Copper-Mediated Valence Tautomerism Enables α -C(sp3)–H Alkylation of 1,3-Dicarbonyl Compounds and Tryptophans via Photocatalysis

Abstract Carbonyl α-C(sp3)–H functionalization is a key approach to access functionalized pharmaceuticals, agrochemicals, and bioactive peptides. Conventional two-electron enol tautomerization strategies for this transformation often suffer from harsh reaction conditions and limited substrate tolerance. While valence tautomerism (VT) enables radical-type C–H activation, such reactivity has been exclusively realized with nickel catalysis, and copper-mediated VT remains unexplored for α-C(sp3)–H activation of carbonyls. Here, we present a dual photoredox/copper catalytic strategy that exploits copper-mediated VT to generate α-carbonyl alkyl radicals. These radicals undergo radical–radical cross-coupling with nucleophilic radicals generated by photocatalytic decarboxylation, delivering α-carbonyl alkylation products. The protocol features mild conditions and broad functional group tolerance, supporting peptide late-stage modification and gram-scale synthesis. Mechanistic studies and density functional theory (DFT) calculations validate a Cu(III)-mediated VT pathway for radical generation. This work establishes copper as a viable VT catalytic platform, expands the scope of dual photoredox/metal catalysis, and offers a versatile tool for biomolecular derivatization.