Nickel-catalysed enantioselective cross-electrophile coupling reaction with the retention of the β-fluorine atom

Abstract

Monofluoromethyl compounds meet the criteria for designing and developing sustainable organofluorines without the presence of per- or polyfluorinated fragments. Nevertheless, the asymmetric synthesis of chiral monofluoromethyl compounds under mild conditions remains a demanding task in this field, partially owing to the challenge that β-fluorine elimination is often observed as a competitive side-reaction during metal-catalysed cross-coupling reactions. In this study, we disclose a nickel-catalysed enantioselective reductive cross-coupling reaction of acid chlorides with a newly developed monofluoromethyl building block—brominated fluoroethanol benzoate (BFEB). This transformation enables the preparation of a series of chiral α-monofluoromethyl acyloin derivatives in good yields with high enantioselectivities. Experimental and computational mechanistic studies reveal that the key to the realization of this protocol hinges upon the generation and harnessing of an unprecedented nucleophilic monofluoromethyl ketyl-type radical. The undesired β-fluoride elimination process was largely inhibited, attributed to the utilization of the bulky bisoxazoline ligand.