THE DEVELOPMENT OF ORGANOTIN REAGENTS FOR ORGANIC SYNTHESIS by David Scott Hays B. S. Chemistry, University of Illinois Submitted to the Department of Chemistry in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY IN ORGANIC CHEMISTRY at the Massachusetts Institute of Technology June 1998 © Massachusetts Institute of Technology, 1998 All rights reserved Signature of Author Department of Chemistry May 14, 1998 Certified by Gregory C. Fu t' Thesis Supervisor Accepted by Dietmar Seyferth Chairman, Departmental Committee on Graduate Students JUN I 13998 scienct LIBRARIES This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: Professor Peter H. Seeberger I_ _ /1 Chairman Professor Gregory C. Fu J _J Thesis Supervisor Professor Rick L. Danheiser THE DEVELOPMENT OF ORGANOTIN REAGENTS FOR ORGANIC SYNTHESIS by David Scott Hays Submitted to the Department of Chemistry on May 14, 1998 in partial fulfillment of the requirements for the Degree of Doctor of Philosophy at the Massachusetts Institute of Technology ABSTRACT A method for the intramolecular pinacol coupling of dialdehydes and ketoaldehydes is described. The method was found to be useful for synthesizing 1,2-cyclopentanediols with very high degrees of diastereoselectivity in favor of the cis stereochemistry. 1,2- Cyclohexanediols were generated with lower degrees of stereoselection. This free radical chain process involves as the key steps: 1) an intramolecular addition of a tin ketyl radical to a pendant carbonyl group, followed by 2) a rapid intramolecular homolytic displacement by an oxygen radical at the tin center to liberate an alkyl radical. The development of a Bu 3 SnH-catalyzed carbon-carbon bond forming reaction (the reductive cyclization of enals and enones) is described, followed by a catalytic variant of the Barton-McCombie deoxygenation reaction. Both of these methods rely on the reduction of an intermediate Sn-O species to a Sn-H species by a silicon hydride reagent in the turnover step. A new fundamental reaction of organotin compounds is described: the generation of Sn-H bonds by treatment of tin amides with silicon hyrdides. The scope of organotin hydride catalysis was broadened to include reactions which generate Sn-N bonds, and in this context, a new Bu3SnH-catalyzed reduction of azides to amines was developed. Thesis Supervisor: Gregory C. Fu Title: Assistant Professor of Chemistry ACKNOWLEDGMENTS Throughout my educational career, I have been fortunate to have been taught by some of the best, and they deserve a special thanks. Most notably: Miss Woolard (6th grade); Ms. Whitis (7th grade English); Mr. Wilken (8th grade math); Mr. Leech (9th grade science; Mr. Wenner (Jr. High instructor, high school spiritual advisor); Ken Johnston (Jr. High instructor). The teachers in the Newark High English Department stand out for encouraging me to state my opinion and not minding too much that it differed from their own: Mrs. Jones; Ms. Harriman; and Ms. Anderson. Without my experiences in the sciences at Newark High, I probably wouldn't be writing this Thesis. Mr. MacGregor, Mr. Miller, and Dr. Doyle all deserve recognition for their excellent curricula which prepared me so well for college. And of course, Mr. Holekamp, who went far above and beyond the call of duty in taking me under his wing. He is truly a star. A number of individuals have had a significant impact on my professional career. I will always be indebted to my friends and mentors at the Eastman Kodak Company who took unselfish interests in my success. First, Ms. Jeanne Kaeding, who taught me the difference between labwork and bookwork. I will always be deeply indebted to Dr. (Professor) Mike Detty for his chemistry lessons, friendship, and advice, and I hope we have the chance to work together again. The experience I gained while working with Dr. Doug Bugner will always stand out as some of the most valuable: in particular, his early confidence that I could handle much more responsibility than I'm sure I had earned. At the University of Illinois, I was fortunate to have the opportunity to work with a model scientist and academician: Professor Scott Denmark. I couldn't have been given a better undergraduate project, nor could I have asked for a better balance of guidance and freedom. My collaboration with Dr. David Forbes led to some of the most productive 12-hour days (and 12-ounce curls) I've ever known. I will always be grateful to my thesis advisor, Professor Greg Fu, for allowing me to help start up his lab and his projects, and I expect to hear lots of great chemistry from him over the course of what will certainly be a long academic career. My blood brothers and sisters (fellow Fu group pioneers Chris Garrett, Diego Hoic, Mike Amendola, and Matthias Scholl) deserve a recognition which couldn't be accommodated between the covers of this Thesis. I hope that my future coworkers are as talented, honest, dedicated, responsible, trustworthy, and open to discussion