Enantioselective domino alkyl arylation of vinyl phosphonates by combining photoredox and nickel catalysis

Abstract

A nickel/photoredox mediated asymmetric domino alkyl arylation of vinyl phosphonates to generate a diverse array of enantioenriched α-aryl phosphonates is disclosed. This asymmetric three-component difunctionalization couples aryl halides and alkyl bromides with vinyl phosphonates, exhibiting excellent chemo- and regioselectivity under mild reaction conditions. The method avoids the need for pre-formed organometallics and phosphorus halides. Mechanistic and DFT studies suggest that photoexcited [4CzIPN]∗ oxidizes diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (HEH) to generate the [4CzIPN]^•–, which then reduces the alkyl bromide to form alkyl radicals that undergo Giese addition to the vinyl phosphonate. At the same time, Ni⁰ oxidatively adds the aryl bromide followed by enantiodetermining oxidative radical trapping of the phosphonate-based radical by the tetrahedral Ni^II center followed by reductive elimination. Independent gradient model based on Hirshfeld partition (IGMH) analysis suggests that the orientation of the phosphonate group (PO ^… π interaction) is expected to play an essential role in controlling the enantioselectivity.