Virtual Ligand-Assisted Screening for the Generation of Ketyl Radicals from Alkyl Ketones via Photoexcited Palladium Catalysis

Ketyl radicals are versatile radical intermediates that enable diverse C-C-bond-forming reactions. However, their generation from substrates with highly negative potentials such as alkyl ketones via single-electron reduction remains underdeveloped. In this study, we report a new strategy that harnesses the strong reducing power of photoexcited palladium species to provide access to ketyl radicals from alkyl ketones and to promote subsequent C-C-bond-forming reactions. The key to this approach is a computationally guided virtual ligand-assisted screening (VLAS) strategy. Mechanistic investigations revealed that back-electron transfer (BET) is the major factor suppressing reactivity. By systematically evaluating virtual phosphine ligands with varying electronic and steric properties, we established design guidelines for ligands that effectively suppress BET and promote the desired transformations. Using the optimized ligands identified through VLAS, we developed efficient reductive couplings and Heck-type reactions involving both unactivated alkenes and alkynes, which are challenging substrates under conventional SmI₂-mediated conditions. This work highlights a powerful paradigm that integrates photoexcited transition-metal catalysis with <i>in-silico</i> ligand design, enabling control over single-electron-transfer processes and opening new avenues for radical-based synthetic transformations.