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  • University of Bath

    PHD

    New aspects of organophosphorus chemistry

    Kawamoto, Aparecida Minhoko

    Award date: 1995

    Awarding institution: University of Bath

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  • NEW ASPECTS OF ORGANOPHOSPHORUS

    CHEMISTRY

    Submitted by

    Aparecida Minhoko Kawamoto

    for the degree of Ph.D.

    of the University of Bath

    1995

    COPYRIGHT

    Attention is drawn to the fact that copyright of this thesis rests with its author.

    This copy of the thesis has been supplied on condition that anyone who consults it is

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    from the thesis and no information derived from it may be published without the prior

    written consent of the author.

    This thesis may not be consulted, photocopied or lent to other libraries without

    the permission of the author for three years from the date of acceptance of the thesis.

  • UMI Number: U601802

    All rights reserved

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    Dissertation Publishing

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  • CONTENTS

    Page

    ACKNOWLEDGEMENTS ii

    ABSTRACT iii

    ABBREVIATIONS iv

    PART I - ORGANOPHOSPHORUS COMPOUNDS

    CHAPTER ONE - INTRODUCTION

    1.1 Introduction 1

    1.2 Commercial Uses of Phosphonates 3

    1.3 The Role of Phosphonates in Living Systems 3

    1.4 Phosphoenol Pyruvate 7

    1.5 Phosphonate Analogues 18

    1.6 Phosphoserine 22

    1.7 Difluorofunctionalized Phosphonates 34

    1.8 Hydrolysis of Difluorophosphonate Compounds 48

    CHAPTER TWO - RESULTS AND DISCUSSION

    2.1 Aims and Objectives 50

    2.2 Synthesis of Methyl 2-[2’,2’-difluoroethy 1-2’-(diethoxy

    phosphinyl)] propenoate and 2- [2 ’ ,2 ’ -Difluoroethyl-2 ’ -

    (diethoxyhosphinyl] propenoic acid 60

    2.2.1 Preparation of Diethyl bromodifluoromethanephospho-

    nate 60

  • 2.2.2 Preparation of [(Diethoxyphosphinyl) difluoromethyl]

    zinc bromide

    2.2.3 Coupling Reaction

    Synthesis of 2-[2\2,-Difluoroethyl-2,-(dihydroxyphosphi-

    nyl)] propenoic acid

    Synthesis of [4,4-Difluoro-4-(diethoxyphosphinyl)-2-bromo]

    butanoic acid

    Synthesis of E-[4,4-Difluoro-4-(diethoxyphosphinyl)] but-2-

    enoic acid

    Synthesis of Z-[4,4-Difluoro-4-(diethoxyphosphinyl)] but-2-

    enoic acid

    Synthesis of [4,4-Difluoro-4-(dihydroxyphosphinyl)-2-amino]

    butanoic acid

    2.7.1 Preparation of Methyl [4,4-difluoro-4-(diethoxyphos-

    phinyl)-2-bromo] butanoate

    2.7.2 Azide displacement of the Bromine Group

    2.7.3 Hydrogenation of the Azido Group

    2.7.4 Deprotection of Diethoxyphosphinyl group and Methyl

    ester

    2.7.5 Coupling Reaction of [4,4-Difluoro-4-(diethoxyphosphi-

    nyl)-2-bromo] butanoic acid with [(lS)-endo]-(-)

    Bomeol

    2.7.6 Formation of Azides from compounds (78) and

    (79)

    2.7.7 Hydrogenation of Bomyl [4,4-Difluoro-4-(diethoxyphos-

    phinyl)-2-azido] butyrate

    2.7.8 Deprotection of Diethoxyphosphinyl group and Methyl

    ester of compounds (82 R), (82 S), (83 R) and

    (83 S)

  • 2.8 Synthesis of Methyl [3,3-difluoro-3-(diethoxyphosphinyl)

