The "magic methyl" effect describes the transformative changes in potency, selectivity, and/or pharmacokinetic properties from adding a methyl group to a compound. This phenomenon motivates the development of synthetic methods capable of adding methyl groups to molecules, preferably at a late stage in the synthetic route. A recent report described a Ni- and light-catalyzed C(sp<sup>3</sup>)–H methylation reaction that seemed promising for achieving robust late-stage methylation. The reaction proceeds by radical pathways, wherein alkoxyl radicals from a peroxide undergo divergent reactivity to form substrate radicals via hydrogen atom transfer and methyl radicals via <i>β</i>-scission. Nickel-catalyzed coupling of the substrate and methyl radicals affords the methylated product. This reactivity has been expanded and adapted to fit an automated high-throughput experimentation screening platform that allows the rapid identification of methylation reaction conditions on micro-scale for late-stage molecules. A complete analytical workflow was established to support reaction triage, micro-scale purification, and structural elucidation of methylation products, which allows them to be evaluated in bioassays.

Late-stage C–H methylation using high-throughput experimentation: The pursuit of “magic methyl” effects

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ACS Fall 2022

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