Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions

Abstract

Trifluoromethyl cationic carbyne (CF₃ C⁺ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF₃ C⁺ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF₃ C⁺ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD₃ -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

Keywords: Cycloadditions; N-heteroarenes; Trifluorodiazoethane; Trifluoromethyl Rh-carbynoid.