Enantioselective synthesis of β- and α-amino ketones through reversible alkane carbonylation

Abstract

The direct incorporation of alkanes and CO into value-added chiral products through alkane carbonylation is a desirable transformation; however, it remains inefficient. The carbonylation of alkanes via photoirradiated radical addition to CO requires mild reaction conditions but suffers from low conversion due to equilibrium constraints. Here an equilibrium-leveraging strategy that combines alkane carbonylation with various enantioselective transformations is reported. The combination of tetra-n-butylammonium decatungstate and chiral sodium phosphate catalysts enables alkane carbonylation/enantioselective Mannich reaction and alkane carbonylation/enantioselective radical addition cascade processes for the enantioselective synthesis of β-amino and α-amino ketones from alkanes, CO and anilines by breaking the equilibrium of reversible photocatalytic C–H carbonylation. While both reactions can tolerate a broad scope of cyclic alkanes and anilines, the synthetic method to synthesize β-amino ketones can use a range of aliphatic ketones as substrates. The synthetic process to form β-amino ketones can be readily scaled-up through use of an integrated continuous-flow and batch set-up, providing efficient gram-scale synthesis. Mechanistic studies reveal that the synthesis of α-amino ketones proceeds through the asymmetric addition of an acyl radical to an imine intermediate. Alkane carbonylation through photocatalytic alkyl radical addition to CO is a challenge. Now, an equilibrium-leveraging strategy which combines the direct carbonylation of alkanes with CO with onwards enantioselective transformations is reported, providing an enantioselective method for the synthesis of β-amino and α-amino ketones.