Advances in Palladium and Nickel Catalyzed Cross-Coupling Reactions by Ryan S. Sawatzky Submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Dalhousie University Halifax, Nova Scotia December, 2017 © Copyright by Ryan S. Sawatzky, 2017 Table of Contents List of Tables .......................................................................................................................v List of Figures .................................................................................................................... vi List of Schemes ................................................................................................................. vii Abstract .............................................................................................................................. ix List of Abbreviations and Symbols Used ............................................................................x Acknowledgements .......................................................................................................... xiv Chapter 1 Introduction .........................................................................................................1 1.1 Introduction to Catalysis ...................................................................................... 1 1.1.1 Homogeneous versus Heterogeneous Catalysis............................................ 2 1.2 Modern Homogeneous Transition Metal Catalysis .............................................. 3 1.2.1 General Mechanism of Palladium Catalyzed Reactions and Ligand Effects 4 1.3 Overview of Thesis Research ............................................................................... 6 Chapter 2 Palladium Catalyzed C-O Coupling at Room Temperature ................................8 2.1 Background: Formation of Alkyl Aryl Ethers Using Aliphatic Alcohols ................. 8 2.2 Palladium Catalyzed C-O Cross-Coupling Using Aliphatic Alcohols...................... 9 2.3 Results and Discussion ............................................................................................ 13 2.4 Summary ................................................................................................................. 18 2.5 Experimental ........................................................................................................... 18 2.5.1 General Considerations..................................................................................... 18 2.5.2 General Procedures ........................................................................................... 19 2.5.3 Characterization Data for Isolated Materials .................................................... 23 Chapter 3 Microwave-Assisted Nickel-Catalyzed Synthesis of Aryl Amines from Aryl Halides and Ammonium Salts ...........................................................................................28 3.1 Buchwald-Hartwig Amination (BHA) ............................................................... 28 3.1.1 Catalytic Mechanism of Buchwald-Hartwig Amination ............................ 29 3.1.2 Buchwald-Hartwig Amination using Ammonia ......................................... 32 3.2 Development of First Row Transition Metal Catalysts ...................................... 32 3.2.1 Nickel Catalyzed Amination Reactions ...................................................... 36 ii 3.3 Microwave-Assisted Catalysis ........................................................................... 39 3.3.1 Microwave Effects ...................................................................................... 40 3.4 Results and Discussion ....................................................................................... 43 3.5 Results and Discussion ............................................................................................ 48 3.6 Summary ................................................................................................................. 52 3.7 Experimental ........................................................................................................... 53 3.7.1 General Considerations..................................................................................... 53 3.7.2 General Procedure ............................................................................................ 54 3.3.2 Characterization Data for Isolated Materials .................................................... 58 Chapter 4 Nickel-Catalyzed Cross-coupling of Secondary Amines/Azoles Using a Wide Bite Angle Ligand ..............................................................................................................66 4.1 Utility of Wide Bite Angle Ligands in Transition Metal Catalysis ........................ 66 4.1.1 Proposed Application to Nickel-Catalyzed C-N Cross-Coupling .................... 70 4.2 Results and Discussion ............................................................................................ 71 4.3 Summary ................................................................................................................. 78 4.4 Experimental ........................................................................................................... 78 4.4.1 General Considerations..................................................................................... 78 4.4.2 General Procedures ........................................................................................... 79 4.4.3 Characterization of Isolated Materials ................................................................. 82 Chapter 5 (DPEphos)Ni(mesityl)Br: An Air-Stable Pre-Catalyst for Suzuki-Miyaura Cross-Couplings Yielding Biheteroaryls ...........................................................................89 5.1 Nickel catalyzed Suzuki-Miyaura Cross-Coupling Reactions ................................ 89 5.2 Results and Discussion ............................................................................................ 91 5.3 Summary ................................................................................................................. 98 5.4 Experimental ........................................................................................................... 99 5.4.1 General Considerations..................................................................................... 99 5.4.2 General Procedures ......................................................................................... 100 5.4.3 Characterization of isolated products ................................................................. 101 Chapter 6 Conclusions and Future Work .........................................................................114 6.1 Chapter 2: Palladium Catalyzed C-O Cross-Coupling .......................................... 114 6.2 Chapter 3: Microwave Assisted Monoarylation of Ammonium Salts .................. 115 6.3 Chapter 4: Wide Bite Angle Ligands in Nickel-Catalyzed C-N Cross-Coupling . 116 iii 6.4 Chapter 5: Suzuki-Miyaura Cross-Coupling using (DPEphos)Ni(mesityl)Br ...... 116 References ........................................................................................................................118 Appendix ........................................................................................................................... A1 Chapter 2 Characterization Data .................................................................................. A1 Chapter 3 Characterization Data ................................................................................ A13 Chapter 4 Characterization Data ................................................................................ A32 Chapter 5 Characterization Data ................................................................................ A64 iv List of Tables Table 2-1: (Hetero)aryl halide scope with optimal ligand reported……….…….………14 Table 2-2: Alcohol scope with optimal ligand reported……………...…..……………..16 Table 2-3: Examples of C-O coupling with structurally diverse mesylates……….……17 Table 3-1: Select examples of bisphosphines used in cobalt catalyzed asymmetric hydrogenation of alkenes…………….…..…………………….……………34 Table 3-2: Examples of copper catalyzed asymmetric hydroamination………..……….35 Table 3-3: Select examples of nickel-catalyzed amination of aryl chlorides…….……..37 Table 3-4: Ligand complex C3-3 used by Hartwig and examples of nickel-catalyzed ammonia monoarylation……………………………………………….39 Table 3-5: Scope of nickel catalyzed ammonia monoarylation using ammonium acetate under microwave conditions……………………………………………………..50 Table 3-6: Nickel catalyzed aminations using MeNH3Cl and EtNH3Cl using microwave heating……………………………………………….………………………51 Table 4-1: Ligand screen for nickel catalyzed C-N cross-coupling………………………73 Table 4-2: Scope of C(sp2)-N cross-coupling using C4-1……………………………….76 Table 5-1: Optimization of Conditions and Pre-Catalyst Screening……………………..93 Table 5-2: Suzuki-Miyaura Cross-Couplings Using C4-1……………………………….94 Table 5-3: Optimization of Conditions for Pyridinyl Boronic Acids Using C4-1………..96 Table 5-4: Suzuki-Miyaura Cross-couplings of Pyridinyl Boronic Acids Using C4-1…..98 v List of Figures Figure 1-1: General mechanisms for the Suzuki and Heck reactions………………….…5 Figure 2-1: Examples of drugs containing the aryl alkyl ether moiety……………………9 Figure 2-2: General palladium catalyzed C-O cross-coupling mechanism and some useful ligands used in such reactions……….…………………………………………….10 Figure 2-3: Ligands used in catalytic screening for palladium-catalyzed