Leveraging long-lived arenium ions in superacid for meta-selective methylation.

ABSTRACT: Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C-H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, we report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. This study demonstrates that this reaction is driven by the generation of long-lived arenium intermediates generated by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients.

SUBMITTER: Bourbon P 

PROVIDER: S-EPMC11358458 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature