University of Bath PHD Synthesis of substituted hydroxyguanidines and related systems. Peace, Alastair Award date: 1983 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 TO MY FAMILY AND JACQUELINE ^ __ 2 8 MAR 1933 Synthesis of Substituted Hydroxyguanidines and Related Systems. Submitted by Alastair Peace for the degree of Ph.D of the University of Bath 1983. 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 i t is understood to recognise that its copyright rests with its author and that no quotation from the thesis, and no information derived from i t may be published with­ out the prior written consent of the author. RESTRICTIONS ON USE This thesis may not be consulted, photocopied or lent to other libraries without the permission of the author and Organon Laboratories Limited for t^n years from the date of acceptance of the thesis. ProQuest Number: U641671 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U641671 Published by ProQuest LLC(2015). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ACKNOWLEDGEMENTS The work described in this thesis was carried out in the Organic Chemistry Research Laboratories of Heriot-Watt University, Edinburgh, University of Bath, Bath and Organon Laboratories Limited, Newhouse, Lanarkshire. I would like to extend my sincere thanks to Professor Malcolm M Campbell and Dr. Alex C. Campbell for their guidance and encouragement through­ out this research. I would like to thank the technicians of Heriot-Watt University and The University of Bath. I would particularly like to thank Miss Sue Green and Mr.. Richard Hunter for all their help. r am very grateful to Professor J.G. Buchanan of Heriot-Watt for his advice in this project. I would also like to thank a ll the staff of Organon Laboratories Limited who made my visits there so enjoyable. I would particularly like to thank Mr. John Clark, Mr. Wilson Caulfield, Mr. Maurice Maidment, Mr. John Pick and Miss Joanne Topping for their assistance and friendship. I am also very grateful to Miss Mairi Thomson for the excellent typing of this manuscript. I would like to acknowledge Dr. D. Williams, Imperial College, London, for supplying X-ray crystallographic data which were invaluable to the research effo rt and the SERC for a maintainence grant. Finally I would lik e to thank my family and Miss Jacqueline Munro for the support and encouragement they have given me. FOREWORD Bracketed Arabic numerals in the text refer to the compounds and Arabic superscripts indicate references. The following abbreviations have been used in the text:- Ac acetyl Bn benzyl Bu butyl Bz benzoyl DMAD dimethyl acetyl ene dicarboxylate DMF dimethylformamide Et ethyl h hour HMPA hexamethylphosphoric a*id& HPLC high performance liquid chromatography LDA 1ithiumdi-isopropyl amide i . r . infra red min minute mmol millimole mol mol mp melting point NBS N-bromosuccinimide NCS N-chlorosuccinimide Nmr nuclear magnetic resonance Ph phenyl Pr propyl RT room temperature THF tetrahydrofuran tic thin layer chromatography pTSA p-toluene sulphonic acid u.v. ultraviolet z benzyloxycarbonyl A reflux ABSTRACT In an extensive study of the annulation chemistry of 2-benzyloxy- guanidine, several novel synthetic routes to heterocyclic systems containing the N-hydroxyguanidine moiety were developed. Two routes to N-hydroxy imidazolines were developed. 1. Reaction of 2-benzyloxyguanidine with chloroacetyl chloride gave l-chloroacetyl-2-benzyloxyguanidine. Subsequent ring closure to 2-ami no-1-benzyloxy-4-oxo-2-imidazoline followed by catalytic hydrogenation gave 2-ami no-1-hydroxy-4-oxo-2-imidazoline. 