Explorations in Oxidative Carbonylative Couplings Using Palladium and Nickel Restricted; Files Only

Abstract

Part 1. Palladium-catalyzed oxidative carbonylations have been used to synthesize oxaspirocyclic lactones for a variety of natural products. Here I record a highly detailed method for large scale palladium catalyzed carbonylations.

Part 2. Nickel catalysis offers a cheaper and more sustainable approach to cross coupling chemistry. Many methods have been developed for the use of nickel in redox neutral coupling reactions. However, oxidative couplings with nickel are underrepresented in the literature, with carbonylative versions being particularly rare. This report details the use of nickel acetate and TEMPO to synthesize oxaspirocyclic and fused bicyclic lactones from cyclopropanol starting materials. Of particular interest is the mechanism and the dual role of oxidant and ligand that the TEMPO plays.

Table of Contents

TABLE OF CONTENTS

Acknowledgments.........................................................................................................................vi

Table of Contents..........................................................................................................................vii

List of Figures............................................................................................................................... ix

List of Tables.................................................................................................................................xii

List of Schemes.............................................................................................................................xii

Table of Abbreviations…………………………………………………………………………. xiii

Chapter 1: Palladium- and Nickel-Catalyzed Carbonylative Cyclizations...................................1

1.1 Carbon Monoxide ...................................................................................................................1

1.2 Palladium-catalyzed Oxidative Carbonylations......................................................................2

1.2.1 Palladium-catalyzed Oxidative Carbonylations in Total Synthesis..................................8

1.3 Nickel-Catalyzed Carbonylation.............................................................................................13

1.3.1 Avoiding Carbon Monoxide Poisoning of Nickel Catalysts.............................................13

1.3.2 Nickel-Catalyzed Oxidative Carbonylation......................................................................15

1.4 References...............................................................................................................................17

Chapter 2: Palladium-Catalyzed Carbonylative Spirolactonization of Hydroxycyclopropanols .24

2.1 Introduction.............................................................................................................................24

2.2 Synthesis of Cyclopropanol Starting Material........................................................................26

2.3 Choosing the Palladium Catalyst............................................................................................27

2.4 Representative Substrate Scope ..............................................................................................28

2.5 Concluding Remarks...............................................................................................................29

2.6 References...............................................................................................................................29

2.7 Experimental Details...............................................................................................................32

2.7.1 Materials and Methods.........................................................................................................32

2.7.2 Experimental Procedures.....................................................................................................33

Chapter 3: Chapter Three: Nickel Catalyzed Carbonylative Spirocyclization .............................47

3.1 Tetrahydrofuro[2,3b]furanones...............................................................................................47

3.1.1 Tetrahydrofuro[2,3b]furanones in Natural Products............................................................47

3.1.2 Previous Methods for Synthesizing Tetrahydrofuro[2,3b]furanones ..................................48

3.2 Nickel-Catalyzed Carbonylations...........................................................................................50

3.3 Results and Discussion ...........................................................................................................50

3.3.1 Screening Oxidants..............................................................................................................51

3.3.2 Screening Temperature and Solvents...................................................................................52

3.3.3 Ligand and Precatalyst Screening........................................................................................52

3.3.4 Searching for Potential Co-Oxidants and Exploring Other N-Oxy Radicals ......................53

3.3.5 Substrate Scope....................................................................................................................54

3.3.6 Mechanistic Studies.............................................................................................................56

3.4 Conclusion ..............................................................................................................................60

3.5 References...............................................................................................................................60

3.6 Experimental Details...............................................................................................................66

3.6.1 Materials and Methods.........................................................................................................66

3.6.2 Experimental Details............................................................................................................66

Supplemental Characterization .................................................................................................. 104

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	Carbonylation Oxidative Coupling Nickel Catalysis Palladium Catalysis
Committee Chair / Thesis Advisor	Mingji Dai, Emory University
Committee Members	Simon Blakey, Emory University Huw Davies, Emory University

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