    -2-hydroxy-2-methyl] propionate 97

    2.8.1 Preparation of Diethyl (difluoromethyl)phos-

    phonate 97

    2.8.2 Coupling Reaction of Diethyl (difluoromethyl)phos-

    phonate with Methyl pyruvate 98

    2.9 Synthesis of [3,3-Difluoro-3-(dihydroxyphosphinyl)-2-hydro-

    xy-2-methyl] propionic acid 99

    2.10 Attempted Preparation of Methyl 2-[(diethoxyphosphinyl)

    difluoromethyl] propenoate 100

    CHAPTER THREE - EXPERIMENTAL

    3.1 Instrumentation and Experimental Techniques 104

    3.1.1 General 104

    3.1.2 Analysis and Spectroscopy 104

    3.1.3 Solvents and Reagents 105

    3.1.4 Chromatography 105

    3.2 Experimental Procedure 106

    PART H - OXAZIRIDINE COMPOUNDS

    CHAPTER FOUR - INTRODUCTION

    4.1 Introduction 129

    4.2 Synthesis of Oxaziridines 136

    4.3 Reactions of Oxaziridines 143

    4.3.1 Reaction with Acidic Reagents 143

    4.3.2 Reaction with Basic Reagents 145

  • 4.3.3 Pyrolysis and Thermal Decomposition

    4.3.4 Oxidation to Nitrosoalkenes

    4.3.5 Reaction with Ferrous Ions

    145

    146

    146

    CHAPTER FIVE - RESULTS AND DISCUSSION

    5.1 Aims and Objectives 148

    5.2 Synthesis of 2-Benzoyl-3,3-dimethyloxaziridine 153

    5.3 Synthesis of 1,3-Benzenedicarbonyl-bis (3,3-dimethyloxa-

    ziridine 155

    5.4 Synthesis of 1,3,5-Benzenetricarbonyl-tris [3,3-dimethyloxa-

    ziridine] 158

    5.5 The Reactivity of Oxaziridines in Oxidation

    Reactions 159

    CHAPTER SIX - EXPERIMENTAL

    6.1 Experimental Procedure 162

    REFERENCES 167

    APPENDICES 173

    Appendix One 178

    Appendix Two 182

    Appendix Three 202

  • Dedicated to my mother, my sister Rosalina

    and my nephew Gustavo for their love and

    support.

  • ACKNOWLEDGEMENTS

    The work described in this thesis was carried out in the Organic Chemistry

    Department of the University of Bath, between March 1992 and April 1995. Financial

    support from the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico

    -CNPq- Brazil is gratefully acknowledged.

    I am sincerely grateful to Professor Malcom M. Campbell, my supervisor at

    Bath, for his help, guidance, and constant encouragement, throughout this work.

    My appreciation goes to the technical staff at the University of Bath for their

    invaluable services. Special thanks are due to Mr. John Bradley and Mr. Russel Barlow

    (organic stores), Mr. Dave Wood and Mr. Harry Hartnell (NMR spectroscopy), Mr.

    Alan Carver (elemental microanalysis), Mr. Chris Cryer (mass spectrometry), Mrs. Jo

    Curtis and, of course, to June and Freda. For her much appreciated contribution of

    X-ray crystallography, I would like to thank Dr. Mary Mahon.

    My thanks to Centro Tecnico Aeroespacial - Brazil- for providing me with the

    opportunity to study for the Ph.D. degree.

    My special thanks to Mr. Luiz Claudio Pardini and Mr. Barrie Percival for their

    help during the writing of this thesis.

    Finally, I would like to thank my friends and colleagues in the Organic

    Chemistry Department. Specially to Matt Fletcher for his valuable help during this

    work, and to Mark Ashton, Gwo-Sen Lin, Simon Diston, Chris Lacy, Matt Sage, Alan

    Graham, Anne Hackett, Dave Corser for their companionship and good humour.

  • ABSTRACT

    The two principal aims of this research work are the synthesis of new

    organodifluorophosphonates and new oxaziridine compounds.

    The organodifluorophosphonates were hoped to have superior biological

    activity, compared to the natural systems. The oxaziridines were expected to behave as

    effective bonding agents in polymerization processes and possibly to be superior

    oxidizing reagents.

    A new class of difluorovinylphosphonate analogues of PEP, methyl

    2-[2’,2’-difluoroethyl-2’-(diethoxyphosphinyl)] propenoate, methyl 2-[2’,2’-difluoro

    ethyl-2’-(diethoxyphosphinyl)] propenoic acid, 2-(2’,2*-difluoroethy-2’-(dihydroxy

    phosphinyl) propenoic acid, E-[4,4-difluoro-4-(diethoxyphosphinyl)] but-2-enoic acid,

    and Z-[4,4-difluoro 4-(diethoxyphosphinyl)] but-2-enoic acid, have been synthesized.

    The organodifluoro phosphonate, methyl [3,3-difluoro-3-(diethoxyphosphinyl)

    -2-hydrox

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