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Armstrong Washington 0250E © Copyright 2021 Megan Armstrong New Transformations in the Transition-Metal Catalyzed Hydrofunctionalization of Alkynes Megan Armstrong A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2021 Reading Committee: Gojko Lalic, Chair Forrest Michael Alshakim Nelson Program Authorized to Offer Degree: Chemistry University of Washington Abstract New Transformations in the Transition Metal-Catalyzed Hydrofunctionalization of Alkynes Megan Armstrong Chair of the Supervisory Committee: Professor Gojko Lalic Department of Chemistry Hydrofunctionalization reactions are very useful transformations of unsaturated compounds and their development has been a major focus of research in the field of transition metal catalysis. These reactions allow the rapid build up of molecular complexity of simple substrates in a single transformation and recently significant progress has been made in the development of regio-, stereo- and enantioselective hydrofunctionalizations. Here we describe the development of three reactions involving transition metal-catalyzed hydrofunctionalization. The first is the hydroallylation of alkynes furnishing skipped dienes. Regioselective hydroallylation of nonsymmetrical internal alkynes was achieved through the installation of polar functional group in the propargylic position. This resulted in inductive polarization of the alkyne π bond allowed for the regioselective synthesis of trisubstituted alkenes. The second reaction described is the diastereodivergent hydroarylation of alkynes. Both Z- and E-styrenes are accessed from one set of starting materials using synergistic Cu/Pd catalysis. The reaction proceeds through tandem Sonogashira cross-coupling followed by Z-selective semireduction and isomerization, where the diastereoselectivity is determined by the stoichiometry of a methanol additive. The last reaction describes the reductive three-component coupling of terminal alkynes, aryl halides and pinacolborane using synergistic Cu/Pd catalysis. Copper-catalyzed hydroboration followed by hydrocupration generates a key heterobimetallic complex, subsequent palladium-catalyzed cross- coupling with aryl halides provides benzylic alkyl boronates. Investigation of other electrophiles and enantioselective variants is currently underway. TABLE OF CONTENTS List of Abbreviations ....................................................................................................................... i List of Figures ................................................................................................................................ vi List of Schemes ............................................................................................................................. vii List of Tables ................................................................................................................................. ix Acknowledgments .......................................................................................................................... xi Chapter 1. Catalytic Anti-Markovnikov Hydroallylation of Terminal and Functionalized Internal Alkynes: Synthesis of Skipped Dienes and Trisubstituted Alkenes ............................................... 1 1.1 Introduction ..................................................................................................................... 1 1.2 Hydroallylation of Internal Alkynes ............................................................................... 2 1.3 Mechanism of Hydroallylation ....................................................................................... 3 1.3.1 Proposed Mechanism .................................................................................................. 3 1.3.2 Stoichiometric Hydrocupration of Internal Alkynes ................................................... 4 1.3.3 Allylation and Alkylation of Alkenyl Copper Complex ............................................. 5 1.4 Conclusion ...................................................................................................................... 6 1.5 Experimental ................................................................................................................... 6 1.5.1 General Information .................................................................................................... 6 1.5.2 General Procedure for the Hydroallylation of Alkynes .............................................. 7 1.5.3 Characterization of Trisubstituted Alkenes (Table 1.1) .............................................. 8 1.5.4 Alkyne Starting Materials ......................................................................................... 10 1.5.5 Stoichiometric Reaction of Copper Hydride with Internal Alkynes ......................... 13 1.5.6 Stoichiometric Reaction of OTBS-Substituted Alkenyl Copper (1.8) with Allyl Phosphate (1.10) and Alkyl Triflate (1.11) (Scheme 1.5) ..................................................... 15 1.5.7 X-Ray Crystallography Data Tables ......................................................................... 16 1.6 References ..................................................................................................................... 21 Chapter 2. Diastereodivergent Reductive Cross Coupling of Alkynes Through Tandem Catalysis: Z- and E-Selective Hydroarylation of Terminal Alkynes ............................................................. 23 2.1 Introduction ................................................................................................................... 23 2.2 Reaction Development: Z-Selective Hydroarylation of Terminal Alkynes .................. 27 2.3 Substrate Scope: Z-Selective Hydroarylation ............................................................... 30 2.4 Reaction Development: E-Selective Hydroarylation of Terminal Alkynes ................. 33 2.5 Substrate Scope: E-Selective Hydroarylation ............................................................... 35 2.6 Mechanistic Studies ...................................................................................................... 37 2.6.1 Proposed Mechanism: Z-Selective Hydroarylation .................................................. 37 2.6.2 Role of Pd and Cu Catalysts in the Z-Selective Semireduction ................................ 37 2.6.3 Effect of MeOH on Z-Selective Semireduction ........................................................ 38 2.6.4 i-BuOH in Semireduction ......................................................................................... 40 2.6.5 Role of Pd and Cu Catalysts in the E-Selective Hydroarylation .............................. 40 2.6.6 Palladium-Catalyzed Alkene Isomerization ............................................................. 41 2.7 Conclusion .................................................................................................................... 43 2.8 Experimental ................................................................................................................. 44 2.8.1 General Information .................................................................................................. 44 2.8.2 Reaction Development (Table 2.1) ........................................................................... 45 2.8.3 Standard Sonogashira Coupling Followed by Semireduction .................................. 47 2.8.4 General Procedure for the Hydroarylation of Terminal Alkynes: Synthesis of Z- Styrenes (Table 2.2) .............................................................................................................. 48 2.8.5 Characterization of Hydroarylation Products: Z-Styrenes (Table 2.2) ..................... 49 2.8.6 Gram Scale Reaction ................................................................................................. 70 2.8.7 Selectivity Studies (Table 2.3) .................................................................................. 70 2.8.8 Optimization of E-Selective Hydroarylation (Table 2.4) ......................................... 71 2.8.9 General Procedure for the Hydroarylation of Terminal Alkynes: Synthesis of E- Styrenes (Table 2.5) .............................................................................................................. 72 2.8.10 Characterization of Hydroarylation Products: E-Styrenes (Table 2.5) ................. 73 2.8.11 Alkyne Starting Materials ..................................................................................... 86 2.8.12 Aryl Bromide Starting Materials .......................................................................... 89 2.8.13 Synthesis of Internal Alkyne Intermediate ........................................................... 92 2.8.14 Mechanistic Studies: Semireduction ..................................................................... 93 2.8.15 Effect of MeOH Stoichiometry on Copper Catalyzed Semireduction ................ 106 2.8.16 Mechanistic Studies: Isomerization (Scheme 2.9) .............................................. 107 2.8.17 Mechanistic Studies: Deuterium Labeling (Scheme 2.10) ................................. 110 2.9 References ................................................................................................................... 112 Chapter 3. Differential Dihydrofunctionalization of Terminal Alkynes: Synthesis of Benzylic Alkyl Boronates Through Reductive Three-Component Coupling ............................................ 117 3.1 Introduction
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