Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis

Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd-catalyzed g-C(sp(3))-H olefination of aminocyclohexane with gem-dibromoalkenes, followed by a consecutive intramolecular Cu-catalyzed amidation of the 1-bromo-1-alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza- and oxa-analogues. The Cu catalyst of the Ullmann-Goldberg reaction additionally avoids off-cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7-alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio- and diastereoselective Pd-catalyzed g-C(sp(3))-H olefination is achieved.

Automated summary

Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site- and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. The protocol allows for the preparation of substituted analogues with ease, and the use of a Cu catalyst in the Ullmann-Goldberg reaction helps avoid interference from off-cycle Pd catalyst scavenging.