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(sp3)−H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium‐catalyzed α‐CF3‐α‐alkyl carbene insertion in...

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Veröffentlicht in:Angewandte Chemie International Edition 2023-02, Vol.62 (9), p.e202215891-n/a
Hauptverfasser: Wu, Kai, Zhang, Xuyang, Wu, Liang‐Liang, Huang, Jie‐Sheng, Che, Chi‐Ming
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Sprache:eng
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Zusammenfassung:Trifluoromethyl‐bearing 5‐membered rings are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust C(sp3)−H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium‐catalyzed α‐CF3‐α‐alkyl carbene insertion into C(sp3)−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 α‐CF3‐α‐alkyl carbene complexes underwent stoichiometric reactions to give C−H insertion products, lending evidence for the involvement of metal α‐CF3‐α‐alkyl carbene species in the catalytic cycle. DFT calculations revealed that the π⋅⋅⋅π attraction and intra‐carbene C−H⋅⋅⋅F hydrogen bond elucidate the origin of selectivity of the benzylic C−H insertion reactions. A modular approach to access CF3‐bearing 5‐membered carbo‐ and heterocycles via catalytic C (sp3)−H insertion is demonstrated. In the case of carbocycles, an asymmetric benzylic C−H insertion process allowed to reach high regio‐, diastereo‐ and enantioselectivities. This protocol can be applied to the synthesis of chiral CF3 analogues of medicinal agents and natural products. The origin of selectivity was investigated by DFT calculations.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202215891