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Studies in isothiazole chemistry: I. isothiazolo [5,4-b] pyridines. II. approaches to isothiazolynes

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  • Qd Chemistry
  • Chemistry


The first part of this thesis describes investigations on the synthesis and chemistry of isothiazolo[5,4-b] pyridines. The syntheses of a number of alkyl isothiazolo[5,4-b] pyridines from 5-amino-3-methylisothiazole under conditions of the Skraup reaction are described and their nuclear magnetic resonance spectra are discussed. The reactions of 3-methyl- and 3,6-dimethylisothiazolo[5,4-b] pyridine have been studied. In particular they did not undergo nitration under the conditions employed and whereas the 3-methyl compound did not condense with benzaldehyde, 3,6-dimethylisothiazolo[5,4-b] pyridine gave mono-styryl products with benzaldehyde, and p-nitrobenzaldehyde. Potassium permanganate oxidation gave isothiazolo[5,4-b] pyrid-3(2H)-one 1,1-dioxides rather than the expected isothiazolo[5,4-b] pyridine carboxylic acids and chromic acid oxidation resulted in cleavage of the isothiazole ring to give 2,3-disubstituted pyridines. Ethyl 4-hydroxy-3-methylisothiazolo[5,4-b] pyridine-5-earboxylabe was readily obtained by thermal cyclisation of the malonate from 5-amino-3-methylisothiazole and ethoxymethylenemalonic ester. The hydroxyl ester was converted to a number of substituted isothiazolo[5,4-b] pyridines. In addition it has been established that methylation at nitrogen rather than oxygen occurs with both the 4-hydroxy ester and the 4-hydroxy compound which has been shown to exist preferentially in the carbonyl form, namely 3-methylisothiazolo[5,4-b] _7pyrid-4-one. The reaction of 5-amino-3-methylisothiazole with ethylacetoacetate and with acetylacetone under the conditions of the Conrad Limpach reaction and the Combes reaction respectively, did not give isothiazolo[5,4-b] pyridines. The latter gave a product which has been tentatively formulated as 5-acetyl-3,4-dimethylisothiazole. The second part of this work describes the synthesis of 5-amino-3-chloroisothiazole-4-carboxylic acid, 4-amino-3-methylisothiazole- 5-carboxylic acid and 4-aminoisothiazole-3-carboxylic acid and experiments aimed at investigating the possible intermediacy of isothiazolynes. Attempts to generate and trap isothiazolynes by their aprotic diazotisation with isoainyl nitrite in the presence of 2,3,4,5-tetraphenylcyclopentadienone gave only small quantities of isothiazoles in addition to a variety of oxidation products derived from the arynophile. 4-Amino3-methylisothiazole-5-carboxylic acid gave isothiazolyl-substituted products when furan and anthracene were used as trapping agents, and it was found that the reaction of isothiazole-4-diazonium carboxylate hydrochloride and propylene oxide in the presence of furan gave 4,-cyano-1,2,3-thiadiazole. In none of the reactions investigated was there any evidence for the formation of inothiazolyne intermediates.

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