CF2H-synthon enables asymmetric radical difluoroalkylation for synthesis of chiral difluoromethylated amines

Peng Liu, Yan He, Chen-Hui Jiang, Wei-Ran Ren, Ruo-Xing Jin, Ting Zhang, Wang-Xuan Chen, Xuan Nie () and Xi-Sheng Wang ()
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Peng Liu: University of Science and Technology of China
Yan He: University of Science and Technology of China
Chen-Hui Jiang: University of Science and Technology of China
Wei-Ran Ren: University of Science and Technology of China
Ruo-Xing Jin: University of Science and Technology of China
Ting Zhang: University of Science and Technology of China
Wang-Xuan Chen: University of Science and Technology of China
Xuan Nie: University of Science and Technology of China
Xi-Sheng Wang: University of Science and Technology of China

Nature Communications, 2025, vol. 16, issue 1, 1-8

Abstract: Abstract The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules.

Date: 2025
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DOI: 10.1038/s41467-025-55912-z

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