C–H acylation as an enabling tool to tag phenolic drugs

Abstract

The site-selective functionalization of value-added compounds while implementing atom-economical C–H coupling partners represents an unmet challenge of utmost importance within organic synthesis. Herein, we report a Pd-catalyzed directed C–H acylation of a collection of relevant phenol-containing compounds with ethanol and other alcohols and aldehydes. This tagging technique is distinguished by its water compatibility and predictable regioselectivity and features the use of ethanol as renewable feedstock for the modification of intricate phenols, including estrogens and other top-selling pharmaceuticals. Mechanistic studies support the intermediacy of a challenging 6-membered dimeric palladacycle that undergoes the addition of nucleophilic acyl radical species.