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

• Published in: Angewandte Chemie International Edition Vol. 60; no. 27; pp. 15020 - 15027
• Main Authors: Sheng, Jie, Ni, Hui‐Qi, Ni, Shan‐Xiu, He, Yan, Cui, Ru, Liao, Guang‐Xu, Bian, Kang‐Jie, Wu, Bing‐Bing, Wang, Xi‐Sheng
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 25-06-2021
• Edition: International ed. in English
• Subjects: Agrochemicals; Aliphatic compounds; Alkyl compounds; Bioactive compounds; Biological activity; Bromides; Catalysts; Coupling (molecular); Cross coupling; Drugs; Fluorides; Halides; late-stage fluoroalkylation; monofluoromethylation; Nickel; Pharmaceuticals; Raw materials; reductive cross-coupling; Synthesis; Reductive Cross-Coupling; monofluoromethylation; nickel; late-stage fluoroalkylation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202102481

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(sp3)‐C(sp3) 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.
A direct nickel‐catalyzed monofluoroalkylation of unactivated alkyl halides has been established, by demonstrating the first example of reductive C(sp3)−C(sp3) cross‐coupling fluoroalkylation. These transformations exhibited high efficiency, mild conditions, and excellent functional‐group compatibility, especially for a range of pharmaceuticals and biologically active compounds.