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Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis

par Biswas, Sovan;Van Steijvoort, Ben F.;Waeterschoot, Marjo;Bheemireddy, Narendraprasad R.;Evano, Gwilherm ;Maes, Bert U. W.
Référence Angewandte Chemie International Edition in English, 60, page (21988-21996)
Publication Publié, 2021-06-18

Article révisé par les pairs

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Résumé :

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 gamma-C(sp3)-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 gamma-C(sp3)-H olefination is achieved.