Synergistic LMCT and Ni Catalysis for Methylative Cross-Coupling Using <i>tert</i>-Butanol: Modulating Radical Pathways via Selective Bond Homolysis

Abstract

Ligand-to-metal charge transfer (LMCT) excitation has emerged as a potent strategy for the selective generation of heteroatom-centered radicals, yet its full potential in modulating open-shell radical pathways remains underexplored. Here, we present a photocatalytic methylative cross-coupling reaction that capitalizes on the synergistic interplay between LMCT and Ni catalysis, enabling the use of tert -butanol as an efficient and benign methylating reagent. The electron-deficient ligand 2,6-ditrifluoromethyl benzoate facilitates Ce(IV)-mediated bond scission of tert -butanol, generating a methyl radical that is subsequently captured by the Ni catalytic cycle to form C–CH 3 bonds. Under mild reaction conditions, this strategy affords efficient methylation of sp 3 carbons adjacent to carbonyls and sp 2 centers, demonstrating broad functional group tolerance and applicability in late-stage functionalization of bioactive molecules. Additionally, trideuteromethylative coupling can be facilely achieved using commercial tert -butanol- d 10 . This approach circumvents the need for traditional tert -butoxy radical precursors, such as peroxides, while strategically modulating the radical pathway to favor β-scission and suppress unwanted tert -butoxy radical formation in solution. Mechanistic studies reveal that the benzoate ligand plays a crucial role in enabling LMCT excitation and facilitating methyl radical generation, supporting a concerted Ce–OR and β-C–C bond homolysis mechanism, further evidenced by the modulation of regioselectivity in alkoxy radical-mediated β-scission.