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Frontiers in Iridium-Catalyzed CH Borylation Frontiers in Iridium-Catalyzed C-H Borylation: Attaining Novel Reactivity and Selectivity By Matthew Alan Larsen A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor John F. Hartwig, Chair Professor Robert G. Bergman Professor Alexis T. Bell Fall 2016 Abstract Frontiers in Iridium-Catalyzed C-H Borylation: Attaining Novel Reactivity and Selectivity By Matthew Alan Larsen Doctor of Philosophy in Chemistry University of California, Berkeley Professor John F. Hartwig, Chair The following dissertation discusses the development of novel methodology for the catalytic borylation of C-H bonds and includes in-depth studies on the mechanism and selectivity of these synthetic transformations. These methods include the borylation of heteroaryl C-H bonds, the selective borylation of benzylic C-H bonds, and the directed and undirected borylation of unactivated alkyl C-H bonds. Chapter 1 contains a comprehensive review of C-H borylation methodology. This review focuses on the initial development of catalytic C-H borylation and on the state-of- the-art of methodology for the undirected and directed borylation of aryl, benzylic, and alkyl C-H bonds. Additionally, this review highlights knowledge gaps and unsolved challenges. Furthermore, this review provides the author’s opinion on future directions for research on the borylation of C-H bonds. Chapter 2 describes the study of the iridium-catalyzed borylation of heteroaryl C- H bonds. Contained is an examination of the scope of the borylation of heterocycles containing more than one heteroatom and rules for predicting the site-selectivity of this reaction. Also included are experimental and computational studies that reveal the mechanism of this reaction and the origins of the observed regioselectivity. Chapter 3 discusses the development of the selective borylation of the primary benzylic C-H bonds of methylarenes. Key to this development was the discovery that the combination of a novel iridium catalyst and a silylborane allows for the selective borylation of benzylic C-H bonds over aryl C-H bonds. Experimental and computational studies that investigate the origins of this selectivity are also discussed. Chapter 4 discusses the development of the iridium-catalyzed, hydrosilyl-directed borylation of alkyl C-H bonds. This methodology allows for the diastereoselective borylation of secondary alkyl C-H bonds under relatively mild conditions. Chapter 5 explores the effect of ligand structure on the rates of alkyl C-H borylation catalyzed by Ir-phenanthroline complexes. Experimental and computational studies reveal that in addition to the relative electron-donating ability of phenanthrolines, weak interactions involving the phenanthroline in the transition state of the turnover- limiting step for the borylation of alkyl C-H bonds can have a large impact on the relative rates of alkyl C-H borylation catalyzed by various Ir-phenanthroline complexes. ! 1 Table of Contents Chapter 1. C-H Borylation: A Unique and Versatile Method for C-H Bond 1 Functionalization 1.1 Background on C-H Bond Functionalization: Directed vs. 2 Undirected and Mechanism of C-H Bond Cleavage 1.2 A Brief History of Metal-Mediated C-H Bond Functionalization 4 and the Emergence C-H Borylation 1.3 Overview of Methods for Undirected, Catalytic Aryl C-H 7 Borylation 1.4 Overview of Methods for Undirected, Catalytic Benzylic C-H 21 Borylation 1.5 Overview of Methods for Undirected, Catalytic Alkyl C-H 24 Borylation 1.6 Overview of Methods for Directed, Catalytic Borylation of C-H 29 Bonds 1.7 Conclusion 36 1.8 References 38 Chapter 2. Iridium-Catalyzed C–H Borylation of Heteroarenes: Scope, 42 Regioselectivity, Application to Late-Stage Functionalization, and Mechanism 2.1 Introduction 43 2.2 Results and Discussions 45 2.3 Conclusions 67 2.4 Experimental 67 2.5 References 104 Chapter 3. Iridium-Catalyzed Borylation of Primary Benzylic C–H Bonds 107 without a Directing Group: Scope, Mechanism, and Origins of Selectivity 3.1 Introduction 108 3.2 Results and Discussions 109 3.3 Conclusion 128 3.4 Experimental 129 3.5 References 163 Chapter 4. Iridium-Catalyzed, Hydrosilyl-Directed Borylation of 165 Unactivated Alkyl C–H Bonds 4.1 Introduction 166 i 4.2 Results and Discussions 167 4.3 Conclusions 172 4.4 Experimental 172 4.5 References 198 Chapter 5. Effect of Ligand Structure on the Electron-Density and 200 Activity of Iridium Catalysts for the C-H Borylation of Alkanes 5.1 Introduction 201 5.2 Results and Discussions 202 5.3 Conclusions 216 5.4 Experimental 217 5.5 References 239 ii Acknowledgements It is an honor and a relief to be completing my PhD studies at UC Berkeley, and the reality of it has not quite set in yet. My path toward a fulfilling career has been anything but