Synthesis And Antimicrobial Activity Of Benzimidazole,Benzothiazole And Benzoxazole Derivatives

Benzimidazole,benzothiazole and benzoxazole derivatives are a class of important five-membered nitrogen-containing heterocyclic compounds,which have been widely used in medicine,pesticides,materials,dyes,fluorescent probes and so on.In this thesis,the methodology for synthesis of 2-substituted benzimidazole,benzothiazole and benzoxazole derivativeswere studied.A series of novel 2-substituted benzimidazole,benzothiazole and benzoxazole derivatives contianing a 1,2,3-triazole moiety were designed and synthesized.And their antimicrobial activities wereevaluted.In the first chapter of this thesis,synthetic methods and their applications of these compounds in medicine,pesticide and materials have been reviewed.Secondly,an efficient protocol for synthesis of 2-substituted benzimidazoles with high selectivity catalyzed by NaHSO3 in water had been developed.It was found that the amount of NaHSO3 had a great effect on the reaction selectivity of 2-substituted benzimidazole and 1,2-disubstituted benzimidazole when the reaction was carried out in water.When the amount of the catalyst was more than 11 equivalents,the 2-substituted benzimidazole could be highly selectively formed as the sole product.It was presumed that NaHSO3 was firstly reacted with aldehyde to form the aldehyde-sodium bisulfite.Then the formed aldehyde-sodium bisulfite was reacted with o-phenylenediamine to form the 2-substituted benzimidazole and inhibit the formation of 1,2-disubstituted benzimidazole,which solved the poor selectivity problem appearing in traditional method when cyclocondensation between o-phenylenediamine and aldehyde.Besides,the method also had the advantage of simple work up by filtrating the single 2-substituted benzimidazole percipitates from the reaction mixture after the end of the reaction.After drying,the products were obtained withoutfurther column chromatography purification.In addition,the methodwas also suitable for the synthesis of 2-substituted benzothiazoles.Thirdly,an efficient protocol for the synthesis of 2-substituted benzoxazoles catalyzed by copper acetylacetonate(Cu(acac)2)in xylene with O2 as the oxidant was established.It was found that the solvent had a great effect on the yield of the reaction.Cu(acac)2was served as a homogeneous catalyst in non-polar high boiling solvent,which enhanced the catalytic efficiency.The presumed mechanism indicated the formation of imine-copper(II)intermediatesreduced the reaction activation energy,which allowed the reaction proceeding in the direction of product formation.It worth to mention that oxygen as a clean and non-toxic oxidantplayed an important role in the dehydrogenation process.Finally,based on the established NaHSO3-catalyzed method for the synthesis of 2-substituted benzimidazole(benzothiazole)derivatives and Cu(acac)2-catalyzed method for the synthesis of 2-substituted benzoxazole derivatives,thirty-eight 2-substituted benzimidazole(benzothiazole and benzoxazole)derivatives containing a1,2,3-triazole moiety were designed and synthesizedvia the click chemistry according to the principle of substurcture combination strategy in medicinal chemistry.Their structures were confirmed and characterized by NMR,IR and HRMS spectrum.Their antibacterial and antifungal activitiesagainst Escherichia coli,Staphylococcus aureus,Botrytis cinereaandFusariumverticillioide in vitrowere evaluated.It was found that some compounds had good antifungal activities which were expected to be used assterilization drugs forfurther screening and optimization.Unfortunately,those compounds had low inhibitory effect on bacteria.