A Novel Convenient Synthesis of 1,3,4-Oxadiazol-2-ones and -thiones from N-tert-Butyldiacylhydrazines

Abstract

An attractive, novel, convenient process for the preparation of 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones from the reaction of various equivalent and non-equivalent N-tert-butyldiacylhydrazines with potassium tert-butoxide followed by treatment with phosgene or thiophosgene, respectively, has been discovered. The 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones are confirmed both analytically and chemically. Various equivalent and non-equivalent N-tert-butyldiacylhydrazines are conveniently synthesized from the reaction of tert-butylhydrazine hydrochloride in the presence of i-Pr₂NEt, with acid chloride #1 followed by subsequent treatment with acid chloride #2. Both the syntheses of 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones, as well as N-tert-butyldiacylhydrazines, are easily performed on multigram scales.

Key words

cyclization - heterocycles - regioselectivity - hydrazine - phosgene

References

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1

Tebufenozide (1a) is commercially available.

8

We decided to further chemically validate the structure of 4a utilizing Gogoi’s method [7] for the synthesis of 3,5-disubsti-tuted-3H-[1,3,4]-oxadiazol-2-ones. We synthesized N’-(3,5-dimethylbenzoyl)hydrazinecarboxylic acid ethyl ester from the reaction of a CH₂Cl₂ solution of ethyl carbazate with 3,5-dimethylbenzoyl chloride in the presence of i-Pr₂NEt. Reaction of N’-(3,5-dimethylbenzoyl)hydrazinecarboxylic acid ethyl ester with POCl₃ afforded 5-(3,5-dimethylphenyl)-3H-[1,3,4]-oxadiazol-2-one (7), which was analytically identical to compound 7 synthesized via Scheme [2] (Table [2] ). Benzoylation of 7 with 4-ethylbenzoyl chloride afforded 5-(3,5-dimethylphenyl)-3-(4-ethylbenozyl)-3H-[1,3,4]-oxadiazol-2-one (4a), which was identical in all respects to 4a synthesized via our phosgene/N-tert-butyldiacylhydrazine route.