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.
Modular Strategy for the Synthesis of Functionalized Aryl-Fused Azabicyclo[2.2.2]octanes via Radical-Mediated Cascade Cyclization. -Phenylidene (IVa) gives exclusively the (Z)-diastereoisomer, whereas electron rich groups in the arylidene substituent [e.g. (IVb)] afford product mixtures. -(MALINAKOVA*, H. C.; RAIKAR, S. N.; MCCORMICK, L. F.; Tetrahedron Lett. 55 (2014) 30, 4152-4155, http://dx.
This reaction sequence is suitable for substituted benzimines (I) to give products (IV), (V), and (VI), while an imine derived from 3‐bromo‐thiophen‐2‐yl carbaldehyde does not yield a corresponding Heck product.
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