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 biorelevant nucleophiles remain elusive. Here, we report an electrophilic azetidinylation strategy leveraging the underexplored reagents azetidinyl trichloroacetimidates and the novel reagents azetidinyl o-alkynylbenzoates, allowing for the “any-stage” installation of azetidine rings. A wide range of nucleophiles can be readily azetidinylated, providing a diverse library of functionalized 3-aryl and 3-alkyl 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.