Nickel-Catalyzed, Enantioselective Hydrofluoromethylation of Olefins: Access to Chiral α-Fluoromethylated Amides and Esters
Yiming Du, Shuxin Chen, Hexiang Cao, Yichen Zhang, Hongtao Lei, Guoqin Xia*, Huicai Huang* and Zhaodong Li*
*Zhongshan Institute for Drug Discovery, Guangdong 528400; Guangzhou University of Chinese Medicine, Guangzhou 510006; South China Agricultural University, 510642 Guangzhou, China,
Email: xiaguoqin
simm.ac.cn, huanghcgzucm.edu.cn,
scaulizhaodongscau.edu.cn
Y. Du, S. Chen, H. Cao, Y. Zhang, H. Lei, G. Xia, H. Huang, Z. Li, Org. Lett., 2023, 25, 2218-2222.
DOI: 10.1021/acs.orglett.3c00357
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Abstract
A nickel-catalyzed enantioselective hydrofluoromethylation of enamides and enol esters with ICH2F as the fluoromethyl source provides chiral α-fluoromethylated amides as well as esters with wide functional group compatibility as well as excellent enantioselectivity.
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General Experimental Procedure for Nickel-Catalyzed Hydrofluoromethylation of Olefins
A Schlenk-tube equipped with a magnetic stir bar was charged with enamide or enol ester (1.0 equiv, 0.2 mmol), NiI2 (10 mol%, 0.02 mmol), ligand (12 mol%, 0.024 mmol), KF (2.0 equiv, 0.4 mmol) and then evacuated and backfilled with N2 for 3 times. Afterwards, ICH2F (2.0 equiv, 0.4 mmol), PMHS (100 μL), DMA (1.0 mL) were added consecutively under N2 atmosphere. The tight tube was stirred at room temperature for 24 h. After 24 h, the resulting mixture was extracted with DCM (3 x 15 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by column chromatography on silica gel to give the desired product.
Key Words
fluorohydrins, 1,2-fluoroamines, PMHS
ID: J54-Y2023