2, Reaction of 2-benzyloxyguanidine with maleic anhydride gave 2- amino-T-benzyloxy-4-oxo-2-imidazoline-5-ethanoic acid. Catalytic hydrogenation then gave 2-ami no-1-hydroxy-4-oxo-2-imidazoline-5- ethanoic acid. A third method involving ring expansion of|2-phenylaziridine-l-carboxamide oxime to give 2-amino-l-hydroxy-S-phenyl-I-imidazoline was also developed. Reaction of 2-benzyloxyguanidine with methyl propiolate by ester attack followed by internal Michael Addition gave 2-ami no-1-benzyloxy-4-pyrim- idone. Débenzylation with boron tribromide then gave 2-amino-l-hydroxy- 4-pyrimidone hydrobromide. Finally débenzylation of Uchloroacetyl-2-benzyloxyguanidine with boron tribromide gave by yet another mode of cyclisation, 3-ami no-1,2,4- oxad iazi ne-5-one di hydrobromide. INTRODUCTION Page 1 General Introduction. 1 - 2 2 Biological A ctivity of Hydroxyguanidines. 3 2.1 Antiviral and Anti tumour Activity. 3-5 2.2 Antihyperfcensitive A ctivity - Central Nervous System A ctivity. 6 - 7 2.3 Antidepressant A ctivity. 7 - 8 2.4 Antijarrhythmic Activity. 8 2.5 The Biosynthesis of Hydroxyguanidine in the Mammal. 8 - 9 3 Biological Activity of 2 , 4-Diamino pyriraidi.ne-3-oxicles lo 3.1 AntihyperEensitive Activity. 10 4 Chemistry of Hydroxyguanidines (Hydroxyimino Systems). 11 4.1 Synthesis of Hydroxyguanidines. 11 4.1.1 From Cyanamides. 11 - 13 4.1.2 From Methyl thioureas. 13-14 4.1.3 From Carbodi-imides. 14 - 15 4.1.4 From C-Chloroformadinium Chloride Salts. 16 4.1.5 From Cyclisation of Phosgene Oxime and Diamine. 17 4.2 Reactions of Hydroxyguanidines. 18 4.2.1 Acétylations. 18 4.2.2 Benzoylation. 19 - 20 4.2.3 With Ethyl Chloroformate. 20 - 21 4.2.4 With Dichloroisocyanate 21 - 22 4.2.5 With Isocyanate and Isothiocyanates. 22 - 23 4.2.6 With Oxalyl Chloride. 23 4.2.7 Alkylation. 23 4.2.8 Bromination. 24 4.2.9 Hydrogenation. 24 4.2.10 Reversible Rearrangement; Hydroxyguanidines Aminoformamides. 25-26 Page 4.3 Spectroscopic Properties. 26 4.3.1 N.M.R. 26 - 27 4.3.2. I.R. 27 - 28 4.4 Physical Properties. 28 4.4.1 Geometrical Isomérisation. 28 - 31 4.4.2 Molecular Bond Lengths and Angles. 31 - 32 5 Chemistry of Hydroxyguanidines (Hydroxyamino Systems). 33 5.1 Synthesis of Hydroxyamino Hydroxyguanidines. 33 5.1.1 From Carbodi-imides. 33 5.1.2 By Direct Oxidation of a 2-Amino Pyridine. 33 - 35 5.1.3 By Cyclisation. 35 - 36 5.2 Reactions of Hydroxyamino Hydroxyguanidines. 37 5.2.1 All kyloxycarbonyl ation 37 5.2.2 With Thiophosgene. 37 5.2.3 With Chloroacetylchloride. 38 5.2.4 Hydrolysis. 28 - 39 5.2.5 2,4-Diamino-3-oxide Pyrimidines and Acid Anhydrides. 39 - 40 6 Structurally Related Compounds 41 6.1 Synthesis of 3-Hydroxypurines. 41 6.2 Reactions of 3-Hydroxypurines. 41 - 43 6.3 Oncogenic A ctivity 43 - 44 DISCUSSION 5-membered Ring N-Hydroxy Heterocycles 7 Displacement of Methanethiol from CyclicThioureas with Hydroxylamine. 45 7.1 Synthetic Strategy. 45 - 47 7.2 Preparation of 2-Hydroxyimino-2-imidazoline acetate and hydrochloride. 47 - 49 7.3 Attempted Preparations of 2-Hydroxyimino- 2-imidazoline. 49 - 53 Page 8 Ring Annulation Chemistry of 2-Benzyloxy- guanidine and Chloroacetyl Chloride. 54 8.1 Synthetic Strategy. 54 - 55 8.2 Synthesis of 2-Ami no-1-hydroxy-4-oxo- 2-imidazoline. 55 - 61 8.3 Attempted Alkylations of 2-Ami no-1-benzyloxy- 4-oxo-2-imidazoline. 61 - 63 8.4 Attempted Protection of 2-Ami no-1-hydroxy-4- oxo-2-imidazoline. 64 8.5 Preparation of 2-Ami no-1-hydroxy-4-oxo- 5!tetradecy>2-imidazoline. 64 - 67 8.6 Attempted Trapping of Decomposition Product from 2-Ami no-1-benzyloxy-4-oxo-2-imidazoline. 67 - 68 8.7 Attempted Acétylation, Diazotization and Oxidation of 2-Ami no-1-benzyloxy-4-oxo-2-imidazoline and 2- amino-l-hydroxy-4-oxo-2-imidazoline. 68 - 70 8.8 Reactions of 2-Ami no-1-benzyloxy-4-oxo- 2-imidazoline. 70 - 71 8.9 Arbuzov Reaction of 2-Benzyloxy-1- chloroacetylguanidine. 72 - 73 8.10 Conclusions. 73 9 Synthesis of 2-Amino-1-hydroxy-s-phenyTz-imidazoline. 74 9.1 Synthetic Strategy. 74 9.2 Attempted formation of 1-Cyanoaziridine. 74 - 75 9.3 Preparation of 2-Phenylaziridine-l-carboxamide oxime 76 - 81 6-Membered Ring N-Hydroxyheterocycles. 10 Ring Annulation Chemistry of Benxyloxyguanidine and Methyl Propiolate. 82 10.1 Synthetic Strategy. 82 - 83 10.2 Synthesis of 2-Ami no-1-hydroxy-4-pyrimidone. 83 - 89 10.3 Attempted formation of Glycosides from 2-Amino- 1-hydroxy-4-pyrimidone hydrobromide.