Modular Access to Thiazoles Using Bromoisocyanoalkenes

Significance

Isocyanoalkenes are often employed as a ‘convertible isocyanide’ in multicomponent reactions for the installation of the terminal isocyanide carbon, though there are very few reports of protocols that exploit the reactivity of the C = C bond. However, functionalizing this moiety can be challenging as the two π-systems are not conjugated, leading to the β-carbon being weakly polarized and to nucleophiles preferentially attacking the carbenoid-like terminal isocyanide. The current report describes the synthesis of a range of substituted thiazoles through use of bromoisocyanoalkenes, in which the addition of NaSH to the β-position occurs through a S_NV_p displacement as opposed to the conventional addition–elimination.

Comment

The synthesis of the desired β-bromoisocyanoalkenes was achieved through a two-step bromination–dehydration of the corresponding vinyl formamides. While mixtures of Z/E geometric isomers are obtained, it is important to note that the E-isomer does not react in the subsequent cyclization, which is consistent with the proposed S_NV_p mechanism. For the cyclization step, judicious selection of the solvent was critical to minimize hydrolysis of the isocyanide, with acetonitrile proving to be optimal even though NaSH was only sparingly soluble in the reaction medium. A range of 4-/5-monosubstituted and 4,5-disubstituted thiazoles was synthesized with deuterium incorporation experiments supporting a mechanism involving the intermediacy of an enethiolate.

Publication History

Article published online:
23 June 2025

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