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Magic methyls added with ease

One-step radical reaction adds methyl groups to drug-like molecules

by Bethany Halford
May 2, 2021 | A version of this story appeared in Volume 99, Issue 16

Radical reaction uses light, organic peroxide, and a nickel catalyst to add a methyl group to the antidepressant agomelatine.

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.


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