 126.4, 124.9, 110.7, 37.7, 29.0, 22.6, 21.5; + HRMS (ESI) calcd for [C18H21NO2S + Na] 338.1185, found 338.1182.

4.8.6 Synthesis of cyanamide substrates

Chapter 4 | 170

Scheme 4.26. Synthesis of substrates 4.40

CAUTION! Cyanogen bromide (BrCN) is highly toxic and hydrolyzes readily to release hydrogen cyanide. This preparation must be carried out in a well-ventilated fume hood. Excess BrCN should be destroyed with aqueous NaOH solution, and the resulting aqueous solution should be disposed of properly. Synthesis of 4.40a:* In a fume hood, a stirred solution of 4.45a (301 mg, 1.0 mmol,

1.0 equiv) in anhydrous Et2O (5.0 mL)* was cooled to 0 °C. Cyanogen bromide (127 mg, 1.2 mmol, 1.2 equiv) was added in one portion followed by dropwise addition of triethylamine (reagent grade, 0.20 mL, 1.4 mmol, 1.4 equiv). The resulting white suspension was vigorously stirred at 0 °C for 3 h at which point TLC analysis (1:4

EtOAc/hexanes or 1:1 CH2Cl2/hexanes) indicated the complete consumption of starting material and formation of a lower-running spot (visualized by UV light, followed by

KMnO4 stain). The reaction mixture was diluted with Et2O (40 mL), filtered through a pad of Celite and washed with saturated aqueous K2CO3 (5 mL). The organic layer was separated, dried over Na2SO4, and concentrated onto Celite. Flash column chromatography (1:9 EtOAc/hexanes) provided the cyanamide product 4.40a (313 mg, 0.96 mmol, 96% yield) as an off-white solid.

*Note: A CH2Cl2/Et2O (1:1 v/v) solvent system was used when the starting sulfonamide would not completely dissolve in pure Et2O. All other subsrates were prepared in the same manner as 4.40a. 4.40 was further purified by preparative thin-layer chromatography.

* Procedure was adapted from: Koester, D. C.; Kobayashi, M.; Werz, D. B.; Nakao, Y. J. Am. Chem. Soc. 2012, 134, 6544.

Chapter 4 | 171 1 4.40a: Rf = 0.50 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 2H), 7.41 – 7.39 (m, 3H), 7.34 (d, J = 7.3 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 4.92 (app s, 1H), 4.67 (app s, 1H), 3.38 (br s, 2H), 2.51 (s, 3H), 1.66 13 (s, 3H); C NMR (125 MHz, CDCl3) δ 146.7, 142.6, 139.8, 133.2, 133.0, 131.3, 130.9, 130.3, 128.6, 128.1, 127.6, 113.8, 108.6, 39.3, 22.3, 21.8; IR (thin film) 3056, 2983, + 2228, 1650, 1596; HRMS (ESI) calcd for [C18H18N2O2S + Na] 349.0981, found 349.0974.

4.40b: Prepared from 2.3 mmol of 4.45b, 69% yield; colorless solid; Rf = 0.23 (1:9 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 1.3 Hz, 1H), 6.97 (dd, J = 8.1, 1.6 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 4.90 (s, 1H), 4.67 (s, 1H), 3.33 (s, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 1.65 (s, 3H); 13C NMR

(125 MHz, CDCl3) δ 146.6, 142.7, 141.3, 139.2, 132.9, 131.8, 130.5, 130.2, 128.5, 128.3, 127.7, 113.6, 108.6, 39.2, 22.2, 21.7, 21.2; IR (thin film) 2923, 2230, 1650, 1596; + HRMS (ESI) calcd for [C19H20N2O2S + Na] 363.1143, found 363.1145.

4.40c: Prepared from 1.4 mmol of 4.45c, 29% yield; colorless solid; Rf = 0.28 (1:9 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.3, 2.4 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 4.91 (app s, 1H), 4.66 (app s, 1H), 3.36 (br s, 2H), 2.51 (s, 3H), 1.67 (s, 3H), 1.29 (s, 9H); 13 C NMR (125 MHz, CDCl3) δ 154.2, 146.6, 142.8, 138.8, 133.2, 130.5, 130.3, 128.6, 128.5, 127.5, 124.6, 113.5, 108.7, 39.6, 34.8, 31.1, 22.3, 21.8; IR (thin film) 2965, 2229, + 1652, 1595; HRMS (ESI) calcd for [C22H26N2O2S + Na] 405.1613, found 405.1614.

4.40d: Prepared from 2.0 mmol of 4.45d, 92% yield; colorless solid; Rf = 0.46 1 (15:85 EtOAc/hexanes); H NMR* (500 MHz, CDCl3) δ 7.73 (dt, J = 8.5, 2.5 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.04 (dd, J = 9.3, 2.9 Hz, 1H), 6.88 (ddd, J = 8.8, 7.3, 2.9 Hz, 1H), 6.81 (dd, J = 8.8, 5.1 Hz, 1H), 4.95 (app s, 1H), 4.71 (app s, 1H), 3.33 (br s, 2H), 13 1 2.51 (s, 3H), 1.65 (s, 3H); C NMR (125 MHz, CDCl3) δ 163.6 (d, JF-C = 251.7 Hz), 3 3 147.0, 142.7 (d, JF-C = 8.1 Hz), 141.8, 132.6, 130.4, 130.0 (d, JF-C = 10.1 Hz), 128.9 (d, 4 2 2 JF-C = 3.0 Hz), 128.5, 117.8 (d, JF-C = 23.2 Hz), 114.7 (d, JF-C = 23.2 Hz), 114.5, 108.3,

Chapter 4 | 172 39.3, 22.0, 21.8; IR (thin film) 3080, 2975, 2224, 1651, 1595; HRMS (ESI) calcd for + [C18H17FN2O2S + Na] 367.0887, found 367.0883. *Note: Coupling constants reported as observed. No attempt was made to distinguish

JH–H vs. JF–H.

4.40e: Prepared from 2.3 mmol of 4.45e, 88% yield; off-white solid; Rf = 0.51 1 (15:85 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 8.3, 2.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.96 (app s, 1H), 4.71 (app s, 1H), 3.32 (br s, 2H), 2.51 (s, 3H), 1.65 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 147.0, 141.7, 141.65, 137.1, 132.6, 131.6, 131.1, 130.4, 129.3, 128.5, 127.9, 114.5, 108.2, 39.1, 22.1, 21.8; IR (thin film) 2978, 2227, 1649, 1595; + HRMS (ESI) calcd for [C18H17ClN2O2S + Na] 383.0591, found 383.0597.

4.40f: Prepared from 0.93 mmol of 4.45f, 96% yield; viscous colorless oil; Rf = 0.56 1 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.32 (dd, J = 8.3, 2.0 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 4.95 (app s, 1H), 4.70 (app s, 1H), 3.32 (s, 2H), 2.51 (s, 3H), 1.65 (s, 3H); 13C NMR

(125 MHz, CDCl3) δ 147.0, 141.9, 141.8, 134.2, 132.6, 132.2, 130.9, 130.4, 129.5, 128.6, 125.4, 114.6, 108.1, 39.1, 22.2, 21.9; IR (thin film) 3081, 2973, 2231, 1650, 1594; + HRMS (ESI) calcd for [C18H17BrN2O2S + Na] 427.0086, found 427.0063.

4.40g: Prepared from 2.1 mmol of 4.45g, 94% yield; pale yellow solid; Rf = 0.62 1 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 4.98 (app s, 1H), 4.69 (app s, 1H), 3.42 (s, 2H), 2.52 (s, 3H), 1.66 (s, 3H); 13C NMR 2 (125 MHz, CDCl3) δ 147.3, 141.6, 141.0, 136.1, 132.9 (q, JC–F = 33.2 Hz), 132.5, 130.5, 3 2 1 128.8, 128.5, 128.2 (app q, JC–F = 3.0 Hz), 124.6 (q, JC–F = 4.0 Hz), 123.2 (q, JC–F = 272.8 Hz), 114.8, 107.9, 39.2, 22.2, 21.8; IR (thin film) 3081, 2976, 2234, 1652, 1595; + HRMS (ESI) calcd for [C19H17F3N2O2S + Na] 417.0855, found 417.0845. 4.40h: Prepared from 0.86 mmol of 4.45h, 73% yield after prep-TLC; viscous 1 brown oil; Rf = 0.38 (1:1 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 2.9 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H),

Chapter 4 | 173 6.86 (dd, J = 8.8, 2.9 Hz, 1H), 4.92 (app s, 1H), 4.70 (app s, 1H), 3.79 (s, 3H), 3.31 (br s, 13 2H), 2.50 (s, 3H), 1.66 (s, 3H); C NMR (75 MHz, CDCl3) δ 161.1, 146.6, 142.5, 141.3, 133.0, 130.3, 129.3, 128.6, 125.6, 116.0, 113.9, 112.8, 108.7, 55.5 (app q), 39.5, 22.2,

21.8; IR (thin film) 2970, 2227, 1650, 1597, 1285; HRMS (ESI) calcd for [C19H20N2O3S + Na]+ 379.1087, found 379.1081.

4.40i: Prepared from 1.5 mmol of 4.45i, 90% yield; off-white solid; Rf = 0.40 (15:85 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.41 – 7.38 (m, 3H), 7.33 (dd, J = 7.8, 1.5 Hz, 1H), 7.17 (td, J = 7.8, 1.5 Hz, 1H), 6.78 (dd, J = 7.8, 1.0 Hz, 1H), 4.93 (app s, 1H), 4.63 (app s, 1H), 3.42 (br s, 2H), 2.51 (s, 3H), 1.95 (q, J = 7.3 13 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H); C NMR (125 MHz, CDCl3) δ 148.3, 146.7, 140.1, 133.2, 133.0, 131.5, 130.9, 130.3, 128.6, 128.0, 127.6, 111.5, 108.6, 38.1, 28.6, 21.8, 12.1;

IR (thin film) 3071, 2967, 2228, 1649, 1596; HRMS (ESI) calcd for [C19H20N2O2S + Na]+ 363.1138, found 363.1148.

4.40j: Prepared from 0.62 mmol of 4.45j, 90% yield; off-white solid; Rf = 0.35 (1:1 1 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 7.76 (dt, J = 8.3, 2.0 Hz, 2H), 7.41 – 7.38 (m, 4H), 7.35 – 7.28 (m, 4H), 7.26 – 7.23 (m, 1H), 7.15 (ddd, J = 7.8, 6.4, 2.4 Hz, 1H), 6.80 (dd, J = 7.8, 1.0 Hz, 1H), 5.58 – 5.57 (m, 1H), 4.99 – 4.98 (m, 1H), 3.91 (br s, 13 2H), 2.50 (s, 3H); C NMR (125 MHz, CDCl3) δ 146.8, 144.7, 139.9, 139.6, 133.0, 132.9, 131.4, 130.9, 130.3, 128.6, 128.4, 128.0, 127.7, 126.0, 115.9, 115.9, 108.5, 36.7, + 21.8; IR (thin film) 2227, 1627, 1595; HRMS (ESI) calcd for [C23H20N2O2S + Na] 411.1138, found 411.1137.

4.40k: Prepared from 1.5 mmol of 4.45k, 78% yield; off-white solid; Rf = 0.47 (1:4 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 2H), 7.41 – 7.38 (m, 3H), 7.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.16 (td, J = 7.8, 1.5 Hz, 1H), 6.83 (dd, J = 7.8, 1.0 Hz, 1H), 4.75 (app s, 1H), 4.66 (app s, 1H), 2.74 (m, 2H), 2.50 (s, 3H), 2.29 (t, J = 7.8 Hz, 13 2H), 1.77 (s, 3H); C NMR (125 MHz, CDCl3) δ 146.8, 144.3, 141.8, 132.9, 132.7, 130.9, 130.7, 130.3, 128.5, 128.1, 127.2, 110.7, 108.7, 37.8, 29.0, 22.3, 21.8; IR (thin + film) 3073, 2969, 2227, 1650, 1595; HRMS (ESI) calcd for [C19H20N2O2S + Na] 363.1138, found 363.1141.

Chapter 4 | 174

4.40l: Prepared from 1.0 mmol of 4.45l, 89% yield; yellow solid; Rf = 0.49 (1:4 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.47 (app dt, J = 8.8, 2.0 Hz, 2H), 8.07 (app dt, J = 8.8, 2.0 Hz, 2H), 7.46 (td, J = 7.3, 1.0 Hz, 1H), 7.39 (dd, J = 7.8, 1.5 Hz, 1H), 7.22 (td, J = 7.8, 1.5 Hz, 1H), 6.76 (dd, J = 7.8, 1.0 Hz, 1H), 4.93 (app s, 1H), 4.67 (app s, 13 1H), 3.41 (br s, 2H), 1.67 (s, 3H); C NMR (125 MHz, CDCl3) δ 151.5, 142.3, 141.2, 139.8, 132.6, 131.9, 131.5, 130.0, 128.0, 127.6, 124.9, 114.0, 107.6, 39.5, 22.3; IR (thin film) 3106, 2977, 2230, 1650, 1608, 1536, 1349; HRMS (ESI) calcd for [C17H15N3O4S + Na]+ 380.0675, found 380.0692.

4.40n: Prepared from 2.0 mmol of 4.45n, 99% yield; viscous brown oil; Rf = 0.45 1 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.74 (td, J = 8.3, 2.0 Hz, 2H), 7.43 – 7.39 (m, 3H), 7.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.21 (td, J = 7.8, 1.5 Hz, 1H), 6.87 (dd, J = 7.8, 1.5 Hz, 1H), 5.29 – 5.28 (m, 1H), 4.99 (app s, 1H), 2.49 (s, 3H), 2.10 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 146.6, 143.9, 140.8, 133.3, 131.1, 130.6, 130.2, 130.1, 128.4, 128.1, 127.9, 117.9, 109.0, 23.7, 21.7; IR (thin film) 3066, 2975, 2226, 1640, 1596; + HRMS (ESI) calcd for [C17H16N2O2S + Na] 335.0825, found 335.0821.

4.40o: Prepared from 2.3 mmol of 4.45o, 84% yield; off-white solid; Rf = 0.36 (1:1 1 CH2Cl2/hexanes); H NMR (500 MHz, CDCl3) δ 7.73 (dt, J = 8.3, 2.0 Hz, 2H), 7.41 – 7.39 (m, 3H), 7.34 (dd, J = 7.3, 1.5 Hz, 1H), 7.18 (td, J = 7.8, 1.5 Hz, 1H), 6.82 (dd, J = 8.3, 1.5 Hz, 1H), 5.85 (ddt, J = 16.8, 10.1, 6.7 Hz, 1H), 5.15 (ddd, J = 10.3, 2.9, 1.5 Hz, 1H), 5.09 (ddd, J = 17.1, 3.4, 2.0 Hz ,1H), 3.40 (d, J = 5.9 Hz, 1H), 2.51 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 146.8, 140.0, 134.8, 132.8, 132.7, 131.1, 131.0, 130.3, 128.5, 128.1, 127.6, 117.6, 108.6, 35.1, 21.8; IR (thin film) 3079, 2226, 1639, 1595; HRMS + (ESI) calcd for [C17H16N2O2S + Na] 335.0825, found 335.0832.

4.40r: Prepared from 0.97 mmol of 4.45r, 90% yield; off-white solid; Rf = 0.41 (1:4 1 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.3 Hz, 2H), 7.40 – 7.34 (m, 8H), 7.31 – 7.27 (m, 1H), 7.18 (td, J = 8.3, 2.0 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.25 (app s, 1H), 4.86 (app s, 1H), 4.50 (s, 2H), 3.92 (s, 2H), 3.52 (br s, 2H), 2.49 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 146.8, 143.2, 139.5, 138.2, 133.3, 132.9, 131.9, 130.9, 130.3, 128.6, 128.3, 128.1, 127.8, 127.7, 127.5, 115.1, 108.6, 72.6, 72.0, 35.2, 21.8; IR (thin

Chapter 4 | 175 + film) 3064, 2855, 2227, 1652, 1595, 1253; HRMS (ESI) calcd for [C25H24N2O3S + Na] 455.1400, found 455.1438.

4.8.7 Intramolecular aminocyanation of cyanamides

B(C6F5)3-promoted intramolecular aminocyanation of cyanamide 4.40a. A representative procedure: In a nitrogen-filled glove box, a 1 dram vial was charged with a magnetic stirring bar, cyanamide 4.40a (32.6 mg, 0.10 mmol, 1.0 equiv), tris(pentafluorophenyl)borane (52.0 mg, 0.10 mmol, 1.0 equiv) and toluene (0.5 mL). The resulting mixture was sealed with a PTFE lined cap, removed from the glove box, and heated at 90 °C in an aluminum heating block for 24 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (1.0 mL). TLC analysis (1:4 EtOAc/hexanes) indicated the complete consumption of starting material and formation of a lower-running spot (visualized by UV light). The resulting solution was concentrated onto Celite and purified by flash column chromatography (1:9 → 1:4 EtOAc/hexanes) to give indoline 4.46a as a viscous colorless oil (29.3 mg, 0.90 mmol, 90% yield). All other cyanamide substrates were subjected to the same conditions described above. The reactions of 4.46n and 4.40n retained unconsumed starting material. The reaction of 4.40n gave sulfonamide 4.46n in quantitative yield. The structure of 4.46n was assigned by comparing its 1H and 13C NMR spectra as well as HRMS data with a

Chapter 4 | 176 recently reported literature.* All other reactions were complete after 24 h except for the reaction of 4.40k, which was complete after 28 h. 1 4.46a: Rf = 0.14 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.18 – 7.14 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H), 3.39 (d, J = 16.1 Hz, 1H), 3.21 (app s, 2H), 3.07 (d, J = 16.1 Hz, 1H), 13 2.40 (s, 3H), 1.78 (s, 3H); C NMR (125 MHz, CDCl3) δ 144.3, 141.3, 138.1, 129.9, 128.2, 126.8, 126.6, 125.2, 123.5, 117.1, 114.1, 68.9, 43.5, 29.8, 25.3, 21.5; IR (thin film) + 3053, 2980, 2254, 1598; HRMS (ESI) calcd for [C18H18N2O2S + Na] 349.0981, found 349.0994. 4.46b: Prepared from 0.10 mmol of 4.40b, 31.3 mg, 0.092 mmol, 92% yield; 1 viscous light yellow oil; Rf = 0.28 (1:4 EtOAc/hexanes); H NMR (500 MHz, CD2Cl2) δ 7.82 (dt, J = 8.7, 2.1 Hz, 2H), 7.30 (dd, J = 8.7, 0.6 Hz, 2H), 7.24 (d, J = 8.2 Hz, 1H), 6.99-6.96 (m, 2H), 3.32 (d, J = 16.3 Hz, 1H), 3.22 (d, J = 16.7 Hz, 1H), 3.08 (d, J = 16.7 Hz, 1H), 3.03 (d, J = 16.3 Hz, 1H), 2.39 (s, 3H), 2.27 (s, 3H), 1.71 (s, 3H); 13C NMR

(125 MHz, CDCl3) δ 144.1, 139.0, 138.2, 133.2, 129.8, 128.6, 126.8, 126.7, 125.8, 117.2, 113.9, 68.9, 43.4, 29.9, 25.2, 21.5, 20.7; IR (thin film) 2978, 2253, 2598, 1488; HRMS + (ESI) calcd for [C19H20N2O2S + Na] 363.1143, found 363.1140. 4.46c: Prepared from 0.10 mmol of 4.40c, 36.0 mg, 0.094 mmol, 94% yield; white 1 solid; Rf = 0.33 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 8.3, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.24 (s, 1H), 7.17 – 7.16 (m, 2H), 3.38 (d, J = 16.1 Hz, 1H), 3.24 (d, J = 16.6 Hz, 1H), 3.19 (d, J = 16.6 Hz, 1H), 3.05 (d, J = 16.1 Hz, 1H), 2.40 (s, 13 3H), 1.78 (s, 3H), 1.27 (s, 9H); C NMR (125 MHz, CDCl3) δ 146.6, 144.1, 138.8, 138.2, 129.8, 126.9, 126.2, 125.1, 122.2, 117.3, 113.4, 69.1, 43.6, 34.3, 31.4, 29.8, 25.3,

21.6; IR (thin film) 2963, 2254, 1598, 1492; HRMS (ESI) calcd for [C22H26N2O2S + Na]+ 405.1613, found 405.1619. A second reaction with 1c (38.3 mg, 0.10 mmol) gave 2c (33.6 mg, 0.087 mmol, 88 % yield) after chromatography.

* The spectroscopic data of 4.46n were consistent with those previously reported: Wang, R.; Falck, J. R. Chem. Commun. 2013, 49, 6516.

Chapter 4 | 177 4.46d: Prepared from 0.10 mmol of 4.40d, 34.3 mg, 0.10 mmol, quantitative yield; 1 viscous colorless oil; Rf = 0.16 (1:9 EtOAc/hexanes); H NMR* (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.33 (dd, J = 8.8, 4.4 Hz, 1H), 7.29 (d, J = 8.3 Hz, 2H), 6.88 – 6.84 (m, 2H), 3.35 (d, J = 16.6 Hz, 1H), 3.22 (d, J = 16.6 Hz, 1H), 3.15 (d, J = 16.6 Hz, 13 1H), 3.04 (d, J = 16.5 Hz, 1H), 2.41 (s, 3H), 1.76 (s, 3H); C NMR (125 MHz, CDCl3) δ 1 4 3 159.2 (d, JF-C = 242.6 Hz), 144.4, 137.9, 137.4 (d, JF-C = 2.0 Hz), 129.9, 128.5 (d, JF-C 3 2 = 8.1 Hz), 126.8, 116.9, 114.9 (d, JF-C = 8.1 Hz), 114.6 (d, JF-C = 23.1 Hz), 112.5 (d, 2 JF-C = 24.2 Hz), 69.3, 43.2, 29.9, 25.2, 21.5; IR (thin film) 2980, 2254, 1598, 1482; + HRMS (ESI) calcd for [C18H17FN2O2S + Na] 367.0887, found 367.0895. *Note: Coupling constants reported as observed. No attempt was made to distinguish

JH–H vs. JF–H. 4.46e: Prepared from 0.10 mmol of 4.40e, 34.4 mg, 0.095 mmol, 95% yield; viscous 1 colorless oil; Rf = 0.20 (1:9 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.33 – 7.29 (m, 3H), 7.14 – 7.12 (m, 2H), 3.35 (d, J = 16.1 Hz, 1H), 3.22 (d, J = 16.6 Hz, 1H), 3.16 (d, J = 17.1 Hz, 1H), 3.04 (d, J = 16.1 Hz, 1H), 2.41 (s, 3H), 1.75 13 (s, 3H); C NMR (125 MHz, CDCl3) δ 144.6, 140.0, 137.8, 130.0, 128.6, 128.5, 128.2, 126.8, 125.3, 116.9, 114.9, 69.3, 43.1, 29.9, 25.3, 21.6; IR (thin film) 2980, 2253, 1598, + 1472; HRMS (ESI) calcd for [C18H17ClN2O2S + Na] 383.0591, found 383.0599. 4.46f: Prepared from 0.10 mmol of 4.40f, 39.9 mg, 0.096 mmol, 96% yield; viscous 1 colorless oil; Rf = 0.39 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.3 Hz, 2H), 7.30 – 7.26 (m, 5H), 3.36 (d, J = 16.6 Hz, 1H), 3.21 (d, J = 16.6 Hz, 1H), 3.16 (d, J = 16.6 Hz, 1H), 3.04 (d, J = 16.6 Hz, 1H), 2.41 (s, 3H), 1.75 (s, 3H); 13C NMR

(125 MHz, CDCl3) δ 144.6, 140.6, 137.7, 131.1, 130.0, 128.9, 128.2, 126.8, 116.9, 115.9, 115.4, 69.3, 43.0, 29.9, 25.3, 21.6; IR (thin film) 2979, 2254, 1597, 1471; HRMS (ESI) + calcd for [C18H17BrN2O2S + Na] 427.0086, found 427.0081. 4.46g: Prepared from 0.10 mmol of 4.40g, 37.6 mg, 0.094 mmol, 94% yield; viscous 1 colorless oil; Rf = 0.38 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.85 (dt, J = 8.8, 2.0 Hz, 2H), 7.45 – 7.40 (m, 3H), 7.32 (d, J = 8.8 Hz, 2H), 3.44 (d, J = 16.1 Hz, 1H), 3.27 (d, J = 16.6 Hz, 1H), 3.19 (d, J = 16.6 Hz, 1H), 3.11 (d, J = 16.6 Hz, 1H), 2.42 (s,

