The Studies On A Novel Strategy For The Synthesis Of 1,5-benzodiazepines Substituted By Indole Ring Or Alkoxycarbonyl Alkyl Groups

1,5-benzodiazepines are a class of nitrogen heterocyclic compounds with physiological activity and pharmacological activity.They have been used as anticonvulsant,antianxiety,antidepressant,hypnotic and other drugs,as well as in the treatment of cancer,viral infection,cardiovascular disease and many other diseases.1,5-benzodiazepines can also be used as intermediate raw materials for the synthesis of fused nitrogen heterocyclic compounds and participate in the synthesis of some photosensitive materials.Therefore,the synthesis of1,5-benzodiazepines with various structures is of great significance for pharmaceutical chemistry and industrial production.In view of this,in order to enrich the variety of1,5-benzodiazepines and realize the green and efficient synthesis process,series of magnetic nano-supported catalysts catalyzed multi-component tandem reaction were developed,and a total of 54 new compounds were synthesized which have not been reported in literatures.The advantages of these methods are novel reaction,unique product structure,green reaction process,easy separation of magnetic catalysts,mild reaction conditions,short reaction time and high yields of products.The study of new approaches also enriched the modern synthesis methodology of 1,5-benzodiazepines.The main work of this paper is as follows.1.Four novel approaches for the synthesis of indole ring substituted 1,5-benzodiazepines were developed via three-component one-pot or multi-component tandem reaction,and 30target compounds were synthesized which have not been reported in literatures.Through michael addition,nucleophilic addition,dehydration,cyclization,proton transfer and other reaction processes,the structure units of diaza seven-membered ring and indole compounds were spliced together under mild reaction conditions,and acyl,ester or aryl groups were introduced into the seven membered ring skeleton.In the three-component reaction,o-phenylenediamine compounds,1,3-dicarbonyl compounds or?,?-unsaturated carbonyl compounds,and isatin are used as raw materials;while in the four-component reaction,N,N-dimethylformamide dimethyl acetals,aromatic ketone compounds,o-phenylenediamine compounds,and isatin are used as raw materials.At the same time,the above reactions were all carried out under the condition of anhydrous ethanol as green solvent and magnetic nano-supported p-toluene sulfonic acid(Fe₃O₄@Si O₂-PTSA)made by the research group in the early stage as catalyst.The synthesized compounds were characterized by ¹H NMR,¹³C NMR,IR,MS and elemental analysis.Combined with the single crystal structure of compound IVcc,the structure of these compounds was proved to be correct and the possible reaction mechanism was proposed.2.A novel approach for the synthesis of alkoxycarbonyl alkyl substituted1,5-benzodiazepines has been developed via three-component tandem reaction,and 24 new compounds with a-CH₂COOR outside the ring were synthesized which have not been reported in literature.This method used o-phenylenediamine compounds,1,3-cyclodione(1,3-cyclopentadione,1,3-cyclohexanedione or 5,5-dimethyl-1,3-cyclohexanedione),ethyl acetoacetate or ethyl propiolate as raw materials,and anhydrous ethanol as solvent.The active intermediate of enamine-enamine structure is formed by constructing two enamine structures in the molecule,then the magnetic nano-supported cerium trichloride(?-Fe₂O₃@Si O₂-Ce Cl₃)made by the research group in the early stage promoted the carbon-carbon cross-coupling reaction to achieve intramolecular cyclization,and polycyclic fused 1,5-benzodiazepine compounds were synthesized.In a one-pot operation,one new nitrogen heterocycle(diazepine)and four new chemical bonds(one C-C,two C-N and one C=C)and a-CH₂COOR outside the ring were constructed.All the compounds were characterized by ¹H NMR,¹³C NMR,IR,MS and elemental analysis.Combined with the single crystal structure of compound XIIdad,the structural correctness of these compounds was proved and the possible reaction mechanism was proposed.These products can be used for further functionalization to form molecular diversity,which is of great significance for the synthesis of 1,5-benzodiazepine compounds with structural diversity.