Catalytic Asymmetric C(sp3)–H Carbene Insertion Approach to Access Enantioenriched 3‑Fluoroalkyl 2,3-Dihydrobenzofurans

• Published in: ACS catalysis Vol. 11; no. 22; pp. 14293 - 14301
• Main Authors: Zhang, Xinyu, Sivaguru, Paramasivam, Zanoni, Giuseppe, Han, Xinyue, Tong, Minghui, Bi, Xihe
• Format: Journal Article
• Language: English
• Published: American Chemical Society 19.11.2021
• Subjects: rhodium carbene; fluoroalkyl diazo; chiral dihydrobenzofurans; fluoroalkyl N-triftosylhydrazones; asymmetric C−H insertion
• ISSN: 2155-5435; 2155-5435
• DOI: 10.1021/acscatal.1c04523

Fluoroalkyl diazo compounds are versatile reagents for introducing fluoroalkyl groups into organic compounds. Despite their uses as carbene precursors in many reactions, asymmetric fluoroalkyl carbene insertion into C­(sp3)–H bonds remains quite rare. Herein we report the rhodium-catalyzed enantioselective intramolecular insertion of a carbene into ether α-C­(sp3)–H bonds under mild conditions using operationally safe and easily decomposable fluoroalkyl N-triftosylhydrazones as the carbene source. This method enables the efficient synthesis of a range of previously inaccessible chiral fluoroalkyl 2,3-dihydrobenzofuran derivatives in good to high yields with excellent diastereoselectivities and high enantioselectivities. The usefulness of this transformation is exemplified in the straightforward synthesis of several CF3 analogues of natural products and bioactive molecules. DFT calculations provide insights into the underlying stepwise pathway and the origin of the enantioselectivity.