An N-Trifluoromethylation/Cyclization Strategy for Accessing Diverse N-Trifluoromethyl Azoles from Nitriles and 1,3-Dipoles

N-Trifluoromethyl azoles are valuable targets in medicinal chemistry, but their synthesis is challenging. Classical preparation of N-CF₃ azoles relies on the functional group interconversions but suffers from tedious N-pre-functionalization and unfriendly agents. Introduction of the CF₃ 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 NCF₃-containing synthons for constructing N-CF₃ azoles. The approach involves the N-trifluoromethylation of nitriles followed by a [3+2] cyclization between resulting N-CF₃ nitrilium derivatives and 1,3-dipoles. PhICF₃Cl was an effective CF₃ 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.