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

Paul Bourbon, Kassandra Vitse, Agnès Martin-Mingot, Hugo Geindre, Frédéric Guégan, Bastien Michelet () and Sébastien Thibaudeau ()
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Paul Bourbon: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)
Kassandra Vitse: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)
Agnès Martin-Mingot: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)
Hugo Geindre: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)
Frédéric Guégan: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)
Bastien Michelet: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)
Sébastien Thibaudeau: Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP)

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49421-8

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