Iron-Catalyzed Friedel–Crafts Reactions of Unactivated 3-Aryl-Oxetanols Exploiting HFIP Stabilization of Carbocations

High Resolution Image Download MS PowerPoint Slide Robust methods to access 3,3-disubstituted oxetanes are desired due to the attractive physicochemical properties offered by the polar 4-membered rings and their potential use as replacement groups for carbonyl or gem -dimethyl functionality in medicinal chemistry. The generation of benzylic oxetane carbocations from oxetanols offers considerable potential, particularly in the generation of diaryloxetanes, a structural type that is seldom reported. To date, however, Friedel–Crafts reactions have been limited to oxetanols bearing an electron-rich aromatic group due to the carbocation destabilizing nature of the oxetane. Here, an alternative Fe-catalyzed Friedel–Crafts reaction is described, employing HFIP as a solvent, enabling oxetanyl carbocation formation directly from oxetanols bearing phenyl and other electron-poor arenes. HFIP with its strong hydrogen bond donor (HBD) ability and enhanced Brønsted acidity cooperatively promotes the generation of the carbocations in the presence of the Lewis acid. The oxetane-HFIP adduct was detected, likely formed reversibly as a stabilizing off-cycle intermediate. The developed methodology enabled the concise synthesis of oxetane analogues of Fenofibrate and Tesmilifene, replacing diarylmethane and benzophenone motifs, respectively. Additional mechanistic studies into the fate of these carbocation intermediates provide insights into the reaction mechanism.