Merging Carbonyl Addition with Photocatalysis

The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role insynthetically important chemical reactions in both academic and industrial contexts. Venerabletransformations, 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 carbonyladdition and radicals can harness several unique and increasingly sustainable transformations. Inparticular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach oftwo-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward theutilization of simple carbonyl compounds as intermolecular radical acceptors was developed. Thereaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Bronsted acid activationof the carbonyl moiety prevents beta-scission from occurring. Furthermore, this regioselective alkylradical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree ofatom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefincross-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 therevered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polarcrossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation ofaldehydes 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 dialkylationof 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition inmulticomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural productarchitectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoniand MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our grouparticulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonylalkynylation and aldehyde trifluoromethylthiolation. This Account, in addition to the narrative of our group and others'contributions at the interface between carbonyl addition andradical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. Weenvisage 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 eminentbreakthroughs in the near future.