Magic methyls added with ease

Most synthetic organic chemists view methyl groups as milquetoast substituents, but they can be magical when appended to pharmaceutical candidates. So-called magic methyls can boost potency, reduce toxicity, and increase stability in drugs. But the state-of-the-art reaction for adding methyl groups to C(sp³)–H bonds requires cryogenic temperatures and pyrophoric reagents. Now, Shannon S. Stahl and Aristidis Vasilopoulos of the University of Wisconsin–Madison and Shane W. Krska of Merck & Co. have developed a one-step method for tacking methyl groups onto C(sp³)–H bonds that are adjacent to nitrogen or aromatic rings (Science 2021, DOI: 10.1126/science.abh2623). The radical reaction uses light to break the O–O bond in an organic peroxide. The resulting alkoxy radicals either pluck a hydrogen from a C(sp³)–H bond in the substrate or generate methyl radicals that then join to the substrate with the help of a nickel catalyst. The chemists demonstrate that the reaction can be used to add methyl groups to many drugs or drug-like molecules, including agomelatine (shown), an antidepressant marketed in Europe and Australia.