Yi‐Hua Lee, C. -M. Hsu, Shinje Miñoza, Ya‐Fang Shih, Yu‐Chun Ding, Tzu‐Yao Hsu, Song‐Ting Chen, Kuei‐Chen Chang, Wen‐Hsuan Lee, Yuya A. Lin, Hsuan‐Hung Liao
Despite the high demands for azetidines as privileged motifs in medicinal chemistry, efficient synthesis platforms that enable the rapid preparation of diversely decorated azetidines remain limited. Although the bis-functionalization of highly strained 1-azabicyclobutane (ABB) has been one of the most viable, modular, and versatile methods for the synthesis of structurally diverse azetidines, the catalytic installation of aliphatic pendants to ABB remains underexplored. In this work, we report the multicomponent synthesis of the elusive all-carbon quaternary azetidines from ABBs through the radical addition of azetidines to various α,β-unsaturated esters, amides, ketones, a 1,3-enyne, and a vinylphosphonate ester. The reaction is facilitated by a bromide/nickel dual-catalyzed polar-radical relay strategy, enabling the radical difunctionalization of α,β-unsaturated carbonyl compounds via sequential ring-strain-release azetidinylation and Suzuki-type arylation or alkenylation. Variation in the individual components enabled the synthesis of >60 azetidine derivatives, including modifications of selected biorelevant molecules. The functional group interconversion of representative azetidine derivatives illustrates the method's potential to produce unprecedented spirocyclic azetidine hybrids, which may be useful for exploring uncharted areas of chemical space in drug design. Additionally, a diastereoselective synthesis using Evans' oxazolidinone enabled the preparation of an enantiopure azetidine, potentially useful as a platform for library preparation of stereochemically diverse azetidines.