STUDIES on the SYNTHESIS and REACTIVITY of FIVE-MEMBERED HETEROCYCLIC DIAZONIUM CATIONS by WILLIAM NICOL DUFF, B.Sc. Thesis Pres

STUDIES ON THE SYNTHESIS AND REACTIVITY OF FIVE-MEMBERED HETEROCYCLIC DIAZONIUM CATIONS by WILLIAM NICOL DUFF, B.Sc. Thesis presented for the degree of Doctor of Philosophy University of Edinburgh 1981 Ez 08 rn Ze 0 8 X1 DECLARATION I declare that this thesis is my own composition, that the work of which it is a record has been carried out by myself and that it has not been submitted in any previous application for a Higher Degree. The thesis describes the results of research carried out in the Department of Chemistry, University of Edinburgh, under the supervision of Dr. G. Tennant between October 1976 and September 1979. ACKNOWLEDGEMENTS I should like to place on record my appreciation of the guidance and encouragement provided by my supervisor Dr. G. Tennant. I am grateful for the patience he displayed over the years of our association. I should like to thank the Science Research Council in collaboration with I. C. I. Organics Division, Blackley, Manchester for the award of a C.A.S.E. studentship over three years. lam also grateful to the University of Edinburgh for the provision of laboratory and library facilities. I am further indebted to the technical staff of the Department of Chemistry, University of Edinburgh for their help and assistance. I should also like to acknowledge Dr. D. B. Baird of I.C.I. Organics Division for his many helpful suggestions and his supervision during my stay in Blackley. I should like to thank Mrs. C. Ranken for her care and patience typing this manuscript. POSTGRADUATE LECTURE COURSES ATTENDED BETWEEN OCTOBER 1976 AND SEPTEMBER 1979 "Optical Properties of Transition Metal Complexes, 11 Dr. T. A. Stephenson, University of Edinburgh. "Electrode Reactions, 11 Dr. W. D. Cooper, university of Edinburgh. "Organic Sulphur Compounds in General Synthesis, Dr. D. Leaver, University of Edinburgh. "Stratagem for Organic Synthesis, Dr. I. Gosney, University of Edinburgh. "The Encouragement and Exploitation of Inventiveness in the Oil Industry, Mr. D. H. Desty and colleagues, B. P. Ltd. "Lectures on the Science and Technology of Dyestuffs, " Staff of LC. I. Organics Division Blackley, Manchester. Chemical Society, Third Lakeland Heterocyclic Symposium, Grasmere 1977. Chemical Society, Fourth Lakeland Heterocyclic Symposium, Grasmere 1979. Organic Research Group Seminars, 1976-77, 1977-78 and 1978-79. Departmental Colloquia 1976-79. Summary The diazotisation of a series of five-membered heterocyclic primary amines has been examined and after satisfactory conditions had been established the resulting "diazo intermediates" were subjected to dediazoniation reactions and coupling with active methylene compounds, in the latter case with the objective of the cyclisation of the hydrazone products to novel bicyclic systems. 5 -Amino- 3-phenylisoxazole was prepared and diazotised under several sets of conditions to give principally 3-phenyl-A 2- isoxazoline-4, 5-dione 4-oxime and 5-amino-3-phenyl-4-(3'- phenyl- isoxazol-5'-ylazo) hydrazone. An investigation was carried out into the chemistry of 3-phenyl-A 2-isoxazoline-4, 5-dione 4-oxime with particular regard to its reactions with nucleophiles. The diazotisation of 2- aminothiazole and 2-aminob enzothiazole was achieved and in situ dediazoniation and coupling reactions with active methylene compounds met with limited success. 2-N-Hydroxy- azobenzothiazo].e and benzothiazole-2-diazonjum fluoroborate were prepared and their reactions were examined, with particular reference to dediazoniation processes. Methyl 4-amino-2-methylmercapto- thiazole-5-carboxylate was prepared and under suitable conditions was diazotised and the diazonium salt subjected successfully to dediazoniation and coupling under controlled pH with active methylene compounds. 5 -Amino -3-methylisothiazole-4-carbonjtrile was prepared, diazotised and coupled with acetylacetone to give the corresponding hydrazone in moderate yield. 5- Nitro s amino - 3-methylisothiazole- 4-carbonitrile was also prepared and was found to be a synthetically useful intermediate. The corresponding diazonium salt could not be isolated. Two 5-amino-1, 2,4-thiadiazoles were synthesised, their respective nitrosamines prepared, and 3-phenyl-1, 2,4-thiadiazole- 5-diazonium fluoroborate isolated from the corresponding nitrosamine. However only limited success was achieved in utilising these isolable intermediates as diazonium salt precursors. The diazotisation of 5-amino-1, 2,4-thiadiazoles and subsequent in situ reactions of the resulting diazonium salts were not particularly fruitful. The synthesis and diazotisation of 3-amino-5-phenyl-1, 2, 4- thiadiazole was achieved but satisfactory transformations of derived diazonium salts were not successful. Neither 3-nitrosamino-5-phenyl-1, 2,4- thiadiazole nor 5-phenyl-1, 2, 4- thiadiazole- 3- diazonium fluoroborate could be isolated, 2-Amino- 5-phenyl-1, 3,4-thiadiazole was prepared and satisfactorily diazotised and coupled with acetylacetone. 