Chemoselective synthesis of 1,3,4-thiadiazoles from acyl hydrazines and nitroalkanes using elemental sulfur

Abstract

Substituted 1,3,4-thiadiazoles find extensive use in pharmaceutical, agricultural, and materials chemistry. The incorporation of adaptable heterocyclic pharmacophores results in tunable hybrid molecules with diverse medicinal properties. In this study, the direct coupling of primary nitroalkanes and acyl hydrazines (hydrazides) is achieved simply by the mild action of S₈ and Na₂S. This method now delivers wide varieties of multi-functionalized 1,3,4-thiadiazoles in excellent yields. The reaction is scalable, shows a broad substrate scope, and tolerates a wide range of functional groups. The power of this method is exemplified with over twenty acyl hydrazines, spanning a diverse range of nitroalkane substrate classes, as well as the concise and scalable synthesis of 1,3,4-thiadiazole derivatives of over ten distinct types of drugs and peptides.