Chapter 4 | 178 13 3H), 1.79 (s, 3H); C NMR (125 MHz, CDCl3) δ 144.9, 144.2, 137.4, 130.0, 127.3, 3 2 1 126.9, 125.8 (q, JC–F = 3.0 Hz), 125.6 (q, JC–F = 32.2 Hz), 124.0 (q, JC–F = 271.8 Hz), 3 122.3 (q, JC–F = 3.0 Hz), 116.8, 113.6, 69.7, 43.0, 29.9, 25.5, 21.6; IR (thin film) 2981, + 2255, 1598, 1495; HRMS (ESI) calcd for [C19H17F3N2O2S + Na] 417.0855, found 417.0860. 4.46h: Prepared from 0.10 mmol of 4.40h, 35.5 mg, 0.099 mmol, 99% yield; 1 viscous colorless oil; Rf = 0.29 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.80 (app d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.71 – 6.69 (m, 2H), 3.75 (s, 3H), 3.32 (d, J = 16.1 Hz, 1H), 3.16 (app s, 2H), 3.01 (d, J = 16.1 Hz, 1H), 13 2.40 (s, 3H), 1.75 (s, 3H); C NMR (125 MHz, CDCl3) δ 156.3, 144.1, 138.2, 134.8, 129.8, 128.2, 126.7, 117.1, 114.9, 113.1, 111.2, 68.9, 55.6, 43.5, 29.9, 25.1, 21.5; IR + (thin film) 2940, 2254, 1598, 1487, 1275; HRMS (ESI) calcd for [C19H20N2O3S + Na] 379.1087, found 379.1093. 4.46i: Prepared from 0.10 mmol of 4.40i, 34.0 mg, 0.10 mmol, quantitative yield; 1 viscous colorless oil; Rf = 0.37 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.93 (dt, J = 8.3, 2.0 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 7.14 – 7.09 (m, 2H), 6.96 (td, J = 7.3, 1.0 Hz, 1H), 3.41 (d, J = 16.6 Hz, 1H), 3.38 (d, J = 16.1 Hz, 1H), 3.23 (d, J = 16.1 Hz, 1H), 3.12 (d, J = 16.6 Hz, 1H), 2.40 (s, 1H), 2.36 (dq, J = 14.6, 7.4 Hz, 1H), 1.97 (dq, J = 14.4, 7.3 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (125

MHz, CDCl3) δ 144.3, 142.1, 137.7, 129.9, 127.8, 127.1, 126.9, 124.6, 123.1, 117.4, 113.2, 73.0, 40.1, 32.5, 29.1, 21.5, 8.4; IR (thin film) 2976, 2251, 1598, 1481; HRMS + (ESI) calcd for [C19H20N2O2S + Na] 363.1138, found 363.1143. 4.46j: Prepared from 0.10 mmol of 4.40j, 38.9 mg, 0.10 mmol, quantitative yield; 1 viscous colorless oil; Rf = 0.27 (15:85 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 7.8 Hz, 1H), 7.29 – 7.25 (m, 2H), 7.22 – 7.14 (m, 7H), 7.06 (td, J = 7.3, 1.0 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 3.93 (d, J = 16.6 Hz, 1H), 3.78 (d, J = 16.6 Hz, 1H), 3.67 (d, J = 16.6 Hz, 1H), 3.66 (d, J = 17.1 Hz, 1H); 2.31 (s, 3H); 13C NMR (125 MHz,

CDCl3) δ 143.6, 141.7, 139.9, 136.9, 129.1, 128.4, 126.7, 126.6, 126.1, 124.9, 123.4,

Chapter 4 | 179 117.1, 113.5, 71.2, 47.2, 29.0, 21.4; IR (thin film) 3067, 2252, 1598, 1497; HRMS (ESI) + calcd for [C23H20N2O2S + Na] 411.1138, found 411.1152. 4.46k: Prepared from 0.10 mmol of 4.40k, 31.6 mg, 0.093 mmol, 93% yield; 1 viscous colorless oil; Rf = 0.29 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 7.65 (dd, J = 8.3, 1.5 Hz, 1H), 7.49 (app d, J = 8.3 Hz, 2H), 7.25 – 7.22 (m, 3H), 7.18 (td, J = 7.3, 1.5 Hz, 1H), 7.09 (d, J = 7.3 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 2.67 (d, J =16.6 Hz, 1H), 2.57 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 2.00 (dt, J = 13.5, 6.7 Hz, 1H), 1.80 (dt, J = 13 14.0, 7.1 Hz, 1H), 1.67 (s, 3H); C NMR (125 MHz, CDCl3) δ 143.7, 138.9, 136.7, 133.3, 129.6, 129.0, 127.9, 127.1, 126.6, 126.58, 116.9, 60.1, 35.3, 30.9, 26.1, 24.1, 21.5; + IR (thin film) 2945, 2251, 1598, 1487; HRMS (ESI) calcd for [C19H20N2O2S + Na] 363.1138, found 363.1132. 4.46l: Prepared from 0.10 mmol of 4.40l, 35.5 mg, 0.099 mmol, 99% yield; viscous 1 yellow oil; Rf = 0.26 (1:4 EtOAc/hexanes); H NMR (500 MHz, CDCl3) δ 8.34 (dt, J = 8.8, 2.0 Hz, 2H), 8.15 (dt, J = 8.8, 2.0 Hz, 2H), 7.44 (d, J = 8.3 Hz, 1H), 7.23 – 7.19 (m, 2H), 7.07 (t, J = 7.3 Hz, 1H), 3.42 (d, J = 16.1 Hz, 1H), 3.25 (d, J = 17.1 Hz, 1H), 3.13 (d, 13 J = 17.1 Hz, 1H), 3.09 (d, J = 16.1 Hz, 1H), 1.76 (s, 3H); C NMR (125 MHz, CDCl3) δ 150.3, 146.5, 140.5, 128.5, 128.0, 126.8, 125.6, 124.6, 124.4, 116.7, 114.0, 69.5, 43.3, 30.0, 25.4; IR (thin film) 2980, 2255, 1606, 1532, 1480, 1350; HRMS (ESI) calcd for + [C17H15N3O4S + Na] 380.0675, found 380.0687. 4.46n: Prepared from 0.10 mmol of 4.40n, 31.3 mg, 0.10 mmol, quantitative yield; 1 viscous colorless oil; H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 7.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.66 (s, 1H), 4.90 (app s, 1H), 2.41 (s, 3H), 2.12 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 159.1, 144.4, 136.1, 134.3, 132.3, 129.9, 129.8, 127.9, 127.2,

126.0, 124.4, 115.9, 100.7 (app d), 22.8, 21.5; HRMS (ESI) calcd for [C17H16N2O2S + Na]+ 335.0825, found 335.0818.

4.8.8 Crossover experiments

Chapter 4 | 180

The 13C-labeled cyanamide 4.40a-13CN was prepared from cyanation of 4.45a using Br13CN, which followed the procedure previously described. 4.40a-13CN: Prepared from 1 0.67 mmol of 4.45a, 90% yield; off-white solid; Rf = 0.52 (1:4 EtOAc/hexanes); H

NMR (500 MHz, CDCl3) δ 7.74 (dt, J = 8.3, 1.5 Hz, 2H), 7.41 – 7.38 (m, 3H), 7.34 (dd, J = 8.3, 1.0 Hz, 1H), 7.18 (td, J = 7.8, 1.5 Hz, 1H), 6.80 (dd, J = 8.3, 1.0 Hz, 1H), 4.92 (s, 13 1H), 4.67 (s, 1H), 3.38 (br s, 2H), 2.51 (s, 3H), 1.66 (s, 3H); C NMR (125 MHz, CDCl3) δ 146.7, 142.6, 139.8, 133.2, 133.0, 131.3, 130.9, 130.3, 128.6, 128.1, 127.6, 113.8, 108.6 (13CN), 39.3, 22.2, 21.8; IR (thin film) 2172, 1386, 1191, 1178, 1088; HRMS (ESI) 13 + calcd for [C17 CH18N2O2S + Na] 350.1015, found 350.1017. The crossover experiment of 4.40a-13CN and 4.40d followed the general procedure of aminocyanation described above. The reaction was carried out using 4.40a-13CN (32.7 mg, 0.10 mmol), 4.40d (34.4 mg, 0.10 mmol), B(C6F5)3 (52.0 mg, 0.1 mmol) and Toluene (0.5 mL). The reaction mixture was heated at 90 °C for 48 h, concentrated onto Celite and purified by flash column chromatography (1:9 EtOAc/hexanes) to give an inseparable mixture (61.6 mg) of 4.46a-13CN and 4.46d. The yields were determined by integration of 1H NMR spectrum of the product mixture. 4.46d showed no detectable enrichment in 13C by analysis of the 1H and 13C NMR spectra, or the HRMS data for the mixture. The crossover experiment of 4.40d and 4.40l followed the general procedure of aminocyanation described above. The reaction was carried out using 4.40d (34.4 mg,

0.10 mmol), 4.40l (35.7 mg, 0.10 mmol), B(C6F5)3 (52.0 mg, 0.1 mmol) and Toluene (0.5 mL). The reaction mixture was heated at 90 °C for 48 h, concentrated in vacuo and purified by preparative thin-layer chromatography (3:7 EtOAc/hexanes) to give 4.46d

Chapter 4 | 181 (33.5 mg, 0.097 mmol, 97% yield) and 4.46l (31.8 mg, 0.089 mmol, 89% yield) respectively. The 1H NMR spectroscopic data of 4.46d and 4.46l were consistent with the data previously described. 13 13 + HRMS (ESI) 4.46a- CN: calcd for [C17 CH18N2O2S + Na] 350.1015, found + 350.1018; 4.46d: calcd for [C18H17FN2O2S + Na] 367.0887, found 367.0882.

Chapter 5 | 182 Chapter 5 Progress in Developing a Palladium/Lewis Acid-Catalyzed Aminocyanation Reaction for the Construction of Nitrogen Heterocycles

Over the past two to three years, a number of catalytic aminocyanation reactions involving a direct or formal cleavage of N–CN bond have appeared. This chapter reviews the recent advances in this area and connects to our recent efforts in developing a palladium-catalyzed aminocyanation reaction to synthesize a broad scope of nitrogen- heterocycles.

5.1 Formal aminocyanation reactions not involving N–CN bond cleavage

In 2014, Lee and co-workers developed a formal 1,2-aminocyanation reaction of α,β-unsaturated cyclic enones for the synthesis of α-amino ketones.140 Cyclic enone 5.1 underwent selective 1,4-addition–cyclization with lithium trimethylsilyldiazomethane 5.2 to provide Δ2-pyrazoline 5.3 as a formal dipolar cycloaddition product (Scheme 5-1). The exclusive selectivity for the 1,4-addition over 1,2-addition was tentatively attributed to the unfavorable steric interaction between the sterically demanding trimethylsilyl group and the α-methylene carbon of the enone moiety. Treating 5.3 with TsOH facilely cleaved the N–N bond in a non-reductive manner and revealed the amino ketone product 5.4 bearing a β-cyano group, thereby achieving a formal aminocyanation process across the enone C–C double bond. A diverse range of cyclic enones with substituents at both the α- and β-positions of enone were well-tolerated, allowing facile construction vicinal quaternary stereocenters (5.4a–c). Enones bearing an exocyclic C–C double bond proceeded to the corresponding amino ketones in excellent yields (5.4d and 5.4e). An amino tetralone backbone was also readily prepared (5.4f). Further extension of this method to N-alkyl pyrazolines (5.5), prepared by routine N-alkylation of the unprotected precursors (5.3), afforded the corresponding N-alkylamino ketones with consistently high efficacy (5.4g–j).

Chapter 5 | 183

Scheme 5-1 Formal aminocyanation of α,β-unsaturated cyclic enones

This method was successfully extended to the chemo- and diastereoselective aminocyanation of α,β-unsaturated esters and further highlighted in the total synthesis of amathaspiramides.141 Reaction of cinnamate derivative 5.6 with 5.2 afforded bicyclic pyrazoline 5.8 with complete diastereoselectivity, via an intramolecular trapping of the

Chapter 5 | 184 initially formed lithiumamide with the pendant ethyl ester (5.8). Subsequent N–N bond cleavage revealed the aminocyanation product 5.9, which was further elaborated into the target natural products. Jiang et al. reported a palladium-catalyzed aminative cyclization of aniline derivatives (5.10) by the addition of tert-butyl isocyanide (5.11) to access 2-substituted indoline and pyrrolidine heterocycles (Scheme 5-2).142 The reaction proceeded through an aminoamidation path and led to amidated product 5.12 when DABCO was employed as a base additive, whereas a formal aminocyanation took place in the presence of TFA, giving nitrile 5.13 along with a indole by-product 5.13'. A broad scope of amine substrates were examined mainly under the aminoamidation conditions, affording the corresponding indolines with substituents on the aromatic ring (5.12a–h) or on the nitrogen atom (5.12i–p) in generally good to excellent yields. Pyrrolidines (5.12q–s) and indolines derived from isocyanides other than 5.11 (not shown) were also readily obtained. On the other hand, the aminocyanation conditions were only briefly examined, affording substituted N-sulfonyl indolines bearing a cyano group in moderate yields (5.13a–e). In the proposed catalytic cycle, intramolecular migratory insertion of alkene into the N–Pd bond (i.e., aminopallation) of complexes 5.14 gave the alkylpalladium intermediate 5.15. Subsequent insertion of isocyanide generated the tert-butyliminopalladium complex 5.16, which underwent base-assisted ligand displacement with water, * followed by reductive elimination and tautomerization to provide the aminoamidation product. Alternatively, TFA-promoted β-tert-butyl elimination of 5.16 accounted for the aminocyanation product 5.13.

* The source of water was not clearly indicated.

Chapter 5 | 185

Scheme 5-2 Palladium-catalyzed aminoamidation and aminocyanation of alkenes

5.2 Aminocyanation reactions involving N–CN bond cleavage

The addition reactions of a σ-bond across an aryne to form 1,2-difunctionalized arenes are well-established. The addition of N–CN bond is not an exception.143 Zeng and Rao developed an useful protocol to access 1,2-difunctionalized aminobenzonitriles 5.20

Chapter 5 | 186 by cleaving the N–CN bond of aryl cyanamides 5.19 with arynes under mild and metal- free conditions (Scheme 5-3).144 A competitive N–H bond addition was also observed. However, under the optimized conditions, an up to 93:1 selectivity was achieved, favoring the addition of N–CN bond. However, aliphatic cyanamides and N,N- disubstituted cyanamides (e.g., N-benzylcyanamide, N-methyl-N-phenylcyanamide, and N,N-diphenylcyanamide) were inert towards addition.* A wide scope electron-neutral (5.20a and 5.20b), electron-donating (5.20c), electron-withdrawing (5.20g–j), and halogens (5.20d–f) para to the cyanamide moiety proceeded to the corresponding aminobenzonitriles in consistently high yields. Functional groups at the ortho and meta position were well-tolerated (5.20k–o). Products derived from other symmetric arynes were obtained in comparable yields (5.20p–r). Not surprisingly, a methyl-substituted nonsymmetric aryne resulted in poor selectivity of product (5.20s and 5.20s'). The proposed mechanism was consistent with the generally accepted mechanism for aryne addition. Nucleophilic attack of the deprotonated cyanamide to the aryne generated the phenyl anion 5.21, which cyclized to four-membered intermediate 5.22, followed by strain-releasing C–N bond cleavage and protonation of the resulting anion to afford the addition product. A control experiment was performed by treating cyanamide 5.23 with nBuLi, followed by quenching with water. The same aminobenzonitrile was obtained in 62% yield, indicating that anion 5.21 was involved in the proposed mechanism.

* The author of this Thesis independently discovered the addition reaction of N–CN bond of N-cyano-N-phenyl-p- toluenesulfonamide across benzyne to generate the aminobenzonitrile product in ca. 30% isolated yield, as indicated below. For details, see Pan, Z. Laboratory Notebook II, p 263, September 17, 2013, and Laboratory Notebook III, p 24, October 8, 2013.

Chapter 5 | 187

Scheme 5-3 Aminocyanation of arynes by N–CN bond cleavage

Concurrent with our work on metal-free aminocyanation, the Nakao group also reported an intramolecular alkene aminocyanation reaction (Scheme 5-4).145 Following their previous success with palladium/Lewis acid-catalyzed oxyacylation reaction, Nakao et al. achieved the N–CN bond activation of N-acetyl cyanamides 5.24 and subsequent alkene addition by employing the cooperative palladium/Lewis acid catalytic system composing of CpPd(allyl), Xantphos, and BPh3, affording the corresponding N-acetyl indoline bearing an aza-quaternary stereocenter and a cyano group in 69% yield (5.25). Early screening of reaction conditions revealed the critical role of each component of the palladium–Lewis acid–ligand combination. Reactions without added metal or other palladium and nickel sources were far less effective than those with CpPd(allyl) (Scheme

5-4, Table, variation of metals). BEt3 promoted the aminocyanation equally well, yet

Chapter 5 | 188

B(C6F5)3 and AlEt3 were ineffective. Furthermore, Xantphos demonstrated an unique reactivity among other less effective ligands.

Scheme 5-4 Palladium–Lewis acid-catalyzed intramolecular aminocyanation of alkenes

Chapter 5 | 189 Under the optimized conditions, both N-acetyl and N-tert-butyloxycarbonyl (Boc) indolines were obtained in excellent yields (5.25a and 5.25b). Alkene substituents other than a methyl group, including ethyl, siloxymethyl, and phenyl groups were tolerated (5.25c–e). Impressively, the reaction was perfectly compatible with a monosubstituted alkene, leading to the corresponding indoline bearing tertiary carbon center in 94% yield (5.25f). Substituents para to the cyanamide moiety were briefly examined (5.25g and 5.25h). Substituted tetrahydroquinoline and pyrrolidines were successfully constructed in a similar fashion (5.25i–k). Furthermore, Nakao et al. also achieved preliminary success with asymmetric aminocyanation of 5.24a and 5.24l by employing the chiral SKP ligands. Despite the limited scope, this asymmetric aminocyanation represented the only enantioselective variant of a heteroatom–cyano bond activation reaction. Stoichiometric aminocyanation reactions provided evidence for the N–CN bond cleavage process (Scheme 5-5). Mixing N-cyano-N-phenylacetamide 5.26 with

CpPd(allyl), Xantphos, and BPh3, which was the optimal combination for catalytic aminocyanation resulted in sluggish reaction. Interestingly, the reaction of 5.26 with

Pd(PPh3)4 and BPh3 in benezene at 80 °C smoothly afforded the oxidative adduct 5.27, whose structure was confirmed by X-ray crystallography. Oxidative addition did not take place in the absence of BPh3. The proposed catalytic cycle was similar to that of the oxyacylation reaction, which was initiated by a Lewis acid-assisted oxidative addition of the N–CN bond to Pd(0) center to give adduct 5.28. Subsequent migratory insertion of alkene into the N–Pd bond (aminopalladation) was feasible since the resulting alkylpalladium complex 5.29 was further stabilized through a six-membered chelation with the aminocarbonyl moiety. Such chelation suppressed competitive β-hydride elimination (R = H). Intermediate 5.29 further underwent reductive elimination to product 5.25 and regenerated active catalyst.

Chapter 5 | 190

Scheme 5-5 Proposed mechanism for aminocyanation reaction

A close comparison of aminocyanation conditions reported by us and the Nakao group revealed interesting coincidences regarding substrate design and reaction discovery (Scheme 5-6). Nakao and co-workes used an N-acetyl cyanamide (5.24) as the substrate and discovered the metal-catalyzed conditions. We designed an N-tosyl cyanamide (5.30) as our first attempt, leading to the metal-free conditions. Interestingly, during the reaction optimization, Nakao and co-workers identified the “metal-free” conditions by heating

5.24 with B(C6F5)3 at a higher temperature with prolonged reaction time, and the cyclization product was obtained in 11% yield. They commented, “The preliminary but interesting reactivity observed with B(C6F5)3 would be an issue for further investigation.” We, on the other hand, attempted to prepare the same N-acetyl cyanamide substrate 5.24

Chapter 5 | 191 during our substrate scope study. However, the corresponding cyanation reaction, which was used to prepare substrates like 5.20 failed to give 5.24.*

Scheme 5-6 Coincidence of substrate design and reaction discovery

5.3 Research proposal: Intramolecular aminocyanation of alkenes towards a broader scope of nitrogen heterocycles

* Cyanamide 5.24 was prepared by N-acylation of the corresponding aryl cyanamide, see the scheme below for a summary.

Chapter 5 | 192 The alkene aminocyanation reactions developed by us and Nakao's group have demonstrated the union of N–CN bond activation with the insertion of an alkene in a intramolecular context, allowing a rapid construction of valuable nitrogen heterocycles, including indoline, tetrahydroquinoline, and pyrrolidone in an atom-economical fashion. Meanwhile, compared with the established aminofunctionalization strategies for synthesizing nitrogen-heterocycles (Scheme 5-7, top),8–11 the alkene aminocyanation reactions provided a direct addition approach that simultaneously introduces both an amino and a cyano group onto the alkene double bonds to generate the desired heterocycles in a regioselective manner, which also obviates the need for exogenous reagents (Scheme 5-7, bottom).

Scheme 5-7 Synthesis of nitrogen heterocycles in a direct addition approach

To this end, we are motivated to extend our current method to a broader scope of cyanamides (Scheme 5-8), including N-sulfonyl and N-acyl cyanamides bearing an aromatic tether, and cyanamides bearing an alkyl tether. The aminocyanation of these substrates would allow the synthesis of new heterocyclic backbones, including sultam, isoindolinone, pyrrolidone, and piperidinone, among others.

Chapter 5 | 193

Scheme 5-8 Current focus of alkene aminocyanation reactions

5.4 Results and discussion

5.4.1 Aminocyanation of N-sulfonyl cyanamide 5.33*

We first studied the aminocyanation reaction of N-sulfonyl cyanamide 5.33, which was prepared by a condensation reaction between N-(p-tolyl)cyanamide (TolNHCN) and the corresponding sulfonyl chloride. Heating 5.33 with 1.0 equivalent of B(C6F5)3 in toluene under the metal-free conditions (Chapter 4) did not provide any detectable amount of cyclized product 5.34 (Table 5-1, entry 1). Switching to BF3•OEt2 or BPh3 was unfruitful (entries 2 and 3). In contrast, the reaction proceeded under palladium–Lewis acid catalysis, resulting in complete conversion and providingd 5.34 in 83% yield, along with a small amount of decyanation by-product 5.35 (entry 4). Further screening of palladium sources revealed that Pd2dba3 was the optimal choice of catalyst (entries 5–8).

* All experiments discussed in section 5.4.1 were performed by Shengyang Wang.

Chapter 5 | 194 Lowering the reaction temperature from 100 °C to 80 °C was beneficial, providing a near quantitative yield of product (entries 9–11). Further decreasing the temperature to 70 °C , however, gave a lower yield (entry 11). A control experiment performed without BPh3 returned only unconsumed starting material, clearly indicating the necessity of Lewis acid

(entry 12). Under the optimal conditions (5 mo% Pd2dba3, 10 mol% Xantphos, 40 mol%

BPh3, toluene, 80 °C ), sultam 5.34 was isolated in 99% yield as a off-white solid (entry 10).

Table 5-1 Screening of conditions for aminocyanation of 5.33

Entry Pd[a] L[b] LA (equiv) T (°C ) Conv. (%)[c] Yield of 5.34 (%)

1 none none B(C6F5)3 (1.0) 100 0 none

2 none none BF3•OEt2 (1.0) 100 0 none

3 none none BPh3 (0.4) 100 0 none [d] 4 Pd2dba3 Xantphos BPh3 (0.4) 100 > 95 83 [e] 5 Pd(OAc)2 Xantphos BPh3 (0.4) 100 > 95 69 [e] 6 Pd(PPh3)4 Xantphos BPh3 (0.4) 100 63 32 [e] 7 Pd(TFA)2 Xantphos BPh3 (0.4) 100 > 95 63 [e] 8 Pd2dba3 Xantphos BPh3 (0.4) 100 > 95 85 [e] 9 Pd2dba3 Xantphos BPh3 (0.4) 90 > 95 95 [f] 10 Pd2dba3 Xantphos BPh3 (0.4) 80 > 95 99 [e] 11 Pd2dba3 Xantphos BPh3 (0.4) 70 > 95 78

12 Pd2dba3 Xantphos none 100 0 none [a] 10 mol% Pd metal. [b] 10 mol% Xantphos. [c] Estimated by 1H NMR analysis. [d] 1 1 Determined by H NMR analysis using CDCl3 as the solvent. [e] Determined by H NMR

Chapter 5 | 195 analysis using DMSO-d6 as the solvent and p-methoxyacetophenone as the internal standard. [f] Isolated yield after column chromatography.

A brief substrate scope was examined with substrates bearing substituents on the aromatic ring, including tBu, F, Cl, OMe, and CF3 groups (Scheme 5-9). Under the optimal conditions, all reactions proceeded smoothly to the corresponding sultams in excellent yields (5.34b–f).

Scheme 5-9 Preliminary substrate scope for aminocyanation of 5.33

5.4.2 Aminocyanation of N-acyl cyanamide 5.36

Next, we directed our attention to the aminocyanation reaction of N-acyl cyanamide 5.36, aiming at the pyrrolidone product 5.37. Our first experiment using CpPd(1- phenylallyl), Xantphos, and BPh3 was successful, affording 5.37 in 87% yield (Scheme 5- 10). This result demonstrated that the palladium–Lewis acid cooperative catalysis was also applicable to N-acyl cyanamides with an alkyl-tethered alkene.

