Palladium Catalyzed Suzuki-Miyaura Cross-Coupling of Axially Chiral Biaryls THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By William D. Andert Graduate Program in Chemistry The Ohio State University 2013 Master's Examination Committee: Professor T. V. RajanBabu, Advisor Professor Jon R. Parquette Copyright by William D. Andert 2013 ABSTRACT Cross-coupling reactions have been of interest to organic chemists much of the past century. It has only been in the last half century that prominent advances have been discovered, all of which take advantage of organometallic chemistry. The most widely explored reactions use palladium or nickel complexes to promote the cross-coupling of a wide variety of functionalized aryl groups. One such reaction is the Suzuki-Miyaura cross-coupling, which is a transition-metal mediated coupling of an organohalide and an organoborane. As a carbon-carbon bond forming reaction, the Suzuki-Miyaura cross- coupling has great potential in synthetic applications due to its mild conditions and functional group tolerance. An important aspect of the reaction is the ability to impart specific configurations during the formation of new carbon-carbon bonds. Such selectivity has been thoroughly explored in the Suzuki-Miyaura cross-coupling of sp2-sp2 carbon-carbon bonds with the retention of E or Z stereochemistry. However, the formation of axially chiral biaryls still presents an ongoing challenge. Biaryls containing at least three substituents ortho to the aryl-aryl bond exhibit atropisomerism, which gives rise to axial chirality. Thus, the application of asymmetric catalysis to the formation of axial chiral biaryls was of interest. The work presented in this thesis investigates the synthesis of several chiral ligands for use in cross-coupling reactions and a study of the Suzuki-Miyaura cross-coupling of biaryls. ii DEDICATION Dedicated to my parents Tom and Sandy Andert iii ACKNOWLEDGMENTS First, I would like to thank my advisor Dr. T. V. RajanBabu for giving me the opportunity to do research in his lab. His enthusiasm for teaching and research has helped me become a better chemist. I also want to thank all of the professors at Ohio State with whom I had the opportunity to learn and teach. I would like to thank the members of the RajanBabu group that I have had the pleasure of working with while at Ohio State. I would especially like to thank Dr. Ramakrishna Singidi for all of his guidance when I first joined the laboratory and Dr. Jordan Page for his help throughout my research. Another individual I want to acknowledge is Dr. Andrew French at Albion College, who originally fostered my interest in organic chemistry and suggested I pursue a graduate degree. I want to thank my family for all of their support. My parents have always encouraged me in everything I have done, and their support during my time in graduate school was no exception. Lastly, I want to acknowledge my wife, Carmen. All the support she has given has helped me get through one of the biggest challenges in my life to date. iv VITA April 10, 1987 .................................................................................. Born – Kalamazoo, MI May 2009 ..................................................................................................... B.A. Chemistry Albion College 2009-2013 ............................................................................................. Teaching Associate The Ohio State University FIELDS OF STUDY Major Field: Chemistry v TABLE OF CONTENTS Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iii Acknowledgments.............................................................................................................. iv Vita ................................................................................................................................. v Fields of Study .................................................................................................................... v Table of Contents ............................................................................................................... vi List of Schemes .................................................................................................................. ix List of Tables ...................................................................................................................... x List of Figures .................................................................................................................... xi List of Abbreviations ........................................................................................................ xii Chapter 1: Development of Cross-Coupling Reactions and the Synthesis of Axially Chiral Biaryl Compounds ....................................................................................... 1 1.1 Background and Significance ....................................................................................... 1 1.2 Axial Chirality in Natural Product Synthesis................................................................ 3 1.3 Development of Coupling Reactions ............................................................................ 5 1.3.1 Ullmann Coupling .......................................................................................... 7 vi 1.3.2 Kumada Cross-Coupling ................................................................................ 9 1.3.3 Suzuki-Miyaura Cross-Coupling ................................................................. 11 1.4 Investigation of Biaryl Synthesis by Cross-Coupling Reactions ................................ 16 1.4.1 Cross-Coupling Reactions using Pd Catalysts ............................................. 18 1.4.2 Cross-Coupling Reactions using Ni Catalysts ............................................. 24 1.5 Conclusions ................................................................................................................. 26 Chapter 2: Palladium Catalyzed Asymmetric Suzuki-Miyaura Cross Coupling Reactions of Biaryl Compounds ............................................................................................ 27 2.1 Background and Significance ..................................................................................... 27 2.2 Chiral Ligands for Cross-Coupling Reactions ............................................................ 28 2.3 Cross-Coupling Reactions of Biaryls.......................................................................... 38 2.3.1 Preparation of Cross-Coupling Precursors................................................... 38 2.3.2 Cross-Coupling Reactions with S-Phos Ligands ......................................... 41 2.3.3 Cross-Coupling Reactions with Chiral Ligands .......................................... 43 2.4 Conclusions ................................................................................................................. 45 2.5 Experimental Procedures ............................................................................................ 45 2.5.1 General Methods .......................................................................................... 45 2.5.2 Synthesis of Chiral Pyridinooxazoline (PyOX) Ligand............................... 46 2.5.3 Synthesis of Chiral Bicyclic Sulfoxide-Alkene Ligand ............................... 48 vii 2.5.4 Synthesis of Chiral Aryl Sulfoxide-Alkene Ligand ..................................... 54 2.5.5 Synthesis of Cross-Coupling Reagents ........................................................ 56 Bibliography ..................................................................................................................... 61 Appendices ........................................................................................................................ 67 Appendix A: 1H and 13C NMR Spectra ............................................................................ 67 Appendix B: HPLC Chromatograms ................................................................................ 94 viii LIST OF SCHEMES Scheme 1.1. Ullmann Coupling in the Synthesis of Ellagitannins ........................ 9 Scheme 1.2. Catalytic Cycle of the Kumada Coupling ....................................... 11 Scheme 1.3. Proposed Catalytic Cycles for Suzuki-Miyaura Cross-Coupling .... 13 Scheme 1.4. Cross-Coupling in the Synthesis of Palytoxin Carboxylic Acid ..... 16 Scheme 2.1. Synthesis of Pyridyl Oxazoline (PyOX) Ligand ............................. 30 Scheme 2.2. Synthesis of Bicyclic Ketone .......................................................... 31 Scheme 2.3. Synthesis of Bicyclic Alkene .......................................................... 34 Scheme 2.4. Synthesis of Alkene in Aryl Sulfoxide-Alkene Ligand .................. 37 Scheme 2.5. Synthesis of Naphthalene Sulfoxide ............................................... 38 ix LIST OF TABLES Table 1.1. History of Coupling Reactions ............................................................. 6 Table 2.1. Preparation of Grignard Reagents for Addition to Ketones ............... 33 Table 2.2. Results of Cross-Coupling Optimization ............................................ 42 Table 2.3. Results of Chiral Cross-Coupling ......................................................