Divergent Synthesis of 1-Azabicyclo[n.1.1]alkane Bioisosteres via Photoinduced Palladium Catalysis
Ying Zhang, Kai‐Dian Li, Song Yu, Kangyin Pan, Hongtao Xu, Huan‐Ming Huang
Abstract
Nitrogen heterocycles are indispensable structural motifs in pharmaceuticals, agrochemicals, and materials science. However, the development of new synthetic methods to access these frameworks remains a significant challenge. Here, we describe a switchable radical approach for the synthesis of 1-azabicyclo[2.1.1]hexanes and 1-azabicyclo[4.1.1]octenes through the coupling of azabicyclo[1.1.0]butanes with 1,3-dienes, mediated by a visible-light-driven palladium photocatalytic system. This method exhibits a broad substrate scope, excellent functional group compatibility, and the capacity to assemble complex architectures, underscoring its utility in accessing valuable aza-bioisosteres. The strategy has also been employed successfully in DNA-encoded library (DEL) synthesis. Mechanistic studies, synthetic applications, and computational analyses corroborate the proposed open-shell pathway, revealing that allylic palladium intermediate formation and regiodivergent nucleophilic addition are key to achieving divergent synthesis.