Modular Access to Functionalized Azetidines via Electrophilic Azetidinylation

General methods for the rapid and direct incorporation of unconventional ring motifs into core scaffolds are highly sought-after in medicinal chemistry. However, approaches enabling the direct attachment of privileged azetidine rings to the oft-encountered biorelevent nucleophiles remain elusive. Here, we report an electrophilic azetinylation protocol based on the underexplored reagents azetidinyl trichloroacetimidates, allowing for the “any-stage” installation of azetidine rings. More than 20 classes of nucleophiles can be readily azetidinylated, providing a diverse library of functionalized azetidines. The power of this method is further demonstrated by the simplified synthesis of multiple medicinally relevant structures and the facile access to azetidine analogues for bioactive compounds.