Chapter 5 | 196

Scheme 5-10 Aminocyanation of N-acyl cyanamide 5.36

Encouraged by this result, we carried out extensive screening of reaction parameters using the one-factor-at-a-time (OFAT) method, including palladium sources, ligands, Lewis acids, solvents, and temperatures. The screened parameters are briefly summarized in Table 5-2. * Our observations through the optimization process were generally consistent with the Nakao group's reports regarding the oxyacylation and aminocyanation reactions. Representative results are provided in Table 5-3. Table 5-2 OFAT Screening for aminocyanation of 5.36

* See the experimental section for a complete summary.

Chapter 5 | 197

Table 5-3 Representative optimization results for aminocyanation of 5.36

Entry Palladium (10 mol% Pd) L (mol%) LA (40 or 50 mol%)[a] Solvent T (°C ) Conv. (%)[b] Yield of 5.37 (%)[c]

1 CpPd(1-phenylallyl) Xantphos (10) BPh3 PhMe 100 > 95 66

2 Pd(dba)2 Xantphos (15) BPh3 PhMe 100 22 7

3 [Pd(allyl)Cl]2 Xantphos (10) BPh3 PhMe 100 0 0

4 Pd(dppf)Cl2 Xantphos (15) BPh3 PhMe 100 0 0

5 Pd(PCy3)2Cl2 Xantphos (15) BPh3 PhMe 100 0 0

6 PdCl2 Xantphos (15) BPh3 PhMe 100 0 0 ™ 7 PEPPSI -IPr Xantphos (15) BPh3 PhMe 100 0 0

8 Pd(TFA)2 Xantphos (15) BPh3 PhMe 100 95 48

9 Pd(OAc)2 Xantphos (10) BPh3 PhMe 100 > 95 62

10 Pd(PPh3)4 Xantphos (10) BPh3 PhMe 100 > 95 59

11 CpPd(1-phenylallyl) Xantphos (15) BPh3 PhMe 100 > 95 75 [d] 12 CpPd(1-phenylallyl) Xantphos (15) B(C6F5)3 PhMe 100 – 0 [d] 13 CpPd(1-phenylallyl) Xantphos (15) AlMe2Cl PhMe 100 – 0 [d] 14 CpPd(1-phenylallyl) Xantphos (15) AlCl3 PhMe 100 – 0

Chapter 5 | 198

Entry Palladium (10 mol% Pd) L (mol%) LA (40 or 50 mol%)[a] Solvent T (°C ) Conv. (%)[b] Yield of 5.37 (%)[c]

15 CpPd(1-phenylallyl) Xantphos (15) ZnCl2 PhMe 100 0 0

16 CpPd(1-phenylallyl) Xantphos (15) Zn(OTf)2 PhMe 100 0 0

17 CpPd(1-phenylallyl) Xantphos (10) BPh3 PhMe 80 > 95 93

18 CpPd(1-phenylallyl) DPEphos (10) BPh3 PhMe 80 > 95 72

19 CpPd(1-phenylallyl) Nixantphos (10) BPh3 PhMe 80 > 95 81

20 CpPd(1-phenylallyl) DBFphos (10) BPh3 PhMe 80 86 0

21 CpPd(1-phenylallyl) dppe (10) BPh3 PhMe 80 86 0

22 CpPd(1-phenylallyl) dppp (10) BPh3 PhMe 80 91 23

23 CpPd(1-phenylallyl) dppb (10) BPh3 PhMe 80 75 49

24 CpPd(1-phenylallyl) Xantphos (15) BPh3 THF 80 49 26

25 CpPd(1-phenylallyl) Xantphos (15) BPh3 PhCF3 80 0 0

26 CpPd(1-phenylallyl) Xantphos (15) BPh3 1,4-dixane 80 55 20

27 CpPd(1-phenylallyl) Xantphos (15) BPh3 1,2-DCE 80 24 0

28 CpPd(1-phenylallyl) Xantphos (15) BPh3 DMF 80 0 0

29 CpPd(1-phenylallyl) Xantphos (15) BPh3 cyclohexane 80 > 95 85 [a] 50 mol% for entries 1–16, 40 mol% for entries 17–29. [b] Estimated by 1H NMR analysis. [c] Determined by 1H NMR analysis using p- methoxyacetophenone as the internal standard. [d] Almost complete decyanation product 5.38. PEPPSI™-IPr = [1,3-bis(2,6-diisopropylphenyl)imidazol- 2-ylidene](3-chloropyridyl)palladium(II) dichloride.

Chapter 5 | 199 Like CpPd(allyl), the CpPd(1-phenylallyl) complex * is known to undergo facile reductive elimination upon reacting with phosphine ligands to allow a “clean” formation of palladium(0) species, which presumably accounts for its remarkable reactivity towards N–CN bond activation (Table 5-3, entry 1). In contrast, a variety of Pd(0) and Pd(II) sources, including Pd(dba)2, [Pd(allyl)Cl]2, Pd(dppf)Cl2, Pd(PCy3)2Cl2, PdCl2, and PEPPSI™-IPr were completely ineffective (entries 2–7). Lower, yet comparable yields were obtained with Pd(TFA)2 and Pd(OAc)2, indicating the corresponding reduction of

Pd(II) to Pd(0) was feasible under the reaction conditions (entries 8 and 9). Pd(PPh3)4 was also a working catalyst, affording 5.37 in 59% yield (entry 10).

The use of Lewis acids other than BPh3, including B(C6F5)3, AlMe2Cl, and AlCl3 resulted in substantial amount of decyanation product 5.38, whereas zinc Lewis acids were merely ineffective (entries 12–16). Previous reports from the Nakao group indicated that bidentate phosphines with a large bite angle,146 especially Xantphos and Nixantphos, were particularly effective in promoting oxyacylation and aminocyanation reactions. Consistently, Xantphos, DPEphos, and Nixantphos performed well in our study, whereas further increasing the bite angle (e.g., DBFphos) shut down the reaction (entries 17–20).† In addition, bidentate phosphines such as dppe, dppp, and dppb resulted in lower yields of 5.37 and the formation of significant amounts of decyanation byproduct (entries 21– 23). A pronounced solvent effect was observed. Lewis basic solvents (e.g., THF and 1,4- dioxane) and halogenated solvents (1,2-DCE) led to incomplete reaction, whereas PhCF3 and DMF inhibited the reactivity (entries 24–28). On the other hand, hydrocarbons such as cyclohexane gave a competitive conversion and yield (entry 29). Under the optimized conditions shown in Scheme 5-11, pyrrolidone 5.37 was isolated in 89% and 99% yield using BPh3 and BEt3 as the Lewis acid, respectively.

* CpPd(1-phenylallyl) is commercially available and easier to handle than the volatile CpPd(allyl). We prepared CpPd(1-phenylallyl) following a known procedure: Fraser, A. W.; Besaw, J. E.; Hull, L. E.; Baird, M. C. Organometallics 2012, 31, 2470. † Bite angle data extracted from ref. 146: DPEphos, 102°; Xantphos, 111°; Nixantphos, 114°; DBFphos, 131°.

Chapter 5 | 200

Scheme 5-11 Optimized conditions for aminocyanation of 5.36

5.4.3 Substrate scope and limitations

We proceeded to examine the substrate scope of the new aminocyanation reaction, focusing mainly on N-acyl cyanamides. N-phenyl cyanamide 5.36 (Table 5-4, entry 2) and substrates bearing alkyl, halogen, and electron-donating groups para to the cyanamide moiety provided the corresponding pyrrolidones in excellent yields (5.37c–g, entries 3–7). Competing decyanation was observed with substrates bearing an electron- withdrawing group on the phenyl ring, such as 5.36h. A generally useful solution was to increase the equivalency of Lewis acid while decreasing the temperature, which gave a 67% yield of 5.37h (entry 8). Likewise, substrates with meta substituents reacted smoothly in good to excellent yields (5.37i–m, entries 9–13) under standard or modified conditions. Methyl group ortho to the cyanamide moiety was tolerated with modest yield (5.37n, entry 14), albeit requiring higher catalyst loading (15 mol%) and extended time (53 h). In contrast, a pyridine ring was incorporated into the substrate (5.37o, entry 15). Products with different geminal substituents α to the carbonyl, including methyl and benzyl groups, as well as spirocyclic systems were effectively constructed (5.37p–t, entries 16–20). Substrates with alkyl substituents other than a methyl group reacted with comparable efficiency (5.37u and 5.37v, entries 21 and 22, respectively), whereas a benzyloxymethyl group significantly hampered the alkene addition and led to much lower yield even with 20 mol% palladium (5.37w, entry 23). The cyclization of a styrene- type double bond was sluggish, yet still proceeded upon increasing the catalyst loading and reaction time (5.37x, entry 24). The addition across a monosubstituted alkene was challenging because the highly competitive β-hydride elimination would result in the

Chapter 5 | 201 formation of by-products and palladium(II) cyanide complexes, which lead to further catalyst deactivation. To our delight, the cyanamide moiety cyclized onto a monosubstituted alkene in modest yield at 70 °C with extended reaction time (5.37y, entry 25). Activation of an N-alkyl cyanamide such as 5.36z was met with limited success by heating the reaction at higher temperature with increased catalyst loading (entry 26). The higher temperature was required for the oxidative addition of the less electrophilic N–CN bond, which was inevitably outcompeted by decyanation and other decomposition pathways. On the other hand, cyanamides with a benzene-tethered alkene cyclized smoothly to the corresponding isoindolinones (5.37aa and 5.37ab) and dihydroisoquinolinone (5.37ac) in excellent yields (entries 27–29). Finally, a pyrrolidone without the geminal substituents (5.37ad) and a piperidinone (5.37ae) were obtained in lower yield, indicating a significant Thorpe–Ingold effect during the cyclization event (entries 30 and 31).

Chapter 5 | 202

Table 5-4 Substrate scope for aminocyanation reaction[a]

Entry Substrate Product LA (equiv.) T (°C ) Yield (%)[b]

1 5.36a, R = Me 5.37a, R = Me BEt3 (0.4) 80 99

2 5.36b, R = H 5.37b, R = H BEt3 (0.4) 80 96

3 5.36c, R = tBu 5.37c, R = tBu BEt3 (0.4) 80 93 [c] 4 5.36d, R = F 5.37d, R = F BEt3 (0.4) 80 90, 93

5 5.36e, R = Cl 5.37e, R = Cl BPh3 (0.8) 80 86 [d] 6 5.36f, R = OMe 5.37f, R = OMe BEt3 (0.4) 80 95, 98

7 5.36g, R = OAc 5.37g, R = OAc BEt3 (0.4) 80 90 [e] 8 5.36h, R = COMe 5.37h, R = COMe BEt3 (1.0) 70 67

9 5.36i, R = OMe 5.37i, R = OMe BEt3 (0.4) 80 84

10 5.36j, R = Cl 5.37j, R = Cl BEt3 (0.8) 70 76

11 5.36k, R = CF3 5.37k, R = CF3 BEt3 (0.6) 70 86

12 5.36l, R = CO2Me 5.37l, R = CO2Me BEt3 (0.6) 70 92

Chapter 5 | 203 Entry Substrate Product LA (equiv.) T (°C ) Yield (%)[b]

[e] 13 BEt3 (0.4) 70 87

5.36m 5.37m

[f],[g] 14 BEt3 (1.0) 70 43

5.36n 5.37n

15 BEt3 (0.8) 80 96

5.36o 5.37o

16 BEt3 (0.4) 80 88

5.36p 5.37p

[h] 17 BEt3 (0.8) 70 82

5.36q 5.37q

18 BEt3 (0.6) 70 93

5.36r 5.37r

Chapter 5 | 204 Entry Substrate Product LA (equiv.) T (°C ) Yield (%)[b]

[i] 19 BEt3 (1.0) 70 96

5.36s 5.37s

20 BEt3 (0.6) 80 85

5.36t 5.37t

21 5.36u, R = nBu 5.37u, R = nBu BEt3 (0.6) 80 90 [i] 22 5.36v, R = CH2CH2Ph 5.37v, R = CH2CH2Ph BEt3 (1.0) 70 80 [j] 23 5.36w, R = CH2OBn 5.37w, R = CH2OBn BEt3 (1.0) 90 37

[g],[i] 24 BEt3 (1.0) 80 85

5.36x 5.37x

[h] 25 BEt3 (0.6) 70 47

5.36y 5.37y

[g] [k] 26 BPh3 (0.5) 120 29

5.36z 5.37z

Chapter 5 | 205 Entry Substrate Product LA (equiv.) T (°C ) Yield (%)[b]

27 5.36aa, R = Me 5.37aa, R = Me BEt3 (0.6) 80 99

28 5.36ab, R = Ph 5.37ab, R = Ph BEt3 (0.6) 80 99

[g] 29 BEt3 (1.0) 80 94

5.36ac 5.37ac

[k] 30 BPh3 (0.4) 120 33

5.36ad 5.37ad

[h],[j] 31 BEt3 (1.0) 70 49

5.36ae 5.37ae [a] Standard conditions: substrate 0.2 mmol, CpPd(1-phenylallyl) 10 mol%, Xantphos 10 mol%,

BPh3 or BEt3 0.4 equiv, PhMe 1.0 mL, 80 °C , 24 h. [b] Isolated yields after column chromatography. [c] Reaction performed on 1.3 g scale. [d] Reaction performed on 1.1 g scale. [e] Reaction time: 30 h. [f] Reaction time: 53 h. [g] 15 mol% CpPd(1-phenylallyl) and 15 mol% Xantphos. [h] Reaction time: 48 h. [i] Reaction time: 36 h. [j] 20 mol% CpPd(1-phenylallyl) and 20 mol% Xantphos. [k] m-Xylene was used as solvent. Tol = para-methylphenyl; PMP = para- methoxyphenyl.

Incompatible substrates were also identified (Table 5-5). Substrate bearing a bromo- group on the aromatic ring returned unconsumed starting material, likely a result of competitive oxidative addition of the C–Br bond (5.36af). An N-acetyl substituent (5.36ag) rendered the N–CN bond inert towards activation, even at 120 °C . Electron-

Chapter 5 | 206 deficient alkene (5.36ah) and conjugated enyne (5.36ai) were unreactive, likely due to a reluctant alkene insertion. Attempt to prepare an indole-fused ring was unfruitful (5.36aj). In addition, geminal dichloro substituents and a 2-pyridyl group were incompatible with the aminocyanation conditions (5.36ak and 5.36al).

Table 5-5 Incompatible substrates[a]

5.4.4 Mechanistic considerations

We propose a catalytic cycle similar to that in the Nakao group's study,145 which is initiated by Lewis acid-promoted oxidative addition of the N–CN bond to the Pd(0) center, giving rise to amidopalladium(II) cyanide complex 5.39 (Scheme 5-12). Intramolecular syn-addition of the N–Pd bond across the alkene double bond provides alkylpalladium(II) cyanide complex 5.40, which, upon C–CN bond-forming reductive elimination, released the product and regenerates the active catalyst. On the other hand, the competing decyanation of 5.39 accounts for by-product formation and catalyst deactivation, although the detailed mechanism remaines to be elucidated. Substrate study has revealed a pronounced Thorpe–Ingold effect and electronic effect of alkene

Chapter 5 | 207 substituents on the cyclization event, suggesting that the alkene addition step may be rate determining.

Scheme 5-12 Proposed mechanism for aminocyanation

5.5 Conclusion and future work

At this stage, we have successfully extended the alkene aminocyanation reaction to the construction of a broader scope of nitrogen heterocycles, including sultams, isoindolinones, pyrrolidones, and piperidinones. Current efforts are directed towards further elucidating the mechanistic details, particularly, the stereochemical outcome and potential kinetic isotope effect through the alkene addition step. Future work will be focused on developing enantioselective aminocyanation induced by chiral phosphine ligands or other ligand scaffolds (e.g., chiral N-heterocyclic carbenes).

5.6 Experimental section

5.6.1 General details

Chapter 5 | 208 Unless otherwise noted, all reactions were carried out using oven-dried glassware under a nitrogen atmosphere. Dichloromethane (CH2Cl2) and toluene were distilled from

CaH2 prior to use. Tetrahydrofuran (THF) was distilled from Na/benzophenone prior to use. m-Xylene and toluene were further degassed by bubbling a stream of argon through the liquid in a Strauss flask and then stored in a nitrogen-filled glove box. Acetonitrile

(CH3CN), benzene, methanol (MeOH), anhydrous N,N-dimethylformamide (DMF) and anhydrous diethyl ether (Et2O) were purchased from Sigma-Aldrich and Alfa Aesar, and used without further purification. Unless otherwise noted, all chemicals were purchased from commercial sources and used as received. All transition-metal complexes, except for CpPd(1-phenylallyl), were purchased from Sigma-Aldrich or Strem and used as received. CpPd(1-phenylallyl) was synthesized following a known procedure. *

Triphenylborane (BPh3) was purchased from Strem and recrystallized from anhydrous † heptane under nitrogen. Tris(pentafluorophenyl)borane [B(C6F5)3] was purchased from

Strem and used as received. All B(C6F5)3-promoted or palladium-catalyzed aminocyanation reactions were carried out in a Vacuum Atmospheres nitrogen-filled glove box in 1 dram vials (Chemglass) with PTFE lined caps and heating was applied by aluminum block heaters.

Analytical thin-layer chromatography (TLC) and preparative thin-layer chromatography were carried out using 250 μm and 1000 μm silica plates (SiliCycle), respectively. Eluted plates were visualized first with a UV lamp (254 nm) and then stained with potassium permanganate, iodine, or bromocresol green. Flash column chromatography was performed using 230–400 mesh (particle size 40–63 μm) silica gel purchased from SiliCycle.

1H NMR (300 and 500 MHz) and 13C NMR (75 and 125 MHz) spectra were obtained on Varian Inova and Bruker Avance instruments. 1H NMR spectra data were

* Fraser, A. W.; Besaw, J. E.; Hull, L. E.; Baird, M. C. Organometallics 2012, 31, 2470. † Köster, R.; Binger, P.; Fenzl, W. Inorg. Synth. 1974, 15, 134.

Chapter 5 | 209 reported as δ values in ppm relative to TMS (δ 0.00) or chloroform (7.26) if collected in 13 CDCl3, or dimethyl sulfoxide (δ 2.50) if collected in DMSO-d6. C NMR spectra data were reported as δ values in ppm relative to chloroform (δ 77.00) if collected in CDCl3 or 1 dimethyl sulfoxide (δ 39.50) if collected in DMSO-d6. H NMR coupling constants were reported in Hz, and multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet); quint (quintet); m (multiplet); dd (doublet of doublets); ddd (doublet of doublet of doublets); dddd (doublet of doublet of doublet of doublets); dt (doublet of triplets); td (triplet of doublets); ddt (doublet of doublet of triplets); dq (doublet of quartets); app (apparent); br (broad). Infrared (IR) spectra were obtained on a MIDAC

FT-IR spectrometer. A thin-film of sample was prepared by evaporating solvent (CH2Cl2 or CDCl3) on NaCl plates. Low-resolution mass spectra (LRMS) in chemical ionization (CI) experiments were performed on a Varian Saturn 2200 GC-MS system. High- resolution mass spectra (HRMS) in electrospray ionization (ESI) experiments were performed on a Bruker BioTOF II (Time-of-flight) instrument using PEG-300, PEG-400 or PPG-400 as an internal standard.

5.6.2 Optimization of conditions for aminocyanation of 5.36a

A general procedure: In a nitrogen-filled glove box, a one-dram vial was charged with a magnetic stirring bar, substrate 5.36a (38.1 mg, 0.1 mmol), BPh3 (9.7 mg, 0.04 mmol), Xantphos (5.8 mg, 0.01 mmol), and a solution of CpPd(1-phenylallyl) in toluene (0.02 M, 0.5 mL, 0.01 mmol). The reaction mixture was sealed with a PTFE lined cap, removed from the glovebox, and heated in an aluminum heating block for 24 h. The resulting mixture was allowed to cool to room temperature and a stock solution of p- methoxyacetophenone (0.1 M in toluene, 0.3 mL, 0.03 mmol) was added as the internal NMR-standard. The resulting mixture was concentrated in vacuo and the yield of 5.37a was determined by 1H NMR analysis. The isolated yield was obtained by concentrating the crude mixture onto Celite, followed by flash column chromatography.

Chapter 5 | 210

Table 5-6 Complete reaction screening for aminocyanation of 5.36a

Entry Metal (mol%) Ligand (mol%) Lewis acid (mol%) Solvent T (C) Yield of 5.37a (%)[a]

1 CpPd(1-phenylallyl) (10) Xantphos (10) BPh3 (50) PhMe 90 87

2 CpPd(1-phenylallyl) (10) Xantphos (10) BPh3 (50) PhMe 100 66

3 Pd2dba3 (5) Xantphos (10) BPh3 (50) PhMe 100 n.d.

4 Pd(OAc)2 (10) Xantphos (10) BPh3 (50) PhMe 100 62

5 [Pd(allyl)Cl]2 (5) Xantphos (10) BPh3 (50) PhMe 100 0

6 Pd(PPh3)4 (10) Xantphos (10) BPh3 (50) PhMe 100 59

7 XPhos Palladacycle (10) Xantphos (10) BPh3 (50) PhMe 100 0

8 CpPd(1-phenylallyl) (10) Xantphos (12) BPh3 (50) PhMe 100 75

9 CpPd(1-phenylallyl) (10) PPh3 (20) BPh3 (50) PhMe 100 36

10 Pd2dba3 (5) Xantphos (12) BPh3 (50) PhMe 100 52

11 Pd2dba3 (5) none BPh3 (50) PhMe 100 0

Chapter 5 | 211

Entry Metal (mol%) Ligand (mol%) Lewis acid (mol%) Solvent T (C) Yield of 5.37a (%)[a]

12 Pd(OAc)2 (10) Xantphos (12) BPh3 (50) PhMe 100 64

13 Pd(OAc)2 (10) PPh3 (20) BPh3 (50) PhMe 100 0

14 Pd(PPh3)4 (10) Xantphos (12) BPh3 (50) PhMe 100 58

15 Pd(PPh3)4 (10) none BPh3 (50) PhMe 100 60

16 Pd(OAc)2 (10) Xantphos (15) BPh3 (50) PhMe 100 73

17 Pd(OAc)2 (10) Xantphos (15) none PhMe 100 0

18 Pd(OAc)2 (10) none BPh3 (50) PhMe 100 0

19 none Xantphos (15) BPh3 (50) PhMe 100 0

20 none none BPh3 (50) PhMe 100 0

21 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (50) PhMe 100 75

22 Pd(dppf)Cl2 (10) Xantphos (15) BPh3 (50) PhMe 100 0

23 Pd(PCy3)2Cl2 (10) Xantphos (15) BPh3 (50) PhMe 100 0

24 PdCl2 (10) Xantphos (15) BPh3 (50) PhMe 100 0

25 PEPPSI-IPr (10) Xantphos (15) BPh3 (50) PhMe 100 0

26 Pd(dba)2 (10) Xantphos (15) BPh3 (50) PhMe 100 7

27 Pd(OCOCF3)2 (10) Xantphos (15) BPh3 (50) PhMe 100 48

28 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (50) PhMe 100 89

29 CpPd(1-phenylallyl) (10) Xantphos (15) B(C6F5)3 (50) PhMe 100 0

30 CpPd(1-phenylallyl) (10) Xantphos (15) AlMe2Cl (50) PhMe 100 0

Chapter 5 | 212

Entry Metal (mol%) Ligand (mol%) Lewis acid (mol%) Solvent T (C) Yield of 5.37a (%)[a]

31 CpPd(1-phenylallyl) (10) Xantphos (15) AlCl3 (50) PhMe 100 0

32 CpPd(1-phenylallyl) (10) Xantphos (15) ZnCl2 (50) PhMe 100 0

33 CpPd(1-phenylallyl) (10) Xantphos (15) Zn(OTf)2 (50) PhMe 100 0

34 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (10) PhMe 100 55

35 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (20) PhMe 100 75

36 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (30) PhMe 100 n.d.

37 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 100 87

38 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (50) PhMe 100 87

39 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 80 91

40 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 90 87

41 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 100 81

42 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (50) PhMe 80 93

43 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (50) PhMe 90 87

44 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (50) PhMe 100 83

45 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 70 87

46 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 60 38

47 CpPd(1-phenylallyl) (5) Xantphos (7.5) BPh3 (40) PhMe 80 79

48 CpPd(1-phenylallyl) (5) Xantphos (7.5) BPh3 (40) PhMe 70 0

49 CpPd(1-phenylallyl) (5) Xantphos (7.5) BPh3 (40) PhMe 60 0

Chapter 5 | 213

Entry Metal (mol%) Ligand (mol%) Lewis acid (mol%) Solvent T (C) Yield of 5.37a (%)[a]

50 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) THF 80 27

51 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhCF3 80 0

52 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) 1,4-dioxane 80 20

53 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) 1,2-DCE 80 0

54 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) DMF 80 0

55 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) cyclohexane 80 85

56 CpPd(1-phenylallyl) (10) Xantphos (10) BPh3 (40) PhMe 80 93

57 CpPd(1-phenylallyl) (10) Xantphos (15) BPh3 (40) PhMe 80 88

58 CpPd(1-phenylallyl) (10) Xantphos (20) BPh3 (40) PhMe 80 27

59 CpPd(1-phenylallyl) (10) dppp (10) BPh3 (40) PhMe 80 23

60 CpPd(1-phenylallyl) (10) dCype (10) BPh3 (40) PhMe 80 0

61 CpPd(1-phenylallyl) (10) rac. BINAP (10) BPh3 (40) PhMe 80 30

62 CpPd(1-phenylallyl) (10) DPEphos (10) BPh3 (40) PhMe 80 72

63 CpPd(1-phenylallyl) (10) Nixantphos (10) BPh3 (40) PhMe 80 81

64 CpPd(1-phenylallyl) (10) DBFphos (10) BPh3 (40) PhMe 80 0

65 CpPd(1-phenylallyl) (10) dppe (10) BPh3 (40) PhMe 80 0

66 CpPd(1-phenylallyl) (10) dppb (10) BPh3 (40) PhMe 80 49

67 CpPd(1-phenylallyl) (10) dppf (10) BPh3 (40) PhMe 80 75 [a] Determined by 1H NMR analysis.

Chapter 5 | 214

5.6.3 Overview of substrate synthesis

All N-acyl cyanamide substrates 5.36 were synthesized in 3 steps. Step 1 synthesizes aryl cyanamides 5.42 from the corresponding anilines 5.41. Step 2 synthesizes carboxylic acids 5.44. Step 3 synthesizes substrates 5.36 by coupling cyanamides 5.42 with acids 5.44.

