Proline-promoted electrophilic dichloromethylation of α-enaminones via stereochemically gated resolution

Electrophilic β-dichloromethylation of carbonyl derivatives has remained unexplored due to the presumed incompatibility of closed-shell reagents with electron-poor systems. Here we describe a proline-promoted transformation in which α-enaminones, under ambient and non-radical conditions, undergo selective β-dichloromethylation with anti-stereochemistry. The reaction proceeds without metals, strong bases, light, or carbene intermediates—conditions previously thought incompatible with such transformations. Mechanistic analysis reveals a stereochemically gated resolution: one diastereomeric intermediate selectively evolves toward the product, while the other is diverted and fragmented to the parent amine. This bifurcation, supported by kinetic profiling, isotopic labeling, and crystallographic analysis, defines a unique resolution-type control mode that channels molecular topology into chemical outcome. Control experiments confirm that the intact α-enaminone scaffold is essential—neither enamine nor enone fragments react independently. The resulting dichloromethylated enaminones feature a triad of orthogonal functional groups, positioning them as synthetically versatile building blocks. This study establishes a conceptually distinct reactivity paradigm for α-enaminones and expands the synthetic repertoire for the direct incorporation of halomethyl groups.