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

Abstract

N-Trifluoromethyl azoles are valuable targets in medicinal chemistry,b ut their synthesis is challenging.C lassical preparation of N-CF 3 azoles relies on the functional group interconversions but suffers from tedious N-pre-functionalization and unfriendly agents.I ntroduction of the CF 3 onto the nitrogen of heterocycles provides adirect 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.T he approach involves the N-trifluoromethylationo f nitriles followed by a[ 3 + +2] cyclization between resulting N-CF 3 nitrilium derivatives and 1,3-dipoles.P hICF 3 Cl was an effective CF 3 source for the transformation. As ar esult, ag eneric platform is established to divergently synthesizeNtrifluoromethylated tetrazoles,i midazoles,a nd 1,2,3-triazoles by using sodium azide,a ctivated methylene isocyanides,a nd diazoc ompounds as dipoles.

A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles

“…Xu, Guan, and Wang et al [ 80 ] reported an alternative and scalable cyclization strategy based on N -CF 3 -containing synthons for constructing diverse N -CF 3 azoles, including N -CF 3 tetrazoles, N -CF 3 imidazoles, and N -CF 3 1,2,3-triazoles ( Scheme 13 ). This method involved using a hypervalent iodine reagent for trifluoromethylation in combination with a base to efficiently carry out the reaction.…”

Radical hydrotrifluoromethylation of ynamides: a route toward β-CF3enamides

“…During our ongoing explorations in the field of trifluoromethylation, an externally coordinated CF 3 -containing λ 3 -iodane (PhICF 3 Cl) 8 was synthesized to be used in a set of trifluoromethylation reactions. 9 Efficient trifluoromethylative bifunctionalization reactions of alkenes have been developed by our group recently. 9 a – d In order to extend the synthetic applications of PhICF 3 Cl, the trifluoromethylation of alkynes was investigated in the follow-up work.…”

Electrochemical cyclization ofN-cyanamide alkenes with CF3SO2Na to access C,N-(bis)trifluoromethylated cyclic amidines and related compounds

“…1 a–c ,2 In addition to the typical methods which relied on the functional group interconversions with tedious N -prefunctionalizations and the emerging N -CF 3 synthon approaches, 6,7 several elegant works have been reported to achieve direct electrophilic N -trifluoromethylations (Scheme 1b). 8 Recently, Bolm et al and Selander et al have accomplished a transition metal (TM)-mediated radical N -trifluoromethylation of sulfoximines and aryl nitroso derivatives, respectively. 9 However, it is still highly desirable to develop efficient approaches for the formation of N -CF 3 bonds to access structurally diverse heterocyclic scaffolds.…”