Divergent Synthesis of 1-Azabicyclo[n.1.1]alkane Bioisosteres via Photoinduced Palladium Catalysis

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.