as they have been, as well as the remaining Fu group members: Shuang Qiao, Adam Littke, Dr. Ken Stockman, Dr. Jordi Tormo, Dr. Rosa Lopez, Jack Liang, Dr. Hallie Latham, Beata Tao, and Michael Lo. My parents have always served as an endless source of inspiration, and I only hope I can do the same for my own children. They, as well as Jack and Phoebe Harden, helped to make the last 5 years a success. And finally my wife Jennifer, the most natural and capable mother on the planet, who earned this degree as much as I did. It would not have been possible without her unconditional optimism and support. She, along with our children Samuel and Brooke, taught me everything that is important. DEDICATION To my beautiful wife Jennifer, and to our spectacularchildren Samuel, Brooke, and those not yet conceived. PREFACE Parts of this thesis have been adapted from the following articles co-written by the author. Hays, D. S.; Fu, G. C. "Metal Hydride Mediated Intramolecular Pinacol Coupling of Dialdehydes and Ketoaldehydes," J. Am. Chem. Soc. 1995, 117, 7283-7284. Hays, D. S.; Fu, G. C. "Organotin Hydride Catalyzed Carbon-Carbon Bond Formation: Radical-Mediated Reductive Cyclization of Enals and Enones," J. Org. Chem. 1996, 61, 4-5. Hays, D. S.; Scholl, M.; Fu, G. C. "Organotin Hydride-Catalyzed Conjugate Reduction of a,x,-Unsaturated Ketones," J. Org. Chem. 1996, 61, 6751-6752. Lopez, R. M.; Hays, D. S.; Fu, G. C. "Bu 3 SnH-Catalyzed Barton-McCombie Deoxygenation of Alcohols," J. Am. Chem. Soc. 1997, 119, 6949-6950. Hays, D. S.; Fu, G. C. "A New Method for Generating Sn-H Bonds: Reactions of Tin Amides with Silicon Hydrides," J. Org. Chem. 1997, 62, 7070-7071. Tormo, J.; Hays, D. S.; Fu, G. C. "Diastereoselective Synthesis of P-Amino Alcohols via Bu 3 SnH-Mediated Reductive Cyclization of Carbonyl-Oxime Ethers," J. Org. Chem. 1998, 63, 201-202. Hays, D. S.; Fu, G. C. "The Development of Bu 3 SnH-Catalyzed Processes: Efficient Reduction of Azides to Amines," J. Org. Chem., 1998, 63, 2796-2797. TABLE OF CONTENTS ABBREVIATIONS INTRODUCTION CHAPTER 1. Bu 3SnH-MEDIATED INTRAMOLECULAR PINACOL COUPLING OF DIALDEHYDES AND KETOALDEHYDES Background Results and Discussion Experimental References CHAPTER 2. DEVELOPMENT OF ORGANOTIN HYDRIDE- CATALYZED PROCESSES I. SYNTHETIC TRANSFORMATIONS INVOLVING Sn-O INTERMEDIATES Part 2.1 Introduction Part 2.2 Organotin Hydride Catalyzed Carbon-Carbon Bond Formation: Radical-Mediated Reductive Cyclization of Enals and Enones Background Results and Dicussion Experimental Part 2.3 Discovery and Optimization of the Bu3SnH-Catalyzed Barton-McCombie Deoxygenation of Alcohols Background Results and Discussion Experimental 104 Part 2.4 References 108 CHAPTER 3. DEVELOPMENT OF ORGANOTIN HYDRIDE- CATALYZED PROCESSES II. SYNTHETIC TRANSFORMATIONS INVOLVING Sn-N INTERMEDIATES 111 Part 3.1 Introduction 112 Part 3.2 A New Method for Generating Sn-H Bonds: Reactions of Tin Amides with Silicon Hydrides 114 Background 114 Results and Discussion 116 Experimental 123 Part 3.3 Bu3SnH-Catalyzed, Silicon Hydride-Mediated Reduction of Azides to Amines 146 Background 146 Results and Discussion 146 Experimental 155 Part 3.4 Organotin-Catalyzed, Silicon Hydride-Mediated Room Temperature Reduction of Azides to Amines 174 Background 174 Results and Discussion 176 Experimental 179 Part 3.5 References 184 APPENDIX 186 ABBREVIATIONS ACHN 1,1'-Azobis(cyclohexnanecarbonitrile) AIBN 2,2'-Azobisisobutyronitrile d doublet DBATO bis(dibutylacetoxytin) oxide eq equation equiv equivalent(s) GC gas chromatography h hour(s) HRMS high resolution mass spectroscopy IR infrared min minute(s) NMR nuclear magnetic resonance PMHS polymethylhydrosiloxane PMHS dimer 1,3-bis(trimethylsiloxy)-1,3-dimethyldisiloxane ppm parts per million q quartet quint quintet r.t. room temperature s singlet t triplet THF tetrahydrofuran TLC thin-layer chromatography Introduction Over the last 30-40 years, organotin reagents have become indispensible tools for synthetic organic chemists.1 Their utility can largely be attributed to the unmatched ability with which organotin species participate in radical chain reactions, thus carving out a niche distinct from polar chemistry. As a consequence, modes of reactivity which cannot be accessed in the polar realm are readily available in a mild, neutral, often chemo- and stereoselective manner 2 by using organotin reagents. As a testimony to the synthetic utility of organotin reagents, chemists continue to widely use them despite two significant drawbacks: toxicity3-5 and difficulty in removal of organotin residues from crude reaction mixtures.6 Both of these issues could be addressed by a protocol which requires less than stoichiometric quantities of the organotin reagent.7-10 Thus, the development of organotin catalysis is the central focus of this thesis. The development of a new catalytic cycle can be envisioned as occurring in three stages. In the first stage, a mechanism for catalysis must be proposed.