Metallaphotoredox Decarboxylative Arylation of Natural Amino Acids via an Elusive Mechanistic Pathway

The merger of photoredox and nickel catalysis for the decarboxylative arylation of carboxylic acids has evolved into an effective strategy to forge C-C bonds from readily available feedstock. Despite its rapid industrial adoption, the mechanism of this dual-catalyzed cross-coupling reaction has remained unclear and under-studied. Here, we propose an alternative mechanism for the photoredox-Ni dual-catalyzed decarboxylative arylation of alpha-amino acids based on control experiments with (NiArBr)-Ar-II complexes, cyclic voltammetry (CV), and computational studies. Our mechanistic studies revealed that a Ni-0-Ni-II-Ni-I-Ni-II-Ni-0 cycle is feasible in the dual- catalyzed C-sp(2)-C-sp(3) cross-coupling. Distinct from previous mechanism proposals, we show with a series of CV studies and density functional theory (DFT) calculations that a single electron transfer reduction of (NiArBr)-Ar-II to (NiAr)-Ar-I by Ir-II is thermodynamically favorable. Reductive elimination via a Ni-II-species rather than via a Ni-III-species is also supported by DFT calculations. Those mechanistic insights allowed for the reaction scope to be extended to encompass alpha-amino acids bearing pharmacophoric elements, which were previously unexplored coupling partners. alpha-Amino acids bearing broad functional groups, including heterocycles, successfully underwent decarboxylative arylation with a diverse set of aryl bromides. This strategy represents an advance in photoredox and Ni-catalysis and broadens its industrial applicability as well as mechanistic understanding.