5.6.4 Synthesis of cyanamides 5.42 (Step 1)

CAUTION! Cyanogen bromide (BrCN) is highly toxic and hydrolyzes readily to release hydrogen cyanide. The below preparations must be carried out in a well- ventilated fume hood. Excess BrCN should be destroyed with aqueous NaOH solution, and the resulting aqueous solution should be disposed of properly.

Chapter 5 | 215

Method A: A solution of BrCN (1271 mg, 12 mmol) in Et2O (10 mL) was slowly added to aniline 5.41 (20 mmol) in Et2O (20 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stir for 24 h. Upon completion, the mixture was diluted with Et2O (40 mL) and filtered through a pad of Celite. The filtrate was washed with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL), and were dried over anhydrous MgSO4, and concentrated. The crude product was purified by flash column chromatography or precipitation from Et2O/Hex or CH2Cl2/Hex at 0 °C. Method B: A solution of BrCN (2542 mg, 24 mmol) in MeOH (30 mL) was slowly added to a mixture of aniline (20 mmol) and NaOAc (60 mmol) in MeOH (30 mL) at 0 °C. The reaction mixture was stirred for 1 h, then was allowed to warm to room temperature and stir overnight. Upon completion, the reaction was neutralized with saturated aqueous NaHCO3 (20 mL) and concentrated. The residue was taken up with water (50 mL) and extracted with CH2Cl2 (30 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous MgSO4, and concentrated. The crude product was purified by flash column chromatography. Method C: To a solution of aniline 5.41 (10 mmol) in THF (15 mL) was added benzoyl isothiocyanate (1.48 mL, 11 mmol) in THF (10 mL) at room temperature. The resulting solution was stirred for 2–3 h. Upon completion, the reaction was concentrated, and the residue was suspended in MeOH (30 mL) and treated with a solution of K2CO3

(30 mmol) in H2O (10 mL). The reaction was stirred overnight, concentrated, and taken up with water (100 mL), which resulted in the precipitation of the thiourea product. The

Chapter 5 | 216 thiourea was collected by filtration and used without further purification. Next, to a suspension of the thiourea obtained above (10 mmol theoretical) in EtOAc (30 mL) was added H2O (2 mL) and Et3N (2.8 mL, 20 mmol), followed by addition of I2 (2792 mg, 11 mol) in 6–7 batches at room temperature. Upon complete addition of I2, the reaction was stirred for additional 5 min and quenched by addition of saturated aqueous NaHSO3 (2 mL). The resulting mixture was diluted with EtOAc (50 mL) and filtered through a pad of

Celite. The filtrate was washed with H2O (10 mL) and brine (10 mL), dried over anhydrous MgSO4, and concentrated. The crude product was purified by flash column chromatography.

5.42a, 5.42b, 5.42d, 5.42e, 5.42f, 5.42i, and 5.42p were known compounds, and were prepared following known procedures.* 5.42c: Prepared from 4-(tert-butyl)aniline on a 20.0 mmol scale, using Method A.

5.42c was purified by flash column chromatography (2:100 MeOH/CH2Cl2) as an off- 1 white solid (9.36 mmol, 94% yield). Rf = 0.44 (5:95 MeOH/CH2Cl2); mp 86–88 °C ; H

NMR (500 MHz, CDCl3) δ 7.38 – 7.32 (m, 2H), 7.00 – 6.90 (m, 2H), 6.10 (br s, 1H),

* 5.42a, 5.42b, 5.42d, 5.42e, 5.42f, and 5.42i: (a) Rao, B.; Zeng, X. Org. Lett. 2014, 16, 314. (b) Kumar, V.; Kaushik, M. P. Mazumdar, A. Euro. J. Org. Chem. 2008, 1910. (c) Li, J.; Neuville, L. Org. Lett. 2013, 15, 6124. 5.42p: Stolley, R. M.; Guo, W.; Louie, J. Org. Lett. 2012, 14, 322.

Chapter 5 | 217 13 1.30 (s, 9H); C NMR (126 MHz, CDCl3) δ 146.8, 134.4, 126.6, 115.1, 111.3, 34.3, 31.3; + HRMS (ESI) calcd for [C11H14N2 + Na] 197.1049, found 197.1047; IR (thin film) 3159, 2227, 1517, 1253. 5.42g: Prepared from 4-aminophenyl acetate* on a 9.7 mmol scale, using Method B.

5.42g was purified by precipitation (CH2Cl2/Hex) as an off-white solid (8.2 mmol, 85% 1 yield). Rf = 0.54 (1:1 EtOAc/Hex); mp 95–97 °C ; H NMR (500 MHz, CDCl3) δ 7.04 (dd, J = 8.8, 1.1 Hz, 2H), 6.97 – 6.90 (m, 2H), 2.31 (d, J = 1.0 Hz, 3H); 13C NMR (126

MHz, CDCl3) δ 170.2, 146.3, 135.1, 122.8, 116.3, 111.0, 21.1; HRMS (ESI) calcd for + [C9H8N2O2 + Na] 199.0478, found 199.0505; IR (thin film) 3183, 2237, 1757, 1510, 1221, 1195. 5.42h: Prepared from 1-(4-aminophenyl)ethan-1-one on a 10.0 mmol scale, using

Method C. 5.42h was purified by flash column chromatography (2:100 MeOH/CH2Cl2) as a pale yellow solid (6.2 mmol, 62% yield). Rf = 0.45 (5:95 MeOH/CH2Cl2); mp 110– 1 112 °C ; H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.05 13 (d, J = 8.7 Hz, 2H), 2.51 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 196.2, 143.2, 131.5, – 130.5, 114.7, 111.2, 26.4; HRMS (ESI) calcd for [C9H8N2O – H] 159.0564, found 159.0526; IR (thin film) 3188, 2229, 1740, 1272. 5.42j: Prepared from 3-chloroaniline on a 15.0 mmol scale, using Method C. 5.42j was purified by flash column chromatography (2:100 MeOH/CH2Cl2) as a pale yellow 1 solid (10.51 mmol, 71% yield). Rf = 0.48 (5:95 MeOH/CH2Cl2); mp 68–70 °C ; H NMR

(500 MHz, CDCl3) δ 7.30 – 7.22 (m, 1H), 7.07 (dd, J = 8.0, 1.8 Hz, 1H), 7.04 (t, J = 2.2 13 Hz, 1H), 6.92 (dd, J = 8.2, 2.3 Hz, 1H); C NMR (126 MHz, CDCl3) δ 138.3, 135.5, – 130.8, 123.9, 115.7, 113.6, 110.7; HRMS (ESI) calcd for [C7H5ClN2 – H] 151.0068, found 151.0060; IR (thin film) 3396, 2237, 1600. 5.42k: Prepared from 3-(trifluoromethyl)aniline on a 20.0 mmol scale, using

Method C. 5.42k was purified by flash column chromatography (2:100 MeOH/CH2Cl2) as a pale yellow solid (16.8 mmol, 84% yield). Rf = 0.46 (5:95 MeOH/CH2Cl2); mp 85–

* Prepared by reduction of 4-nitrophenyl acetate following a known procedure: Bargota, R. S.; Akhtar, M.; Biggadike, K.; Gani, D.; Allemann, R. Bioorg. Med. Chem. Lett. 2003, 13, 1623.

Chapter 5 | 218 1 87 °C ; H NMR (500 MHz, CDCl3) δ 7.48 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 13 7.27 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.2, 2.3 Hz, 1H); C NMR (126 MHz, CDCl3) δ 2 1 3 137.9, 132.3 (q, JF–C = 32.8 Hz), 130.5, 123.4 (q, JF–C = 270.8 Hz), 120.5 (q, JF–C = 3.8 3 – Hz), 118.6, 112.3 (q, JF–C = 3.9 Hz), 110.7; LRMS (ESI) calcd for [C8H5F3O2 – H] 185.0, found 185.1; IR (thin film) 3110, 2242, 1331. The NMR data is consistent with a literature report.* 5.42l: Prepared from methyl 3-aminobenzoate on a 15.0 mmol scale, using Method

C. 5.42l was purified by flash column chromatography (1:100 → 2:100 MeOH/CH2Cl2) as a pale yellow solid (13.5 mmol, 90% yield). Rf = 0.46 (5:95 MeOH/CH2Cl2); mp 88– 1 91 °C ; H NMR (500 MHz, CDCl3) δ 7.76 (dd, J = 7.7, 1.3 Hz, 1H), 7.71 (app s, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.28 (dd, J = 8.1, 2.6 Hz, 1H), 3.94 (d, J = 1.0 Hz, 3H); 13C

NMR (126 MHz, CDCl3) δ 166.6, 137.8, 131.5, 130.0, 124.6, 119.6, 116.4, 110.8, 52.6; + HRMS (ESI) calcd for [C9H8N2O2 + Na] 199.0478, found 199.0478; IR (thin film) 3152, 2227, 1594, 1251. 5.42m: Prepared from 3,5-dimethoxyaniline on a 10.0 mmol scale, using Method B.

5.42m was purified by flash column chromatography (3:100 MeOH/CH2Cl2) as a white 1 solid (5.2 mmol, 52% yield). Rf = 0.44 (5:95 MeOH/CH2Cl2); mp 138–140 °C ; H NMR

(500 MHz, CDCl3) δ 7.26 (s, 1H), 6.19 (d, J = 2.1 Hz, 1H), 6.16 (d, J = 2.1 Hz, 2H), 3.78 13 (s, 6H); C NMR (126 MHz, CDCl3) δ 161.9, 138.8, 110.4, 95.8, 94.0, 55.5; HRMS – (ESI) calcd for [C9H10N2O2 – H] 177.0670, found 177.0689. 5.42n: Prepared from 2,4-dimethylaniline on a 10.0 mmol scale, using Method A.

5.42n was purified by precipitation (Et2O/Hex) as an off-white solid (8.4 mmol, 84% 1 yield). Rf = 0.46 (5:95 MeOH/CH2Cl2); mp 102–104 °C ; H NMR (500 MHz, CDCl3) δ 7.08 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.96 (app s, 1H), 6.06 (br s, 1H), 2.28 13 (s, 3H), 2.20 (s, 3H); C NMR (126 MHz, CDCl3) δ 133.3, 132.9, 131.6, 127.9, 124.1, + 115.6, 111.9, 20.6, 16.9; HRMS (ESI) calcd for [C9H10N2 + Na] 169.0736, found 169.0740; IR (thin film) 3184, 2220, 1514.

* Sahoo, S. K.; Jamir, L.; Guin, S.; Patel, B. K. Adv. Synth. Catal. 2010, 352, 2358.

Chapter 5 | 219 5.42o: Prepared from 6-methoxypyridin-3-amine on a 10.0 mmol scale, using Method C. 5.42o was purified by flash column chromatography (3:97 → 5:95

MeOH/CH2Cl2) as a brick red solid (6.75 mmol, 68% yield). Rf = 0.44 (5:95 1 MeOH/CH2Cl2); mp 105–107 °C ; H NMR (500 MHz, DMSO-d6) δ 10.11 (br s, 1H), 7.84 (dd, J = 3.0, 0.7 Hz, 1H), 7.36 (dd, J = 8.8, 3.0 Hz, 1H), 6.84 (dd, J = 8.8, 0.7 Hz, 1H), 3.80 (s, 3H); 13C NMR (126 MHz, DMSO) δ 159.6, 133.0, 129.6, 127.3, 112.1, + 111.3, 53.3; HRMS (ESI) calcd for [C7H7N3O + H] 150.0662, found 150.0654; IR (thin film) 3054, 2210, 1495.

5.6.5 Synthesis of carboxylic acids 5.44 (Step 2)

5.44j, 5.44k, 5.44l, 5.44m, and 5.44o were known compounds and were synthesized following known procedures.*

* 5.44j: Zhang, Z.; Liu, F. Org. Biomol. Chem. 2015, 13, 6690. 5.44k: Marion Merrell Dow Inc. Patent: US5039691 A1, 1991. 5.44l, 5.44m, and 5.44o: Nicolai, S.; Erard, S.; González, D. F.; Waser, J. Org. Lett. 2010, 12, 384.

Chapter 5 | 220

Synthesis of 5.44a following a modified procedure:* At 0 °C , to a solution of diphenylacetic acid 5.43a (10.610g, 50 mmol) in THF (100 mL) was slowly added nBuLi (2.5 M Hex solution, 44 mL, 110 mmol) via syringe or dropping funnel. The mixture was stirred at 0 °C for 30 min, followed by slow addition of methally chloride (7.04 mL, 65 mmol). The reaction was warmed and maintained at 45 °C for 5 hours, which was then cooled in an ice bath and acidified with 2 N HCl to pH ≤ 2. The layers were separated and the aqueous layer was extracted with Et2O (30 mL × 3). The combined organic phase was washed with water and brine, dried over Na2SO4, and concentrated to a small volume, whereupon the product started to precipitate. Hexanes (ca. 80 mL) was added to further promote the precipitation with the aid of vigorous stirring, and the precipitated 5.44a was collected by vacuum filtration as a white powder (8.65g, 65% yield). Rf = 0.32 (1:4 1 EA/Hex); mp 117–118 °C ; H NMR (500 MHz, CDCl3) δ 7.36 – 7.32 (m, 4H), 7.31 – 7.21 (m, 6H), 4.71 (t, J = 1.7 Hz, 1H), 4.55 (app s, 1H), 3.18 (s, 2H), 1.33 (s, 3H); 13C

NMR (126 MHz, CDCl3) δ 180.1, 142.6, 141.8, 129.0, 127.8, 126.9, 115.6, 60.1, 45.6, – 24.3; LRMS (ESI) calcd for [C18H18O2 – H – CO2] 221.1, found 221.1; IR (thin film) 3059, 1699, 1495, 1215. The NMR data is consistent with a literature report.*

† 5.43b: To a solution of iPr2NH (3.36 mL, 24 mmol) in THF (15 mL) was added nBuLi (2.5 M Hex, 9.2 mL, 23 mmol) dropwise at –78 °C . The resulting solution was stirred at –78 °C for 40 min, then a solution of methyl isobutyrate (2043 mg, 20 mmol) in

* Kozo, S.; Koji, U.; Masayuku, S. Heterocycles 1994, 38, 641. † Procedure was modified from: Kelly, B. D.; Allen, J. M.; Tundel, R. E.; Lambert, T. H. Org. Lett. 2009, 11, 1381.

Chapter 5 | 221 THF (10 mL) was added. The reaction mixture was stirred at –78 °C for additional 1 h, followed by slow addition of methallyl bromide (2.62 mL, 26 mmol) at the same temperature. The resulting mixture was allowed to warm to room temperature and stirred overnight, which was then quenched with sat. NH4Cl (10 mL) and extracted with Et2O (20 mL × 3). The combined organic extracts were combined, washed with brine, dried over Na2SO4, and concentrated. The resulting mixture was purified by flash column chromatography (2:98 → 10:90 Et2O/Hex) to give ester 5.43b as a colorless oil (2.34 g, 1 15 mmol, 75% yield). Rf = 0.44 (5:95 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 4.81 – 4.74 (m, 1H), 4.62 – 4.60 (m, 1H), 3.64 (s, 3H), 2.28 (s, 2H), 1.62 (s, 3H), 1.16 (s, 6H); 13 C NMR (126 MHz, CDCl3) δ 178.3, 142.4, 114.1, 51.6, 48.5, 42.0, 25.5, 23.4; IR (thin film) 1734, 1643, 1199, 1131. 5.44b: A mixture of 5.43b (1562 mg, 10 mmol), NaOH (800 mg, 20 mmol), MeOH

(10 mL), and H2O (10 mL) was heated at 80 °C for 20 h. The reaction was cooled to 0 °C , acidified with 2 N HCl to pH ≤ 2, and extracted with Et2O (20 mL × 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give 5.44b as a bright yellow oil (1.39 g, 9.8 mmol, 98% crude yield). 5.44b was diluted with benzene, concentrated again, and used without further purification. 1H NMR (500 MHz,

CDCl3) δ 4.84 – 4.82 (m, 1H), 4.71 – 4.69 (m, 1H), 2.34 (s, 2H), 1.71 (s, 3H), 1.21 (s, 13 6H); C NMR (126 MHz, CDCl3) δ 185.2, 142.2, 114.4, 48.2, 42.0, 25.3, 23.6. The NMR data is consistent with a literature report.*

† 5.44c: To a solution of iPr2NH (1.05 mL, 7.5 mmol) in THF (6 mL) was added nBuLi (2.5 M Hex, 2.9 mL, 7.2 mmol) dropwise at 0 °C . The resulting solution was

* Nicolai, S.; Erard, S.; Gonzalez, D. F.; Waser, J. Org. Lett. 2010, 12, 384. † Procedure was modified from: Nicolai, S.; Piemontesi, C.; Waser, J. Angew. Chem., Int. Ed. 2011, 50, 4680.

Chapter 5 | 222 stirred at 0 °C for 10 min, then a solution of 2-benzyl-3-phenylpropanoic acid 5.43c* (721 mg, 3.0 mmol) in THF (3 mL) was slowly added. The reaction mixture was warmed and maintained at 55–60 °C for 1 h to allow complete dianion formation, which was then cooled back to 0 °C and methallyl bromide (0.43 mL, 4.2 mmol) was slowly added. The reaction was allowed to warm to room temperature and stir overnight, then it was quenched with H2O, acidified with 2 N HCl to pH ≤ 2, and extracted with Et2O (20 mL ×

3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The resulting mixture was purified by flash column chromatography (1:4

→ 3:7 Et2O/Hex) to give acid 5.44c as a pale yellow oil (795 mg, 2.7 mmol, 90% yield). 1 Rf = 0.39 (3:7 Et2O/Hex); H NMR (500 MHz, CDCl3) δ 7.32 – 7.16 (m, 10H), 5.02 (app s, 1H), 4.87 (app s, 1H), 3.10 (d, J = 14.0 Hz, 2H), 3.05 (d, J = 14.0 Hz, 2H), 2.26 (s, 2H), 13 1.73 (s, 3H); C NMR (126 MHz, CDCl3) δ 182.6, 142.1, 137.1, 130.4, 128.0, 126.6, – 113.1, 50.5, 41.1, 40.9, 25.1; HRMS (ESI) calcd for [C20H22O2 – H] 293.1547, found 193.1536; IR (thin film) 1700, 1454, 1265.

5.44d and 5.44e were synthesized in the manner as 5.44c. 5.44d was synthesized from cyclobutanecarboxylic acid 5.43d on a 5.0 mmol scale. 5.44d was purified by flash column chromatography (1:9 → 15:85 EtOAc/Hex) as a 1 colorless oil (648 mg, 4.2 mmol, 84% yield). Rf = 0.52 (1:4 EtOAc/Hex); H NMR (500

MHz, CDCl3) δ 4.76 (app s, 1H), 4.60 (app s, 1H), 2.56 (s, 2H), 2.55 – 2.47 (m, 2H), 2.06 13 – 1.98 (m, 2H), 1.98 – 1.90 (m, 2H), 1.69 (s, 3H); C NMR (126 MHz, CDCl3) δ 183.7, – 142.3, 112.1, 47.0, 45.4, 30.5, 23.3, 15.8; LRMS (ESI) calcd for [C9H14O2 – H] 153.1, found 153.1; IR (thin film) 3076, 1698, 1650, 1256, 1225.

* Prepared following a known procedure: Koder, R. L.; Lichtenstein, B. R.; Cerda, J. F.; Miller, A.; Dutton, P. L. Tetrahedron Lett. 2007, 48, 5517.

Chapter 5 | 223 5.44e was synthesized from cyclopentanecarboxylic acid 5.43e on a 15 mmol scale.

5.44d was purified by flash column chromatography twice (1st: 1:4 → 1:3 Et2O/Hex) as 1 a pale yellow oil (1.80 g, 10.68 mmol, 71% yield). Rf = 0.32 (3:7 Et2O/Hex); H NMR

(500 MHz, CDCl3) δ 4.78 – 4.77 (m, 1H), 4.67 (d, J = 1.1 Hz, 1H), 2.42 (s, 2H), 2.19 – 13 2.11 (m, 2H), 1.70 (s, 3H), 1.68 – 1.50 (m, 6H); C NMR (126 MHz, CDCl3) δ 184.6, – 142.8, 113.2, 53.3, 46.4, 36.2, 24.8, 23.3; HRMS (ESI) calcd for [C10H16O2 – H] 167.1078, found 167.1049; IR (thin film) 3075, 1697, 1650, 1453, 1223.

5.43f was synthesized in the same manner as 5.43b, starting from methyl tetrahydro- 2H-pyran-4-carboxylate * on a 7.3 mmol scale. 5.43f was purified by flash column chromatography (1:9 → 15:85 Et2O/Hex) as a light yellow oil (1.23 g, 6.2 mmol, 85% 1 yield). Rf = 0.42 (1:9 Et2O/Hex); H NMR (500 MHz, CDCl3) δ 4.84 – 4.83 (m, 1H), 4.66 (dd, J = 2.1, 1.0 Hz, 1H), 3.82 (dt, J = 11.9, 3.8 Hz, 2H), 3.71 (s, 3H), 3.45 (td, J = 11.6, 2.3 Hz, 2H), 2.31 (s, 2H), 2.09 (dd, J = 13.9, 2.7 Hz, 2H), 1.67 (s, 3H), 1.55 (ddd, J 13 = 13.8, 11.2, 4.4 Hz, 2H); C NMR (126 MHz, CDCl3) δ 176.0, 140.9, 114.9, 65.3, 51.6, + 48.7, 45.0, 34.6, 23.7; HRMS (ESI) calcd for [C11H18O3 + Na] 221.1148, found 221.1168; IR (thin film) 1730, 1647, 1194, 1134. 5.44f was synthesized in the same manner as 5.44b, from the hydrolysis of 5.43f on a 10.0 mmol scale. 5.44f was obtained as a white solid (1.78 g, 9.7 mmol, 97% crude 1 yield), and was used without further purification. H NMR (500 MHz, CDCl3) δ 4.88 – 4.83 (m, 1H), 4.72 (app s, 1H), 3.86 (dt, J = 12.0, 3.8 Hz, 2H), 3.53 (td, J = 11.7, 2.3 Hz, 2H), 2.35 (s, 2H), 2.09 (dd, J = 13.9, 2.6 Hz, 2H), 1.73 (s, 3H), 1.59 (ddd, J = 13.8, 11.2, 4.5 Hz, 2H).

* Prepared by esterification of the corresponding carboxylic acid.

