Expanding the chemical space of 3(5)-functionalized 1,2,4-triazoles.

Abstract

An efficient approach to the gram-scale synthesis of 3(5)-substituted, 1,3- and 1,5-disubstituted 1,2,4-triazole-derived building blocks is described. The key synthetic precursors – 1,2,4-triazole-3(5)-carboxylates (20 examples, 35–89% yield) were prepared from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydrochloride. Further transformations were performed following the convergent synthetic strategy and allowed the preparation of 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters (16 examples, 25–75% yield), 3(5)-substituted, 1,3- and 1,5-disubstituted carboxylate salts (18 examples, 78–93% yield), amides (5 examples, 82–93% yield), nitriles (5 examples, 30–85% yield), hydrazides (6 examples, 84–89% yield), and hydroxamic acids (3 examples, 73–78% yield). Considering wide applications of the 1,2,4-triazole motif in medicinal chemistry, these compounds are valuable building blocks for lead-oriented synthesis; they have also great potential for coordination chemistry.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10593-022-03064-z.