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OXIDATIVE HECK REACTIONS with TERMINAL OLEFINS by JARED H. DELCAMP DISSERTATION Submitted in Partial Fulfillment of the Requirem

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OXIDATIVE HECK REACTIONS with TERMINAL OLEFINS by JARED H. DELCAMP DISSERTATION Submitted in Partial Fulfillment of the Requirem OXIDATIVE HECK REACTIONS WITH TERMINAL OLEFINS BY JARED H. DELCAMP 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, 2010 Urbana, Illinois Doctoral Committee: Associate Professor M. Christina White Professor Scott E. Denmark Associate Professor Paul J. Hergenrother Professor John A. Rogers ABSTRACT Sequential transformations in a single reaction have the potential to dramatically increase efficiency with respect to resources, time, and number of steps to access key intermediates. When sequential C-H bonds are activated a bifunctional handle arises from seemingly inert functionality. This work describes a one-pot sequential allylic C-H esterification, vinylic C-H arylation. A previously reported Pd(II)/sulfoxide system is used to generate branched allylic esters from α-olefins with only the addition of an aryl boronic acid to the reaction mixture. Styrenyl allylic esters are generated in good overall yield and excellent selectivities. The wide functional group tolerance and mild conditions of this three-component coupling reaction provide an attractive manifold for the rapid build-up of dense functionality around terminal olefins with minimal protecting group strategies or undesirable oxidation/reduction reactions. The synthetic utility of this reaction has been demonstrated through the synthesis of several intermediates to biologically active molecules. The ready availability and inertness of α-olefins relative to the oxidized precursors required for other C—C bond forming methods means that fewer steps are required for their installation and maintenance throughout a synthetic sequence. Previously, allylic esters served as non-resonance directing groups on terminal olefin for the vinylic C—H arylation (Heck reaction). This manifold is unique because previous intermolecular Heck reaction conditions require an excess of resonance activated olefin coupling partner. Further exploration of directing groups to determine the underlying directing factors led to the discovery of several terminal olefin classes with diverse ii directing elements. A general and highly selective intermolecular Heck arylation of non- resonance stabilized α-olefins with aryl and stryenyl boronic reagents has been developed. The Pd(II)/sulfoxide catalyzed Heck reaction is performed under oxidative, acidic conditions and proceeds with good yields and excellent regio- and stereoselectivities to generate linear E-arylated olefins. Polyenes are prevalent motiefs in natural products and pharmaceuticals. Polyene functionality often requires mild and selective synthetic methods. The Heck vinylation uses orthogonally reactive C-H bonds and these bonds are often easy to carry through synthetic sequences. Despite this advantage, the synthetic potential of the intermolecular Heck reaction has not been realized in complex molecule formation. A method has been developed which overcomes the previous intermolecular Heck-vinylation shortcomings of excess terminal olefin and required resonance activation for regio- and stereoselectivities. The Pd(II)/sulfoxide catalyzed oxidative Heck vinylation proceeds under mild conditions to give polyene products with a variety of substitution patterns amid diverse functionality. The polyenes are formed in synthetically relevant yields with excellent stereoselectivities. Overall, the oxidative Heck vinylation compares favorably with many of the methods commonly used to synthesize polyunsaturated hydrocarbon segments. This method increases the synthetic potential of the intermolecular Heck reaction closer to that of other classic palladium cross-couplings. iii ACKNOWLEDGMENTS I would like to thank Professor M. Christina White for excellent guidance with regard to which problems to attack, persistence in aiding my development as a writer, and for understanding some insanity properly directed can be useful. I have learned countless lessons about becoming an advisor vastly ranging from the importance of recruiting quality people which will one day be called colleagues to the importance of how to use criticism to its fullest to become better. I will certainly miss her unabated passion for solving problems as evidence through belt buckles, tattoos, and work ethic. I have appreciated her big picture analysis of methods developed in and out of this lab and it was this attitude which originally attracted me to this lab. I will undoubtedly take this attitude that fosters courage to attack global problems by asking the correct (often risky) questions to any future areas of research. I would like to thank