clear throughout the years, but now, all of a sudden, it seems that my future has come sharply into focus. I have to say, that I am very pleased with what lies ahead, and for that reason, I have a lot to be thankful for. I would first like to thank my grandfather and my late grandmother for their unending support through the years. I was rarely the model grandson, but they saw my potential and always provided both emotional and financial support, which has allowed me to focus on my studies and excel. I realize that such support is a privilege that not every aspiring student receives, and without it, I doubt I would be where I am today. My parents have also been a powerful source of motivation and inspiration over the years. I would like to thank them for helping me rally when my morale was low. I also would like to thank them for their tolerance and patience. With regards to mentorship in chemistry, I would first like to thank Steve Dwight who taught me many of the synthetic skills that I still use today. My time at Promega Biosciences under his mentorship was invaluable to my overall development as a chemist. Furthermore, I’d like to thank him for being a solid friend. When I came to Berkeley as a prospective student, I had the privilege of working under Carl Liskey in the Hartwig group. I am thankful for his guidance that help set me on my path toward developing and executing projects related to C-H borylation. He proved to be an excellent conduit for the collective knowledge related to borylation and C-H functionalization that the Hartwig group has amassed over the years. I also thank my graduate mentor, John Hartwig, for the incredible research experience that I have had over the last four and a half years. He always encouraged me to take a deeper look at my research, and as a result, I feel that I have a firm, fundamental understanding of chemistry that will be applicable to a wide range of tasks in my future career. Lastly, and most importantly, I’d like to thank my wife and my son. I met my wife about halfway through my time as an undergraduate, so she has been with me and supported me through most of my academic journey. She has been a rock and has kept me grounded throughout the process. My son came into the picture late in my graduate studies, and even though he is only a year and a half old, he has taught me so much. He reminds me constantly of what my priorities are, and that the simple things are the most important. iii Chapter 1 Chapter 1 C-H Borylation: A Unique and Versatile Method for C-H Bond Functionalization 1 Chapter 1 1.1 Background on C-H Bond Functionalization: Directed vs. Undirected and Mechanism of C-H Bond Cleavage The replacement of an unactivated C-H bond with a functional group, termed C-H bond functionalization, has the potential to change the strategies used to prepare organic molecules.1,2 Such reactions could convert light alkanes to higher-value, functionalized chemical feedstocks,3 or they could introduce functionality at specific positions of molecules already possessing one or many other functional groups.2,4 In classical organic chemistry, some functional groups will make nearby C-H bonds acidic and sites for the classical sequence of deprotonation and quenching of the resulting nucleophiles with electrophilic reagents (Figure 1.1a). The catalytic functionalization of C-H bonds seeks to provide access to the functionalization of C-H bonds that lack the activating influence of existing functional groups (Figure 1.1b). So far, most practical functionalizations of C-H bonds have occurred to add new groups at typically unreactive C-H bonds in molecules containing existing functionality. B. Catalytic Functionalization of A. Classical Functionalization of Acidic C-H Bonds Unactivated C-H Bonds Catalyst E H Base E+ Reagent EWG EWG H FG EWG R R Figure 1.1 Comparison of classical C-H bond functionalization and catalytic C-H bond functionalization In many cases, such functionalizations occur near existing functional groups, often after modification of this existing functionality.5 Such modifications often convert a common functional group to one that can serve as a ligand for a transition-metal complex (Figure 1.2). For example, a ketone has been converted to an imine, which binds the catalyst as a Lewis base.6 Alternatively, a carboxylic acid has been converted to a picolinamide that chelates a transition metal center and binds as a formally anionic ligand.7 A carboxylic acid has even been converted to an amide that possesses a “U- shape” and will cause the catalyst to react at a C-H bond distal to the position of the existing functionality.8-10 After the C-H bond functionalization occurs, the directing group is removed and the original functional group is restored to its original form.
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