Chapter 5 | 224

5.44g, 5.44h, and 5.44i were synthesized in the same manner as 5.44c, by quenching the dianion with the corresponding substituted allyl bromides. 5.44g was synthesized from methyl isobutyrate on a 8.0 mmol scale, using 2- (bromomethyl)hex-1-ene * as the quenching electrophile. 5.44g was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a colorless oil (1.07 g, 5.78 mmol, 1 72% yield). Rf = 0.60 (1:4 EtOAc/Hex); H NMR (400 MHz, CDCl3) δ 4.84 (q, J = 1.5 Hz, 1H), 4.73 (app s, 1H), 2.33 (s, 2H), 1.97 (t, J = 7.3 Hz, 2H), 1.45 – 1.35 (m, 2H), 1.34 13 – 1.23 (m, 2H), 1.21 (s, 6H), 0.89 (t, J = 7.3 Hz, 3H); C NMR (101 MHz, CDCl3) δ 184.9, 146.3, 112.9, 46.2, 42.2, 36.7, 30.1, 25.4, 22.4, 13.9; LRMS (ESI) calcd for – [C11H20O2 – H] 183.1, found 183.2; IR (thin film) 3053, 1699, 1640, 1474. 5.44h was synthesized from methyl isobutyrate on a 6.0 mmol scale, using 2(3- (bromomethyl)but-3-en-1-yl)benzene† as the quenching electrophile. 5.44h was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a pale yellow oil (981 mg, 1 4.22 mmol, 70% yield). Rf = 0.41 (15:85 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.30 – 7.23 (m, 2H), 7.20 – 7.12 (m, 3H), 4.88 (q, J = 1.5 Hz, 1H), 4.78 (app s, 1H), 2.79 – 2.69 (m, 2H), 2.37 (s, 2H), 2.33 – 2.22 (m, 2H), 1.22 (s, 6H); 13C NMR (126 MHz,

CDCl3) δ 184.8, 145.5, 142.0, 128.3, 128.3, 125.7, 113.8, 46.1, 42.2, 38.9, 34.6, 25.4; – HRMS (ESI) calcd for [C15H20O2 – H] 231.1391, found 231.1375; IR (thin film) 3064, 1697, 1641, 1474, 1219. 5.44i was synthesized from methyl isobutyrate on a 8.0 mmol scale, using 2(((2- (bromomethyl)allyl)oxy)methyl)benzene ‡ as the quenching electrophile (performed at

* Prepared following a known procedure: Ma, S.; Ni, B.; Chem. Eur. J. 2004, 10, 3286. † Prepared following a known procedure: Lipshutz, B. H.; Sharma, S.; Dimock, S. H.; Behling, J. R. Synthesis 1992, 191. ‡ Prepared in several steps, starting from methyl 2-(hydroxymethyl)acrylate: (1) Kippo, T.; Fukuyama, T.; Ryu, L. Org. Lett. 2011, 13, 3864. (2) Sagot, E.; Pickering, D. S.; Pu, X.; Umberti, M.; Stensbol, T. B.; Nielsen, B.; Chapelet,

Chapter 5 | 225 –78 °C instead of 0 °C ). Unfortunately, several attempts to purify 5.44i by flash column chromatography were unsuccessful. 5.44i was thus taken to the next step without further treatment.

5.44n:* To a THF solution of i-PrMgCl·LiCl (0.77 M in THF, 14.3 mL, 11 mmol) was slowly added 1,2-dibromobenzene (1.23 mL, 10 mmol, neat) at –15 °C . The resulting solution was stirred at –15 °C for 2 h, whereupon methallyl bromide (1.21 mL, 12 mmol) and CuCN·2LiCl (1.0 M in THF, 1.0 mL, 1.0 mmol) were sequentially added at –15 °C. The reaction was allowed to warm to room temperature and stir overnight, which was then quenched by sat. NH4Cl (10 mL) and extracted with Et2O (20 mL × 3).

The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to afford crude 5.43n as a pale yellow oil (1972 mg, 9.3 mmol, 93% crude yield), which was taken to the next step without further purification. 1H NMR (500 MHz,

CDCl3) δ 7.54 (dd, J = 7.9, 1.2 Hz, 1H), 7.28 – 7.20 (m, 2H), 7.07 (ddd, J = 7.9, 6.7, 2.3 Hz, 1H), 4.86 (app s, 1H), 4.59 (app s, 1H), 3.46 (s, 2H), 1.76 (s, 3H). The NMR data is consistent with a literature report.† Next, to a solution of 5.43n (ca. 9.3 mmol) in THF (10 mL) was added nBuLi (2.5 M Hex, 4.1 mL, 10.2 mmol) at –78 °C . The reaction was stirred at –78 °C for 30 min, then CO2 was bubbled through the reaction at the same temperature for 10 min. The reaction was allowed to warm to room temperature and stir for additional 20 min under

M; Bolte, J.; Gefflaut, T.; Bunch, L. J. Med. Chem. 2008, 51, 4093. (3) Maguire, R. J.; Mulzer, J.; Bats, J. W. J. Org. Chem. 1996, 61, 6936. * The first step was adopted from a known procedure: Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333. † Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056.

Chapter 5 | 226

CO2 bubbling, which was then acidified with 2 N HCl to pH ≤ 2 and extracted with Et2O

(20 mL × 3). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The resulting mixture was purified by flash column chromatography

(1:99 → 3:97 MeOH/CH2Cl2) to afford acid 5.44n as an oily white solid (1.04 g, 5.9 1 mmol, 59% yield over 2 steps). Rf = 0.38 (5:95 MeOH/CH2Cl2). H NMR (500 MHz,

CDCl3) δ 8.05 (dd, J = 7.8, 1.5 Hz, 1H), 7.50 (td, J = 7.5, 1.5 Hz, 1H), 7.37 – 7.28 (m, 2H), 4.80 (app s, 1H), 4.50 – 4.44 (m, 1H), 3.79 (s, 2H), 1.77 (s, 3H); 13C NMR (126

MHz, CDCl3) δ 173.2, 145.4, 142.2, 132.7, 131.6, 131.5, 128.8, 126.3, 111.6, 41.8, 23.0; – HRMS (ESI) calcd for [C11H12O2 – H] 175.0765, found 175.0767; IR (thin film) 3076, 1691, 1272. The NMR data is consistent with a literature report.*

5.43p was synthesized in the same manner as 5.43b, starting from methyl isobutyrate on a 20 mmol scale, and using 4-iodo-2-methylbut-1-ene† as the quenching electrophile. 5.43p was purified by flash column chromatography (5:95 Et2O/Hex) as a 1 colorless oil (2348 mg, 13.8 mmol, 69% yield). Rf = 0.48 (5:95 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 4.69 (app s, 1H), 4.67 (app s, 1H), 3.67 (s, 3H), 1.96 – 1.88 (m, 2H), 13 1.72 (s, 2H), 1.68 – 1.63 (m, 2H), 1.19 (s, 6H); C NMR (126 MHz, CDCl3) δ 178.3, 145.7, 109.7, 51.6, 42.1, 38.8, 33.1, 25.1, 22.6; IR (thin film) 1734, 1650, 1194, 1133. 5.44p was synthesized in the same manner as 5.44b, from the hydrolysis of 5.43p on a 13.8 mmol scale. 5.44p was obtained as a pale yellow oil (2.05 g, 13.1 mmol, 95% 1 crude yield), and was used without further purification. H NMR (500 MHz, CDCl3) δ

* Nicolai, S.; Piemontesi, C.; Waser, J. Angew. Chem., Int. Ed. 2011, 50, 4680. † Prepared following a known procedure: Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172.

Chapter 5 | 227 4.71 – 4.69 (m, 1H), 4.69 – 4.68 (m, 1H), 2.05 – 1.93 (m, 2H), 1.77 – 1.64 (m, 5H), 1.22 (s, 6H).

5.6.6 Synthesis of substrates 5.36 (Step 3)

Synthesis of 5.36a as a representative example, standard conditions: To a suspension of acid 5.43a (1598 mg, 6.0 mmol) in CH2Cl2 (5.0 mL) was added DMF (3 drops via glass pipet), followed by dropwise addition of (COCl)2 (2.0 M in CH2Cl2, 2.8 mL, 5.5 mmol) at room temperature. The mixture was stirred for 15–20 minutes, whereupon gas evolution ceased and all acid dissolved. The reaction flask was cooled to

–12 °C in an ethylene glycol/dry ice bath and a solution of Et3N (1.67 mL, 12.0 mmol) in

CH2Cl2 (4.0 mL) was dropwise added. Thereafter, a solution of N-(p-tolyl)cyanamide

S2a (661 mg, 5.0 mmol) in CH2Cl2/THF (3.0 and 1.0 mL, respectively) was slowly added at the same temperature. The resulting mixture was allowed to warm up to room temperature and stir for 20 h. Et2O (30 mL) was added to allow triethylamine hydrochloride to precipitate, which was filtrated through a short Celite column. Without further treatment,* the filtrate was concentrated in vacuo and the resulting oily residue was purified by flash column chromatography to afford substrate 5.36a as a white powder 1 (681 mg, 1.79 mmol, 36% yield). Rf = 0.49 (1:9 EtOAc/Hex); mp 108–110 °C ; H NMR

(500 MHz, CDCl3) δ 7.53 (dt, J = 6.2, 1.3 Hz, 4H), 7.40 (dd, J = 8.6, 6.8 Hz, 4H), 7.36 – 7.30 (m, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.10 – 7.03 (m, 2H), 4.77 (app s, 1H), 4.48 (app s, 13 1H), 3.42 (s, 2H), 2.35 (s, 3H), 1.42 (s, 3H); C NMR (125 MHz, CDCl3) δ 173.0, 141.0,

* Washing the organic extracts with aqueous solutions (e.g., H2O or 1 M HCl) led to extensive emulsion.

Chapter 5 | 228 139.4, 139.2, 133.7, 130.2, 128.8, 128.3, 127.6, 125.9, 116.5, 109.3, 62.1, 47.1, 24.5, 21.1; + HRMS (ESI) calcd for [C26H24N2O + Na] 403.1781, found 403.1778; IR (thin film) 2230, 1725, 1508, 1203.

Modified conditions: In step i), 5,5-dimethyl-3,3-diphenyldihydrofuran-2(3H)-one was formed as a by-product. This compound frequently coeluted with product 1 during column chromatography. It was found that the addition of 2-methyl-2-butene (8–10 equivalents) at step i) significantly reduced the amount of this by-product in the crude reaction mixture. Under such conditions, most substrates were readily purified after one column chromatography and were obtained as thick oil or tacky solid. Some substrates were further precipitated from CH2Cl2/Hex or CH2Cl2/pentane and converted to crystalline solids.

Chapter 5 | 229

Chapter 5 | 230 5.36b: Prepared from 5.42b on a 5.0 mmol scale under standard conditions. 5.36b was purified by flash column chromatography (4:6 → 1:1 CH2Cl2/Hex) as a white powder (718 mg, 1.96 mmol, 39% yield). Rf = 0.53 (15:85 EtOAc/Hex); mp 101–103 °C ; 1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.7 Hz, 4H), 7.44 – 7.31 (m, 9H), 7.20 (d, J = 7.6 Hz, 2H), 4.78 (app s, 1H), 4.49 (app s, 1H), 3.43 (s, 2H), 1.43 (s, 3H); 13C NMR (126

MHz, CDCl3) δ 172.9, 141.0, 139.1, 136.3, 129.6, 129.1, 128.8, 128.4, 127.7, 126.1, + 116.6, 109.2, 62.2, 47.1, 24.5; HRMS (ESI) calcd for [C25H22N2O + Na] 389.1624, found 389.1622; IR (thin film) 2231, 1725, 1491, 1204. 5.36c: Prepared from 5.42c on a 5.0 mmol scale under standard conditions. 5.36c was purified by flash column chromatography (3:7 → 4:6 CH2Cl2/Hex) as a white solid 1 (963 mg, 2.28 mmol, 46% yield). Rf = 0.68 (1:1 CH2Cl2/Hex); mp 118–121 °C ; H NMR

(500 MHz, CDCl3) δ 7.53 (d, J = 8.5 Hz, 4H), 7.44 – 7.38 (m, 6H), 7.36 – 7.30 (m, 2H), 7.12 (dd, J = 8.6, 1.0 Hz, 2H), 4.78 (d, J = 1.6 Hz, 1H), 4.49 (app s, 1H), 3.43 (s, 2H), 13 1.42 (s, 3H), 1.30 (s, 9H); C NMR (126 MHz, CDCl3) δ 173.1, 152.4, 141.1, 139.2, 133.6, 128.8, 128.3, 127.6, 126.6, 125.5, 116.6, 109.3, 62.2, 47.1, 34.7, 31.2, 24.5; + HRMS (ESI) calcd for [C29H30N2O + Na] 445.2250, found 445.2256; IR (thin film) 2231, 1725, 1510, 1205. 5.36d: Prepared from 5.42d on a 5.0 mmol scale under standard conditions. 5.36d was purified by flash column chromatography (3:7 → 1:1 CH2Cl2/Hex), and further precipitated (CH2Cl2/pentane, 1:40 v/v) as a white powder (850 mg, 2.21 mmol, 44% 1 yield). Rf = 0.48 (1:1 CH2Cl2/Hex); mp 110–112 °C ; H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.8 Hz, 4H), 7.41 (dd, J = 8.5, 6.9 Hz, 4H), 7.34 (t, J = 7.3 Hz, 2H), 7.20 – 7.14 (m, 2H), 7.10 (t, J = 8.5 Hz, 2H), 4.78 (app s, 1H), 4.49 (app s, 1H), 3.42 (s, 2H), 1.42 (s, 13 1 3H); C NMR (126 MHz, CDCl3) δ 173.0, 162.4 (d, JF–C = 250.1 Hz), 141.0, 139.0, 4 3 2 132.2 (d, JF–C = 3.2 Hz), 128.7, 128.4, 128.2 (d, JF–C = 9.0 Hz), 127.8, 116.7 (d, JF–C = + 23.3 Hz), 116.58, 109.0, 62.2, 47.1, 24.5; HRMS (ESI) calcd for [C25H21FN2O + Na] 407.1530, found 407.1530; IR (thin film) 2233, 1727, 1506, 1202. 5.36e: Prepared from 5.42e on a 5.0 mmol scale under standard conditions. 5.36e was purified by flash column chromatography (35:65 → 4:6 CH2Cl2/Hex), and further

Chapter 5 | 231 precipitated (CH2Cl2/Hex, 1:40 v/v) as a white powder (922 mg, 2.30 mmol, 46% yield). 1 Rf = 0.38 (1:1 CH2Cl2/Hex); mp 116–118 °C ; H NMR (500 MHz, CDCl3) δ 7.55 – 7.47 (m, 4H), 7.44 – 7.36 (m, 6H), 7.36 – 7.30 (m, 2H), 7.14 (d, J = 8.7 Hz, 2H), 4.78 (app s, 13 1H), 4.48 (app s, 1H), 3.42 (s, 2H), 1.41 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.8, 141.0, 138.9, 135.1, 134.7, 129.8, 128.7, 128.4, 127.8, 127.4, 116.6, 108.8, 62.2, 47.1, + 24.5; HRMS (ESI) calcd for [C25H21ClN2O + Na] 423.1235, found 423.1242; IR (thin film) 2232, 1727, 1488, 1191. 5.36f: Prepared from 5.42f on a 5.0 mmol scale under standard conditions. 5.36f was purified by flash column chromatography (3:7 → 1:1 CH2Cl2/Hex) as a white solid 1 (940 mg, 2.37 mmol, 47% yield). Rf = 0.42 (1:1 CH2Cl2/Hex); mp 90–92 °C ; H NMR

(500 MHz, CDCl3) δ 7.56 (d, J = 8.3 Hz, 4H), 7.40 (t, J = 7.7 Hz, 4H), 7.37 (t, J = 7.1 Hz, 2H), 7.10 – 7.06 (m, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.77 (d, J = 1.4 Hz, 1H), 4.48 (app s, 13 1H), 3.79 (s, 3H), 3.42 (s, 2H), 1.42 (d, J = 1.4 Hz, 3H); C NMR (126 MHz, CDCl3) δ 173.2, 159.9, 141.1, 139.2, 128.9, 128.8, 128.3, 127.6, 127.5, 116.5, 114.8, 109.4, 62.1, + 55.5, 47.1, 24.5; HRMS (ESI) calcd for [C26H24N2O2 + Na] 419.1730, found 419.1736; IR (thin film) 2230, 1725, 1508, 1249. 5.36g: Prepared from 5.42g on a 5.0 mmol scale under standard conditions. 5.36g was purified by flash column chromatography (1:1 CH2Cl2/Hex → 15:85 EtOAc/Hex), and further precipitated (CH2Cl2/Hex, 1:40 v/v) as a white powder (569 mg, 1.34 mmol, 1 27% yield). Rf = 0.35 (1:4 EtOAc/Hex); mp 120–121 °C ; H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 8.3 Hz, 4H), 7.40 (t, J = 7.3 Hz, 4H), 7.33 (d, J = 7.6 Hz, 2H), 7.23 – 7.19 (m, 2H), 7.18 – 7.12 (m, 2H), 4.78 (d, J = 1.5 Hz, 1H), 4.48 (app s, 1H), 3.42 (s, 2H), 2.29 (d, 13 J = 0.9 Hz, 3H), 1.42 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.8, 168.8, 150.7, 141.0, 139.0, 133.5, 128.7, 128.4, 127.7, 127.2, 122.8, 116.6, 109.0, 62.2, 47.1, 24.5, 21.1; + HRMS (ESI) calcd for [C27H24N2O3 + Na] 447.1679, found 447.1676; IR (thin film) 2232, 1765, 1726, 1503, 1190. 5.36h: Prepared from 5.42h on a 4.0 mmol scale under standard conditions. 5.36h was purified by flash column chromatography (1:9 acetone/Hex) as a thick yellow oil 1 (425 mg, 1.04 mmol, 26% yield). Rf = 0.37 (1:4 acetone/Hex); H NMR (500 MHz,

Chapter 5 | 232

CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H), 7.53 (m, J = 7.5 Hz, 4H), 7.42 (t, J = 8.5 Hz, 4H), 7.35 (td, J = 8.5, 1.6 Hz, 4H), 4.79 (t, J = 1.8 Hz, 1H), 4.49 (app s, 1H), 3.43 (s, 2H), 2.60 (s, 13 3H), 1.41 (d, J = 1.4 Hz, 3H); C NMR (126 MHz, CDCl3) δ 196.5, 172.6, 140.9, 140.1, 138.8, 137.1, 129.6, 128.7, 128.5, 127.8, 126.0, 116.7, 108.6, 62.4, 47.1, 26.7, 24.5; + HRMS (ESI) calcd for [C27H24N2O2 + Na] 431.1730, found 431.1721; IR (thin film) 2232, 1728, 1688, 1600, 1178. 5.36i: Prepared from 5.42i on a 5.0 mmol scale under standard conditions. 5.36i was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a thick colorless oil, which gradually solidified into a white waxy solid (730 mg, 1.84 mmol, 37% yield). 1 Rf = 0.42 (15:85 EtOAc/Hex); mp 80–83 °C ; H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.8 Hz, 4H), 7.40 (t, J = 7.7 Hz, 4H), 7.36 – 7.27 (m, 3H), 6.90 (dd, J = 8.4, 2.5 Hz, 1H), 6.78 (dd, J = 8.0, 2.0 Hz, 1H), 6.70 (t, J = 2.3 Hz, 1H), 4.78 (app s, 1H), 4.49 (app s, 1H), 13 3.76 (s, 3H), 3.42 (s, 2H), 1.42 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.9, 160.3, 141.0, 139.1, 137.2, 130.2, 128.8, 128.3, 127.6, 118.2, 116.5, 114.7, 112.1, 109.1, 62.2, + 55.5, 47.1, 24.5; HRMS (ESI) calcd for [C26H24N2O2 + Na] 419.1730, found 419.1725; IR (thin film) 2231, 1727, 1606, 1490, 1204. 5.36j: Prepared from 5.42j on a 5.0 mmol scale under standard conditions. 5.36j was purified by flash column chromatography (3:7 → 4:6 CH2Cl2/Hex), and further precipitated (CH2Cl2/Hex, 1:40 v/v) as a white powder (910 mg, 2.27 mmol, 45% yield). 1 Rf = 0.44 (1:9 EtOAc/Hex); mp 114–116 °C ; H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.7 Hz, 4H), 7.42 (t, J = 7.7 Hz, 4H), 7.38 – 7.32 (m, 4H), 7.22 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 6.1, 2.7 Hz, 1H), 4.79 (app s, 1H), 4.48 (app s, 1H), 3.42 (s, 2H), 1.41 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 172.7, 140.9, 138.9, 137.2, 135.1, 130.5, 129.4, 128.7, 128.5, 127.8, 126.5, 124.3, 116.7, 108.7, 62.3, 47.1, 24.5; HRMS (ESI) calcd for + [C25H21ClN2O + Na] 423.1235, found 423.1238; IR (thin film) 2232, 1729, 1589, 1190. 5.36k: Prepared from 5.42k on a 5.0 mmol scale under standard conditions. 5.36k was purified by flash column chromatography (3:7 → 4:6 CH2Cl2/Hex) as a colorless oil, which solidified into a white solid upon mixing with pentane (ca. 15 mL) at room temperature for ca. 10 min (1.00 g, 2.31 mmol, 46% yield). Rf = 0.57 (1:1 CH2Cl2/Hex);

Chapter 5 | 233 1 mp 111–112 °C ; H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.59 – 7.50 (m, 5H), 7.48 (app s, 1H), 7.45 – 7.38 (m, 5H), 7.38 – 7.32 (m, 2H), 4.80 (app s, 1H), 4.50 13 (app s, 1H), 3.44 (s, 2H), 1.42 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.8, 140.9, 2 3 138.8, 136.8, 132.2 (q, JF–C = 33.5 Hz), 130.3, 129.4, 128.7, 128.5, 127.9, 126.0 (q, JF–C 3 1 = 3.7 Hz), 123.3 (q, JF–C = 3.8 Hz), 123.1 (q, JF–C = 271.0 Hz), 116.7, 108.6, 62.3, 47.1, + 24.5; HRMS (ESI) calcd for [C26H21F3N2O + Na] 457.1498, found 457.1501; IR (thin film) 2233, 1728, 1328, 1177. 5.36l: Prepared from 5.42l on a 5.0 mmol scale under standard conditions. 5.36l was purified by flash column chromatography (3:7 → 6:4 CH2Cl2/Hex) as a tacky white solid 1 (1.30 g, 3.07 mmol, 61% yield). Rf = 0.32 (1:1 CH2Cl2/Hex); H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 7.8, 1.4 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.54 (dt, J = 8.2, 1.3 Hz, 4H), 7.50 (td, J = 7.9, 1.0 Hz, 1H), 7.42 (dd, J = 8.2, 6.8 Hz, 4H), 7.39 – 7.32 (m, 3H), 4.79 (app s, 1H), 4.50 (app s, 1H), 3.93 (s, 3H), 3.43 (s, 2H), 1.42 (s, 3H); 13C NMR (126

MHz, CDCl3) δ 172.8, 165.5, 141.0, 138.9, 136.5, 131.9, 130.5, 130.2, 129.7, 128.8, 128.5, 127.8, 127.3, 116.7, 108.8, 62.3, 52.5, 47.1, 24.5; HRMS (ESI) calcd for + [C27H24N2O3 + Na] 447.1679, found 447.1684; IR (thin film) 2233, 1727, 1289. 5.36m: Prepared from 5.42m on a 4.5 mmol scale under standard conditions. 5.36m was purified by flash column chromatography twice (8:92 → 12:88 acetone/Hex) as a thick colorless oil (836 mg, 1.96 mmol, 44% yield). Rf = 0.23 (1:9 EtOAc/Hex); mp 116– 1 118 °C ; H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 4H), 7.40 (t, J = 7.6 Hz, 4H), 7.36 – 7.30 (m, 2H), 6.44 (t, J = 2.3 Hz, 1H), 6.30 (d, J = 2.3 Hz, 2H), 4.77 (app s, 1H), 13 4.47 (app s, 1H), 3.75 (s, 6H), 3.41 (s, 2H), 1.41 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.8, 161.2, 141.1, 139.1, 137.7, 128.8, 128.4, 127.7, 116.6, 109.1, 104.6, 101.1, 62.3, + 55.5, 47.2, 24.5; HRMS (ESI) calcd for [C27H26N2O3 + Na] 449.1836, found 449.1828; IR (thin film) 2231, 1728, 1206, 1158. 5.36n: Prepared from 5.42n on a 5.0 mmol scale under standard conditions. 5.36n was purified by flash column chromatography twice (3:7 → 1:1 CH2Cl2/Hex), and further precipitated (pentane) as a white powder (181 mg, 0.46 mmol, 9% yield). Rf = 0.44 (1:9 1 EtOAc/Hex); mp 108–110 °C ; H NMR (500 MHz, CDCl3) δ 7.73 – 7.30 (m, 10H), 7.04

Chapter 5 | 234 (d, J = 8.6 Hz, 2H), 6.97 (d, J = 7.9 Hz, 1H), 4.69 (app s, 1H), 4.40 (app s, 1H), 3.41 (app s, 1H), 3.35 (app s, 1H), 2.30 (s, 3H), 1.87 (s, 3H), 1.31 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 172.8, 141.0, 140.0, 135.5, 132.6, 132.2, 129.4, 128.9, 128.4, 128.3, 128.0, 127.8, 127.0, 116.7, 108.9, 62.5, 47.8, 24.5, 21.1, 16.8; HRMS (ESI) calcd for + [C27H26N2O + Na] 417.1937, found 417.1944; IR (thin film) 2230, 1721, 1499, 1209. 5.36o: Prepared from 5.42o on a 4.0 mmol scale under modified conditions. 5.36o was purified by flash column chromatography (1:9 → 15:85 EtOAc/Hex), and further precipitated (CH2Cl2/pentane, 1:40 v/v) as a tacky white powder (1.28 g, 3.22 mmol, 81% 1 yield). Rf = 0.62 (1:4 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 2.7 Hz, 1H), 7.51 (dd, J = 8.5, 1.3 Hz, 4H), 7.40 (dd, J = 8.6, 6.8 Hz, 4H), 7.37 – 7.31 (m, 3H), 6.76 (d, J = 8.9 Hz, 1H), 4.79 (t, J = 1.7 Hz, 1H), 4.53 – 4.46 (m, 1H), 3.93 (s, 3H), 3.43 13 (s, 2H), 1.42 (s, 3H); C NMR (126 MHz, CDCl3) δ 173.2, 164.0, 144.7, 140.9, 139.0, 136.6, 128.7, 128.4, 127.8, 127.0, 116.6, 111.7, 108.9, 62.1, 54.0, 46.9, 24.4; HRMS + (ESI) calcd for [C25H23N3O2 + Na] 420.1682, found 420.1694; IR (thin film) 2233, 1728, 1492, 1388, 1202. 5.36p: Prepared from 5.42f on a 5.0 mmol scale under standard conditions. 5.36p was purified by flash column chromatography (3:7 → 1:1 CH2Cl2/Hex) as a colorless oil 1 (983 mg, 3.61 mmol, 72% yield). Rf = 0.36 (1:9 EtOAc/Hex); H NMR (500 MHz,

