Bis(trimethylstannyl)benzopinacolate Promoted Radical Carbon-Carbon Bond Forming Reactions and Related Studies Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Franklin Lee Seely Graduate Program in Chemistry The Ohio State University 2010 Dissertation Committee: Robert S. Coleman, Co-Advisor David J. Hart, Co-Advisor T. V. RajanBabu Abstract This research has dealt primarily with the development of novel methods for radical carbon-carbon bond formation. A major focus of this research has been the hydrogen atom free generation of trialkyltin radicals. The bulk of this thesis will deal with the use of bis(trimethylstannyl)benzopinacolate 1 in mediating radical reactions. We have demonstrated that these conditions allow a wide variety of inter and intramolecular free radical addition reactions. We have given evidence that these reactions proceed via a novel non-chain free radical mechanism. ii Dedication This thesis is dedicated to Tracy Lynne Court. You have given me the courage to try again. iii Acknowledgments I would like to sincerely thank Dr. David J. Hart for all his help, the countless hours of work he put in, and for making this possible. I would like to thank Dr. Robert S. Coleman for agreeing to act as my advisor, and all the support and guidance he has given. I would like to than Dr. T. V. RajanBabu for reading my thesis and all his thoughtful suggestions. iv Vita Education 1981-1985 ………………………………………………………..B.S., The University of Utah 201 0 …………………………………………….……………Ph.D., The Ohio State University Major Field of Study: Chemistry Experience 1982-1985 ………………………………………Research Assistant, The University of Utah 1985-1990 …………………………………..Research Assistant, The Ohio State University 1990-1994 ………………………………….Principle Investigator, Pfizer, Central Research Awards Graduate Research Award – The Ohio State University ……………………………….1990 Conoco Graduate Research Fellowship – The Ohio State University ………………..1986 Special Chemistry Department Scholarship – The University of Utah …………1981-1986 Publications Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631. Hart, D. J.; Krishnamurthy, R.; Pook, L. M.; Seely, F. L. Tetrahedron Lett. 1993, 34, 7819. Dener, J.M.; Hart, D. J.; Huang, H. C.; Seely, F. L.; Wu, S. C. “Radical Reactions for Use in Organic Synthesis” in Organic Free Radicals for Use in Organic synthesis” in Organic Free Radicals, Fischer, H., and Haimgartner, H., Eds, Springer Verlag, Berlin, 1989, 77. Takacs, J. M.; Anderson, L. G.; Madhaven, G. V. B.; Seely, F. L. Angew. Chem. Chem. Int. Ed. Engl. 1987, 26, 1013. Takacs, J. M., Helle, M.A., Seely, F. L. Tetrahedron Lett. 1986, 11, 1257. Takacs, J. M.; Anderson, L. G.; Madhaven, G. B. V.; Creswell. M. W.; Seely, F. L.; Devroy, W. F. Organometallics 1986, 5, 2395. v Table of Contents Abstract ………………………………………………………………………………………….ii Dedication ………………………………………………………………………………………iii Acknowledgments ….………………………………………………………………………….iv Vita ………………………………………………………………………………………...........v List of Schemes ………………………………………………………………………….......vii List of Tables ….………………………………………………………………………………vii Chapter 1. Introduction .………………………………………………………………….........1 Chapter 2. A Free Radical One Carbon Homologation .…………………………………..31 Chapter 3. Bis(trimethylstannyl)benzopinacolate Mediated Free Radical Conjugate Additions ....……………………………………………………………….54 Chapter 4. Mechanistic Studies Concerning Bis(trimethylstannyl)benzopinacolate Mediated Free Radical Carbon-Carbon Bond Forming Reactions …....……...…67 Chapter 5. Studies Concerning Reagent Development Using Alternative Tin Sources and Pinacols .…..……………………………………..….………….93 Chapter 6. Experimental ……………………………………………………………………105 References……………………………………………………………………………………163 vi List of Schemes Scheme 1. A Typical Chain Reaction …………………………………………...……………2 Scheme 2. Trialkyltin Hydride Mediated Conjugate Addition …..…………………………..5 Scheme 3. Mechanism of Cobalt Mediated Coupling Reactions ………….…………….22 Scheme 4. A Possible Endgame for Pleurotin ……………………………………………..31 Scheme 5. Predicted Behavior of Iodooxime 100 …………………………………………42 Scheme 6. Synthesis of Radical Cyclization Precursors 133 and 135 ……………........54 Scheme 7. Potential Mechanisms for Diethyl Fumarate Reduction ……………………..64 Scheme 8. A Potential Chain Mechanism …………………………………………………68 Scheme 9. A Non-Chain Reaction Mechanism …………………………………………...78 Scheme 10. A Non-Chain One Carbon Homologation ……………………………………80 Scheme 11. Proposed Mechanism for the Hexamethylditin Mediated Coupling of Cyclohexyl Bromide and Benzophenone ………………...…………..84 Scheme 12. A Proposed Mechanism for the Formation of 137 and 138 ………………85 Scheme 13. The Barton Reaction …………………………………………………………..87 Scheme 14. Equilibrium Formed Upon Mixing N,N-Diethyltrimethyl- stannylamine and benzopinacol 234 ……………………………………...