Direct phenolic alkylation of unactivated secondary alcohols by dual-zinc/CSA-catalyzed Friedel-Crafts reactions

The intermolecular Friedel-Crafts alkylation represents a straightforward approach to synthesizing C(sp2)–C(sp3) bonds. When readily accessible alcohols are utilized directly as the alkylating agents, the sole byproduct generated is water. Traditional Friedel-Crafts alkylation reactions are typically limited to alkyl (pseudo)halides and activated alcohols that form stabilized carbocations. However, by using inexpensive and abundant ZnCl2 and camphorsulfonic acid (CSA) as catalysts, we present a site-selective Friedel-Crafts alkylation of phenolic derivatives with unactivated secondary alcohols. This catalytic process favors ortho-selectivity, even in the absence of steric influence. Mechanistic studies elucidate the origin of site selectivity, favoring an SN1 pathway in which zinc and CSA function to scaffold both the phenolic and alcohol reactants for ortho-functionalization. This work highlights the efficacy of simple catalysts for achieving C(sp2)–C(sp3) bond synthesis, departing from conventional transition-metal-catalyzed cross-coupling methods.