C(sp 3 )-H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

• Published in: Science (American Association for the Advancement of Science) Vol. 372; no. 6540; pp. 398 - 403
• Main Authors: Vasilopoulos, Aristidis, Krska, Shane W, Stahl, Shannon S
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 23.04.2021
• Subjects: Benzyl Compounds - chemistry; Carbon - chemistry; Catalysts; Cleavage; Coupling (molecular); Cross coupling; Dicumyl peroxide; Divergence; Energy Transfer; Free Radicals - chemistry; Hydrogen - chemistry; Hydrogen Bonding; Hydrogen bonds; Light; Methyl radicals; Methylation; Nickel; Nickel - chemistry; Oxidants; Oxidizing agents; Oxygen - chemistry; Peroxide; Peroxides - chemistry; Pharmaceuticals; Photosensitization; Radicals; Selectivity; Substrates
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.abh2623

The "magic methyl" effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp )-H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light-initiated triplet energy transfer promotes homolysis of the O-O bond in di- -butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C-H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.