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Approaches to Hydrocarbon Functionalization Using Heteroatom-Centered Radicals

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Approaches to Hydrocarbon Functionalization Using Heteroatom-Centered Radicals APPROACHES TO HYDROCARBON FUNCTIONALIZATION USING HETEROATOM-CENTERED RADICALS Ryan Kemper Quinn A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry Chapel Hill 2016 Approved by: Erik J. Alexanian Simon J. Meek Jeffery S. Johnson Michel R. Gagne Jeffrey Aube ©2016 Ryan Kemper Quinn ALL RIGHTS RESERVED ii ABSTRACT RYAN KEMPER QUINN: Approaches to Hydrocarbon Functionalization Using Heteroatom- Centered Radicals (Under the direction of Erik J. Alexanian) I. Intermolecular Aliphatic C-H Functionalizations An overview of intermolecular aliphatic C-H functionalization reactions is presented. The historical perspective and current state-of-the art methodologies are presented in the areas of C-H oxidation, halogenation, and amination reactions. II. Aliphatic C-H Bromination Using N-Bromoamides A site-selective approach for C-H bromination is outlined. The reactions proceed efficiently with 1 equivalent of alkane substrate. Selectivity, scope and mechanism are discussed. III. Aliphatic C-H Chlorination Using N-Chloroamides iii A site-selective approach for C-H chlorination is outlined. The reaction shows improved efficiency and scope compared to the bromination study. An application toward the synthesis of (+)-chlorolissoclimide is included. IV. Catalytic C-H Functionalizations Using Amidyl Radicals Efforts to convert the C-H chlorination to a catalytic variant are summarized; promising lead results are highlighted. Generation of amidyl radicals using proton coupled electron transfer is also discussed. Initial promising results in this area are highlighted. V. Alkene Carbooxygenations Using Hydroxamic Acids A radical mediated approach to alkene carbooxygenation using hydroxamic acids is described. These reactions deliver a divers set of carbon-carbon bond forming reactions to a variety of alkene substrates. iv ACKNOWLEDGEMENTS The axiom “no man is an island” applies as much in science as in other walks of life. Accordingly I would like to thank all those who have helped me attain my goals. Firstly, I would like to acknowledge my PhD advisor, Prof. Erik J. Alexanian, for his guidance, patience, and intellectual contributions to my doctoral research projects. Erik’s guidance has helped grow from a student who possesses a love for synthetic organic chemistry into a scientist who has a more complete understanding of what it takes to develop new and impactful chemical reactions – and, more importantly, what it takes to make a meaningful contribution to our field. Secondly, I would like to thank others who took the time to personally serve as my mentors in helping me develop the skills of an organic chemist. My undergraduate research advisor, Prof. Bianca R. Sculimbrene, taught me how to be more intellectually curious and appreciate the value of basic research. Dr. Valerie Schmidt, Andy Bruscoe, and Kyla Bloome each served to varying degrees as my graduate student mentors. Together they helped me succeed as a graduate student by teaching how to run and analyze chemical reactions, read and understand the chemical literature, and think more critically about my research projects. I would also like to thank all members of the Alexanian group past and present. Lastly I would like to thank my parents, Michael Quinn and Theresa Kemper, and my brothers McLean Quinn and Carter Quinn. The space here is not nearly adequate to describe how grateful I am to them. Their unwavering encouragement, support and companionship has propelled me to heights I couldn’t have imagined. v To Dad, I miss you every day. vi TABLE OF CONTENTS LIST OF FIGURES……………………………………………………………..………………xi LIST OF TABLES……………………………………………………………...……………….xv LIST OF ABBREVIATIONS AND SYMBOLS…………………………………………….xviii 1 CHAPTER ONE Intermolecular Aliphatic C-H Functionalizations .......................... 1 1.1 Introduction ................................................................................................................ 1 1.2 Background ................................................................................................................ 2 1.2.1 Aliphatic C-H Oxidation ................................................................................ 2 1.2.2 Aliphatic C-H Halogenation .......................................................................... 7 1.2.3 Aliphatic C-H Amination ............................................................................. 16 1.3 Summary and Outlook ............................................................................................. 18 1.4 References ................................................................................................................ 19 2. CHAPTER TWO Aliphatic C-H Bromination Using N-Bromoamides..................... 22 2.1 Introduction .............................................................................................................. 22 2.2 Background .............................................................................................................. 22 2.3 Reaction Development ............................................................................................. 23 2.3.1 Initial Studies ............................................................................................... 23 vii 2.3.2 Substrate Scope – Steric Selectivity ............................................................ 26 2.3.3 Substrate Scope- Electronic Selectivity ....................................................... 30 2.3.4 Substrate Scope – Complex Molecules........................................................ 32 2.3.5 Mechanistic Studies and Proposed Mechanism ........................................... 34 2.3.6 Substrate Scope – Bromination of activated C-H bonds ............................. 37 2.4 Summary .................................................................................................................. 38 2.5 Experimental Data ................................................................................................... 39 2.5.1 General Methods .......................................................................................... 39 2.5.2 Compound Preparation ................................................................................ 40 2.5.3 C-H Bromination Procedures with N-Bromoamides ................................... 60 2.6 References ................................................................................................................ 93 3. CHAPTER THREE Aliphatic C-H Chlorination Using N-Chloroamides ................ 96 3.1 Introduction .............................................................................................................. 96 3.2 Background .............................................................................................................. 97 3.3 Reaction Development ............................................................................................. 97 3.3.1 Initial Studies ............................................................................................... 98 3.3.2 Substrate Scope – Steric Selectivity ............................................................ 99 3.3.3 Substrate Scope- Electronic Selectivity ..................................................... 101 3.3.4 Substrate Scope – Complex Molecules...................................................... 105 3.3.5 Mechanistic Studies and Proposed Mechanism ......................................... 106 viii 3.4 Synthesis of (+)-Chlorolissoclimide ...................................................................... 107 3.5 Summary ................................................................................................................ 112 3.6 Experimental Data ................................................................................................. 113 3.6.1 General Methods ........................................................................................ 113 3.6.2 Compound Preparation .............................................................................. 115 3.6.3 C-H Chlorination Procedures with N-Chloroamides ................................. 132 3.6.4 Synthesis of Chlorolissoclimide: Experimental Procedures ...................... 164 3.6.5 Comparison Tables for chlorolissoclimide (1) and haterumaimide Q (2). 179 3.6.6 Cell Viability Assays ................................................................................. 181 3.7 References .............................................................................................................. 182 4. CHAPTER FOUR Catalytic C-H Functionalizations Using Amidyl Radicals ....... 185 4.1 Introduction ............................................................................................................ 185 4.2 Background ............................................................................................................ 186 4.3 Reaction Development ........................................................................................... 188 4.3.1 Initial Studies – Stoichiometric Halogen Sources ..................................... 188 4.3.2 Initial Studies – Photoredox Manifolds ..................................................... 192 4.4 Summary ................................................................................................................ 195 4.5 Experimental Data ................................................................................................
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