Ring-Expansion/Cross-Coupling Cascade of Ketones via Radical Sorting

Abstract

Ring-expansion/cross-coupling cascade of saturated carbocycles remains an underdeveloped strategy, despite its immense potential to provide rapid access to molecular architectures that are challenging to synthesize in a single operation. Herein, we report a dual photoredox/nickel catalyzed ring-expansion/cross-coupling cascade of ketones through radical sorting, employing carboxylic acid derivatives as C(sp3) coupling partners. This protocol is broadly applicable to the one-carbon ring-expansion and concomitant functionalization of diverse 5-, 6-, 7-, 8-, 12-, 13-, 14-, and 16-membered ketones using various redox-active esters that bear a wide range of functional groups. Remarkably, the strategy can also be extended to three-carbon ring-expansion, enabling remote functionalization of ketone frameworks. Furthermore, the methodology is applicable to acyclic ketones, enabling a chain-extension/cross-coupling cascade. The synthetic utility of the methodology is demonstrated through late-stage scaffold remodeling of drugs and natural products, as well as the synthesis of 3-methylmuscone. Mechanistic investigations, supported by DFT calculations, shed light on selectivity in the coupling step and provide compelling evidence for a homolytic bimolecular substitution (SH2) pathway.