DEVELOPMENT OF NICKEL-CATALYZED CYCLOADDITION AND COUPLING REACTIONS by Ananda H. B. Herath-Mudiyansela A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in The University of Michigan 2008 Doctoral Committee: Professor John Montgomery, Chair Professor Edwin Vedejs Associate Professor Melanie S. Sanford Assistant Professor Jason E. Gestwicki To my mother Tikirimenike and my wife Shyama ii ACKNOWLEDGMENTS I would like to thank my advisor, Professor John Montgomery for his encouragement, guidance and financial support during my study at University of Michigan and Wayne State University. Many thanks to my wonderful colleagues in the Montgomery group, both present and past for their assistance and friendship. My special thanks goes to Dr. Minsoo Song for his assistance at the initial stage of my research work. I would like to thank Zachary Buchan and Dr. John Phillips for proofreading the manuscript of this dissertation and for all the valuable discussions about chemistry. I would also like to thank Wei Li and Benjamin Thompson for their contribution to my research work. I wish to extend my thanks to my committee members, Dr. Edwin Vedejs, Dr. Melanie S. Sanford and Dr. Jason E. Gestwicki for their time and attention in regards to my work. I wish to thank my former committee members Dr. Jin K. Cha and Dr. Dana Spence for their time and help given when I was at Wayne State University. My special thanks also goes to my friends, Ruchira, Irine, Chamani, Sandamali, Saroja and Apsara for their encouragement and support. iii I would like to extend my appreciation to Aiko Nakatani and Linda Deitert at University of Michigan and Sharon Kelly, Mary Wood and Debbie McCreless at Wayne State University for their excellent job, which has made my stay here easy and enjoyable. Finally, and most importantly I would like to thank my mother, Tikrimenike, my brothers Nalin and Dheera and my wife Shyama for their love, support, understanding and patience. iv TABLE OF CONTENTS DEDICATION………………………………………………………………………ii ACKNOWLEDGMENTS………………………………………………………….iii LIST OF TABLES………………………………………………………………….x LIST OF SCHEMES………………………………………………………………xii ABBREVIATIONS.........................................................................................xix ABSTRACT ..................................................................................................xxiv CHAPTERS CHAPTER 1 – NICKEL-CATALYZED [3+2] REDUCTIVE CYCLOADDITION OF ENALS AND ALKYNES 1.1 Introduction.............................................................................................1 1.1.1 [3+2] Cycloaddition ...........................................................................2 1.1.1.1 Anionic [3+2] Cycloaddition.........................................................3 1.1.1.2 Cationic [3+2] Cycloaddition........................................................4 1.1.1.3 Transition Metal Catalyzed [3+2] Cycloaddition ..........................6 v 1.1.1.4 Involvement of Dianionic and Dicationic Building Blocks in [3+2] Cycloaddition................................................................................14 1.1.2 [2+2+1] Cycloaddition .......................................................................16 1.1.3 [4+1] Cycloaddition ...........................................................................19 1.1.4 Nickel-Catalyzed Cyclization of Alkynyl Enones ...............................22 1.1.5 Nickel Catalyzed [3+2] Cycloaddition................................................27 1.2 Results and Discussion…………………………………………………….. 30 1.2.1 Development of a Catalytic Version of the [3+2] Cycloaddition…….30 1.2.2 Intermolecular Nickel Catalyzed [3+2] Cycloaddition of Alkynes and Enals…………………………………………………………………38 1.2.3 Effect of Ligand Structure on Product Distribution…………………...48 1.2.4 Unusual Regioselectivity with Alkynol…………………………………51 1.3 Summary……………………………………………………………………..54 CHAPTER 2 – NICKEL-CATALYZED INTERMOLECULAR REDUCTIVE COUPLING OF ENONES AND ALKYNES 2.1 Introduction ………………………………………………………………… 55 2.1.1 Conjugate Addition of Organocopper Reagents ..............................55 2.1.2 Conjugate Addition of Organozirconium Reagents………………….61 2.1.3 Transition Metal Catalyzed Coupling of Enones and Alkynes..........64 vi 2.1.4 Synthesis of Silyl Enol Ethers ..........................................................72 2.1.5 Nickel-Catalyzed Processes Involving Trialkylsilanes......................84 2.2 Results and Discussion ..........................................................................89 2.2.1 Nickel-Catalyzed Intermolecular Reductive Coupling of Alkynes and Enones........................................................................89 2.2.2 Summary of Reductive Coupling of Alkynes and Enones...............98 