Synthesis Of Functionalized And Polycyclic Fused 1,5-benzodiazepine Compounds By Multicomponent Tandem Reactions

1,5-benzodiazepines are a unique class of benzoazepine heterocyclic compounds,which play an important role in anti-depression,anti-anxiety,anti-inflammatory and the treatment of cardiovascular and cerebrovascular diseases,and are widely used in the field of drug synthesis.The latest research results indicate that 1,5-benzodiazepines modified with different functional groups or1,5-benzodiazepines with cohesive structures also have significant development potential in the field of organic synthesis.Therefore,while designing and modifying seven-membered nitrogen heterocyclic skeleton structure,exploring green and effective synthesis methods has become a research hotspot in this field.In recent years,our research group has been devoted to the design and development of novel 1,5-benzodiazepines by using scientific and effective synthesis methods.Tandem reaction is an efficient method for the synthesis of novel 1,5-benzodiazepine compounds,which has the advantages of mild and green,strong atomic economy and simple experimental procedure.In view of this,39 unreported 1,5-benzodiazepine compounds were synthesized by three-component and four-component tandem reactions,respectively.The specific work of this paper is as follows:1.Four kinds of 1,5-benzodiazepines with special extra-ring double bond structure and 15kinds of polycyclic 1,5-benzodiazepines with intra ring double bond structure were synthesized by three-component series reaction.A total of 19 1,5-benzodiazepines have not been reported in literature.The target compounds were synthesized by using Co Fe₂O₄@Si O₂@APTES@ATA-Ce Cl₃as catalyst and anhydrous ethanol as solvent.Using substituted 1,2-benzoylenediamine,benzoylacetone and acetone as reaction materials,the 1,5-benzodiazepines with special extra-cyclic double bond structure were synthesized by three-component tandem reaction under the condition of heating reflux;using substituted 1,2-benzenediamine,cyclodione（1,3-cyclohexanedione,1,3-cyclopentadione,5,5-dimethyl-1,3-cyclohexanedione）and acetone as reaction materials,the polycyclic fused 1,5-benzodiazepine compounds with intra-ring double bond structure were synthesized in tandem reaction at room temperature.The optimal conditions for the reaction were effectively screened,the substrate expansion was carried out,and the possible reaction mechanism was proposed.The obtained target compounds were characterized and analyzed by ¹H NMR,¹³C NMR,IR,MS and elemental analysis,and the correctness of the structure was confirmed by combining the single crystal structure of the target compound II-6ec.2.Twenty 1,5-benzodiazepines containing multiple functional groups,which have not been reported before,were synthesized by four-component tandem reaction.Substituted1,2-benzenediamine,N,N-dimethylformamide dimethylacetal,heterocyclic aromatic ketones（2-acetyl thiazoles,2-acetyl thiophene）,and diketones（2,3-butanedione,Ethyl pyruvate）was used as the starting material for the synthesis of 1,5-benzodiazepines at room temperature using Co Fe₂O₄@Si O₂@APTES@ATA-Ce Cl₃,which was prepared by our research group in the previous stage,as the catalyst and anhydrous ethanol as the solvent.Compared with the traditional step synthesis method,the four-component tandem reaction simplifies the experimental steps,makes the synthesis reaction more efficient,reduces the amount of reaction solvent,and makes the reaction process more green.The optimal conditions for the reaction were effectively screened,the substrate expansion was carried out,and the possible reaction mechanism was proposed.The obtained target compounds were characterized and analyzed by ¹H NMR,¹³C NMR,IR,MS and elemental analysis,and the correctness of the structure was confirmed by combining the single crystal structure of the target compound III-5bda.