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

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Development of Catalytic C–CN, C–O, and N–CN Sigma-Bonds Activation and Alkene Addition Reactions 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 © Zhongda Pan 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. i Dedication To my parents ii 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 iv 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 viii 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
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