new aspects of organophosphorus chemistry kawamoto ... university of bath
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University of Bath
New aspects of organophosphorus chemistry
Kawamoto, Aparecida Minhoko
Award date: 1995
Awarding institution: University of Bath
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NEW ASPECTS OF ORGANOPHOSPHORUS
Aparecida Minhoko Kawamoto
for the degree of Ph.D.
of the University of Bath
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
understood to recognise that its copyright rests with its author and that no quotation
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
INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted.
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a note will indicate the deletion.
UMI U601802 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author.
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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-
2.2.2 Preparation of [(Diethoxyphosphinyl) difluoromethyl]
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]
Synthesis of E-[4,4-Difluoro-4-(diethoxyphosphinyl)] but-2-
Synthesis of Z-[4,4-Difluoro-4-(diethoxyphosphinyl)] but-2-
Synthesis of [4,4-Difluoro-4-(dihydroxyphosphinyl)-2-amino]
2.7.1 Preparation of Methyl [4,4-difluoro-4-(diethoxyphos-
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
2.7.5 Coupling Reaction of [4,4-Difluoro-4-(diethoxyphosphi-
nyl)-2-bromo] butanoic acid with [(lS)-endo]-(-)
2.7.6 Formation of Azides from compounds (78) and
2.7.7 Hydrogenation of Bomyl [4,4-Difluoro-4-(diethoxyphos-
2.7.8 Deprotection of Diethoxyphosphinyl group and Methyl
ester of compounds (82 R), (82 S), (83 R) and
2.8 Synthesis of Methyl [3,3-difluoro-3-(diethoxyphosphinyl)
-2-hydroxy-2-methyl] propionate 97
2.8.1 Preparation of Diethyl (difluoromethyl)phos-
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
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-
5.4 Synthesis of 1,3,5-Benzenetricarbonyl-tris [3,3-dimethyloxa-
5.5 The Reactivity of Oxaziridines in Oxidation
CHAPTER SIX - EXPERIMENTAL
6.1 Experimental Procedure 162
Appendix One 178
Appendix Two 182
Appendix Three 202
Dedicated to my mother, my sister Rosalina
and my nephew Gustavo for their love and
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.
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
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)