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(sp 2 )–C(sp 3 ) 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 ZnCl 2 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 S N 1 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(sp 2 )–C(sp 3 ) bond synthesis, departing from conventional transition-metal-catalyzed cross-coupling methods.