Nickel Catalyzed Regioselective Reductive Coupling Reactions A Dissertation Submitted to the Graduate School of the University of Cincinnati in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY (Ph. D.) In the Department of Chemistry of McMicken College of Arts and Sciences by Sanjeewa Kumara Rodrigo Bachelor of Science (B. Sc.), Chemistry Faculty of Science, University of Peradeniya, Sri Lanka, 2007 Dissertation Advisor: Hairong Guan, Ph. D. Nickel Catalyzed Regioselective Reductive Coupling Reactions ABSTRACT Coupling or cycloaddition of two different π-components for the construction of more complex structural motifs is commonly used in organic synthesis. Most of these systems involve a transition metal based catalyst and for reductive coupling reactions, various reducing agents are also employed. This dissertation is focused on the development and mechanistic investigation of nickel-catalyzed reductive coupling processes for useful organic transformations, specifically the coupling of aldehydes and alkynes and the cyclotrimerization of alkynes. Ni(COD)2 combined with an N-heterocyclic carbene (NHC) ligand catalyzes the reductive coupling of ynoates and aldehydes to give 1,4-difuntioalized products. This particular catalytic system shows broad substrate scope and high regioselectivity. To accomplish this transformation, a silane has been used as the reducing agent and PPh3 has been added to extend the lifetime of the nickel catalyst. For this newly developed multicomponent coupling reactions, more than a dozen invaluable silyl-protected γ-hydroxy-α,β-enoates have been synthesized. This methodology also provides a quick entry to many other 1,4-difunctional compounds and oxygen- containing five-membered rings. The mechanistic studies on nickel-catalyzed and silane-mediated reductive coupling of ynoates and aldehydes have been carried out. Kinetics data, deuterium-labeling studies, and kinetic isotope effect are consistent with a reaction pathway involving a rate-determining oxidative cyclization to form a metallacycle intermediate, followed by fast silane-facilitated release of the final product. Inverse first-order dependence of rate on [ynoate] indicates that the alkyne component binds to the nickel center first. An initial oxidative addition of the Si-H bond ii to nickel followed by the sequential insertion of the substrates can be ruled out based on these data. An effective nickel system, Ni(COD)2/PPh3 or Ni(COD)2/NHC (NHC = an N- heterocyclic carbene) has been also found to catalyze cyclotrimerization of ynoates and related alkynes. This methodology provides access to a diverse array of tri- or hexa-substituted benzene derivatives in an efficient and highly regioselective manner. This system provides several advantages. First of all, catalysts can be easily generated in situ by mixing commercially available reagents. More importantly, the catalytic process is quite efficient; turnover numbers as high as 2,000 is the highest for any transition-metal-catalyzed cyclotrimerization reaction, allowing the synthesis to be carried out on the gram scale. Moreover, the observed regioselectivity is typically high and in a number of cases only one regioisomer is formed. iii iv Nickel Catalyzed Regioselective Reductive Coupling Reactions TABLE OF CONTENTS Chapter 1: Introduction 1.1 Nickel-Catalyzed Reductive Coupling Reactions 2 1.2 Cyclotrimerization of Alkynes 6 1.3 Research Objectives 10 Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to Access 1,4-Difunctionality 2.1 Introduction 12 2.2 Plan for the Synthesis 13 2.3 Nickel-Catalyzed Reductive Coupling of an Ynoate and an Aldehyde 15 2.4 Optimization of the Reaction Conditions 17 2.5 Control Experiments 19 2.6 Substrate Scope 19 2.7 Origin of the Regioselectivity 22 2.8 Synthetic Applications 24 2.9 Conclusions 25 2.10 Experimental 25 Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes 3.1 Introduction 44 3.2 General Mechanistic Consideration 47 3.3 Previous Mechanistic Studies on Nickel-Catalyzed Reductive Coupling of Alkynes and Aldehydes 49 v 3.4 Mechanistic Studies of the Coupling of Ynoates and Aldehydes 56 3.4.1 Mechanistic Hypothesis 56 3.4.2 Deuterium Labeling Studies 58 3.4.3 Kinetics Studies of a Related System Reported by Montgomery 59 3.4.4 Screening Conditions for the Kinetics Study 60 3.4.5 Kinetics Experiments 64 3.4.6 Kinetic Isotope Effect 69 3.4.7 Kinetics Model 70 3.5 Conclusions 71 3.6 Experimental 71 Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes 4.1 Introduction 90 4.2 Optimization of the Reaction Conditions 92 4.3 Substrate Scope 95 4.4 Large Scale Synthesis of 1,2,4-C6H3(CO2Me)3 100 4.5 Mechanism and Regioselectivity 101 4.6 