Controllable Regioselective [3+2] Cyclizations of N-CF3 Imidoyl Chlorides and Ph3PNNC: Divergent Synthesis of N-CF3 Triazoles.

Presented herein are two distinct regiodivergent [3+2] cyclization reactions between N-CF3 imidoyl chlorides and N-isocyaniminotriphenylphosphorane (NIITP) that include flexible modulation of the electronic properties of NIITP. The regioselectivity of reactions was different in the absence and presence of the Mo catalyst. The approach provides alternative efficient and scalable routes for N-CF3 triazole synthesis, demonstrating a broad substrate scope, excellent functional group tolerance, and practical advantages.

N-CF3 Imidoyl Chlorides: Scalable N-CF3 Nitrilium Precursors for the Construction of N-CF3 Compounds.

A wide range of N-CF3 imidoyl chlorides were synthesized for the first time via the N-trifluoromethylation of nitriles in DCM by using AlCl3-activated PhICF3Cl as the CF3 source. The reactions of them with N-/O-/S-nucleophiles, as well as with 1,3-dipoles, were carried out to efficiently deliver N-CF3 amidines/imidates/thioimidates and N-CF3 azoles, demonstrating that they are a class of scalable NCF3-containing synthons in the synthesis of N-CF3 compounds.

Synthesis of N-CF3 Amidines/Imidates/Thioimidates via N-CF3 Nitrilium Ions.

An efficient methodology for the synthesis of a wide range of N-CF3 imidic acid derivatives is presented. In this reaction, N-CF3 nitrilium ions were generated via N-trifluoromethylation of nitriles using PhICF3Cl under catalysis with DMAP, followed by the capture of N-, O-, or S-centered nucleophiles to give diverse N-CF3 amidines, imidates, and thioimidates. The method provides a platform for preparing N-CF3 compounds with potential applications.

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. PhICF3 Cl 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.