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 NiII center followed by reductive elimination. Independent gradient model based on Hirshfeld partition (IGMH) analysis suggests that the orientation of the phosphonate group (P=O…π interaction) is expected to play an essential role in controlling the enantioselectivity.

Keywords: three-component, enantioselective, nickel/visible light-catalyzed, reductive cross-coupling reactions, chiral α-aryl phosphonates