2-Nitros- amino-5-phenyl-1, 3,4-thiadiazole was also prepared and its synthetic usefulness demonstrated. The discovery of a novel thermal and photochemical decomposition of 5- azido - 3-methylisothiazole-4-carbonitrile to afford 2-amino- 1, i-dicyanoprop-l-ene inspired the synthesis of other 5-azidoiso- thiazole-4 - carbonitriles (via dediazoniation reactions of the corrés - ponding diazonium salts) and the study of their similar thermal and photochemical decomposition. A mechanism is proposed for such fragmentation reactions but attempts to prove it were unsuccessful. Azidodediazoniation reactions of most of the heterocyclic diazonium salts prepared before were carried out and the thermolysis and photolysis of the resulting azido compounds investigated. However no general decomposition pathway was observed. CONTENTS Page CHAPTER ONE Introduction 1 CHAPTER TWO Studies of the Products derived by Nitrosation of 5-Amino-3-phenylisoxazole Discussion 30 Experimental 49 CHAPTER THREE Investigations on the Preparation and Dediazoniation and Coupling Reactions of Thiazoledia.zonium Salts Discussion 74 Experimental 94 CHAPTER FOUR Studies of the Synthesis and Reactivity of 4-Cyano-3-methylisothiazole-5-diazonium Salts Discussion 141 Experimental 148 CHAPTER FIVE Studies of the Synthesis and Reactivity of 1, 2,4- and 1,3,4- Thiadiazolediazoniurn Salts Discussion 158 Experimental 179 Page CHAPTER SIX Studies of the Synthesis and Fragmentation Reactions of Azidoazoles Discussion 209 Experimental 228 BIBLIOGRAPHY 261 APPENDIX CHAPTER ONE Introduction 1 INTRODUCTION The following thesis is concerned with the general study of the diazotisationof heterocyclic amines having a five-membered ring containing an oxygen or sulphur atom and one or two nitrogen atoms, and with the synthetic utility of the resulting diazonium and nitro'samino products. By way of introduction the discussion of the results obtained is preceded by a review of the chemistry of arenediazonium salts in general and hetyldiazonium salts in particular. A Review of the Chemistry of Diazonium Salts (a) Arenediazonium Salts (i) Synthesis The process of diazotisation can be defined as the transformation of a primary amine (1) into the corresponding diazonium salt (2) (Scheme 1). In the present section discussion will be confined to the R==NH2 X (1) () .h4'ry 1 diazotisation of primary arylamines and the chemistry of the resulting arenediazonium salts. The study of the diazotisation of aniline and similar compounds has a long history, stretching back to 1858 when Griess inadvertently produced the diazonium salt of picramic acid by passing NH Co +2HNO2 CO2+2N2 +3H20 11si I +HNO2 H2SON2+H20 Scheme 3 2 nitrous gases through an alcoholic solution of the corresponding 1 arylamine. Knoevenagel 2 used esters of nitrous acid, such as ethyl nitrite and amyl nitrite, as nitrosating agents for the diazotisation of arylamines and succeeded in isolating the corresponding diazonium salts. However as arenediazonium salts are not very stable, they are normally reacted in situ and not isolated. Martius discovered that the most convenient method for the preparation of arenediazonium salts was to treat a solution of the amine in a mineral acid with sodium nitrite (Scheme 2), and this is the usual method of choice. From Scheme 2 Ar—NH 2 + 2HX + NaNO2 ==Ar= 2 X+NaX+2H20 2 it can be seen that to effect diazotisation two equivalents of acid are required and normally at least another half equivalent is used. However, only one equivalent of sodium nitrite is necessary and it is normally disadvantageous to have excess of nitrite in the reaction mixture. Gies and Pfeil 4 have shown that excess of nitrite can reduce the stability of diazoniurri solutions and can also result in unwanted nitrosation of the reactants. Excess of nitrite ion can be destroyed by adding urea (3) or sulphamic acid (4) to the reaction mixture (Scheme 3). Diazotisation is normally carried out at 0 °C, achieved by external cooling or by adding ice to the reaction mixture, conditions which inevitably result in a lower rate of reaction and reduced solubility of the amine. However these undesirable features are outweighed by the necessity of maintaining as 3 low a temperature as possible in order to minimise decomposition of the diazonium product and to maximise the solubility of the free nitrous acid in the acid medium. The pH at which diazotisation is carried out is also important and is normally lower than pH2 to ensure that the equilibrium between the free base (5) and the ammonium salt (6) (Scheme 4) lies towards the right

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