C(sp3)−H AMINATION REACTIONS UNDER FIRST ROW TRANSITION METAL CATALYSIS BY SHAUNA MARIE PARADINE DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2015 Urbana, Illinois Doctoral Committee: Professor M. Christina White, Chair Professor Scott E. Denmark Professor Wilfred A. van der Donk Professor John A. Katzenellenbogen C(sp3)—H AMINATIONS UNDER FIRST ROW TRANSITION METAL CATALYSIS Shauna M. Paradine University of Illinois at Urbana-Champaign Research Advisor: Prof. M. Christina White February 2015 ABSTRACT Nitrogen functionality is ubiquitous in biologically active molecules, from naturally occurring alkaloids and peptides to synthetic pharmaceuticals. However, due to its promiscuous reactivity, nitrogen can be challenging to incorporate into molecules and carry through synthetic sequences. Traditional methods to introduce nitrogen (e.g. Mannich, reductive amination) often rely on pre-existing functionality and require additional transformations such as oxidation state changes and/or protecting group maniuplations. C—H amination represents a powerful alternative synthetic strategy. This approach involves the direct functionalization of highly robust sp3 C—H bonds, which allows for the introduction of nitrogen functionality at late stages in synthetic sequences, both obviating the requirement for lengthy functional group manipulation strategies and enabling rapid access to a diversity of structures. Although small molecule iron and manganese catalysts were first explored for metallonitrene-mediated C—H amination reactions, the majority of synthetic advances in the field have been with noble metal dirhodium carboxylate catalysts. These catalysts are highly reactive and have collectively displayed the ability to efficiently aminate benzylic, ethereal, and aliphatic C—H bonds. However, they are poorly chemoselective in the presence of π- functionality such as olefins and alkynes, and direct addition to these π-bonds is often competitive with desired C—H amination reactivity. It is likely that rhodium’s concerted asynchronous C—H insertion mechanism, which favors functionalization at more electron-rich ii sites, is responsible for this lack of chemoselectivity. Conversely, first row transition metal catalysts like iron and manganese are thought to react through a stepwise homolytic C—H abstraction/rebound mechanism. We hypothesized that this different mechanism would lead to orthogonal reactivity under first row transition metal catalysis, including the ability to functionalize allylic C—H bonds with high chemoselectivity. In addition, iron and manganese are highly abundant and non-toxic base metals that have been relatively unexplored. The first chapter of this dissertation describes the development of the first synthetically useful C—H amination method under iron catalysis. This reaction, which employs the bulk commodity complex [FeIIIPc], confirms our initial hypothesis, displaying excellent chemoselectivity (generally >20:1 ins./azir.) for allylic C—H amination over a range of olefin classes and exhibiting site-selectivity trends that are orthogonal to those observed under rhodium catalysis. In addition, this bulky, electrophilic catalyst is able to differentiate between allylic C— H bonds in polyolefinic substrates on the basis of their electronic and steric nature. Mechanistic studies support a stepwise mechanism involving discrete electrophilic intermediates. In seeking to expand the scope of this C—H amination methodology, we were struck by a clear divergence in the literature between reactivity and selectivity. Existing catalysts for C(sp3)—H amination, including our [FeIIIPc] catalyst, are either highly reactive or highly selective, but not both. We sought to exploit the exquisite chemoselectivity of first row transition metals in order to develop a small molecule C—H amination catalyst that was truly general. The second chapter of this dissertation describes the discovery and development of [Mn(tBuPc)], a novel manganese catalyst that for the first time is able to effectively functionalize all types of sp3 C—H bonds with preparative product yields (>50%) even for very strong 2° and 1° aliphatic C— H bonds, while maintaining excellent chemoselectivity for C—H amination (>20:1) in the iii presence of readily oxidizable π-bonds. We conduct mechanistic studies to investigate the often drastic reactivity differences between [Mn(tBuPc)] and our previous [FeIIIPc], finding subtle changes in the C—H cleavage step that suggest attenuated radical behavior with manganese relative to iron. The generality of this method and versatility of the oxathiazinane C—H amination product lend it well for application to the diversification of topologically and functionally complex bioactive molecules. This is demonstrated for picrotoxinin and isosteviol derivatives, which maintain (or magnify) the reactivity and selectivity trends observed with the corresponding simple substructural units. iv ACKNOWLEDGEMENTS I am wholly indebted to my