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

Abstract

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(NHCO(t)Bu)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 sp(2)-hybridized carbon.

Construction of Functionalized Azapolycyclic Architectures via Formal Amide Insertion at a Low Catalyst Loading of Copper Trifluoroacetylacetonate

“…1 H and 13 C NMR, IR, and MS of products 8a , 8e , 8f , 8g , 8j , and 8l were identical to those reported . For copies of the 1 H and 13 C NMR spectra, see the Supporting Information.…”

“…The substrates 7a , 7e – g , 7j , and 7l were prepared according to the reported procedure . 1 H and 13 C NMR, IR, and MS of products were identical to those reported …”

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

“…[21] Based by the Worsencroft's work, Nemoto group developed a mild Rh 2 (NHCO t Bu) 4 catalysis for the synthesis of nitrogen bridge bicycles in 2015 (Scheme 25). [22] A key acyl group Stevens [1,2]-shift was involved, leading to 9-azabicyclo [4.2.1] nonanes, which might find application in the rapid construction of bioactive molecules.…”

Formal group insertion into aryl C‒N bonds through an aromaticity destruction-reconstruction process

“…In this context, given the abundance and the ready availability of anilines and their derivatives, the selective insertion of atoms into the aryl carbon–nitrogen bonds will be an appealing route for the synthesis of nitrogen-containing aromatic molecules. However, compared with the cleavage and functionalization of aliphatic carbon–nitrogen bonds 10 – 18 , because aryl carbon–nitrogen bonds are particularly inert, the direct cleavage of these bonds is very difficult 19 – 23 . Anilines are normally activated by conversion to more reactive intermediates such as aryldiazonium salts 24 – 27 , arylammonium salts 28 – 30 , triazenes 31 , 32 , or amides 33 , which serve as electrophiles in various reactions thus forming carbon–heteroatom or carbon–carbon bonds (Fig.…”