Merging Carbonyl Addition with Photocatalysis

Abstract

The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role in synthetically important chemical reactions in both academic and industrial contexts. Venerable transformations, including the aldol reaction, Grignard reaction, Wittig reaction, and Nozaki-Hiyama-Kishi reaction, constitute a vast and empowering synthetic arsenal. Notwithstanding, two-electron mechanisms inherently confine the breadth of accessible reactivity and topological patterns.Fostered by the rapid development of photoredox catalysis, combing well-entrenched carbonyl addition and radicals can harness several unique and increasingly sustainable transformations. In particular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach of two-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward the utilization of simple carbonyl compounds as intermolecular radical acceptors was developed. The reaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Brønsted acid activation of the carbonyl moiety prevents β-scission from occurring. Furthermore, this regioselective alkyl radical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree of atom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefin cross-metathesis, induced by visible light, has also been achieved, leveraging a radical Prins-elimination sequence.Recently, dual chromium and photoredox catalysis has been developed by us and Kanai, offering a complementary approach to the revered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polar crossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation of aldehydes and radical carbonyl alkylation can harvest the power of light and enable the use of catalytic chromium metal. Overall, exquisite levels of diastereoselectivity can be enforced via highly compact transition states. Other examples, such as the dialkylation of 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition in multicomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural product architectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoni and MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our group articulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonyl alkynylation and aldehyde trifluoromethylthiolation.This Account, in addition to the narrative of our group and others' contributions at the interface between carbonyl addition and radical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. We envisage that extending radical-to-polar crossovers beyond Nozaki-Hiyama-Kishi manifolds, taming less-activated carbonyls, leveraging multicomponent processes, and merging single electron steps with energy-transfer events will propel eminent breakthroughs in the near future.