The mechanism of two reactions leading to isomeric 2-(N,N-disubstituted amino)thiazol-5-yl ketones

Abstract

A study has been made of the condensations between N-acyl-N′,N′-disubstituted thioureas and α-halogeno ketones [reaction (I)], and between N,N-disubstituted thioureas and 2-bromo-1,3-diketones [reaction (II)]. The mechanistic details were elucidated by using substrates with pairs of (almost) equally reactive but spectrometrically distinguishable acyl groups, e.g., CH₃CO and CD₃CO. In the presence of added base (triethylamine) both reactions proceed through a common open-chain 1,3-diketone; from this, isomeric products are formed by nucleophilic attack at the alternative carbonyl groups to give cyclic intermediates which then undergo rate-limiting dehydration. If base is not added the media become acidic. Reaction (II) follows its previous course but the relative rates of the stages are reversed. In reaction (I) the initial cyclic intermediate is dehydrated so rapidly that the open-chain 1,3-diketone is not formed, and only one isomer is produced.

Both reactions are useful preparatively. For example, by adding or omitting triethylamine a typical reaction (I) was induced to give 1-(5-p-methoxybenzoyl-4-p-nitrophenylthiazol-2-yl)hexahydroazepine (yield 79%) or the isomeric 4-p-methoxyphenyl-5-p-nitrophenyl compound (78%).