Desulfitative Coupling Reactions for the Mild Construction of Carbon-Carbon, Carbon-Nitrogen, and Carbon-Oxygen Bonds Open Access

Lindale, Matthew (2015)

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A novel cross-coupling of thiol esters bearing an ortho-directing group and organostannanes is explored using stoichiometric copper carboxylate to mediate the coupling, generating ketones. When the imine is carefully selected, it is possible to couple boronic acids/esters as well as organostannanes. The coordination of copper to the ortho-imine directing group as well as the thiol ester activates the system, allowing the reaction to occur under mild conditions (50 °C). The reaction is the first reported base-free coupling on thiol esters and boronic esters. The second generation Liebeskind-Srogl reaction, an aerobic cross-coupling of S-acylthiosalicyamides and boronic acids, is a mild, base-free reaction that has been utilized to generate a variety of diverse ketones. Unfortunately, the reaction generates a stoichiometric amount of an undesired thioether byproduct. An investigation to prevent thioether formation was undertaken by altering the core structure of the S-acylthiosalicylamide as well as the ligand environment of the copper catalyst. Optimization of the reaction conditions provided a mild reaction for ketoconjugation, eliminating the undesired thioether byproduct in favor of the generation of benzoisothiazolone (BIT). The BIT byproduct could be recycled back to S-acythiosalicylamide by gentle reaction with triethylphosphite and carboxylic acid. This discovery allowed for the one-pot ketoconjugation of carboxylic acids and boronic acids. A variety of benzoisothiazolones (BITs) were tested as oxidation-reduction condensation catalysts for the formation of amide bonds from carboxylic acids and amines. It was found that a number of BITs proved effective as organocatalysts for the reaction, however, 4-pyridyl-N-isopropylbenzisothiazolone proved the most effective, providing high yields of the desired amides in 24 hours at 50 °C. The rate of oxidative closure of the reduced BIT was studied, and disulfide was found to form as an intermediate before closure to BIT occurred.

Table of Contents

Chapter 1: Mild, Copper-Templated Cross-Coupling of Thiol Esters with Boronic Acids and Esters. 1

1.1 Introduction. 2

1.2 Results. 11

1.2.1 Oxime-Templated Anaerobic Coupling of Thiol Esters and Boronic Acids. 11

1.2.2 Aldimine Templated Cross-Coupling with Stoichiometric Copper. 14

1.3 Conclusion. 22

1.4 Experimental. 22

1.4.1 General Procedure. 22

1.4.2 Preparation of Oxime Starting Materials. 23

1.4.3 General Procedure for Microwave Irradiation Experiments. 25

1.4.4 Preparation of Imine Starting Materials. 26

1.4.5 General Procedure for the Production of Imines. 29

1.4.6 General Procedure for Desulfitative Coupling. 34

1.5 References. 37

Chapter 2: Recyclable Reagent for the Keto-Conjugation of Carboxylic Acids with Boronic Acids. 43

2.1 Introduction. 44

2.2 Results. 51

2.2.1 Synthesis of Starting Materials. 51

2.2.2 Thiol Ester Formation. 55

2.2.3 Ketone Formation. 57

2.2.4 Benzoisothiazolone Mediated, One-Pot Cross-Coupling. 60

2.2.5 Triethylphosphite as a Reducing Agent 62

2.3 Conclusion. 67

2.4 Experimental. 68

2.4.1 General Experimental 68

2.4.2 General Procedure for the Synthesis of Amides 11a-i 69

2.4.3 General Procedure for the Synthesis of Thioethers 12a-h. 76

2.4.4 General Procedure for the Synthesis of Benzoisothiazolones (BITs) 13a-h. 84

2.4.5 General Procedure for the Synthesis of Benzoisothiazolones (BITs) 17a-c and 21a-c. 88

2.4.6 General Procedure for the One-Pot Ketoconjugation (Triphenylphosphine). 96

2.4.7 General Procedure for the Generation of Thiol Esters from Triethylphosphite. 102

2.4.8 General Procedure for the One-Pot Ketoconjugation (Triethylphosphite). 105

2.5 References. 110

Chapter 3: Organocatalytic Oxidation-Reduction Condensation for Amide and Ester Formation.. 114

3.1 Introduction. 115

3.2 Results. 121

3.2.1 Stoichiometric Amidation. 121

3.2.2 Catalytic Amidation and Esterification. 126

3.2.3 Mechanistic Considerations: Aerobic Oxidation of Thiosalicylamide. 130

3.3 Conclusion. 133

3.4 Experimental. 133

3.4.1 General Experimental 133

3.4.2 General Method for the Synthesis of S-Acylthiosalicylamides. 134

3.4.3 General Procedure for the Stoichiometric Synthesis of Amides. 136

3.4.4 General Procedure for the Stoichiometric Synthesis of Esters. 138

3.4.5 General Procedure for Organocatalytic Amidation. 142

3.4.6 Procedure for Monitoring Thiol Oxidation by HPLC.. 146

3.4.7 Isolation of Oxidation Intermediate. 147

3.5 References. 147

Appendix A.. 151

A.1 Introduction. 152

A.2 Results. 153

A.3 Conclusion. 158

A.4 Experimental. 158

A.4.1 General Experimental 158

A.4.2 General Procedure for the Coupling of Carboxylic Esters with Boronic Acids:. 159

A.5 References. 161

Appendix B.. 163

B.1 Introduction. 164

B.2 Results. 164

B.3 Conclusion. 167

B.4 Experimental. 167

B.4.1 General Experimental 167

B.4.2 Procedures. 168

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