A single-pot synthesis of 4-hydroxybenzophenones via acid-catalyzed alkoxylation of p-quinone methides followed by DDQ-assisted oxo-demethoxylation

Abstract

A highly efficient protocol has been developed in this work to synthesize promising pharmacophore synthons, namely 4-hydroxybenzophenones (4-HBP), with yields ranging from 80–99%. Interestingly, the method utilizes p-QMs as substrates and involves a single-pot, two-step alkoxylation/oxo-demethoxylation reaction sequence that uses easily accessible Amberlyst-15 and DDQ, respectively, in methanol at room temperature. The protocol demonstrates a broad substrate scope for diverse p-QMs with excellent functional group tolerance and complete regioselectivity for oxidation at the methide group. Moreover, the synthesized compounds 1 could be readily dealkylated to 4-HBPs (9), a key starting material of top-selling drugs. The simple starting materials, and the scalability (1 g) and recyclability of both Amberlyst-15 and DDQ over at least five cycles make the protocol eco-friendly and commercially viable.