Cooperative Lewis Acid/Metal Dual Catalysis for the Selective ortho-Alkylation of Phenols

Alkylated phenols hold significant importance in industrial chemistry, as many pharmaceuticals and polymer additives are based on these scaffolds. However, synthesizing these products in a sustainable way is still challenging because stoichiometric amounts of Lewis acids to promote Friedel-Crafts reactions on benzene and phenol derivatives are often employed, together with drastic and unsafe reaction conditions. In this paper, we present a regioselective process to produce ortho-alkylated phenols, with high atom- and step-economy that minimizes the formation of waste associated with it. The key role is pursued by the dual catalytic system palladium on carbon (Pd/C) and scandium trifluoromethanesulfonate (Sc-(OTf)₃), which together promote the partial hydrogenation of phenol to cyclohexenone, while the alcohol is oxidized to aldehyde. The so-formed partners couple in an aldol condensation promoted by Sc-(OTf)₃, which is then rearomatized in the air atmosphere. Amylmetacresol (antiseptic) was successfully obtained with this protocol in a one-step synthesis for the first time. Moreover, this process permits the recovery and reuse of the Pd/C catalyst for up to 5 runs. This paved the way for the development of a gram scale-up flow protocol associated with this strategy in an innovative tube-in-tube setup.