Fig. 1: Toward a new approach for the meta-selective Friedel–Crafts methylation.
From: Leveraging long-lived arenium ions in superacid for meta-selective methylation
a Distribution of di-, tri- and tetra-substituted benzenoid substitution patterns in small molecule active pharmaceutical ingredients; 1,2-, 1,4-, and 1,2,4-substituted rings dominate this chemical space2. b Comparison of the regioisomeric distribution of different electrophilic aromatic substitutions of toluene reveals a large discrepancy on regioselectivity depending on the nature of the electrophile4. c Representative examples of the late efforts for the development of para-selective SEAr for the introduction of a synthetic handle. d Conceptual backgrounds: regiodiversion of σ-complexes as an alternative approach toward SEAr-inconsistent benzenoid ring diversification. e Reaction design: our strategy for meta-methylation relies on consecutive Friedel–Crafts type alkylation with a superelectrophilic methylating reagent followed by σ-complex regioconversion through the generation of long-lived arenium ions in superacid.
