One-pot click chemistry using hydrazine as an azide surrogate: easy access to 1,2,3-triazole functionalities

Abstract

Click chemistry, particularly copper-catalyzed azide–alkyne cycloaddition (CuAAC), represents a powerful tool for synthesizing 1,2,3-triazoles with broad applications in medicinal chemistry and materials science. However, the handling and storage of azides pose significant safety challenges. Here we report a one-pot, chromatography-free method employing phenylhydrazine hydrochloride as an azide surrogate, which upon reaction with tert-butyl nitrite generates azides in situ, enabling efficient CuAAC with terminal alkynes in a PEG-400 : H₂O solvent system. This approach affords 1,2,3-triazoles in good to excellent yields, tolerates diverse functional groups, and facilitates late-stage functionalization of natural products. The method demonstrates excellent green chemistry metrics, including a low E-factor and process mass intensity, underscoring its sustainability and operational simplicity. This strategy offers a practical and safer alternative for triazole synthesis with potential utility in drug discovery and chemical biology.