[4+1] Annulation of in situ generated azoalkenes with amines: A powerful approach to access 1-substituted 1,2,3-triazoles

1-Substituted 1,2,3-triazoles represents `privileged' structural scaffolds of many clinical pharmaceuticals. However, the traditional methods for their preparation mainly rely on thermal [3 + 2] cycloaddition of potentially dangerous acetylene and azides. Here we report a base-mediated [4 + 1] annulation of azoalkenes generated in situ from readily available difluoroacetaldehyde N-tosylhydrazones (DFHZ-Ts) with amines under relatively mild conditions. This azide- and acetylene-free strategy provides facile access to diverse 1-substituted 1,2,3-triazole derivatives in high yield in a regiospecific manner. This transformation has great functional group tolerance and can suit a broad substrate scope. Furthermore, the application of this novel methodology in the gram-scale synthesis of an antibiotic drug PH-027 and in the late-stage derivatization of several bioactive small molecules and clinical drugs demonstrated its generality, practicability and applicability. (C) 2021 Published by Elsevier B.V. on be half of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

This article reports a substrate-based method for the [4 + 1] annulation reaction of azoalkenes generated from readily available difluoroacetaldehyde N-tosylhydrazones (DFHZ-Ts) with amines, leading to the high-yield synthesis of diverse 1-substituted 1,2,3-triazole derivatives under relatively mild conditions.