Metal-Free C-H Difluoromethylation of Imidazoles with the Ruppert-Prakash Reagent
J. Org. Chem. 2023, 88 (1), 163-171
The reaction of trimethyl(trifluoromethyl)silane–tetrabutylammonium difluorotriphenylsilicate (CF3SiMe3‑TBAT) with a series of imidazoles gives products of the formal difluorocarbene insertion into the C–H bond at the C‑2 position (i.e., C-difluoromethylation). According to NMR spectra, the corresponding 2‑(trimethylsilyl)difluoromethyl-substituted derivatives are likely formed as the intermediates in the reaction, and then, they slowly convert to 2‑difluoromethyl‑substituted imidazoles. Quantum chemical calculations of two plausible reaction mechanisms indicate that it proceeds through the intermediate imidazolide anion stabilized through the interaction with solvent molecules and counterions. In the first proposed mechanism, the anion reacts with difluorocarbene without an activation barrier, and then, the CF2 moiety of the adduct attacks the CF3SiMe3 molecule. After the elimination of the CF3 anion, 2‑(trimethylsilyl)difluromethyl-substituted imidazole is formed. Another possible reaction pathway includes silylation of imidazolide anion at the N‑3 atom, followed by the barrierless addition of difluorocarbene at the C‑2 atom and then by 1,3‑shift of the SiMe3 group from N‑3 to the carbon atom of the CF2 moiety. Both proposed mechanisms do not include steps with high activation barriers.