Homologative Alkene Difunctionalization

Abstract Systematic evaluation of homologous series plays a pivotal role in synthetic and medicinal chemistry1,2. Despite their structural resemblance, the preparation of homologs often requires individual synthetic planning tailored to distinct precursors and reactions. Here, we introduce a conceptually new strategy that integrates single-carbon insertion into established methods, specifically redirecting alkene vicinal difunctionalization towards direct routes for 1,3-difunctionalized products. This transformation is enabled by a designer methylene dication reagent, iodomethylthianthrenium salt, which facilitates the photocatalytic conversion of alkenes into linchpin 1,3-dielectrophilic intermediates, allowing seamless incorporation of nucleophiles at distal positions. Mechanistic studies suggest that the reaction proceeds via an α-thianthrenium methyl radical with unusual ambiphilic reactivity governed by multiple stereoelectronic effects. This approach shows high compatibility in pharmaceutical and late-stage settings, providing broad access to diverse 1,3-difunctionalized products, including azetidines, 1,3-diazides, and 1,3-dihalides. This work establishes “homologative alkene difunctionalization” as a powerful platform for repurposing ubiquitous alkenes as meritorious synthetic intermediates to unveil heretofore unknown 1,3-substitution patterns.