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.