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 information: The online version contains supplementary material available at 10.1007/s10593-022-03064-z.

Keywords: 1,2,4-triazoles; acyl hydrazides; alkylation; cyclization; functional groups; regioisomers.

Figure 1.

The chemical structures of ribavirin and voriconazole.

Scheme 1.

The literature methods for the synthesis of 1,2,4-triazole-3(5)-carboxylates 1

Figure 2.

Important correlations observed for compounds 14b and 15a,b,f.

Scheme 2.

Synthesis of 1,2,4-triazole-derived carbonitriles 30b, 31b, and 32b,h,p