Ph.D. advisor, Prof. M. Christina White. Christina has been doing something truly special with her research program, and it’s an honor to be a part of that. She offered me exactly what I was looking for in graduate school: the opportunity to engage in exploratory and transformative research. She has challenged me and supported me throughout my time in graduate school, pushing me to be able to reach high and far. Her talent for pursuing and finding solutions for the most interesting and challenging problems in organic synthetic methodology is exquisite, and her vision, optimism, energy, and passion for the field are infectious. I expect to carry that tremendous influence with me throughout my own career. I would like to thank my thesis committee members, Prof. Wilfred van der Donk, Prof. Scott Denmark, and Prof. Thomas Rauchfuss. I’ve learned much from their broad expertise and deep knowledge of the field. Their insight, helpful suggestions and constructive criticisms have been instrumental in aiding my growth as a chemist and independent researcher. In addition, I am grateful to Prof. John Katzenellenbogen (Dr. K) for serving as a committee member for my final defense. I have an immense amount of respect for his intelligence, creativity, and the excellent example he sets as a senior member of the chemical community. These past several years I’ve had the immense pleasure of working with the best group of people out there. I’m thankful to all White group members, past and present, who have made our lab such a fulfilling and humbling environment in which to work. They have guided me, challenged me, grown with me, laughed with me, and pushed me much farther than I could have gone on my own. I’m especially grateful to Prof. Jared Delcamp and Dr. Dustin Covell, who had different research styles, but who both helped me as I began my graduate career and taught me how to be an effective chemist. The talent of my classmates, Dr. Iulia Strambeanu and Dr. Paul v Gormisky, has humbled me and I’m glad to have shared all the ups and downs of grad school with them. Dr. Jennifer Howell’s broad expertise, organization and rigor, creativity, and honesty have been invaluable to me. Over the last year, I’ve had the wonderful fortune to work directly with Jennifer Griffin, Aaron Petronico, and Jinpeng Zhao. There’s nothing more satisfying than sharing in the growth of research that I care so much about, and I’ve learned so much from their knowledge and fresh insight. They have elevated this C—H amination method to something that is truly special, and I’m excited to see what amazing things they accomplish in the coming years. Shannon Miller has set an impossibly high standard in my mind for undergraduate researchers – her incredible talent, quick mind, and strong work ethic will take her far in her future career, and it’s been a pleasure to work with her. As they say, life is a journey and not a destination, and there have been many people along the way who have collectively led me to this point in my career. I’m grateful to my teachers at the Kalamazoo Area Mathematics & Science Center (KAMSC), who awakened the scientist in me by showing me how big, fascinating, fun, challenging, messy, and thriving science is. I will always appreciate their knowledge, creativity, and all-consuming love of science. The chemistry department at Albion College was another collection of highly intelligent and zealous individuals. Prof. Vanessa McCaffrey, Prof. Cliff Harris, Prof. Craig Bieler, Prof. Amy Beilstein Bethune, Prof. David Green, Prof. Dan Steffenson, Prof. Lisa Lewis, and Prof. Chris Rohlman all contributed to deepening my conviction to pursue a career in chemistry research through their infectious passion and love for the field. And of course I am forever grateful to my undergraduate research advisor, Prof. Andrew French, who was as energetic and passionate as any. He introduced me to research as college freshman, and through my four years he went out of his way to create learning and research opportunities for me both at Albion and vi abroad. He was instrumental in laying the foundation that has made it possible for me to reach out and find success at a high level in the field. I wouldn’t be where I am today if I weren’t blessed with such a wonderful family. I come from a long line of strong women who worked hard, took risks, and challenged what society expected of them. My humble family history, from my parents to my grandparents and beyond, is one of dreaming big, overcoming obstacles and having a passion both for learning and for life. My parents, especially, have been the best role models I could ask for. They’ve lovingly supported me from the very beginning of my “scientific career” as a highly inquisitive four year old, never forcing me in any direction but always encouraging me to continually challenge myself and grow in every way. They raised my sisters and me with the earnest belief that we could accomplish anything if we were willing to work hard enough for it.