Difluorocarbene enables to access 2-fluoroindoles from ortho-vinylanilines

Jianke Su, Xinyuan Hu, Hua Huang, Yu Guo and Qiuling Song ()
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Jianke Su: Huaqiao University
Xinyuan Hu: Huaqiao University
Hua Huang: Huaqiao University
Yu Guo: Huaqiao University
Qiuling Song: Huaqiao University

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract 2-Fluoroindoles as an important structural scaffold are widely existing in many bioactive or therapeutic agents. Despite their potential usefulness, efficient constructions of 2-fluoroindole derivatives are very sparce. The development of straightforward synthetic approaches to access 2-fluoroindoles is highly desirable for studying their fundamental properties and applications. Herein, we report an efficient and general strategy for the construction of 2-fluoroindoles in which a wide variety of 2-fluoroindoles were accessed with high efficiency and chemoselectivity. Instead of starting from indole skeletons, our strategy constructs indole scaffolds alongside the incorporation of fluorine atom on C2 position in a formal [4+1] cyclization from readily accessible ortho-vinylanilines and difluorocarbene. In our protocol, commercially accessible halodifluoroalkylative reagents provide one carbon and one fluorine atom by cleaving one C-N tertiary bond and forming one C-N bond and one C-C double bond with ortho-vinylanilines. Downstream transformations on 2-fluoroindoles lead to various valuable bioactive molecules which demonstrated significant synthetic advantages over previous reports. And mechanistic studies suggest that the reaction undergoes a cascade difluorocarbene-trapping and intramolecular Michael addition reaction followed by Csp3-F bond cleavage.

Date: 2021
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DOI: 10.1038/s41467-021-25313-z

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