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 for the regioselective synthesis of a new class of aliphatic N-substituted pyrazoles has been developed, using azirine-2H-carbaldehydes as versatile building blocks. The transformation proceeds via a copper-catalysed 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.