………..97 vii Bis(trimethylstannyl)benzopinacolate Promoted Radical Carbon-Carbon Bond Forming Reactions and Related Studies Chapter 1. Introduction. This research has dealt primarily with the development of novel methods for radical carbon-carbon bond formation. The major focus of this thesis will deal with the use of bis(trimethylstannyl)benzopinacolate 1 in mediating radical conjugate addition reactions. Since the expanding role of radical reactions has been covered in several excellent reviews,1 I will not review this broad field of recent research. However, I will discuss some key features of radical addition reactions which are especially attractive to synthetic chemists with an emphasis on intermolecular formation of carbon-carbon bonds. A. Historical. Organic radicals are species with an odd unpaired electron. Their lack of charge, and high reactivity lead to important differences with heterolytic processes.2 In heterolytic bond constructions, like-charged species repel one another and generally will not undergo self reaction. It is quite common to form concentrated solutions of anions, and under certain conditions, cations.3 This is not the case with free radical chemistry. 1 Scheme 1. A Typical Chain Reaction Radicals, being uncharged and having a single unpaired electron, can come together to form a bond without encountering any significant energy barrier.4 The very low 2 activation energy of radical termination means the lifetime of individual radicals is extremely short. The extremely short lifetimes of radicals dominates the behavior of such species and accounts for many differences between homolytic and heterolytic processes. Examination of the following pages will demonstrate a plethora of examples of radical bond constructions in which diverse functionality is tolerated. Radical reactive intermediates have such short lifetimes that interference by other functional groups rarely presents a problem. Free radicals are generally formed via thermal or photochemical bond homolysis (Scheme 1: eq.1a).5 The freshly generated radical may undergo various processes including atom transfer (eq. 1b), rearrangement (eq. 1c), addition (eq. 1d), and fragmentation (eq. 1e). These propagation steps involve unimolecular reaction of a radical, or reaction of a radical with a non-radical species to liberate a new radical species. The new species is likely to be as reactive as the original radical and rapidly undergo another transformation. The number and nature of these propagation steps is governed by competitive pathways for a given substrate. Thus, with appropriately designed substrates, and proper reaction conditions, more than one carbon-carbon bond can be formed in a single pot. This series ends when two radicals find each other in solution. Radicals may terminate via recombination (eq. 1f) or disproportionation. The sequence of radical formation (initiation), followed by steps which generate a new radical (propagation), and reactions between two radical species which generate a stable species (termination) is called a chain reaction. Although, as this thesis will attempt to demonstrate, not all radical processes are chain reactions, the chain process may be regarded as typical of free radical behavior. The first organic free radicals were studied by Gomberg.6 During the period from 1850 to 1900, valence theory served as the one reliable guide with regard to structure in 3 organic chemistry. A key aspect of valence theory with respect to organic molecules was the tetravalent nature of carbon. During the infancy of organic chemistry, countless numbers of compounds were assigned definitive structures which adhered to valence theory. In 1900, Gomberg published the first account of an observable compound which did not fit valence theory.7 The original intent of the author was to prepare hexaphenylethane via the reaction of metallic silver with triphenylmethyl chloride. The resulting substance had none of the characteristics of a saturated alkane. Instead of being relatively inert, the product reacted instantly with oxygen and iodine. Gomberg correctly surmised that the triphenylmethyl radical either didn't dimerize or the dimerization was rapidly reversible and the equilibrium favored the triphenylmethyl radical (eq. 2). The next major advance came in the 1920's when Paneth showed that non-stabilized alkyl radicals exist and measured the lifetime for their decay.8 The first organic synthesis involving free radical intermediates came in 1937 when Waters and Hey described the benzoyl peroxide mediated phenylation of aromatic compounds.9 In that same year, Kharasch recognized the anti-Markovnikov addition of hydrogen