An <i>N</i>‐Trifluoromethylation/Cyclization Strategy for Accessing Diverse <i>N</i>‐Trifluoromethyl Azoles from Nitriles and 1,3‐Dipoles
Ru Zhong Zhang, Ru Xue Zhang, Shuang Wang, Cong Xu, Wei Guan, Mang Wang
Abstract
Abstract N‐Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N‐CF 3 azoles relies on the functional group interconversions but suffers from tedious N‐pre‐functionalization and unfriendly agents. Introduction of the CF 3 onto the nitrogen of heterocycles provides a direct route to such motifs, but the N‐trifluoromethylation remains underdeveloped. Reported here is an alternative and scalable cyclization strategy based on NCF 3 ‐containing synthons for constructing N‐CF 3 azoles. The approach involves the N‐trifluoromethylation of nitriles followed by a [3+2] cyclization between resulting N‐CF 3 nitrilium derivatives and 1,3‐dipoles. PhICF 3 Cl was an effective CF 3 source for the transformation. As a result, a generic platform is established to divergently synthesize N‐trifluoromethylated tetrazoles, imidazoles, and 1,2,3‐triazoles by using sodium azide, activated methylene isocyanides, and diazo compounds as dipoles.