Flavin-Photocatalyzed Benzylic Functionalization, Spirocyclization, and Spiroepoxidation of Phenols

Abstract

para-Quinone methides (p-QMs) are versatile, transient electrophilic dearomatized intermediates in organic synthesis, enabling a range of transformations, such as cycloadditions, nucleophilic additions, and cascade reactions. Conventionally, these ephemeral species are generated in situ via acid- or base-mediated activation of phenols prefunctionalized with a leaving group (e.g., hydroxyl, halide, or sulfonate) at the benzylic position or through oxidation of phenols employing toxic heavy metal salts (e.g., lead, silver, or bismuth). We report a photocatalytic approach for in situ generation of p-QMs directly from simple phenolic precursors, thereby circumventing the need for benzylic prefunctionalization or transition-metal reagents. The photogenerated p-QMs undergo efficient transformations, including benzylic functionalization, spirocyclization, and spiroepoxidation, delivering rapid access to benzylic scaffolds and structurally complex sp3-rich spirocyclic frameworks. The synthetic utility of this approach is further demonstrated by the late-stage functionalization of drugs and natural products. © 2025 Elsevier B.V., All rights reserved.