Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2014 Selective Additions to Unsaturated Carbon- Carbon Bonds by the Use of N-Heterocyclic Carbene-Copper(I) Catalysts Brian A. Ondrusek Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES SELECTIVE ADDITIONS TO UNSATURATED CARBON-CARBON BONDS BY THE USE OF N-HETEROCYCLIC CARBENE-COPPER(I) CATALYSTS By BRIAN A. ONDRUSEK A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Summer Semester, 2014 Brian Ondrusek defended this dissertation on July 1st, 2014. The members of his supervisory committee were: D. Tyler McQuade Professor Directing Dissertation Bruce Locke University Representative Michael Roper Committee Member Gregory Dudley Committee Member Igor Alabugin Committee member The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements. ii I dedicate this effort to my family, without whose support I could never have accomplished all that I have. iii ACKNOWLEDGMENTS I would like to acknowledge Dr. Tyler McQuade for taking a very green graduate student and whipping me into shape. I’m sure that at times it was no easier for him than it was for myself, but his constant support has enabled me to develop as I have into a more mature scientist. He was always willing to help me understand concepts with which I was struggling, and he was always willing to allow me to explore topics in which I was interested. I also would like to acknowledge my fellow members of the McQuade group, especially Dr. Suzie Opalka, Dr. Jin Kyoon Park, Ashley Longstreet, Tania Houjiery, Emily Montgomery and Hershel Lackey for always being available to talk though whatever bit of chemistry that was not working at the time. Lastly, I want to extend a special thank you to all of my friends and family both in Tallahassee and in Pittsburgh for providing moral support when I needed it the most. iv TABLE OF CONTENTS List of Tables…………………………………………………………………………… ............ .ix List of Figures……………………………………………………………………………… ..........x Abstract……………………………………………………………………………… ............... xvii 1. INTRODUCTION ......................................................………………………………………1 1.1 Layman’s Introduction ...................................................................................................1 1.2 Alkene Functionalization in Organic Chemistry………………………………………2 1.3 N-Heterocyclic Carbenes as Useful Ligands for Cu(I) Catalysts ……………………..γ 1.3.1 Synthesis of Phosphine and NHC Ligands ................…………………………4 1.3.2 Steric and Electronic Properties of NHCs .........................................................5 1.4 Allylic Substitution ........................................................................................................7 1.5 Addition Reactions to Strained Alkenes………………………………………………9 1.6 Regioselective Functionalizations of Alkynes .............................................................11 2. A STEREOCONVERGENT SYNTHESIS OF CHIRAL ALLYLBORONATES VIA ASYMMETRIC ALLYLIC SUBSTITUTION ....................................................................13 2.1 Background…………………………………………………………………………..13 2.2 Initial Studies and Optimization ..................................................................................15 2.2.1 Optimization Studies ......................................................................................16 2.2.1.1 Catalyst Comparison for Allylic Susbsitution ....................................16 2.2.1.2 Leaving Group Optimization for Allylic Substitution .......................17 2.2.2 Mechanistic Considerations for Stereoconvergence ......................................18 2.3 Substrate Synthesis and Reaction Scope......................................................................22 v 2.4 Conclusions ..................................................................................................................25 3. REACTIVITY OF A FUSED N-HETEROCYCLIC CARBENE-COPPER(I) SYSTEM TOWARD STRAINED AND STYRENIC ALKENES .......................................................27 3.1 Background ..................................................................................................................27 3.2 Preparation of the Cu(I)-NHC Complex ......................................................................28 3.3 Optimization Studies and the Role of Methanol ..........................................................30 3.4 Reaction Scope.............................................................................................................33 3.5 Conclusions ..................................................................................................................35 4. REGIOSELECTIVE CATALYTIC HYDROBORATIONS OF PROPARGYLIC SPECIES USING COPPER(I)-NHC COMPLEXES ............................................................................37 4.1 Background ..................................................................................................................37 4.2 Selectivity and Protection Group Studies ....................................................................39 4.2.1 Initial Experiments .........................................................................................39 4.2.2 Screen of O-Protection Groups and Incorporation of a 5-NHC .....................40 4.3 Substrate Screen ...........................................................................................................43 4.3.1 Regioselectivity of Hydroborations Performed with 6-NHC (1b) ................ 43 4.3.2 Regioselectivity of Hydroborations Performed with 5-NHC (2) .................. 46 4.4 Regioselectivity Experiments and Rationale ...............................................................49 4.5 Conclusions ..................................................................................................................51 5. PREPARATION OF TERTIARY ALLYLBORONATES FROM VINYLBORONATES VIA “ATE-MEDIATED ALLYLIC SUBSTITUTION” (AMAS) ......................................52 5.1 Background ..................................................................................................................52 5.2 Optimization Studies ....................................................................................................54 vi 5.3 Nucleophile Scope .......................................................................................................56 5.4 Representative AMAS Substrates ................................................................................58 5.5 Conclusions ..................................................................................................................60 6. SYNTHESIS OF METHYL AXENOSIDE AND METHYL 3-EPI-AXENOSIDE VIA ATE-MEDIATED ALLYLIC SUBSTITUTION (AMAS)..................................................62 6.1 Background ..................................................................................................................62 6.2 Retrosynthetic Analysis ...............................................................................................64 6.3 Synthesis: Part 1 ...........................................................................................................65 6.4 Asymmetric Dihydroxylation ......................................................................................68 6.4.1 Performing the AD-Reaction ..........................................................................68 6.4.2 Establishing Dihydroxylation Enantioselectivity ...........................................69 6.5 Synthesis: Part 2 ...........................................................................................................73 6.6 Synthesis of Methyl 3-epi-Axenoside ..........................................................................76 6.7 Conclusions ..................................................................................................................77 APPENDIX A: SUPPORTING INFORMATION FOR CHAPTER 2 .........................................79 A.1 Characterization Data...................................................................................................79 A.2 Spectral Data ..............................................................................................................102 APPENDIX B: SUPPORTING INFORMATION FOR CHAPTER 3 .......................................137 B.1 Characterization Data.................................................................................................137 B.2 Spectral Data ..............................................................................................................146 APPENDIX C: SUPPORTING INFORMATION FOR CHAPTER 4 .......................................152 C.1 Characterization Data.................................................................................................152 C.2 Spectral Data ..............................................................................................................177 vii APPENDIX D: SUPPORTING INFORMATION FOR CHAPTER 5 .......................................217 D.1 Characterization Data.................................................................................................217 D.2 Spectral Data ..............................................................................................................230