C(sp3)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

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Science  23 Apr 2021:
Vol. 372, Issue 6540, pp. 398-403
DOI: 10.1126/science.abh2623

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Adding methyl groups with good timing

In pharmaceutical research, swapping out hydrogens for methyl groups is a frequent strategy to optimize small-molecule properties. Vasilopoulos et al. report a versatile, convenient, and comparatively safe method for methylation of carbon centers adjacent to nitrogen or aryl rings. Under carefully optimized conditions, di-tert-butyl peroxide plays a dual role as oxidant and methyl source. Cleaving the O–O bond through photosensitization produces butoxyl radicals, some of which cleave substrate C–H bonds, whereas others release methyl radicals that a nickel catalyst delivers to those activated substrates.

Science, this issue p. 398


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(sp3)–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-tert-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.

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