CDCl3) δ 7.20 – 7.17 (m, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.94 (d, J = 4.5 Hz, 1H), 4.87 (app s, 1H), 3.82 (s, 3H), 2.75 (s, 2H), 1.81 (s, 3H), 1.50 (s, 6H); 13C NMR (126 MHz,

CDCl3) δ 176.2, 159.9, 141.4, 128.8, 127.7, 114.9, 114.8, 111.1, 55.5, 46.9, 44.8, 26.2, + 23.8; HRMS (ESI) calcd for [C16H20N2O2 + Na] 295.1417, found 295.1411; IR (thin film) 2228, 1724, 1509, 1250, 1189. 5.36q: Prepared from 5.42f on a 4.0 mmol scale under standard conditions. 5.36q was purified by flash column chromatography twice (first: 3:7 → 1:1 CH2Cl2/Hex; second: 3:97 → 1:9 EtOAc/Hex) as a thick colorless oil (543 mg, 1.28 mmol, 32% yield). 1 Rf = 0.56 (1:1 CH2Cl2/Hex); H NMR (500 MHz, CDCl3) δ 7.41 – 7.28 (m, 10H), 6.87 (app s, 4H), 5.09 (app s, 1H), 4.91 (app s, 1H), 3.79 (s, 3H), 3.36 (d, J = 14.7 Hz, 2H), 13 3.32 (d, J = 14.8 Hz, 2H), 2.74 (s, 2H), 1.85 (s, 3H); C NMR (126 MHz, CDCl3) δ

Chapter 5 | 235 174.9, 159.9, 141.9, 136.5, 130.5, 128.8, 128.4, 127.7, 127.1, 114.8, 112.5, 110.7, 55.5, + 52.6, 41.1, 40.2, 25.1; HRMS (ESI) calcd for [C28H28N2O2 + Na] 447.2043, found 447.2050; IR (thin film) 2228, 1723, 1508, 1250, 1181. 5.36r: Prepared from 5.42f on a 4.0 mmol scale under modified conditions. 5.36r was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a colorless oil 1 (998 mg, 3.51 mmol, 88% yield). Rf = 0.36 (1:9 EtOAc/Hex); H NMR (400 MHz,

CDCl3) δ 7.20 (dt, J = 9.1, 2.2 Hz, 2H), 6.94 (dt, J = 9.1, 2.2 Hz, 2H), 4.90 – 4.88 (m, 1H), 4.87 (t, J = 1.7 Hz, 1H), 3.82 (s, 3H), 2.96 (s, 2H), 2.84 – 2.73 (m, 2H), 2.32 – 2.21 (m, 2H), 2.12 – 1.99 (m, 1H), 1.96 – 1.83 (m, 1H), 1.75 (s, 3H); 13C NMR (101 MHz,

CDCl3) δ 175.6, 159.8, 142.1, 127.9, 127.4, 114.8, 114.3, 110.4, 55.5, 49.4, 45.1, 31.4, + 23.0, 15.2; HRMS (ESI) calcd for [C17H20N2O2 + Na] 307.1417, found 307.1430; IR (thin film) 2230, 1728, 1509, 1251, 1188. 5.36s: Prepared from 5.42f on a 4.0 mmol scale under modified conditions. 5.36s was purified by flash column chromatography (5:95 → 15:85 EtOAc/Hex) as a pale 1 yellow oil (976 mg, 3.27 mmol, 82% yield). Rf = 0.39 (1:9 EtOAc/Hex); H NMR (400

MHz, CDCl3) δ 7.18 (dt, J = 9.0, 2.1 Hz, 2H), 6.94 (dt, J = 9.0, 2.1 Hz, 2H), 4.93 – 4.92 (m, 1H), 4.91 (t, J = 1.6 Hz, 1H), 3.82 (s, 3H), 2.82 (d, J = 1.1 Hz, 2H), 2.48 (dddd, J = 13.5, 6.8, 3.7, 1.6 Hz, 2H), 1.87 (dddd, J = 13.2, 7.6, 5.2, 1.8 Hz, 2H), 1.79 (s, 3H), 1.76 13 – 1.64 (m, 4H); C NMR (101 MHz, CDCl3) δ 176.1, 159.8, 142.2, 128.7, 127.6, 114.8,

114.4, 111.0, 55.7, 55.5, 46.1, 37.1, 25.1, 23.5; HRMS (ESI) calcd for [C18H22N2O2 + Na]+ 321.1573, found 321.1575; IR (thin film) 2228, 1724, 1509, 1250, 1184. 5.36t: Prepared from 5.42f on a 4.0 mmol scale under modified conditions. 5.36t was purified by flash column chromatography twice (1:9 → 1:4 EtOAc/Hex) as a thick 1 pale yellow oil (644 mg, 2.05 mmol, 51% yield). Rf = 0.34 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.18 (dt, J = 9.0, 2.1 Hz, 2H), 6.97 (dt, J = 8.9, 2.4 Hz, 2H), 4.98 – 4.97 (m, 1H), 4.97 – 4.96 (m, 1H), 3.89 (dt, J = 12.2, 4.0 Hz, 2H), 3.83 (s, 3H), 3.59 (ddd, J = 12.5, 10.5, 2.4 Hz, 2H), 2.81 (s, 2H), 2.54 – 2.48 (m, 2H), 1.89 – 1.77 (m, 5H); 13C

NMR (126 MHz, CDCl3) δ 174.2, 160.1, 140.3, 128.4, 127.8, 115.8, 115.0, 110.8, 64.8,

Chapter 5 | 236 + 55.6, 47.3, 46.1, 34.8, 23.9; HRMS (ESI) calcd for [C18H22N2O3 + Na] 337.1523, found 337.1518; IR (thin film) 2227, 1723, 1509, 1250, 1185, 1114. 5.36u: Prepared from 5.42f on a 4.0 mmol scale under modified conditions. 5.36u was purified by flash column chromatography (4:6 → 6:4 CH2Cl2/Hex) as a colorless oil 1 (855 mg, 2.72 mmol, 68% yield). Rf = 0.44 (1:1 CH2Cl2/Hex); H NMR (500 MHz,

CDCl3) δ 7.18 (dt, J = 9.0, 2.0 Hz, 2H), 6.95 (dt, J = 9.0, 2.4 Hz, 2H), 4.94 (d, J = 1.5 Hz, 1H), 4.87 (d, J = 1.4 Hz, 1H), 3.82 (s, 3H), 2.74 (s, 2H), 2.08 – 2.02 (m, 2H), 1.52 – 1.42 13 (m, 8H), 1.39 – 1.28 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); C NMR (126 MHz, CDCl3) δ 176.2, 159.9, 145.6, 128.8, 127.7, 114.9, 113.0, 111.1, 55.5, 45.1, 45.0, 36.9, 30.1, 26.2, + 22.4, 14.0; HRMS (ESI) calcd for [C19H26N2O2 + Na] 337.1886, found 337.1875; IR (thin film) 2230, 1724, 1509. 5.36v: Prepared from 5.42f on a 3.5 mmol scale under modified conditions. 5.36v was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a pale yellow 1 oil (924 mg, 2.55 mmol, 73% yield). Rf = 0.32 (1:9 EtOAc/Hex); H NMR (400 MHz,

CDCl3) δ 7.31 – 7.25 (m, 2H), 7.23 – 7.17 (m, 3H), 7.10 – 7.05 (m, 2H), 6.91 – 6.85 (m, 2H), 5.00 (d, J = 1.4 Hz, 1H), 4.93 (app s, 1H), 3.80 (s, 3H), 2.87 – 2.75 (m, 4H), 2.36 13 (dd, J = 8.9, 7.4 Hz, 2H), 1.50 (s, 6H); C NMR (101 MHz, CDCl3) δ 176.2, 159.9, 144.8, 141.6, 128.7, 128.4, 128.4, 127.7, 125.9, 114.8, 113.7, 111.1, 55.5, 45.5, 45.0, 38.9, + 34.4, 26.2; HRMS (ESI) calcd for [C23H26N2O2 + Na] 385.1886, found 385.1892; IR (thin film) 2227, 1724, 1508, 1250, 1183. 5.36w: Prepared from 5.42f on a 3.4 mmol scale under modified conditions. 5.36w was purified by flash column chromatography (5:95 → 15:85 EtOAc/Hex) as a colorless 1 oil (651 mg, 1.72 mmol, 51% yield). Rf = 0.42 (15:85 EtOAc/Hex); H NMR (500 MHz,

CDCl3) δ 7.39 – 7.31 (m, 4H), 7.30 – 7.27 (m, 1H), 7.18 – 7.13 (m, 2H), 6.93 – 6.88 (m, 2H), 5.25 (d, J = 1.5 Hz, 1H), 5.12 (d, J = 1.3 Hz, 1H), 4.50 (s, 2H), 3.98 (s, 2H), 3.81 (s, 13 3H), 2.83 (d, J = 1.1 Hz, 2H), 1.50 (s, 6H); C NMR (126 MHz, CDCl3) δ 176.2, 159.9, 142.2, 138.0, 128.8, 128.4, 127.8, 127.8, 127.6, 116.3, 114.8, 111.1, 73.1, 71.8, 55.5, 44.7, + 42.2, 26.1; HRMS (ESI) calcd for [C23H26N2O3 + Na] 401.1836, found 401.1833; IR (thin film) 2230, 1723, 1509, 1250, 1182.

Chapter 5 | 237 5.36x: Prepared from 5.42f on a 4.0 mmol scale under modified conditions. 5.36x was purified by flash column chromatography twice (first: 1:4 → 1:1 CH2Cl2/Hex; second: 8:92 → 1:4 Et2O/Hex) as a thick colorless oil, which turned to a white foam upon placing under high (ca. 0.1 torr) vacuum (1.13 g, 2.46 mmol, 61% yield). Rf = 0.24 (1:9 1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.46 – 7.40 (m, 4H), 7.35 – 7.16 (m, 11H), 6.83 – 6.78 (m, 2H), 6.73 – 6.68 (m, 2H), 5.18 (d, J = 1.4 Hz, 1H), 4.70 (d, J = 1.3 Hz, 13 1H), 3.93 (s, 2H), 3.76 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.6, 159.8, 143.9, 142.3, 139.4, 129.3, 128.7, 128.1, 128.0, 127.6, 127.4, 127.2, 126.7, 120.1, 114.6, 109.5, + 62.0, 55.5, 44.1; HRMS (ESI) calcd for [C31H26N2O2 + Na] 481.1886, found 481.1894; IR (thin film) 2230, 1725, 1508, 1249, 1202. 5.36y: Prepared from 5.42a on a 5.0 mmol scale under standard conditions. 5.36y was purified by flash column chromatography (3:7 → 1:1 CH2Cl2/Hex), and further precipitated (CH2Cl2/Hex, 1:40 v/v) as a white powder (945 mg, 2.58 mmol, 52% yield). 1 Rf = 0.54 (15:85 EtOAc/Hex); mp 99–100 °C ; H NMR (500 MHz, CDCl3) δ 7.51 – 7.39 (m, 8H), 7.39 – 7.31 (m, 2H), 7.24 – 7.18 (m, 2H), 7.12 – 7.05 (m, 2H), 5.65 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.05 (ddd, J = 17.1, 3.4, 1.5 Hz, 1H), 5.01 – 4.98 (m, 1H), 3.36 13 (d, J = 7.0 Hz, 2H), 2.36 (s, 3H); C NMR (126 MHz, CDCl3) δ 173.0, 139.4, 138.9, 133.6, 133.2, 130.2, 128.8, 128.5, 127.8, 126.0, 119.2, 109.2, 62.1, 44.8, 21.1; HRMS + (ESI) calcd for [C25H22N2O + Na] 389.1624, found 389.1626; IR (thin film) 2231, 1725, 1508, 1206. 5.36z: Prepared from 5.42p on a 5.0 mmol scale under standard conditions. 5.36z was purified by flash column chromatography (3:7 → 1:1 CH2Cl2/Hex) as a colorless oil 1 (1.51 g, 3.98 mmol, 80% yield). Rf = 0.55 (15:85 EtOAc/Hex); H NMR (500 MHz,

CDCl3) δ 7.39 – 7.26 (m, 13H), 7.18 (dd, J = 7.4, 1.8 Hz, 2H), 4.72 (s, 2H), 4.63 (d, J = 13 1.9 Hz, 1H), 4.30 (app s, 1H), 3.30 (s, 2H), 1.31 (s, 3H); C NMR (126 MHz, CDCl3) δ 172.8, 140.9, 138.9, 133.8, 128.9, 128.7, 128.7, 128.6, 128.2, 127.5, 116.4, 109.9, 62.0, + 52.7, 47.1, 24.4; HRMS (ESI) calcd for [C26H24N2O + Na] 403.1781, found 403.1781; IR (thin film) 2231, 1710, 1496, 1193.

Chapter 5 | 238 5.36aa: Prepared from 5.42f on a 5.0 mmol scale under modified conditions. 5.36aa was purified by flash column chromatography (4:6 → 6:4 CH2Cl2/Hex) as a colorless thick oil, which solidified into a white waxy solid upon standing in air at room 1 temperature (783 mg, 2.68 mmol, 54% yield). Rf = 0.20 (1:9 EtOAc/Hex); H NMR (500

MHz, CDCl3) δ 7.57 – 7.48 (m, 2H), 7.42 – 7.37 (m, 2H), 7.28 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.34 (app s, 1H), 5.13 (app s, 1H), 3.83 (s, 31H), 2.22 (s, 3H); 13C

NMR (126 MHz, CDCl3) δ 170.0, 159.8, 143.2, 141.7, 131.4, 130.7, 128.1, 127.6, 127.5, + 127.4, 126.8, 117.2, 114.8, 110.0, 55.6, 23.2; HRMS (ESI) calcd for [C18H16N2O2 + Na] 315.1104, found 385.1116; IR (thin film) 2235, 1723, 1509, 1250. 5.36ab: Prepared from 5.42f on a 4.8 mmol scale under modified conditions. 5.36ab was purified by flash column chromatography (1:9 → 1:4 EtOAc/Hex), and further precipitated (CH2Cl2/pentane, 1:40 v/v) as a white powder (1.07 g, 3.02 mmol, 63% 1 yield). Rf = 0.43 (1:4 EtOAc/Hex); mp 103–105 °C; H NMR (500 MHz, CDCl3) δ 7.63 (dd, J = 7.6, 1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.4 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.39 – 7.30 (m, 5H), 6.82 (dt, J = 9.1, 2.1 Hz, 2H), 6.78 (dt, J = 9.2, 2.1 Hz, 2H), 5.74 (app s, 1H), 13 5.49 (app s, 1H), 3.78 (s, 3H); C NMR (126 MHz, CDCl3) δ 168.5, 159.7, 147.6, 141.2, 140.3, 131.9, 131.5, 131.2, 128.5, 128.3, 127.9, 127.9, 127.8, 127.0, 126.8, 117.4, 114.6, + 110.0, 55.5; HRMS (ESI) calcd for [C23H18N2O2 + Na] 377.1260, found 377.1268; IR (thin film) 2253, 1726, 1509.

5.36ac: Prepared from 5.42f on a 5.0 mmol scale, following a different procedure:*

To a solution of 5.44n (1057 mg, 6.0 mmol) and Cl3CCN (1733 mg, 12.0 mmol) in

CH2Cl2 (6.0 mL) was added PPh3 (3147 mg, 12 mmol) in CH2Cl2 (6.0 mL) at room

* Acid 5.44n cyclized exclusively into lactone under the standard and modified coupling conditions.

Chapter 5 | 239 temperature. The resulting mixture was stirred for 1 h and cooled to 0 °C , whereupon a solution of Et3N (1.0 mL, 7.5 mmol) in CH2Cl2 (3.0 mL) was added, followed by cyanamide 5.42f (741 mg, 5.0 mmol) in CH2Cl2–THF (4 mL, 3:1 v/v). The resulting mixture was allowed to warm to room temperature and stir overnight, which was then diluted with Et2O (30 mL), filtered through a short Celite column, concentrated, and purified by flash column chromatography twice (1:9 → 15:85 EtOAc/Hex) to afford 5.36ac as an tacky orange solid (1.40 g, 4.57 mmol, 91% yield). 5.36ac was contaminated with an unidentified impurity, which could not be removed after decolorization using charcoal or several attempts of precipitation. The purity of 5.36ac was determined as 96% by 1H NMR using p-methoxyacetophenone as the internal 1 standard. Rf = 0.42 (15:85 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.3 Hz, 1H), 7.47 (td, J = 7.6, 1.4 Hz, 1H), 7.36 – 7.29 (m, 4H), 6.97 (d, J = 8.9 Hz, 2H), 4.93 (app s, 1H), 4.70 (app s, 1H), 3.84 (s, 3H), 3.53 (s, 2H), 1.73 (s, 3H); 13C NMR (126

MHz, CDCl3) δ 169.0, 159.9, 144.3, 138.7, 131.7, 131.6, 131.3, 127.7, 127.4, 127.0, + 126.4, 114.9, 113.1, 110.0, 55.6, 41.4, 22.4; HRMS (ESI) calcd for [C19H18N2O2 + Na] 329.1260, found 329.1269; IR (thin film) 2236, 1721, 1509, 1252. 5.36ad: Prepared from 5.42f on a 3.0 mmol scale under standard conditions. 5.36ad was purified by flash column chromatography (1:9 → 1:4 EtOAc/Hex) as a light yellow 1 oil (437 mg, 1.79 mmol, 60% yield). Rf = 0.21 (1:9 EtOAc/Hex); H NMR (500 MHz,

CDCl3) δ 7.25 (d, J = 8.5 Hz, 2H), 6.96 (dd, J = 9.0, 0.8 Hz, 2H), 4.81 (app s, 1H), 4.74 (app s, 1H), 3.83 (s, 3H), 2.87 (br s, 2H), 2.45 (t, J = 7.6 Hz, 2H), 1.77 (s, 3H); 13C NMR

(126 MHz, CDCl3) δ 171.7, 160.0, 143.0, 127.3, 127.0, 115.0, 111.3, 110.0, 55.6, 32.7, + 32.0, 22.4; HRMS (ESI) calcd for [C14H16N2O2 + Na] 267.1104, found 267.1106; IR (thin film) 2233, 1735, 1509, 1251. 5.36ae: Prepared from 5.42f on a 4.0 mmol scale under modified conditions. 5.36ae was purified by flash column chromatography (5:95 → 15:85 EtOAc/Hex) as a colorless 1 oil (942 mg, 3.29 mmol, 82% yield). Rf = 0.51 (1:1 CH2Cl2/Hex); H NMR (500 MHz,

CDCl3) δ 7.19 (dt, J = 9.2, 2.4 Hz 2H), 6.95 (dt, J = 8.9, 2.1 Hz 2H), 4.77 (m, 1H), 4.76 (app s, 1H), 3.82 (s, 3H), 2.07 (app s, 4H), 1.80 (s, 3H), 1.49 (s, 6H); 13C NMR (126

Chapter 5 | 240

MHz, CDCl3) δ 176.1, 159.9, 144.7, 128.7, 127.7, 114.9, 110.8, 110.7, 55.5, 44.9, 37.6, + 33.1, 25.2, 22.5; HRMS (ESI) calcd for [C17H22N2O2 + Na] 309.1573, found 309.1569; IR (thin film) 2228, 1725, 1509, 1250.

5.6.7 Synthesis of N-sulfonyl cyanamides 5.33

Synthesis of 5.46: To a solution of 1-bromo-2-(prop-1-en-2-yl)benzene* (8672 mg, 44 mmol) in THF (40 mL) was added nBuLi (2.5 M Hex, 16 mL, 40 mmol) at –78 °C . The reaction was stirred at –78 °C for 30 min, whereupon a solution of stock solution of † SO2 in THF (ca. 2.3 M THF, 34.8 mL, 80 mmol) was dropwise added. Upon completion of addition, the reaction was allowed to warm to room temperature and stirred for additional 2 h, which was then concentrated to dryness to afford crude lithium sulfinate 5.45 as a white solid (ca. 40 mmol). Without further purification, 5.45 was quickly ground in air, suspended in hexanes (150 mL), cooled to –78 °C , and added SO2Cl2 (2.92 mL, 36 mmol) in hexanes (40 mL). The resulting mixture was vigorously stirred at – 78 °C for 20 min, then was allowed to warm to room temperature and stir for additional

* Prepared from 1-(2-bromophenyl)ethan-1-one following a known procedure: Chen, G.; Gui, J.; Li, L.; Liao, J. Angew. Chem., Int. Ed. 2011, 50, 7681. † Prepared by bubbling CaCl2-dried SO2 gas through THF in a Schlenk flask at 0 °C , following a similar report: Li,

W.; Beller, M.; Wu, X. Chem. Commun. 2014, 50, 9513. The concentration of SO2 was estimated by measuring the mass of dissolved SO2 against the total volume of the resulting solution.

Chapter 5 | 241

30 min. The reaction was quenched with sat. NaHCO3 (20 mL, CAUTION: CO2 evolved), diluted with H2O (20 mL), and extracted with Et2O (20 mL × 3). The combined organic extract were washed with brine, dried over MgSO4, and concentrated. The resulting mixture was purified by flash column chromatography (0:100 → 5:95 EtOAc/Hex) to afford sulfonyl chloride 5.46 as a pale yellow oil (6.68 g, 30.8 mmol, 86% yield over 2 1 steps). Rf = 0.59 (1:9 EtOAc/Hex). H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 8.2, 1.3 Hz, 1H), 7.68 (td, J = 7.6, 1.3 Hz, 1H), 7.50 (ddd, J = 8.7, 7.6, 1.4 Hz, 1H), 7.35 (dd, J = 7.6, 1.4 Hz, 1H), 5.38 (t, J = 1.5 Hz, 1H), 5.08 (t, J = 1.2 Hz, 1H), 2.17 (t, J = 1.2 Hz, 3H); 13 C NMR (125 MHz, CDCl3) δ 144.0, 142.3, 141.9, 135.0, 131.5, 128.8, 127.9, 117.6, 25.1. Synthesis of 5.33, a general procedure: To a solution of cyanamide 5.42 (2.0 mmol, see Chapter 5.6.4 for the synthesis) and Et3N (0.42 mL, 3.0 mmol) in CH2Cl2 (4.0 mL) was added sulfonyl chloride 5.46 (520 mg, 2.4 mmol) in CH2Cl2 (2.0 mL) at 0 °C . The resulting mixture was allowed to warm to room temperature and stir for 4–6 h until TLC indicated the complete consumption of staring material. The mixture was then diluted with CH2Cl2 (30 mL), washed with 1 N HCl (10 mL), and separated. The organic phase was washed with brine, dried over MgSO4, and concentrated. The resulting mixture was purified by flash column chromatography to afford the corresponding N-sulfonyl cyanamide 5.33. 5.33a: Prepared from 5.42a on a 2.0 mmol scale. 5.33a was purified by flash column chromatography (0:100 → 1:9 EtOAc/Hex) as a thick pale yellow oil (537 mg, 1 1.72 mmol, 86% yield). Rf = 0.51 (1:4 EtOAc/Hex). H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 8.1, 1.3 Hz, 1H), 7.64 (td, J = 7.6, 1.3 Hz, 1H), 7.40 (ddd, J = 8.5, 7.5, 1.4 Hz, 1H), 7.33 (dd, J = 7.6, 1.4 Hz, 1H), 7.14 (d, J = 8.3 Hz, 2H), 7.09 – 7.03 (m, 2H), 5.30 (t, J = 1.5 Hz, 1H), 4.76 (t, J = 1.1 Hz, 1H), 2.34 (s, 3H), 2.10 (t, J = 1.3 Hz, 3H); 13C NMR

(126 MHz, CDCl3) δ 145.2, 143.0, 140.2, 134.8, 134.0, 131.6, 131.4, 130.9, 130.4, 127.6, + 126.1, 117.2, 108.1, 25.4, 21.1; HRMS (ESI) calcd for [C17H16N2O2S + Na] 335.0825, found 335.0818; IR (thin film) 2236, 1505, 1380, 1181.

