General Approach to Nitrogen-Bridged Bicyclic Frameworks by Rh-Catalyzed Formal Carbenoid Insertion into an Amide C–N Bond

Various
nitrogen-bridged bicyclic skeletons are found in bioactive
natural products and pharmaceuticals. The development of a new reaction
to construct these molecular frameworks has attracted considerable
attention in synthetic organic chemistry. We developed a novel synthetic
method for obtaining a wide variety of nitrogen-bridged bicyclic compounds
with a catalytic process, Rh-catalyzed formal carbenoid insertion
into an amide C–N bond. Using 0.1–0.4 mol % Rh2(NHCOtBu)4 catalyst, various
azabicyclo­[X.Y.Z]­alkane derivatives were obtained in good to excellent
yield, successfully demonstrating the broad substrate scope of the
developed process. Experimental and computational studies to elucidate
the reaction mechanism revealed that the formal insertion reaction
of a carbenoid into an amide C–N bond proceeded via the formation
of Rh-associated N-ylides, followed by an acyl group-selective
Stevens [1,2]-shift
through a concerted addition/elimination process on the sp2-hybridized carbon.