Synthesis,Biological Activity And Reaction Mechanism Of 13-（pyrimidin-2-yl）-6,12-epiminodibenzo[1,5] Diazocine Derivatives

Nitrogen-containing heterocycles are the majority and most crucial category of heterocyclic compounds,which are widely used in natural products,pharmaceuticals,pesticides and functional materials.Pyrimidines and Tr?ger’s Base analogues are two important branches of the nitrogen-containing heterocyclic family.Their potential physiological and pharmacological activities,catalytic and optical properties have made them popular structures in the fields of pharmaceuticals,pesticides,and functional materials.Over the past decades,efforts have been concentrated on the development of novel,flexible and efficient nitrogen-containing heterocyclic compounds and their synthesis methods.Based on the splicing principle,this paper intends to splice the pyrimidine ring unit with the epiminodibenzo[b,f][1,5]diazocine unit of Tr?ger’s Base,hoping to obtain new nitrogen-containing heterocyclic compounds with good biological activity.With these objectives in mind,this paper has undertaken the following four aspects of work:（1）Forty substituted 13-（pyrimidine-2-yl）-6H,12H-6,12-epiminodibenzo[1,5]diazocine derivatives have been synthesized by heating reflux in acetonitrile solution using2-amino-4-X-benzaldehyde and 2-amino-5-Y-pyrimidine as reaction substrates and p-Ts OH as catalyst,where substituents X=H,F,Cl,Br,CH₃,OCH₃,NO₂,Ph;Y=H,Cl,Br,CH₃,OCH₃.The reaction conditions were optimized using 2-aminobenzaldehyde and2-aminopyrimidine as a model reaction,and the optimum conditions were obtained as follows:2-aminopyrimidine:2-aminobenzaldehyde=1:3,10 mol%p-Ts OH as the catalyst,acetonitrile as the reaction solvent,16 hours heating reflux at 80℃.The yields of each target product were determined by High Performance Liquid Chromatography（HPLC）,and the structures of products were characterized by Nuclear Magnetic Resonance ¹³C NMR and~1H NMR.Taking 3,9-dichloro-13-（5-chloropyrimidin-2-yl）-6H,12H-6,12-epimiodibenzo[b,f][1,5]diazocine as a model compound,the Mass Spectra,Infrared Spectroscopy（IR）and the single crystal structure were all determined.（2）The effect of substituents X and Y on the yields of the generated target products has been investigated.A quantitative correlation model between the electronic effect of the substituents and the yields of the reactions was established.The results show that the yields of the target products are mainly influenced by the Hammett parametersσ（X）andσ（Y）of substituents X and Y,the electronegativity parametersχ（X）andχ（Y）,and the polarization parameter P（X）of substituent X.The opposite sign of the coefficients in front of the Hammett parametersσ（X）andσ（Y）in the regression equation indicates that the electronic effects of substituents X and Y have opposite effects on the reactivity.Substituent X is a strong electron-withdrawing group and substituent Y is a strong electron-donating group,which will facilitate the reaction and result in higher yields of the target products.（3）A theoretical study of the reaction mechanism under optimized reaction conditions has been carried out employing Density Functional Theory（DFT）calculations,and a possible reaction path has been suggested.Firstly,two molecules of 2-aminobenzaldehyde undergo their own condensation in the presence of p-Ts OH,which dehydrates to generate an octameric cyclic imine cation intermediate.Then 2-aminopyrimidine undergoes nucleophilic addition-elimination with the imine cation intermediate to produce a N-pyrimidin-2’-yl[1,5]diazocine carbocation intermediate.Finally,the secondary amine group connecting with the pyrimidine ring attacks the carbon cation of diazocine to build a C-N bond to generate the target product.（4）The bactericidal activities of 40 target compounds synthesized were tested,mainly including seven crop pathogens such as Alternaria solani,Fusarium graminearum,and so on.The test results show that the target compounds have excellent fungicidal activities against Physalospora piricola,Sclerotinia Sclerotiorum and Rhizotonia cerealis.In particular,11compounds show fungicidal activities against Physalospora piricola over 90%,the highest up to 98.4%,which are superior to the fungicidal activity of the control drug chlorothalonil（89.3%）at the same concentration（50 ppm）.The highest fungicidal activities against Sclerotinia Sclerotiorum and Rhizotonia cerealis are up to 85.7%and 80.5%,respectively.