Conclusions 104 4.7 Experimental 104 Appendix 1: Asymmetric Reductive Coupling of Ynoates and Aldehydes A1.1 Introduction 116 A1.2 Synthesis and Application of Chiral NHC Ligands 118 vi A1.3 Determination of Enatiomeric Ratios 121 A1.4 An Alternative Way for Deprotecting the Hydroxyl Group 122 A1.5 Suggested Future Work 123 A1.6 Experimental 124 Appendix 2: 1H NMR and 13C NMR Spectra (Chapter 2) 126 Appendix 3: 1H NMR and 13C NMR Spectra (Chapter 3) 177 Appendix 4: 1H NMR and 13C NMR Spectra (Chapter 4) 180 vii Nickel Catalyzed Regioselective Reductive Coupling Reactions LIST OF FIGURES Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to Access 1,4-Difunctionality Figure 1 Selected Natural Products and Medicinal Compounds Containing 1,4- Difunctionality 12 Figure 2 X-ray Structure of [NiCl2(IMes)2] 16 Figure 3 Polarization of the Triple Bond in Ynoates 23 Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes Figure 1 Reaction Profile 64 Figure 2 Rate Dependence on Nickel Catalyst (Low Concentrations) 65 Figure 3 Rate Dependence on Nickel Catalyst (High Concentrations) 66 Figure 4 Rate Dependence on Ynoate 67 Figure 5 Rate Dependence on Aldehyde 68 Figure 6 Rate Dependence on Silane 69 Figure 7 Calibration Plot for Ynoate 88 Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes Figure 1 X-ray Structure of Compound 1,2,4-C6Ph3(CO2Et)3 97 Figure 2 X-ray Structure of Compound 1,2,4-C6H3(C6H4CO2Me)3 100 Figure 3 Polarization of the Triple Bond of Ynoates and Metallacycle Formation 103 Appendix 1: Asymmetric Reductive Coupling of Ynoates and Aldehydes Figure 1 Natural Products with γ-Butyrolactone Core 118 Figure 2 Structures of Sugar Molecules in Chiralpak AD-H and OJ-H 121 viii Nickel Catalyzed Regioselective Reductive Coupling Reactions LIST OF SCHEMES Chapter 1: Introduction Scheme 1 Reductive Coupling of an Alkyne an Aldehyde 3 Scheme 2 A Typical [2+2+2] Cylotrimerization of an Alkyne 6 Scheme 3 Cyclotrimerization Mechanism for Cobalt Systems 8 Scheme 4 Cyclotrimerization Mechanism for Ruthenium Systems 9 Scheme 5 Sequential Insertion Mechanism 9 Scheme 6 Iterative Enyne Metathesis Mechanism 10 Chapter 2: Nickel Catalyzed Coupling of Ynoates and Aldehydes: A New Approach to Access 1,4-Difunctionality Scheme 1 Reductive Coupling of Methyl Propiolate and Benzaldehyde 15 Scheme 2 Proposed Reaction Mechanism 22 Scheme 3 Synthetic Applications of Silyl-Protected γ-Hydroxy-α,β-Enoates 24 Chapter 3: Mechanistic Studies of Nickel Catalyzed Coupling of Ynoates and Aldehydes Scheme 1 Catalytic Coupling of Aldehydes and Alkynes 44 Scheme 2 Organozinc-Mediated Intramolecular Coupling of Alkynes and Aldehydes 45 Scheme 3 Triethylborane-Mediated Intermolecular Reductive Coupling Reaction 45 Scheme 4 Triethylsilane-Mediated Intermolecular Reductive Coupling Reaction 46 Scheme 5 Chromium (II) Chloride-Promoted Intermolecular Reductive Coupling Reaction 47 Scheme 6 Common Mechanisms for Three-Component Coupling Reactions 48 Scheme 7 Ligand Dependent Reductive Coupling Reactions 49 ix Scheme 8 Mechanism Involving a Metallacycle 51 Scheme 9 Mechanisms without a Metallacycle Intermediate 52 Scheme 10 Intermolecular Crossover Experiment 53 Scheme 11 Intramolecular Crossover Experiment 53 Scheme 12 Generation of Nickeladihydrofuran 54 Scheme 13 Reaction of Nickeladihydrofuran with ZnMe2 54 Scheme 14 Theoretical Study on Reductive Coupling of Alkyne and Aldehyde 55 Scheme 15 Nickel-Catalyzed Coupling of Ynoates and Aldehydes 56 Scheme 16 Proposed Mechanism Based on Metallacycle Intermediates 57 Scheme 17 Alternative Mechanism without a Metallacycle Intermediate 57 Scheme 18 Deuterium-Labeling Studies 58 Scheme 19 Attempted Hydrosilylation of Methyl Propiolate 59 Scheme 20 Nickel-Catalyzed Coupling of an Ynal 59 Scheme 21 Kinetics Model 70 Chapter 4: Nickel Catalyzed [2 + 2 + 2] Cyclotrimerization of Ynoates and Related Alkynes Scheme 1 Nickel-Catalyzed Reductive Coupling Reactions 91 Scheme 2 Benzene-1,2,4-Tricarboxylates as Branching Agents in Polymer Synthesis 92 Scheme 3 Plausible Mechanism 101 Scheme 4 Origin of Regioselectivity 103 Appendix 1: Asymmetric Reductive Coupling of Ynoates and Aldehydes Scheme 1 Asymmetric Induction with Chiral Phosphines 116 Scheme 2 Asymmetric Induction with Chiral NHCs 117 Scheme 3 Nickel-Catalyzed Reductive Coupling of Ynoates and Aldehydes 117 x Scheme 4 Synthetic Applications of γ-Hydroxy-α,β-Enoates 117 Scheme 5 Procedure for the Synthesis of Chiral NHCs 119 Scheme 6 Attempted Synthesis of Precursor for PhSIPr 120 Scheme 7 Coupling of Methyl Propiolate and PhCHO 120 Scheme 8 Silyl-Deprotection of γ-Hydroxy-α,β-Enoates 122 Scheme 9 Silyl-Deprotection in Related Systems 122 Scheme 10 Alternative