Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones

Abstract

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

Keywords: carbene; catalysis; density functional theory; late-stage functionalization; photochemistry.

Figure 1.

(A) Selected examples of ketones in pharmaceutically relevant compounds. (B) Standard approaches for ketone synthesis. (C) Acyl azolium radicals for the construction of aryl, alkyl, and α-amino ketones; ORP = oxidatively generated radical precursor, CDI = carbonyldiimidazole.

Figure 2.

(A) Radical coupling accessibility model for aliphatic acyl azoliums with spin density distributions of optimized aliphatic acyl azolium structures (R = CH₂Ph). (B) Proposed mechanism for the combined NHC/photoredox-catalyzed construction of aliphatic and α-amino ketones. Reported energies are for Az-B in kcal/mol.

Figure 3.

Computed potential energy surfaces for benzyl radical coordination to C1 or C2 of the aliphatic acyl azolium radical (III) with Az-A or Az-B.