Nickel-catalyzed reductive cross-coupling of polyfluoroarenes with alkyl electrophiles by site-selective C-F bond activation

A nickel catalyzed reductive cross-coupling reactions between polyfluoroarenes and alkyl electrophiles is reported to access substituted fluoroarenes through chelation-assisted C-F activation. Diverse primary and secondary alkyl (pseudo)halides can be employed to couple with polyfluoroarenes, showing excellent regioselectivity. Furthermore, the nickel-catalyzed asymmetric cross-coupling of polyfluoroarenes with racemic alkyl halides is preliminarily explored. In addition, the practicability of the title transformation is also demonstrated by total synthesis of losmapimod and an analog as key steps. The developed method exhibits many advantages, including economic catalytic systems, commercially available alkyl electrophiles, and lack of sensitive organometallic reagents. (C) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.