Chapter 5 | 242 5.33b: Prepared from 5.42c on a 2.0 mmol scale. 5.33b was purified by flash column chromatography (2:98 → 1:9 EtOAc/Hex) as a white solid (603 mg, 1.70 mmol, 1 85% yield). Rf = 0.55 (1:4 EtOAc/Hex). mp 84–86 °C ; H NMR (500 MHz, CDCl3) δ 7.89 (dd, J = 8.1, 1.3 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.43 (d, J = 1.3 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 7.6, 1.3 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 5.24 (app s, 1H), 13 4.64 (app s, 1H), 2.07 (s, 3H), 1.28 (s, 9H); C NMR (126 MHz, CDCl3) δ 153.3, 145.2, 143.0, 134.8, 134.1, 131.5, 131.4, 130.8, 127.7, 126.8, 125.8, 117.0, 108.2, 34.8, 31.1, + 25.4; HRMS (ESI) calcd for [C20H22N2O2S + Na] 377.1294, found 377.1306; IR (thin film) 2233, 1504, 1381, 1182. 5.33c: Prepared from 5.42d on a 2.0 mmol scale. 5.33c was purified by flash column chromatography (0:100 → 1:9 EtOAc/Hex) as a yellow oil (531 mg, 1.68 mmol, 84% 1 yield). Rf = 0.53 (1:4 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 8.1, 1.3 Hz, 1H), 7.66 (td, J = 7.5, 1.3 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.34 (dd, J = 7.7, 1.4 Hz, 1H), 7.23 – 7.16 (m, 2H), 7.05 (dd, J = 9.1, 7.9 Hz, 2H), 5.30 (app s, 1H), 4.74 (app s, 13 1 1H), 2.11 (s, 3H); C NMR (126 MHz, CDCl3) δ 163.0 (d, JF–C = 251.7 Hz), 145.3, 4 3 143.1, 135.1, 133.7, 131.6, 131.0, 130.1 (d, JF–C =3.2 Hz), 128.6 (d, JF–C = 9.1 Hz), 2 127.8, 117.2, 117.0 (d, JF–C = 23.3 Hz), 107.9, 25.5; HRMS (ESI) calcd for + [C16H13FN2O2S + Na] 339.0574, found 339.0565; IR (thin film) 2237, 1503, 1383, 1181. 5.33d: Prepared from 5.42e on a 2.0 mmol scale. 5.33d was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a light yellow oil (592 mg, 1.78 1 mmol, 89% yield). Rf = 0.49 (1:4 EtOAc/Hex); H NMR (400 MHz, CDCl3) δ 7.85 (dd, J = 8.1, 1.3 Hz, 1H), 7.66 (td, J = 7.5, 1.3 Hz, 1H), 7.43 (ddd, J = 8.6, 7.6, 1.4 Hz, 1H), 7.36 – 7.32 (m, 3H), 7.16 (dt, J = 8.8, 2.2 Hz, 2H), 5.31 (app s, 1H), 4.75 (app s, 1H), 13 2.11 (s, 3H); C NMR (101 MHz, CDCl3) δ 145.2, 143.0, 135.8, 135.2, 133.7, 132.8, 131.6, 131.0, 130.1, 127.8, 127.2, 117.3, 107.6, 25.4; HRMS (ESI) calcd for + [C16H13ClN2O2S + Na] 355.0278, found 355.0275; IR (thin film) 2253, 2239, 1486, 1184. 5.33e: Prepared from 5.42i on a 2.0 mmol scale. 5.33e was purified by flash column chromatography (8:92 → 1:9 EtOAc/Hex) as an thick pale orange oil (470 mg, 1.43

Chapter 5 | 243 1 mmol, 71% yield). Rf = 0.38 (1:4 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.88 (dd, J = 8.2, 1.3 Hz, 1H), 7.64 (td, J = 7.6, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 7.4, 1.4 Hz, 1H), 7.33 (dd, J = 7.7, 1.3 Hz, 1H), 7.23 (t, J = 8.5 Hz, 1H), 6.89 (ddd, J = 8.5, 2.3, 1.1 Hz, 1H), 6.79 – 6.72 (m, 2H), 5.32 (app s, 1H), 4.77 (app s, 1H), 3.74 (s, 3H), 2.11 (d, J = 1.2 13 Hz, 3H); C NMR (126 MHz, CDCl3) δ 160.4, 145.2, 142.9, 135.2, 134.9, 134.1, 131.5, 131.0, 130.4, 127.7, 117.6, 117.3, 115.6, 111.3, 107.8, 55.5, 25.4; HRMS (ESI) calcd for + [C17H16N2O3S + Na] 351.0774, found 351.0785; IR (thin film) 2253, 2234, 1606, 1183. 5.33f: Prepared from 5.42k on a 2.0 mmol scale. 5.33f was purified by flash column chromatography (5:95 → 1:9 EtOAc/Hex) as a thick pale yellow oil (593 mg, 1.62 mmol, 1 81% yield). Rf = 0.49 (1:4 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.91 (dd, J = 8.2, 1.3 Hz, 1H), 7.68 (td, J = 7.6, 1.3 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.49 – 7.42 (m, 3H), 7.35 (dd, J = 7.6, 1.3 Hz, 1H), 5.27 (app s, 1H), 4.67 (app s, 13 1H), 2.10 (s, 3H); C NMR (126 MHz, CDCl3) δ 145.3, 143.0, 135.4, 135.0, 133.5, 2 3 132.5 (d, JF–C = 33.5 Hz), 131.7, 131.0, 130.6, 128.7, 127.9, 126.2 (q, JF–C = 3.7 Hz), 1 3 122.9 (q, JF–C = 271.0 Hz), 122.5 (q, JF–C = 3.9 Hz), 117.2, 107.3, 25.4; HRMS (ESI) + calcd for [C23H26N2O3 + Na] 389.0542, found 389.0539; IR (thin film) 2253, 1386, 1328, 1183, 1139.

5.6.8 Palladium–Lewis acid-catalyzed aminocyanation reactions

Aminocyanation of 5.36a as a representative example: In a nitrogen-filled glove box, a 1 dram vial was charged with a magnetic stirring bar, cyanamide 5.36a (76.2 mg,

0.2 mmol), BPh3 or BEt3 (BPh3: 19.4 mg, 0.08 mmol; BEt3: 1.0 M in Hex, 80 µL, 0.08 mmol), Xantphos (11.6 mg, 0.02 mmol), and a stock solution of CpPd(1-phenylallyl) in toluene (0.02 M, 1.0 mL, 0.02 mmol). The reaction mixture was sealed with a PTFE lined

Chapter 5 | 244 cap, removed from the glove box, and heated at 80 °C in an aluminum heating block for 24 h. The resulting mixture was allowed to cool to room temperature, diluted with

CH2Cl2 (5 mL), and concentrated onto Celite. The crude product was purified by flash column chromatography (1:9 → 15:85 EtOAc/Hex) to afford 5.37a as a pale yellow foam 1 (75.3 mg, 0.198 mmol, 99%). Rf = 0.32 (1:4 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.7 Hz, 2H), 7.46 (d, J = 7.7 Hz, 2H), 7.35 (dt, J = 13.2, 7.6 Hz, 4H), 7.29 – 7.22 (m, 4H), 7.03 (d, J = 7.8 Hz, 2H), 3.33 (d, J = 13.7 Hz, 1H), 3.00 (d, J = 13.7 Hz, 1H), 2.42 (d, J = 16.6 Hz, 1H), 2.37 (s, 3H), 2.33 (d, J = 16.5 Hz, 1H), 1.33 (s, 3H); 13C

NMR (126 MHz, CDCl3) δ 174.9, 142.9, 142.8, 138.9, 132.2, 130.3, 129.2, 128.8, 128.5, 127.7, 127.6, 127.2, 127.0, 116.8, 59.8, 56.9, 46.7, 29.3, 26.5, 21.1; HRMS (ESI) calcd + for [C26H24N2O + Na] 403.1781, found 403.1786; IR (thin film) 2247, 1697, 1513, 1373. Unless otherwise noted, all aminocyanation reactions were performed on a 0.2 mmol scale. The detailed conditions for each substrate were indicated in Table 5-4.

Chapter 5 | 245

5.37b: Purified by flash column chromatography (1:9 → 15:85 EtOAc/Hex) as an 1 off-white foam (70.4 mg, 0.192 mmol, 96% yield). Rf = 0.24 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.55 – 7.49 (m, 2H), 7.50 – 7.31 (m, 9H), 7.28 (td, J = 7.7, 7.1, 1.7 Hz, 2H), 7.20 – 7.14 (m, 2H), 3.36 (d, J = 13.8 Hz, 1H), 3.03 (d, J = 13.7 Hz, 1H), 2.44 (d, J = 16.5 Hz, 1H), 2.36 (d, J = 16.6 Hz, 1H), 1.36 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 175.0, 142.9, 142.7, 135.0, 129.7, 129.5, 128.9, 128.8, 128.6, 127.7, 127.6,

Chapter 5 | 246

127.3, 127.1, 116.8, 59.9, 56.9, 46.8, 29.4, 26.6; HRMS (ESI) calcd for [C25H22N2O + Na]+ 389.1624, found 389.1625; IR (thin film) 2247, 1697, 1493, 1371. 5.37c: Purified by flash column chromatography (1:9 → 1:4 EtOAc/Hex) as a pale 1 yellow foam (78.6 mg, 0.186 mmol, 93% yield). Rf = 0.51 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.52 (d, J = 8.1 Hz, 2H), 7.46 (ddd, J = 8.3, 3.8, 1.3 Hz, 4H), 7.39 – 7.23 (m, 6H), 7.08 (d, J = 7.1 Hz, 2H), 3.34 (d, J = 1.2 Hz, 1H), 3.02 (d, J = 1.1 Hz, 1H), 2.43 (d, J = 1.1 Hz, 1H), 2.36 (d, J = 16.5 Hz, 1H), 1.36 (d, J = 1.2 Hz, 3H), 1.33 (s, 9H); 13 C NMR (126 MHz, CDCl3) δ 175.0, 151.9, 143.0, 142.7, 132.1, 128.9, 128.8, 128.5, 127.7, 127.6, 127.3, 127.0, 126.7, 116.9, 59.9, 56.9, 46.7, 34.7, 31.2, 29.3, 26.6; HRMS + (ESI) calcd for [C29H30N2O + Na] 445.2250, found 445.2244; IR (thin film) 2247, 1696, 1510, 1372. 5.37d: Purified by flash column chromatography (1:9 → 1:4 EtOAc/Hex) as a pale 1 yellow foam (69.2 mg, 0.180 mmol, 90% yield). Rf = 0.29 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.48 (d, J = 7.7 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.36 (dt, J = 10.6, 7.6 Hz, 4H), 7.28 (t, J = 7.1 Hz, 2H), 7.15 (d, J = 6.6 Hz, 4H), 3.34 (d, J = 13.7 Hz, 1H), 3.03 (d, J = 13.7 Hz, 1H), 2.43 (d, J = 16.6 Hz, 1H), 2.35 (d, J = 16.6 Hz, 1H), 1.34 (s, 13 1 3H); C NMR (126 MHz, CDCl3) δ 175.2, 162.6 (d, JF–C = 249.2 Hz), 142.7, 142.6, 3 4 131.4 (d, JF–C = 8.7 Hz), 130.9 (d, JF–C = 3.2 Hz), 128.9, 128.6, 127.7, 127.6, 127.4, 2 127.2, 116.8 (d, JF–C = 22.8 Hz), 116.6, 59.9, 56.9, 46.7, 29.4, 26.5; HRMS (ESI) calcd + for [C25H21FN2O + Na] 407.1530, found 407.1536; IR (thin film) 2247, 1698, 1509, 1374, 1221. 5.37e: Purified by flash column chromatography (1:9 → 15:85 EtOAc/Hex) as an 1 off-white foam (68.9 mg, 0.172 mmol, 86% yield). Rf = 0.32 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.51 – 7.41 (m, 6H), 7.36 (dt, J = 10.3, 7.6 Hz, 4H), 7.30 – 7.26 (m, 2H), 7.12 (d, J = 8.5 Hz, 2H), 3.34 (d, J = 13.7 Hz, 1H), 3.02 (d, J = 13.7 Hz, 1H), 2.42 (d, J = 16.6 Hz, 1H), 2.34 (d, J = 16.5 Hz, 1H), 1.33 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 175.0, 142.6, 142.5, 135.0, 133.6, 130.8, 130.0, 128.9, 128.6, 127.6, 127.5,

127.4, 127.2, 116.6, 59.9, 56.9, 46.7, 29.4, 26.6; HRMS (ESI) calcd for [C25H21ClN2O + Na]+ 423.1235, found 423.1236; IR (thin film) 2247, 1698, 1493, 1371.

Chapter 5 | 247 5.37f: Purified by flash column chromatography (1:3 EtOAc/Hex) as a pale brown 1 oil (75.3 mg, 0.190 mmol, 95% yield). Rf = 0.32 (3:7 EtOAc/Hex); H NMR (500 MHz,

CDCl3) δ 7.51 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.35 (dt, J = 12.5, 7.6 Hz, 4H), 7.30 – 7.24 (m, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.33 (d, J = 13.7 Hz, 1H), 3.00 (d, J = 13.7 Hz, 1H), 2.42 (d, J = 16.6 Hz, 1H), 2.34 (d, J 13 = 16.6 Hz, 1H), 1.33 (s, 3H); C NMR (126 MHz, CDCl3) δ 175.1, 159.7, 143.0, 142.8, 130.6, 128.8, 128.5, 127.7, 127.6, 127.4, 127.2, 127.0, 116.9, 114.9, 59.8, 56.8, 55.5, 46.6, + 29.3, 26.5; HRMS (ESI) calcd for [C26H24N2O2 + Na] 419.1730, found 419.1736; IR (thin film) 2247, 1696, 1512, 1375, 1251. 5.37g: Purified by flash column chromatography (1:3 → 45:55 EtOAc/Hex) as an 1 off-white foam (76.4 mg, 0.180 mmol, 90% yield). Rf = 0.59 (1:1 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.49 (d, J = 7.7 Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.39 – 7.32 (m, 4H), 7.30 – 7.26 (m, 2H), 7.23 – 7.15 (m, 4H), 3.36 (d, J = 13.8 Hz, 1H), 3.03 (d, J = 13.7 Hz, 1H), 2.45 (d, J = 16.5 Hz, 1H), 2.37 (d, J = 16.6 Hz, 1H), 2.31 (s, 3H), 1.34 (s, 13 3H); C NMR (126 MHz, CDCl3) δ 175.1, 169.0, 150.8, 142.7, 142.6, 132.4, 130.6, 128.8, 128.6, 127.7, 127.6, 127.3, 127.1, 122.9, 116.7, 60.0, 57.0, 46.7, 29.4, 26.6, 21.1; + HRMS (ESI) calcd for [C27H24N2O3 + Na] 447.1679, found 447.1682; IR (thin film) 2247, 1755, 1698, 1507, 1371, 1196. 5.37h: Purified by flash column chromatography (1:4 → 3:7 EtOAc/Hex) as a pale 1 yellow foam (54.7 mg, 0.134 mmol, 67% yield). Rf = 0.36 (4:6 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.37 (dt, J = 11.6, 7.7 Hz, 4H), 7.29 (t, J = 7.6 Hz, 4H), 3.38 (d, J = 13.8 Hz, 1H), 3.06 (d, J = 13.7 Hz, 1H), 2.62 (s, 3H), 2.46 (d, J = 16.6 Hz, 1H), 2.38 (d, J = 16.6 13 Hz, 1H), 1.38 (s, 3H); C NMR (126 MHz, CDCl3) δ 197.0, 175.0, 142.5, 142.4, 139.6, 137.1, 129.7, 129.6, 128.9, 128.7, 127.6, 127.5, 127.4, 127.2, 116.5, 60.2, 57.0, 46.9, 29.5, + 26.8, 26.7; HRMS (ESI) calcd for [C27H24N2O2 + Na] 431.1730, found 431.1733; IR (thin film) 2247, 1687, 1600, 1367, 1266. 5.37i: Purified by flash column chromatography (15:85 → 1:4 EtOAc/Hex) as a 1 yellow oil (66.6 mg, 0.168 mmol, 84% yield). Rf = 0.19 (1:4 EtOAc/Hex); H NMR (500

Chapter 5 | 248

MHz, CDCl3) δ 7.52 – 7.49 (m, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.38 – 7.32 (m, 5H), 7.31 – 7.22 (m, 2H), 6.95 (dd, J = 8.4, 2.5 Hz, 1H), 6.74 (dd, J = 7.7, 1.8 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 3.81 (s, 1H), 3.35 (d, J = 13.7 Hz, 1H), 3.01 (d, J = 13.7 Hz, 1H), 2.45 (d, J 13 = 16.6 Hz, 1H), 2.35 (d, J = 16.6 Hz, 1H), 1.34 (s, 3H); C NMR (126 MHz, CDCl3) δ 174.8, 160.4, 142.8, 142.7, 136.1, 130.3, 128.8, 128.5, 127.7, 127.6, 127.3, 127.1, 121.5, 116.8, 115.6, 114.2, 59.9, 56.9, 55.4, 46.7, 29.4, 26.6; HRMS (ESI) calcd for + [C26H24N2O2 + Na] 419.1730, found 419.1732; IR (thin film) 2248, 1697, 1491, 1372, 1287, 1267. 5.37j: Purified by flash column chromatography (1:9 → 15:85 EtOAc/Hex) as a 1 white foam (60.9 mg, 0.152 mmol, 76% yield). Rf = 0.31 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.49 (d, J = 7.7 Hz, 2H), 7.46 – 7.32 (m, 8H), 7.31 – 7.26 (m, 2H), 7.17 (t, J = 1.3 Hz, 1H), 7.12 – 7.07 (m, 1H), 3.36 (d, J = 13.7 Hz, 1H), 3.03 (d, J = 13.7 Hz, 1H), 2.44 (d, J = 16.6 Hz, 1H), 2.36 (d, J = 16.6 Hz, 1H), 1.36 (s, 3H); 13C NMR

(126 MHz, CDCl3) δ 175.0, 142.6, 142.4, 136.3, 135.2, 130.7, 129.7, 129.3, 128.9, 128.6, 127.9, 127.6, 127.5, 127.4, 127.2, 116.5, 60.0, 56.9, 46.8, 29.4, 26.6; HRMS (ESI) calcd + for [C25H21ClN2O + Na] 423.1235, found 423.1234; IR (thin film) 2248, 1699, 1478, 1368. 5.37k: Purified by flash column chromatography (1:9 → 1:4 EtOAc/Hex) as a pale 1 yellow foam (74.7 mg, 0.172 mmol, 86% yield). Rf = 0.29 (1:4 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.69 (d, J = 7.9 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.47 – 7.33 (m, 8H), 7.29 (dd, J = 8.8, 7.2 Hz, 2H), 3.37 (d, J = 13.8 Hz, 1H), 3.05 (d, J = 13.7 Hz, 1H), 2.43 (d, J = 16.6 Hz, 1H), 2.36 (d, J = 16.6 Hz, 1H), 1.37 (s, 13 2 3H); C NMR (126 MHz, CDCl3) δ 175.1, 142.5, 142.4, 135.8, 133.2, 132.2 (q, JF–C = 3 33.0 Hz), 130.4, 128.9, 128.7, 127.6, 127.5, 127.5, 127.3, 126.2 (q, JF–C = 3.7 Hz), 125.8 3 1 (q, JF–C = 3.8 Hz), 122.4 (q, JF–C = 270.9 Hz), 116.4, 60.1, 57.0, 46.8, 29.5, 26.7; + HRMS (ESI) calcd for [C26H21F3N2O + Na] 457.1498, found 457.1502; IR (thin film) 2249, 1700, 1328, 1129. 5.37l: Purified by flash column chromatography (15:85 → 3:7 EtOAc/Hex) as a pale 1 yellow foam (78.1 mg, 0.184 mmol, 92% yield). Rf = 0.39 (3:7 EtOAc/Hex); H NMR

Chapter 5 | 249

(500 MHz, CDCl3) δ 8.10 (dt, J = 7.9, 1.4 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.53 – 7.49 (m, 2H), 7.47 – 7.42 (m, 2H), 7.42 – 7.33 (m, 5H), 7.32 – 7.26 (m, 2H), 3.92 (s, 3H), 3.38 (d, J = 13.8 Hz, 1H), 3.04 (d, J = 13.7 Hz, 1H), 2.45 (d, J = 13 16.5 Hz, 1H), 2.39 (d, J = 16.5 Hz, 1H), 1.39 (s, 3H); C NMR (126 MHz, CDCl3) δ 175.0, 165.9, 142.7, 142.4, 135.4, 134.2, 131.9, 130.3, 130.0, 129.9, 128.9, 128.6, 127.6, 127.5, 127.4, 127.1, 116.5, 60.0, 56.9, 52.4, 46.9, 29.4, 26.7; HRMS (ESI) calcd for + [C27H24N2O3 + Na] 447.1679, found 447.1683; IR (thin film) 2250, 1723, 1699, 1370, 1291. 5.37m: Purified by flash column chromatography (1:4 → 1:3 EtOAc/Hex) as a pale 1 yellow foam (74.2 mg, 0.174 mmol, 87% yield). Rf = 0.36 (3:7 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.49 (d, J = 7.4 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.35 (dt, J = 9.7, 7.6 Hz, 4H), 7.30 – 7.24 (m, 2H), 6.50 (t, J = 2.3 Hz, 1H), 6.30 (d, J = 2.1 Hz, 2H), 3.79 (s, 6H), 3.35 (d, J = 13.7 Hz, 1H), 3.01 (d, J = 13.7 Hz, 1H), 2.49 (d, J = 16.6 Hz, 1H), 13 2.36 (d, J = 16.6 Hz, 1H), 1.34 (s, 3H); C NMR (126 MHz, CDCl3) δ 174.6, 161.3, 142.8, 142.7, 136.6, 128.8, 128.6, 127.7, 127.6, 127.3, 127.1, 116.9, 107.8, 100.6, 59.9, + 56.9, 55.5, 46.8, 29.4, 26.6; HRMS (ESI) calcd for [C27H26N2O3 + Na] 449.1836, found 449.1837; IR (thin film) 2248, 1698, 1206, 1157. 5.37n: Purified by flash column chromatography twice (first: 1:9 EtOAc/Hex; second: CH2Cl2) as a colorless oil (33.9 mg, 0.086 mmol, 43% yield). Rf = 0.49 (1:4 1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.42 – 7.33 (m, 4H), 7.31 – 7.26 (m, 2H), 6.97 (s, 1H), 6.95 (d, J = 1.1 Hz, 3H), 3.29 (d, J = 13.9 Hz, 1H), 3.05 (d, J = 13.9 Hz, 1H), 2.54 (d, J = 16.7 Hz, 1H), 2.49 (d, J = 13 16.7 Hz, 1H), 2.28 (s, 3H), 2.11 (s, 3H), 1.41 (s, 3H); C NMR (126 MHz, CDCl3) δ 161.8, 143.3, 143.3, 142.8, 133.0, 130.9, 129.8, 128.7, 128.4, 128.0, 127.9, 127.4, 127.2, 126.5, 120.7, 116.4, 81.1, 58.6, 48.7, 30.2, 26.9, 20.9, 18.4; HRMS (ESI) calcd for + [C27H26N2O + Na] 417.1937, found 417.1941; IR (thin film) 2253, 1698, 1494, 1125. 5.37o: Purified by flash column chromatography (15:85 → 3:7 EtOAc/Hex) as a 1 pale yellow oil (76.3 mg, 0.192 mmol, 96% yield). Rf = 0.35 (3:7 EtOAc/Hex); H NMR

(500 MHz, CDCl3) δ 7.98 (d, J = 2.6 Hz, 1H), 7.49 – 7.46 (m, 2H), 7.45 – 7.43 (m, 2H),

Chapter 5 | 250 7.41 (dd, J = 8.7, 2.7 Hz, 1H), 7.36 (ddd, J = 11.2, 8.6, 7.0 Hz, 4H), 7.31 – 7.25 (m, 2H), 6.83 (d, J = 8.7 Hz, 1H), 3.95 (s, 1H), 3.34 (d, J = 13.7 Hz, 1H), 3.03 (d, J = 13.7 Hz, 1H), 2.41 (d, J = 16.6 Hz, 1H), 2.33 (d, J = 16.6 Hz, 1H), 1.33 (s, 3H); 13C NMR (126 MHz,

CDCl3) δ 175.5, 163.9, 147.3, 142.5, 142.5, 139.9, 128.9, 128.6, 127.6, 127.5, 127.4, 127.2, 125.1, 116.5, 111.9, 59.8, 56.9, 53.8, 46.6, 29.3, 26.4; HRMS (ESI) calcd for + [C25H23N3O2 + Na] 420.1682, found 420.1690; IR (thin film) 2248, 1698, 1494, 1385, 1285. 5.37p: Purified by flash column chromatography (30:70:0 → 30:70:0.5

EtOAc/Hex/MeOH) as a thick tan oil (47.9 mg, 0.176 mmol, 88% yield). Rf = 0.25 (1:1 1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.10 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.48 (app s, 2H), 2.32 (d, J = 13.7 Hz, 1H), 2.11 (d, J = 13.7 Hz, 1H), 13 1.43 (s, 3H), 1.38 (s, 3H), 1.36 (s, 3H); C NMR (126 MHz, CDCl3) δ 179.6, 159.6, 130.7, 127.5, 117.1, 114.8, 59.6, 55.4, 46.5, 39.6, 30.8, 28.2, 27.8, 27.0; HRMS (ESI) + calcd for [C16H20N2O2 + Na] 295.1417, found 295.1413; IR (thin film) 2247, 1693, 1513, 1394, 1251. 5.37q: Purified by flash column chromatography (1:9 → 3:7 EtOAc/Hex) as a light 1 yellow oil (69.6 mg, 0.164 mmol, 82% yield). Rf = 0.32 (3:7 EtOAc/Hex); H NMR (400

