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New Process in the Synthesis of Fused Azepines
  English.dicp.cas.cn    Posted:2016-02-23    From:Group 202

Recently, Prof. Boshun Wan, Dr. Chunxiang Wang and Mr. Tengfei Li from Catalytic Heterocycle Synthesis Group (Group 202) at Dalian Institute of Chemical Physics made breakthrough in the synthesis of fused azepines. The research paper titled “Ruthenium-Catalyzed C–C Bond Cleavage of 2H-azirines: A Formal [3+2+2] Cycloaddition to Fused Azepine Skeletons” was published online inAngew. Chem. Int. Ed. 2016, 55, 2861-2865.

Cycloadditions or cyclizations of unsaturated nitrogen-containing compound are one of the most powerful strategies methods for constructing various N-heterocycles. Strained rings, due to their diversity chemical properties, have drawn much attention and been applied in the synthesis of natural products, pharmaceuticals and agrochemicals. 2H-azirines are highly strained three-membered heterocyclic compounds, which can undergo diverse ring-opening reactions via different bond cleavage modes. Therefore, 2H-azirines have been utilized in the construction of various nitrogen-containing heterocycles, such as pyrroles, indoles, pyridines, isoquinolines and piperidines. However, the chemistry of 2H-azirines mainly focuses on the cleavage of C–N single bond. In contrast, reactions of 2H-azirines with unsaturated compounds via C–C bond cleavage have been rarely explored possibly because of the higher energy barrier (> 50 kcal/mol under thermal conditions).

New Process in the Synthesis of Fused Azepines (Photo by Fan Wu, Tengfei Li)

The group of Boshun Wan has been devoted to the development of new methods and new strategies for the construction of heterocycles. A series of work on the study of the selective synthesis of heterocycles have been reported, including five- (Angew. Chem. Int. Ed. 2012, 51, 1693; Angew. Chem. Int. Ed. 2015, 54, 10613), six- (Angew. Chem. Int. Ed. 2011, 50, 7162) and eight-membered heterocycles (Angew. Chem. Int. Ed. 2014, 53, 11940). However, the construction of aza-seven-membered rings from diynes is rather challenging. Previous studies by the same group demonstrated that [3+2] rather than [3+2+2] cycloadducts were preferentially constructed in the reaction of diynes with methyleneaziridines (Chem. Commun. 2013, 49, 5073). This time, they surmised that seven-membered heterocycles might be assembled by cycloaddition of diynes with 2H-azirines. After systematic investigations, they successfully developed a formal [3+2+2] approach to construct fused azepine derivatives through the ruthenium-catalyzed cycloaddition of diynes with 2H-azirines under mild conditions, in which 2H-azirines undergo the cleavage of C–C single bond at room temperature. This transformation provides a straightforward method for the synthesis of azepines with broad substrate scope and a wide range of functional groups. Preliminary studies on the mechanism indicate that β-carbon elimination results in C–C bond cleavage. The results of this research may provide new insight into the chemistry of 2H-azirines and find applications in the synthesis of complex heterocycles.

This work is financially supported by National Natural Science Foundation of China. (By Fan Wu, Tengfei Li)




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