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Diversity‐Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp 3 )−C(sp 3 ) Cross‐Coupling Fluoroalkylation
Author(s) -
Sheng Jie,
Ni HuiQi,
Ni ShanXiu,
He Yan,
Cui Ru,
Liao GuangXu,
Bian KangJie,
Wu BingBing,
Wang XiSheng
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202102481
Subject(s) - halide , alkyl , chemistry , catalysis , bromide , alkylation , coupling reaction , nickel , organic chemistry , combinatorial chemistry , medicinal chemistry
Monofluorinated alkyl compounds are of great importance in pharmaceuticals, agrochemicals and materials. Herein, we describe a direct nickel‐catalyzed monofluoromethylation of unactivated alkyl halides using a low‐cost industrial raw material, bromofluoromethane, by demonstrating a general and efficient reductive cross‐coupling of two alkyl halides. Results with 1‐bromo‐1‐fluoroalkane also demonstrate the viability of monofluoroalkylation, which further established the first example of reductive C(sp 3 )‐C(sp 3 ) cross‐coupling fluoroalkylation. These transformations demonstrate high efficiency, mild conditions, and excellent functional‐group compatibility, especially for a range of pharmaceuticals and biologically active compounds. Mechanistic studies support a radical pathway. Kinetic studies reveal that the reaction is first‐order dependent on catalyst and alkyl bromide whereas the generation of monofluoroalkyl radical is not involved in the rate‐determining step. This strategy provides a general and efficient method for the synthesis of aliphatic fluorides.