Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via sequential Cu/Pd/Ru catalysis.

Aryl-fused 2-azabicyclo[2.2.2]octanes were prepared by a novel sequence of Cu-catalyzed three-component coupling of diversely substituted N-benzyl o-bromoaryl imines with methacryloyl chloride and vinyltributyl stannane followed by Pd-catalyzed Heck annulation. Subsequent diversification of the aryl-fused 2-azabicyclo[2.2.2]octane core was achieved by attaching a flexible linker and a potential second pharmacophore via Ru-catalyzed cross-metathesis and a nucleophilic substitution.