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

• Published in: Angewandte Chemie International Edition Vol. 62; no. 9; pp. e202215891 - n/a
• Main Authors: Wu, Kai, Zhang, Xuyang, Wu, Liang‐Liang, Huang, Jie‐Sheng, Che, Chi‐Ming
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 20.02.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Asymmetric Catalysis; Biological activity; Carbenes; Catalytic converters; Chemistry; Chemistry, Multidisciplinary; C−H Activation; Diazo Compounds; Hydrogen bonds; Insertion; Physical Sciences; Rhodium; Ruthenium; Science & Technology; Selectivity; Substrates; Trifluoromethyl; INTRAMOLECULAR CYCLOPROPANATION; A SYNTHETASE INHIBITION; C-H Activation; CRYSTAL-STRUCTURE; Carbenes; IN-SITU GENERATION; C-H BONDS; ALKENES; Asymmetric Catalysis; Diazo Compounds; Trifluoromethyl; CARBENE INSERTION; DUAL ACTIVITIES; F-19 NMR; ANTIASTHMATIC AGENTS; C−H Activation
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202215891

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.