Azirine-Enabled Regioselective Synthesis of N-Alkyl Pyrazoles and Indole–Pyrazole Conjugates via Cu-Catalysed N–N Bond Formation

Abstract

An efficient and sustainable strategy has been developed for the regioselective synthesis of a new class of aliphatic N-substituted pyrazoles using azirine-2H-carbaldehydes as versatile building blocks. The transformation proceeds via a copper-catalyzed intramolecular azirine ring-opening, followed by N-N bond formation in a cascade sequence, affording a library of 55 N-alkyl pyrazoles in good to excellent yields under mild, operationally simple, and ambient conditions. The strategy efficiently accommodates aliphatic amines and α-amino esters, delivering aliphatic pyrazoles with comparable efficiency. Moreover, the synthesis of novel classes of indole-pyrazole conjugates underscores the versatility of this approach. This protocol avoids hazardous reagents and harsh conditions, offering a practical alternative to conventional pyrazole synthesis. The broad substrate scope and synthetic utility of this method, exemplified by the rapid access to drug-like scaffolds, highlight its potential application in medicinal chemistry