MHz, CDCl3) δ 7.46 – 7.26 (m, 10H), 6.89 – 6.82 (m, 2H), 6.58 – 6.51 (m, 2H), 3.77 (s, 3H), 3.49 (d, J = 13.0 Hz, 2H), 2.61 (d, J = 11.6 Hz, 1H), 2.31 (d, J = 14.5 Hz, 1H), 2.12 (d, J = 14.5 Hz, 1H), 1.56 (d, J = 16.0 Hz, 1H), 0.43 (d, J = 16.1 Hz, 1H), 0.36 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 176.7, 159.6, 137.9, 137.5, 130.9, 130.9, 130.5, 128.6, 128.3, 127.4, 127.2, 127.1, 117.0, 114.7, 58.9, 55.4, 51.9, 44.9, 44.8, 36.2, 29.2, 25.9; + HRMS (ESI) calcd for [C28H28N2O2 + Na] 447.2043, found 447.2036; IR (thin film) 2250, 1689, 1512, 1249. 5.37r: Purified by flash column chromatography (30:70:0.5 → 30:70:1

EtOAc/Hex/MeOH) as a pale yellow oil (52.9 mg, 0.186 mmol, 93% yield). Rf = 0.19 1 (30:70:0.5 EtOAc/Hex/MeOH); H NMR (500 MHz, CDCl3) δ 7.08 – 7.02 (m, 2H), 6.98 – 6.92 (m, 2H), 3.82 (s, 3H), 2.70 – 2.57 (m, 2H), 2.51 (d, J = 13.4 Hz, 1H), 2.48 (d, J = 16.7 Hz, 1H), 2.43 (d, J = 16.7 Hz, 1H), 2.33 (d, J = 13.4 Hz, 1H), 2.21 – 2.12 (m, 1H),

Chapter 5 | 251 13 2.12 – 1.97 (m, 3H), 1.37 (s, 3H); C NMR (126 MHz, CDCl3) δ 178.5, 159.5, 130.6, 127.5, 116.8, 114.8, 60.5, 55.4, 46.4, 44.6, 32.3, 31.6, 29.6, 26.8, 16.5; HRMS (ESI) + calcd for [C17H20N2O2 + Na] 307.1417, found 307.1415; IR (thin film) 2248, 1692, 1512, 1386, 1250. 5.37s: Purified by flash column chromatography (20:80:1 → 20:80:2

EtOAc/Hex/MeOH) as a pale yellow oil (57.3 mg, 0.192 mmol, 96% yield). Rf = 0.16 1 (20:80:1 EtOAc/Hex/MeOH); H NMR (500 MHz, CDCl3) δ 7.12 – 7.04 (m, 2H), 6.98 – 6.92 (m, 2H), 3.82 (s, 3H), 2.52 (d, J = 16.5 Hz, 1H), 2.48 (d, J = 16.5 Hz, 1H), 2.34 (d, J = 13.4 Hz, 1H), 2.25 – 2.10 (m, 3H), 1.94 – 1.83 (m, 2H), 1.77 – 1.68 (m, 4H), 1.43 (s, 13 3H); C NMR (126 MHz, CDCl3) δ 179.8, 159.5, 130.7, 127.6, 117.0, 114.8, 60.1, 55.4, + 49.7, 47.1, 39.7, 39.2, 30.3, 27.5, 25.5, 25.5; HRMS (ESI) calcd for [C18H22N2O2 + Na] 321.1573, found 321.1570; IR (thin film) 2246, 1691, 1513, 1387, 1250. 5.37t: Purified by flash column chromatography (40:60:0 → 50:50:2

EtOAc/Hex/MeOH) as a colorless oil (53.4 mg, 0.170 mmol, 85% yield). Rf = 0.21 1 (50:50:1 EtOAc/Hex/MeOH); H NMR (500 MHz, CDCl3) δ 7.14 – 7.06 (m, 2H), 7.00 – 6.92 (m, 2H), 4.05 (ddt, J = 13.8, 11.7, 4.1 Hz, 2H), 3.83 (s, 3H), 3.58 (dddd, J = 16.4, 11.6, 10.6, 2.7 Hz, 2H), 2.52 (d, J = 16.8 Hz, 1H), 2.47 (d, J = 16.8 Hz, 1H), 2.37 (d, J = 13.9 Hz, 1H), 2.26 (d, J = 14.0 Hz, 1H), 2.24 – 2.13 (m, 2H), 1.63 (ddt, J = 13.6, 4.5, 2.4 13 Hz, 1H), 1.52 (ddt, J = 13.5, 4.5, 2.4 Hz, 1H), 1.44 (s, 3H); C NMR (126 MHz, CDCl3) δ 177.8, 159.7, 130.7, 127.1, 117.1, 114.9, 64.1, 63.9, 60.1, 55.5, 43.3, 41.4, 35.4, 35.0, + 30.9, 28.9; HRMS (ESI) calcd for [C18H22N2O3 + Na] 337.1523, found 337.1521; IR (thin film) 2249, 1687, 1513, 1384, 1251. 5.37u: Purified by flash column chromatography (20:80:0 → 30:70:1

EtOAc/Hex/MeOH) as a pale yellow oil (56.6 mg, 0.180 mmol, 90% yield). Rf = 0.16 1 (3:7 EtOAc/Hex); H NMR (400 MHz, CDCl3) δ 7.16 – 7.06 (m, 2H), 7.00 – 6.92 (m, 2H), 3.82 (s, 3H), 2.52 (d, J = 16.8 Hz, 1H), 2.42 (d, J = 16.8 Hz, 1H), 2.21 (d, J = 14.1 Hz, 1H), 2.14 (d, J = 14.1 Hz, 1H), 1.71 – 1.60 (m, 1H), 1.53 (ddd, J = 13.9, 11.6, 3.1 Hz, 1H), 1.41 (s, 3H), 1.33 (s, 3H), 1.45 – 1.22 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR

(101 MHz, CDCl3) δ 180.0, 159.5, 130.5, 127.7, 117.5, 114.8, 62.8, 55.4, 42.8, 39.3, 39.3,

Chapter 5 | 252 + 29.7, 27.7, 27.5, 26.4, 22.7, 13.9; HRMS (ESI) calcd for [C19H26N2O2 + Na] 337.1886, found 337.1892; IR (thin film) 2246, 1694, 1513, 1395, 1252. 5.37v: Purified by flash column chromatography (20:80:0 → 30:70:1

EtOAc/Hex/MeOH) as a pale yellow oil (58.0 mg, 0.160 mmol, 80% yield). Rf = 0.14 1 (3:7 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.33 – 7.27 (m, 2H), 7.24 – 7.20 (m, 1H), 7.19 – 7.10 (m, 4H), 7.00 – 6.89 (m, 2H), 3.81 (s, 3H), 2.74 (td, J = 12.6, 12.2, 4.3 Hz, 1H), 2.66 – 2.55 (m, 2H), 2.50 (d, J = 16.9 Hz, 1H), 2.34 (d, J = 14.2 Hz, 1H), 2.24 (d, J = 14.1 Hz, 1H), 1.98 (ddd, J = 14.1, 12.2, 5.6 Hz, 1H), 1.89 (ddd, J = 14.1, 12.1, 4.3 13 Hz, 1H), 1.45 (s, 3H), 1.39 (s, 3H); C NMR (126 MHz, CDCl3) δ 180.0, 159.6, 139.9, 130.5, 128.8, 128.1, 127.5, 126.5, 117.3, 114.9, 62.6, 55.4, 42.9, 41.4, 39.3, 30.6, 29.8, + 27.6, 27.6; HRMS (ESI) calcd for [C23H26N2O2 + Na] 385.1886, found 385.1888; IR (thin film) 2244, 1693, 1512, 1395, 1252. 5.37w: Purified by preparative thin-layer chromatography (30:70:3

EtOAc/Hex/MeOH) as a thick colorless oil (28.0 mg, 0.074 mmol, 37% yield). Rf = 0.29 1 (3:7 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 7.15 – 7.05 (m, 2H), 6.96 – 6.86 (m, 2H), 4.53 (s, 2H), 3.81 (s, 3H), 3.36 (d, J = 9.2 Hz, 1H), 3.30 (d, J = 9.3 Hz, 1H), 2.59 (d, J = 16.9 Hz, 1H), 2.42 (d, J = 16.9 Hz, 1H), 2.36 (d, J = 13.9 Hz, 13 1H), 2.13 (d, J = 14.0 Hz, 1H), 1.39 (s, 3H), 1.31 (s, 3H); C NMR (126 MHz, CDCl3) δ 180.6, 159.6, 136.8, 130.7, 128.6, 128.1, 127.9, 127.5, 116.9, 114.8, 73.5, 73.1, 62.4, 55.5, + 42.2, 39.4, 27.8, 27.1, 26.8; HRMS (ESI) calcd for [C23H26N2O3 + Na] 401.1836, found 401.1829; IR (thin film) 2253, 1692, 1512, 1396, 1251. 5.37x: Purified by flash column chromatography (15:85 → 3:7 EtOAc/Hex) as a 1 thick pale yellow oil (78.0 mg, 0.170 mmol, 85% yield). Rf = 0.42 (3:7 EtOAc/Hex); H

NMR (500 MHz, CDCl3) δ 7.49 – 7.44 (m, 2H), 7.38 (dd, J = 8.6, 7.0 Hz, 2H), 7.35 – 7.32 (m, 2H), 7.31 – 7.26 (m, 1H), 7.24 – 7.16 (m, 8H), 7.07 – 6.96 (m, 2H), 6.83 – 6.70 (m, 2H), 3.74 (s, 3H), 3.51 (d, J = 14.1 Hz, 1H), 3.46 (d, J = 14.1 Hz, 1H), 3.19 (d, J = 13 16.9 Hz, 1H), 2.83 (d, J = 16.9 Hz, 1H); C NMR (126 MHz, CDCl3) δ 175.5, 158.6, 144.0, 141.0, 140.7, 128.8, 128.53 (two overlapped peaks), 128.46, 128.2 (two overlapped peaks), 127.8, 127.7, 127.2, 127.0, 126.5, 116.8, 114.3, 65.6, 56.9, 55.3, 49.1,

Chapter 5 | 253 + 27.3; HRMS (ESI) calcd for [C31H26N2O2 + Na] 481.1886, found 481.1895; IR (thin film) 2250, 1694, 1511, 1361, 1252. 5.37y: Purified by flash column chromatography (12:88:0 → 20:80:1

EtOAc/Hex/MeOH) as a colorless oil (30.8 mg, 0.084 mmol, 42% yield). Rf = 0.32 (1:4 1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.45 – 7.40 (m, 2H), 7.39 – 7.26 (m, 8H), 7.23 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 4.26 (dddd, J = 11.4, 9.0, 6.8, 3.3 Hz, 1H), 3.22 (dd, J = 13.1, 5.9 Hz, 1H), 2.83 (dd, J = 13.0, 8.3 Hz, 1H), 2.66 (dd, J = 17.0, 13 3.3 Hz, 1H), 2.47 (dd, J = 16.9, 7.4 Hz, 1H), 2.36 (s, 3H); C NMR (126 MHz, CDCl3) δ 174.4, 142.7, 141.1, 137.3, 133.3, 130.1, 128.7, 128.5, 127.9, 127.6, 127.4, 127.2, 124.9, + 115.9, 57.8, 52.4, 40.1, 22.3, 21.1; HRMS (ESI) calcd for [C25H22N2O + Na] 389.1624, found 389.1623; IR (thin film) 2251, 1699, 1514, 1385, 1298. 5.37z: Purified by flash column chromatography (1:9 → 1:4 EtOAc/Hex) as a thick 1 pale yellow oil (22.1 mg, 0.058 mmol, 29% yield). Rf = 0.35 (1:4 EtOAc/Hex); H NMR

(500 MHz, cdcl3) δ 7.55 – 7.48 (m, 2H), 7.41 – 7.18 (m, 13H), 4.85 (d, J = 15.3 Hz, 1H), 4.39 (d, J = 15.3 Hz, 1H), 3.19 (d, J = 13.8 Hz, 1H), 2.84 – 2.71 (m, 1H), 2.11 (d, J = 13 16.7 Hz, 1H), 1.96 (d, J = 16.6 Hz, 1H), 1.39 (s, 3H); C NMR (126 MHz, CDCl3) δ 175.0, 143.3, 142.2, 137.6, 128.9, 128.9, 128.4, 127.9, 127.8, 127.6, 127.5, 127.4, 126.9, + 116.8, 59.0, 56.6, 47.1, 43.6, 28.8, 25.7; HRMS (ESI) calcd for [C26H24N2O + Na] 403.1781, found 403.1782; IR (thin film) 2250, 1689, 1495, 1398.

5.37aa: Purified by flash column chromatography (0.6:100 → 1:100 MeOH/CH2Cl2) as a pale brown oil (57.9 mg, 0.198 mmol, 99% yield). Rf = 0.29 (2:100 MeOH/CH2Cl2); 1 H NMR (500 MHz, CDCl3) δ 7.96 (dt, J = 7.5, 1.0 Hz, 1H), 7.72 – 7.62 (m, 2H), 7.57 (td, J = 7.3, 1.2 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.06 – 7.00 (m, 2H), 3.85 (s, 3H), 2.90 (d, J 13 = 16.6 Hz, 1H), 2.70 (d, J = 16.7 Hz, 1H), 1.67 (s, 3H); C NMR (126 MHz, CDCl3) δ 167.6, 159.9, 147.1, 132.7, 130.9, 130.8, 129.4, 126.6, 124.6, 121.2, 115.9, 115.2, 63.7, + 55.5, 28.5, 24.8; HRMS (ESI) calcd for [C18H16N2O2 + Na] 315.1104, found 315.1101; IR (thin film) 2247, 1697, 1513, 1377, 1249.

5.37ab: Purified by flash column chromatography (1:100 MeOH/CH2Cl2) as a pale 1 yellow oil (70.2 mg, 0.198 mmol, 99% yield). Rf = 0.33 (2:100 MeOH/CH2Cl2); H

Chapter 5 | 254

NMR (400 MHz, CDCl3) δ 8.14 – 7.95 (m, 1H), 7.71 – 7.54 (m, 2H), 7.41 – 7.28 (m, 4H), 7.11 – 7.03 (m, 2H), 6.83 – 6.71 (m, 4H), 3.76 (s, 3H), 3.49 (d, J = 16.4 Hz, 1H), 3.20 (d, 13 J = 16.4 Hz, 1H); C NMR (101 MHz, CDCl3) δ 167.8, 159.3, 147.6, 137.7, 133.1, 131.4, 129.6, 129.6, 129.1, 129.0, 127.0, 126.7, 124.6, 122.5, 115.6, 114.6, 68.8, 55.4, + 25.8; HRMS (ESI) calcd for [C23H18N2O2 + Na] 377.1260, found 388.1269; IR (thin film) 2252, 1698, 1513, 1366, 1250.

5.37ac: Purified by preparative thin-layer chromatography (2:100 MeOH/CH2Cl2) as an orange foam (57.6 mg, 0.188 mmol, 94% yield). Rf = 0.48 (2:100 MeOH/CH2Cl2); 1 H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 7.8, 1.3 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.41 (td, J = 7.6, 1.2 Hz, 1H), 7.32 – 7.26 (m, 1H), 7.14 – 7.08 (m, 2H), 7.00 – 6.92 (m, 2H), 3.84 (s, 3H), 3.40 (d, J = 15.9 Hz, 1H), 3.28 (d, J = 15.9 Hz, 1H), 2.69 (d, J = 13 16.6 Hz, 1H), 2.62 (dd, J = 16.5, 0.9 Hz, 1H), 1.41 (s, 3H); C NMR (101 MHz, CDCl3) δ 164.8, 159.4, 134.7, 132.8, 131.1, 130.4, 130.4, 128.9, 128.3, 127.8, 127.6, 116.6, 115.0, + 114.6, 58.6, 55.5, 40.3, 28.5, 26.2; HRMS (ESI) calcd for [C19H18N2O2 + Na] 329.1260, found 329.1262; IR (thin film) 2247, 1656, 1511, 1372, 1250. 5.37ad: Purified by flash column chromatography (25:75:0 → 40:60:0 → 60:40:5

EtOAc/Hex/MeOH) as a pale yellow oil (16.1 mg, 0.066 mmol, 33% yield). Rf = 0.45 1 (5:95 MeOH/CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.12 – 7.07 (m, 2H), 6.99 – 6.93 (m, 2H), 3.82 (s, 3H), 2.74 (ddd, J = 16.9, 9.9, 6.6 Hz, 1H), 2.63 (ddd, J = 17.5, 9.9, 6.3 Hz, 1H), 2.53 (d, J = 16.8 Hz, 1H), 2.48 (d, J = 16.8 Hz, 1H), 2.40 (ddd, J = 13.3, 9.9, 6.3 13 Hz, 1H), 2.18 (ddd, J = 13.3, 9.9, 6.6 Hz, 1H), 1.40 (s, 3H); C NMR (126 MHz, CDCl3) δ 174.7, 159.8, 130.6, 127.1, 116.8, 115.0, 62.5, 55.5, 31.7, 29.4, 29.2, 26.7; HRMS (ESI) + calcd for [C14H16N2O2 + Na] 267.1104, found 267.1105; IR (thin film) 2244, 1693, 1513, 1387, 1251. 5.37ae: Purified by preparative thin-layer chromatography (40:60:4

EtOAc/Hex/MeOH) as a pale yellow oil (28.1 mg, 0.098 mmol, 49% yield). Rf = 0.48 1 (40:60:4 EtOAc/Hex/MeOH); H NMR (400 MHz, CDCl3) δ 7.13 – 6.85 (m, 4H), 3.81 (s, 3H), 2.54 (d, J = 16.7 Hz, 1H), 2.44 (d, J = 16.7 Hz, 1H), 2.37 (ddd, J = 13.8, 9.7, 4.0 Hz, 1H), 2.06 – 1.81 (m, 3H), 1.39 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H); 13C NMR (101

Chapter 5 | 255

MHz, CDCl3) δ 177.4, 159.0, 131.2 (br), 130.7, 117.1, 114.5, 59.2, 55.4, 38.4, 31.6, 31.5, + 30.5, 27.9, 27.7, 27.5; HRMS (ESI) calcd for [C17H22N2O2 + Na] 309.1573, found 309.1565; IR (thin film) 2241, 1645, 1511, 1390, 1249.

Aminocyanation reactions of 5.33 were carried out in a similar manner as 5.36, except that Pd2dba3 was used instead of CpPd(1-phenylallyl). All reactions were performed on a 0.2 mmol scale, following the exact conditions indicated above.

Note: products 5.34 were not freely soluble in CDCl3, yet for consistency, the 1 13 corresponding H and C NMR spectra were still collected in CDCl3. 5.34a: Purified by flash column chromatography (15:85:1 EtOAc/Hex/MeOH →

3:100 MeOH/CH2Cl2) as an amorphous pale yellow solid (61.9 mg, 0.198 mmol, 99% 1 yield). Rf = 0.50 (1:1 EtOAc/Hex); H NMR (400 MHz, CDCl3) δ 7.98 – 7.87 (m, 1H), 7.79 – 7.70 (m, 2H), 7.67 (ddd, J = 7.7, 5.9, 2.6 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 2.91 (d, J = 16.7 Hz, 1H), 2.85 (d, J = 16.7 Hz, 1H), 2.43 (s, 3H), 1.72 (s, 13 3H); C NMR (101 MHz, CDCl3) δ 140.8, 139.0, 134.3, 133.4, 132.8, 130.7, 130.3,

127.0, 123.3, 121.9, 116.0, 63.4, 29.2, 25.2, 21.3; HRMS (ESI) calcd for [C17H16N2O2S + Na]+ 335.0825, found 335.0831; IR (thin film) 2254, 1508, 1180. 5.34b: Purified by flash column chromatography (15:85:1 EtOAc/Hex/MeOH →

3:100 MeOH/CH2Cl2) as an amorphous pale yellow solid (65.9 mg, 0.186 mmol, 93% 1 yield). Rf = 0.57 (1:1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 1H), 7.76 – 7.71 (m, 2H), 7.65 (ddd, J = 8.3, 5.0, 3.4 Hz, 1H), 7.53 (d, J = 8.6 Hz, 2H),

Chapter 5 | 256 7.43 (d, J = 8.5 Hz, 2H), 2.92 (d, J = 16.7 Hz, 1H), 2.84 (d, J = 16.7 Hz, 1H), 1.71 (s, 3H), 13 1.35 (s, 9H); C NMR (126 MHz, CDCl3) δ 153.5, 139.0, 134.1, 133.3, 132.5, 130.2, 127.0, 126.8, 123.3, 121.7, 116.0, 63.6, 34.8, 31.2, 29.1, 25.2; HRMS (ESI) calcd for + [C20H22N2O2S + Na] 377.1294, found 377.1296; IR (thin film) 2253, 1511, 1297, 1178, 1151. 5.34c: Purified by flash column chromatography (15:85:1 EtOAc/Hex/MeOH →

3:100 MeOH/CH2Cl2) as an amorphous pale yellow solid (59.5 mg, 0.188 mmol, 94% 1 yield). Rf = 0.46 (1:1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.7 Hz, 1H), 7.82 – 7.63 (m, 3H), 7.52 (dd, J = 8.7, 4.9 Hz, 2H), 7.32 – 7.20 (m, 2H), 2.90 (d, J = 13 16.7 Hz, 1H), 2.84 (d, J = 16.8 Hz, 1H), 1.71 (s, 3H); C NMR (126 MHz, CDCl3) δ 1 3 163.7 (d, JF–C = 251.7 Hz), 138.7, 135.0 (d, JF–C = 9.1 Hz), 134.0, 133.6, 130.4, 125.7 4 2 (d, JF–C = 3.3 Hz), 123.3, 121.9, 117.2 (d, JF–C = 22.7 Hz), 115.7, 63.6, 29.3, 25.3; + HRMS (ESI) calcd for [C16H13FN2O2S + Na] 339.0574, found 339.0579; IR (thin film) 2253, 1505, 1302, 1291, 1178, 1152. 5.34d: Purified by flash column chromatography (15:85:1 EtOAc/Hex/MeOH →

3:100 MeOH/CH2Cl2) as an amorphous pale yellow solid (61.9 mg, 0.186 mmol, 93% 1 yield). Rf = 0.49 (1:1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.93 (dt, J = 7.7, 0.9 Hz, 1H), 7.77 (td, J = 7.6, 1.2 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.54 – 7.50 (m, 2H), 7.47 (dt, J = 8.9, 2.1 Hz, 2H), 2.90 (d, J = 16.7 Hz, 1H), 2.83 (d, J = 16.8 Hz, 1H), 1.71 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 138.7, 136.9, 134.3, 134.0, 133.6, 130.5, 130.4, 128.5, + 123.3, 121.9, 115.7, 63.7, 29.3, 25.3; HRMS (ESI) calcd for [C16H13ClN2O2S + Na] 355.0278, found 355.0281; IR (thin film) 2253, 1490, 1302, 1177. 5.34e: Purified by flash column chromatography (15:85:1 EtOAc/Hex/MeOH →

3:100 MeOH/CH2Cl2) as an amorphous pale yellow solid (59.1 mg, 0.180 mmol, 90% 1 yield). Rf = 0.46 (1:1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 7.7 Hz, 1H), 7.79 – 7.69 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.16 – 7.02 (m, 3H), 3.84 (s, 3H), 2.94 (d, J = 16.8 Hz, 1H), 2.85 (d, J = 16.8 Hz, 1H), 1.72 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 160.6, 138.9, 134.2, 133.4, 130.9, 130.5, 130.3, 124.9, 123.3, 121.7, 118.6, 116.1, 115.9, 63.7, 55.5, 29.2, 25.3; HRMS (ESI) calcd for

Chapter 5 | 257 + [C17H16N2O3S + Na] 351.0774, found 351.0782; IR (thin film) 2253, 1600, 1486, 1297, 1178. 5.34f: Purified by flash column chromatography (15:85:1 EtOAc/Hex/MeOH →

3:100 MeOH/CH2Cl2) as an amorphous pale yellow solid (67.4 mg, 0.184 mmol, 92% 1 yield). Rf = 0.47 (1:1 EtOAc/Hex); H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.7 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.80 – 7.63 (m, 6H), 2.91 (d, J = 16.8 Hz, 1H), 2.85 (d, J = 13 16.8 Hz, 1H), 1.73 (s, 3H); C NMR (126 MHz, CDCl3) δ 138.6, 136.5, 133.8, 133.8, 2 3 3 132.7 (q, JF–C = 33.2 Hz), 131.0, 130.8, 130.6, 129.9 (q, JF–C = 3.8 Hz), 127.3 (q, JF–C 1 = 3.6 Hz), 123.3, 123.2 (q, JF–C = 271.1 Hz), 121.9, 115.5, 63.9, 29.4, 25.3; HRMS (ESI) + calcd for [C17H13F3N2O2S + Na] 389.0542, found 389.0549; IR (thin film) 2255, 1332, 1179, 1151.

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