Synthesis And Biological Activity Of Bridged Heterocyclic Compounds Containing Nitrogen Or Nitrogen-oxygen Atoms Combined With Benzimida/Oxa/Thiazole Structural Unit

Heterocyclic compounds are important members of organic compounds library and widely exist in natural and synthesized compounds.In the past decades,scientists have been committed to the research and development of new heterocyclic compounds with good biological activity.Heterocyclic compounds containing benzimida/oxa/thiazole structural unit have rich pharmacological activities and are widely used in the fields of medicine and pesticides.Tr?ger’s base analogs,as a kind of nitrogen-containing bridged heterocyclic compounds with special structures,have potential applications in the fields of biomedicine,molecular recognition,supramolecular chemistry,and so on.Heterocycles with nitrogen and oxygen are important structures in many natural products and pharmaceutical molecules with biological activity,and are also commonly used as structural building blocks in organic synthesis.These findings lay the foundation for the development of novel and efficient heterocyclic compounds.In this paper,based on the splicing principle,a series of6,12-epiminodibenzo[b,f][1,5]diazocine/dioxocine containing benzimida/oxa/thiazole were synthesized by combining benzimida/oxa/thiazole structural unit with Tr?ger’s base analog or bridged heterocyclic structure with nitrogen and oxygen atoms.It is expected to develop novel bridged heterocyclic compounds containing nitrogen or nitrogen-oxygen atoms compounds with good biological activity.Focusing on the above objectives,this paper has carried out the following three aspects of work:（1）2-aminobenzimida（I）/oxa（II）/thiazole（III）react with 2-amino-4-Y benzaldehyde（A）respectively to synthesize the target compound 13-（benzimida/oxa/thiazole-2-yl）-epiminodibenzo[b,f][1,5]diazocine（I-A,II-A,III-A）.Taking the reaction of2-aminobenzaldehydewith2-aminobenzimidazole,2-aminobenzoxazoleand2-aminobenzothiazole as model reactions,their reaction conditions were optimized as follows:for I-A series:Fe Cl₃（10mol%）as the catalyst,dichloroethane as solvent,2-aminobenzimidazole:2-aminobenzaldehyde（mole ratio）=1:3,refluxing at 80℃for 12 hours;for II-A series:p-toluenesulfonic acid（10mol%）as catalyst,toluene as solvent,2-aminobenzoxazole:2-aminobenzaldehyde（mole ratio）=1:3,refluxing at 80℃for 12 hours;for III-A series:p-toluenesulfonic acid（10mol%）as catalyst,dichloroethane as solvent,2-aminobenzothiazole:2-aminobenzaldehyde（mole ratio）=1:2,refluxing at 80℃for 12 hours.Under the above optimal experimental conditions,a total of 50 bridged heterocyclic compounds with nitrogen,13-（benzimida/oxa/thiazole-2-yl）-6,12-epiminodibenzo[b,f][1,5]diazocine were synthesized.The target compounds were separated and obtained by column chromatography.The effect of reactant structures on the reactivity（yield）was analyzed.It was found that the reactivity order is2-aminobenzoxazole>2-aminobenzothiazole>2-aminobenzimidazole.The reactivities of compounds with electron-withdrawing substituent Y are greater than those with electron-donating Y.The compounds with electron-withdrawing substituent Z is more reactive than those with electron-donating substituent Z.The synthesized compounds were characterized by nuclear magnetic resonance ¹H NMR and ¹³C NMR,and three compounds without substituents in I-A,II-A and III-A series（i.e.,Y and Z are H）were determined by high-resolution mass spectrometry.（2）2-aminobenzimida（I）/oxa（II）/thiazole（III）reacted with 2-hydroxyl-4-Y benzaldehyde（B）respectively.It was found that only 2-amino-benzthiazole（III）could generate the target compounds 13-（benzothiazole-2-yl）-6,12-epiminodibenzo[b,f][1,5]dioxane（III-B）,and2-aminobenzimidazole（I）/oxazole（II）reacting with 2-hydroxyl-4-Y benzaldehyde（B）can only obtained Schiff bases（SB-I-B,SB-II-B）,Taking the reaction of 2-hydroxybenzaldehyde with2-aminobenzothiazole as the model reaction,the reaction condition was optimized for the synthesis of III-B series target compounds as follows:Fe Cl₃（10mol%）as catalyst,toluene as solvent,2-aminobenzothiazole:2-hydroxybenzaldehyde（mole ratio）=1:3,refluxing at 110℃for 12 hours.Under the optimum reaction condition,ten bridged heterocyclic compounds bearing nitrogen and oxygen atoms（III-B）and 18 Schiff bases（six for each series:SB-I-B,SB-II-B and SB-III-B）were obtained.The separation yields of these compounds by column chromatographys ranged from 20%to 63%.By analyzing the influence of reactant structures on the reactivity,it is found that the reactivity of 2-aminobenzaldehyde is higher than that of2-hydroxybenzaldehyde in the preparation of the targeted bridged heterocyclic compounds with the approach developed by this work.When reacting with 2-hydroxybenzaldehyde,2-aminobenzothiazole is more reactive than 2-aminobenzoxazole/2-aminobenzimidazole.The structures of the synthesized bridged heterocyclic compounds and Schiff Bases were characterized by nuclear magnetic resonance ¹H NMR and ¹³C NMR.（3）The fungicidal activities of 60 target bridged heterocyclic compounds against seven crop pathogens were tested.The results showed that the target compounds have good fungicidal activities against physalospora piricola,sclerotinia sclerotiorum,rhizotonia cerealis and fusarium moniliforme.The inhibition rate of the most prominent compound（No.4）was 98.2%against physalospora piricola and 92.8%against rhizotonia cerealis.The inhibition rate of compound（No.52）against fusarium moniliforme was 92.5%,which was significantly higher than that of the control drug.The correlation between the fungicidal activities against physalospora piricola and the substituent effect was analyzed.It was found that the bactericidal activity of the target compound is mainly affected by the structure of benzoxazole and the substituent Z on benzothiazole,while the substituent Y on 2-amino/hydroxyl-4-Y benzaldehyde has little effect.This study provides a new method for the preparation of novel bridged heterocyclic compounds containing nitrogen or nitrogen-oxygen atoms.Furthermore,it provides experimental data and theoretical guidance for the investigation and development of new fungicides.