Professor John Anthony for all his guidance beginning with my sophomore year at the University of Kentucky through the present. I was intensely fortunate to have observed his passion for science and listened to his encouragement to stop the medical school route and pursue research. I was even more fortunate to have the opportunity to work on a very successful project from the start. It was that intoxicating success which began my addiction of discovery. He has continued to grant me excellent advice from the beginning and has set a standard for the type of attitude I want to maintain especially toward confused pre-med students. Professor Scott Denmark has set an excellent example of what it really means to love the literature. As a first year student at Illinois I felt as though literature was too vast to ever gain a confident handle on. After several years of Professor Denmark serving on iv my committee and my attendance to his synthesis course, I have realized truly loving a field can grant you the dedication and commitment to know a significant amount of what has happened and is in progress in a field. I am thankful to graduate soon feeling tremendously less overwhelmed but still understanding how vast our scientific literature is. I was granted the blessing of working with both Alex Brucks and Nicolaas Vermeulen on projects. Alex was brave enough to accept guidance from me and is the first student I directly mentored. She was undeniably a large asset to my second major project. At the time of agreeing to help develop her experimental techniques I viewed the time commitment as a real gamble; however, I can say the gamble was well placed. The time investment certainly ‘paid’ for itself; however, I unknowingly gained the opportunity to guide a very gifted student and the rewards of that are hard to measure. While working with Nic I learned the real potential of working with a colleague to achieve a similar goal. The speed of results gathered was astonishing given I had typically worked alone experimentally. I appreciated the opportunity to both learn from and help create the laboratory techniques and philosophies entitled ‘gorilla’ chemistry from a crazed and now doctor Mark Chen. Aside from developing less than orthodox procedures, we have had the opportunity to share in the concept of ‘relative pain’ which not only served to make each of us stronger at the task at hand, but also made difficult tasks both competitive and comical. I both respect and fear what science is gaining in Mark Chen. I admire Dustin Covell for maintaining some level of grasp on reality as Mark and I attempted to spiral toward lawlessness. He has been a good friend and has maintained v an inspiring level of rigorous experimentation no matter what the consequences. His passion is solid. I also suspect he is the ‘minion’ whereas he introduced me to competitive Halo which undoubtedly added at least 6 months to my Ph.D. Thanks? Nicholaas Vermuelen and John Whitteck have both been good friends since the beginning of graduate school. I am thankful for their unique senses of humor and the stabilizing affects each of them have had throughout my graduate school experience. Our many hours of games and drinking have helped me with the play hard portion of my week. I am grateful to have had the opportunity to work beside an incredible group of chemists. I have no doubts great future research will come from: Ken Fraunhoffer, Mark Chen, Dustin Covell, Nicholaas Vermeulen, Erik Stang, Sean Read, Grant Rice, Andrew Young, Alex Brucks, Marinus Bigi, Paul Gormisky, Shauna Paradine, and Iulia Strambeanu. I also have no doubts Mark Chen, Alex Brucks, Paul Gormisky, and Shauna Paradine are socially prepared for a diverse array of scenarios as each was forced to closely interact with me by sharing a bay. To Michael Birbiglia: I am in the future too now. I would like to thank my father, David Delcamp, for teaching me how to ‘build character’ on the farm through what most would call intense manual labor. He also instilled a level of personal discipline in me that has certainly paid off. He has encouraged me to excel in school and to make sure I had some fun too along the way. He is an inspiration in many ways. Last, and undeniably most, I owe a tremendous thanks to my wife Leah Delcamp for a level of understanding and encouragement I could not have dreamed possible from vi someone outside the field. She has seen, heard, and shared every last bit of frustration and success I have experienced in graduate school and been nothing but supportive the entire way. I owe her, Mac, Marley, and Monty my sanity. She not only entertains my ridiculous antics but frequently expands upon them. Because of her continual promotion of creativity and encouragement I now realize the scientific problems solved thus far never stood a chance of remaining unsolved and future
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