Studies On Azomethine-Isocyanide [3+2] Cycloaddition Promoted By Silver And DBU

Azomethines are common 1,3-dipoles for the construction of nitrogen-containing heterocyclic structural motifs with various π-systems.And with the gradual improvement of the reaction conditions,the azomethines cycloaddition is more environmentally friendly,in line with the concept of green chemistry.However,the [3+2] cycloaddition of azomethines are currently limited to electron-deficient enynes,for the development of other more dipoles is a core area of this development.Isocyanides are versatile building blocks and have been widely applied in organic synthesis.In particular,aryl isocyanides as dipolarophiles are a versatile functionality to undergo [3+2] cycloaddition for heterocycle and active molecules.However,the 1,3-dipolar [3+2] cycloaddition reaction of azomethine ylides with isocyanides to obtain the imidazole scaffolds containing ester groups at the C4 position is rare.Imidazoles is one of the important heteroaromatic compounds,especially those with multiple functional groups,are considered to be special structural motifs,which are not only prevalent in various highly bioactive natural products,but also present in many enzymes and metalloenzymes in biological systems.Due to their characteristic properties,many impressive investigations have been developed for constructing imidazole scaffolds from basic chemical materials.However,exploring new strategies and reagents,using transition metal catalysis to develop readily available,simple,and highly efficient reactions acess to 1,2,4-trisubstituted triazoles are very significant.Herein,we report the [3+2] cycloaddition of azomethine ylides with isocyanides for the efficient synthesis of 1,2,4-trisubstituted imidazoles.In this transformation,silver plays a triple role:(1)serving as a catalyst to activate isocyanides;(2)acting as an oxidant to accomplish the aromatization;and(3)promoting the formation of metalated azomethine ylides.And 1,8-diazabicyclo undec-7-ene(DBU)is used as a base to promote the reaction.To further demonstrate the practical usefulness of the method,we derivatize the imidazole compound to obtain an the intermediate of atypical antipsychotic analogue.Considering the extreme importance of 1,2,4-trisubstituted imidazoles in medicinal chemistry,the methodology presented herein undoubtedly will find a wide range of applications in future synthetic endeavors and pharmaceutical synthesis.