A Convergent, Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp3)-H Activation

Trifluoromethyl-bearing 5-membered rings are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust C(sp(3))-H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium-catalyzed alpha-CF3-alpha-alkyl carbene insertion into C(sp(3))-H bonds of a broad range of substrates to access 7 types of CF3-bearing saturated 5-membered carbo- and heterocycles. The reaction is particularly effective for benzylic C-H insertion exerting good site-, diastereo- and enantiocontrol, and applicable to the synthesis of chiral CF3 analogues of bioactive molecules. Ruthenium alpha-CF3-alpha-alkyl carbene complexes underwent stoichiometric reactions to give C-H insertion products, lending evidence for the involvement of metal alpha-CF3-alpha-alkyl carbene species in the catalytic cycle. DFT calculations revealed that the pi center dot center dot center dot pi attraction and intra-carbene C-H center dot center dot center dot F hydrogen bond elucidate the origin of selectivity of the benzylic C-H insertion reactions.

Automated summary

In this study, we reported a modular approach to the synthesis of trifluoromethyl-bearing 5-membered rings through direct rhodium-catalyzed carbene insertion into C(sp(3))-H bonds. The reaction showed good control over site- and stereochemistry, and was applicable for the synthesis of chiral CF3 analogues. Stoichiometric reactions of ruthenium carbene complexes provided evidence for the involvement of metal carbene species in the catalytic cycle. DFT calculations explained the origin of selectivity in the benzylic C-H insertion reactions.