Aerobic, Medal Mediated Ketone Synthesis from Thiol Esters and Boronic Acids Público

Abstract

Thiol esters derived from N-substituted and aryl substituted thiosalicylamides were synthesized. Their aerobic coupling with one equivalent of aryl boronic acids to give ketones was investigated in the presence of catalytic palladium(0) bis(tricyclohexylphosphine) and copper(I) methyl salicylate. The byproducts of the reaction were found to be mixtures S-arylation of the thiosalicylamide pendant and ring closure of the thiosalicylamide to form a benzoisothiazolinone. A novel, aerobic ketone synthesis from simple and complex thiol esters and commercially available boronic acids catalyzed by copper (I) methyl salicylate (CuMeSal) is reported. The reaction is highly chemoselective for thiol esters containing an N-tert-butyl or N-iso-propyl -2-mercaptobenzamide pendant. The reaction occurs under very mild reaction conditions (ambient temperature, aerobic, neutral conditions, and in the presence of a broad range of functional groups). The application of this chemistry may prove useful for selective carbon-carbon bond forming reactions on complex biomolecules. Thiol esters bearing ortho-chelating groups that did not react with copper alone were found to undergo cross-coupling with catalytic amounts of added Pd(PCy3)2. A new ketone synthesis from simple thiol esters and organic halides using copper (I) carboxylates is reported. The reaction requires the use of thiol esters containing an N-isopropyl -2-mercaptobenzamide pendant. The reaction occurs under mild reaction conditions (ambient temperature, neutral conditions, under argon). A preliminary study of the reaction is presented.

Table of Contents

Chapter 1 Aerobic Palladium and Copper Catalyzed Coupling of Boronic Acids and Thiol Esters Derived from Thiosalicylamide: Benzoisothiazolinone Formation versus S-Arylation..3 1.1 Introduction.......4 1.2 Results and Discussion......7 1.2.1 Pyridyl Thiol Esters and Their Reactivity....10 1.2.2 Extending the Thiol Ester Library....16 1.2.3 Ketone Synthesis.......18 1.2.4 Imidazole and Thiazole Derived Thiol Esters and Their Couplings.20 1.2.5 Sterically Hindered Boronic Acids.......22 1.3 Conclusion...23 1.4 References....................................................................................................................23 1.5 Experimental....26 Chapter 2 An Aerobic, Chemoselective Copper-Templated Coupling of Thiol Esters and Boronic Acids.77 2.1 Introduction........78 2.2 Results and Discussion.......79 2.2.1 Reaction Optimization.....81 2.2.2 Cross-Coupling Examples...84 2.2.3 Mechanism...86 2.3 Conclusion..88 2.4 References...................................................................................................................89 2.5 Experimental...93 Chapter 3 An Aerobic, Chemoselective, Palladium-Templated Coupling of Thiol Esters and Boronic acids.120 3.1 Introduction and Initial Studies.......121 3.1.1 Probing Catalysis..121 3.1.2 Summary of Work Completed by Dr. Jiri Srogl and Silvia Cabrera123 3.2 Results and Discussion....125 3.2.1 A Thorough Study of Thiol Ester Pendants.....125 3.2.2 Mechanistic Insights.....128 3.3 Conclusion.......132 3.4 References................................................................................................................132 3.5 Experimental....134 Chapter 4 The Copper Mediated Coupling of Thiol Esters with Aryl and Heteroaryl Iodides.144 4.1 Introduction and Background.....145 4.2 Results and Discussion.......146 4.3 Mechanism..147 4.4 Conclusion......151 4.5 References...............................................................................................................151 4.6 Experimental...152

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic Chemistry, Pharmaceutical Chemistry, Inorganic
Palabra Clave	Copper Catalyzed Aerobic Ketone Synthesis Thiol Esters and Boronic Acids
Committee Chair / Thesis Advisor	Liebeskind, Lanny S, Emory University
Committee Members	Padwa, Albert, Emory University Blakey, Simon, Emory University

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