2.2.3 Nickel-Catalyzed Intermolecular Reductive Coupling of Alkynes and Enals ...........................................................................98 2.2.4 Summary of Reductive Coupling of Alkynes and Enals...................106 CHAPTER 3 – INTERMOLECULAR NICKEL-CATALYZED THREE- COMPONENT COUPLINGS VIA INTERNAL REDOX 3.1 Introduction.............................................................................................108 3.1.1 Organocatalyzed Internal Redox Reactions ...................................109 3.1.2 Transition Metal-Catalyzed Internal Redox Reactions....................114 3.1.2.1 Isomerization of Allylic Alcohols...............................................115 3.1.2.2 Cycloisomerization of Enynes..................................................117 3.1.2.3 Hydroacylation.........................................................................121 3.2 Carbenes................................................................................................129 vii 3.2.1 Nucleophilic Carbenes....................................................................130 3.2.2 N-Heterocyclic Carbenes vs. Phosphine ligands ............................131 3.3 Nickel-Catalyzed Reactions Involving N-Heterocyclic Carbenes ............134 3.4 Results and Discussion ..........................................................................137 3.4.1 Nickel-Catalyzed Three-Component Couplings of Alkynes, Enones and Aldehydes..................................................................137 3.4.2 Intermolecular Nickel-Catalyzed Three-Component Couplings via Internal Redox...........................................................................140 3.5 Summary ................................................................................................150 0BCHAPTER 4 – EXPERIMENTAL SECTION 4.1 Reaction Procedures and Spectral Data of Chapter 1............................152 4.1.1 General Procedure for the Ni(COD)2/DPEphos or DPPF Promoted [3+2] Cycloaddition of Enals and Alkynes .......................................153 4.1.2 General Procedure for the Ni(COD)2/PBu3 Promoted [3+2] Cycloaddition of Enals and Alkynes................................................159 4.2 Reaction Procedures and Spectral Data of Chapter 2............................175 4.2.1 General Procedure for the Ni(COD)2/PBu3 Promoted Reductive Coupling of Enones and Alkynes...................................................176 viii 4.2.2 General Procedure for the Ni(COD)2/PCy3 Promoted Reductive Coupling of Enals and Alkynes .....................................191 4.3 Reaction Procedures and Spectral Data of Chapter 3............................205 4.3.1 General Procedure for the Ni(COD)2/PBu3 Promoted Three- Component Coupling of Enones, Alkynes, and Aldehydes.............207 4.3.2 General Procedure for the Ni(COD)2/IPr Promoted Three- Component Coupling of Enones, Alkynes, and Aldehydes.............209 4.3.3 General Procedure for the Ni(COD)2/PCy3 Promoted Three- Component Coupling of Enones, Alkynes, and Aldehydes.............215 APPENDIX ...................................................................................................224 REFERENCES.............................................................................................312 ix LIST OF TABLES Table 1. Substrate Scope of [3+2] Cycloaddition..........................................27 Table 2. Optimization of Catalytic Version of the [3+2] Cycloaddition ..........32 Table 3. Scope of Ligands............................................................................33 Table 4. Substrate Scope with DPEphos......................................................34 Table 5. Substrate Scope with DPPF ...........................................................35 Table 6. The Influence of the Ligand Structure on the Enantioselectivity .....37 Table 7. Scope of Ligands for Intermolecular Version ..................................38 Table 8. Scope of Enals ...............................................................................40 Table 9. Scope of Alkynes............................................................................41 Table 10. Effect of Ligand Structure on Product Distribution ........................49 Table 11. Substrate Scope of Intramolecular Alkylative and Reductive Coupling ........................................................................................68 Table 12. Ligand Dependence on Product Distribution of the Crossover Reaction ........................................................................................87 Table 13. Intermolecular Crossover Reaction...............................................88 Table 14. Scope of Enones ..........................................................................92