Practical Application and In Situ Kinetic Studies of Dirhodium(II) Tetracarboxylate Catalyzed Carbene Reactions Open Access

Abstract

Dirhodium(II) tetracarboxylates are versatile catalysts for the enantioselective reactions of donor/acceptor carbenes. The overarching goal of the work described in this thesis is to gain deeper kinetic understanding and broader practical application of dirhodium(II) catalyzed carbene chemistry. The first chapter is an overview of carbene chemistry, dirhodium(II) tetracarboxylate catalysts and recent advances in the field.

 

The second chapter investigates the kinetic profiles of Rh(II) catalyzed cyclopropanation under high catalyst turnover number (TON) conditions. A robust method was developed to achieve 100,000 catalyst TONs with consistently high yields and enantioselectivities in various cyclopropanation reactions. 4Å MS and dimethyl carbonate solvent were crucial for the high catalyst TONs reaction efficiency.

 

The third chapter further explores the practicality of Rh(II) catalyzed cyclopropanation by focusing on the flow system generation of diazo compound synthesis and their application in the cyclopropanation reaction. An upstream Cu(OAc)2-H2O/DMAP mixed silica column catalyzed the oxidation of hydrazones and was applied to generate diazo compounds under flow conditions. The crude diazo compounds were subsequently injected directly without extra purification into the downstream dirhodium(II)-catalyzed cyclopropanation reaction. Kinetic studies demonstrated that addition of HFIP in the downstream process is crucial to deliver the desired cyclopropanation products.

 

The fourth chapter shows the application of dirhodium(II)-catalyzed carbene chemistry in the synthesis of a wide variety of heterocycle-functionalized cyclopropanes by applying complementary methodologies. The cyclopropyl-based scaffolds are of pharmaceutical interest and hard to prepare by other methods. The novel method has been utilized in a large-scale synthesis of a key pharmaceutical intermediate.

 

The last chapter concentrated on the kinetic profiles of Rh(II) catalyzed C–H functionalization. The kinetic study gained a comprehensive understanding of the reaction progress at low catalyst loading. The study of the model C–H insertion of cyclohexane revealed the rate-determine step is carbene insertion instead of the carbene formation. The kinetic insights have driven rational optimization of the stoichiometry, carbene precursor structures and additives of the reaction. As a result, about 580,000 Rh(II) catalyst TONs have been achieved in the C–H insertion reaction with 1 mol % N,N'-dicyclohexylcarbodiimide (DCC) as additive.

Table of Contents

Chapter 1. Introduction of Dirhodium(II) Catalyzed Carbene Chemistry

1.1 Introduction

Chapter 2. In Situ Kinetic Studies of Dirhodium(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings.

2.1 Introduction

2.2 Results and Discussions

2.3 Conclusions

Chapter 3. Copper(II)-catalyzed Aerobic Oxidation of Hydrazones to Diazo Compounds under Flow Conditions and Their Application in Carbene Reactions.

3.1 Introduction

3.2 Results and Discussions

3.3 Conclusions

Chapter 4. Pharmaceutically Relevant Asymmetric Cyclopropanation of Vinyl Heterocycles with Aryl- and Heteroaryldiazoacetates.

4.1 Introduction

4.2 Results and Discussions

4.3 Conclusions

Chapter 5. In Situ Kinetics Studies of Dirhodium (II)-Catalyzed C–H Functionalization to Achieve High Catalyst Turnover Numbers.

5.1 Introduction

5.2 Results and Discussions

5.3 Conclusions

Experimental Part

6.1 General Considerations and Reagents

6.2 Experimental Part for Chapter 2

6.3 Experimental Part for Chapter 3

6.4 Experimental Part for Chapter 4

6.5 Experimental Part for Chapter 5

Reference

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	Carbene Reactions Kinetic Studies Dirhodium(II) Tetracarboxylate
Committee Chair / Thesis Advisor	Davies, Huw M. L, Emory University
Committee Members	Blakey, Simon , Emory University Liebeskind, Lanny S , Emory University

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