Diversity-Oriented Synthesis of Aliphatic Fluorides via Reductive C(sp3)-C(sp3) Cross-Coupling Fluoroalkylation

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.

Automated summary

Monofluorinated alkyl compounds play a significant role in pharmaceuticals, agrochemicals, and materials. This study demonstrates a direct nickel-catalyzed monofluoromethylation of unactivated alkyl halides using a cost-effective industrial raw material, bromofluoromethane, showing high efficiency, mild conditions, and excellent functional-group compatibility. The research establishes a new method for the synthesis of aliphatic fluorides through reductive cross-coupling of alkyl halides.