Synthesis And Antifungal Activity Of N-Heterocycles And Biphenyl Triazole Sec-Butanol Derivatives

Nitrogen-containing heterocyclic structure mostly exists in natural products and drug molecules,and is a very important class of heterocyclic compounds.The structure is modified by introducing functionalized groups into nitrogen-containing heterocyclic molecules in order to obtain better bioactive compounds.Isocyanide is a very important reaction raw material,which is widely used in many fields such as organic synthesis,drug discovery and polymer science.At the same time,isocyanide participates in multi-component reactions,such as Passerini reaction,Ugi reaction,oxidized-Ugi reaction and Grorbke-Blackburn-Bienaymé（GBB）reaction.These multi-component reactions have many advantages,such as easy operation,high atom utilization,mild reaction conditions,and are widely concerned by organic and pharmaceutical chemists.The（aza-）Wittig reactions are also good at mild reaction conditions,excellent yield,good substrate expansion,and applied to the synthesis of heterocyclic compounds.In this paper,a series of nitrogen-containing heterocyclic compounds were synthesized by the multi-component reactions of isocyanide and（aza-）Wittig reactions.In addition,biphenyl triazole sec-butanol compounds were synthesized by Suzuki coupling/NBS bromination/nucleophilic substitution/sodium borohydride reduction reaction,and their antifungal activities were also studied.According to the research of the antifungal activity,some of them show good results.1.The research progress of multicomponent reaction,Ugi reaction,oxidative Ugi reaction,Passerini reaction,GBB reaction,Wittig reaction and triazole fungicides were briefly introduced.2.Using quaternary phosphonium salt II-1,isocyanide II-2 and N-aryl-1,2,3,4-tetrahydroisoquinoline II-3 as starting materials,eighteen 2-（1,2,3,4-tetrahydroisoquinolin-1-yl）isoquinolinone compounds II-5 were obtained by DEAD promoted oxidative Ugi/Wittig tandem reaction.This method has the advantages of mild reaction conditions,simple operation and no metal catalysis.The structures of the target compounds II-5 were confirmed by ¹H NMR,¹³C NMR and HRMS.Subsequently,the antifungal activity of compound II-5 was tested at the concentration of 50 mg/L.The results showed that the antifungal activity of compound II-5 against the tested strains was less than 50%.3.Using 2-phosphinoiminobenzyl isocyanide III-1,N-aryl-1,2,3,4-tetrahydroisoquinoline III-2 and carboxylic acid III-3 as starting materials,nineteen polysubstituted 3,4-dihydroquinazoline III-4 were obtained by DEAD promoted oxidative Ugi/aza-Wittig tandem reaction at room temperature.This method has the advantages of metal-free catalysis,simple operation and mild reaction conditions.The structure of polysubstituted 3,4-dihydroquinazoline III-4 was confirmed by¹H NMR,¹³C NMR and HRMS.Then,the antifungal activity of compound III-4 was tested at the concentration of 50 mg/L.The results showed that III-4p showed 80%antifungal activity against Pythium aphanidermatum.4.The product IV-4 was obtained by Passerini reaction using o-azidoaryl formaldehyde IV-1,benzoic acid IV-2 and isocyanide IV-3 as starting materials;then,the Staudinger/aza-Wittig/addition cascade reaction was carried out with PPh₃,CS₂ and secondary amines;finally,the nucleophilic substitution reaction was carried out under the condition of K₂CO₃ as the base to obtain fifteen4H-3,1-benzothiazine derivatives IV-5.The structure of 4H-3,1-benzothiazine derivative IV-5 was confirmed by ¹H NMR,¹³C NMR and HRMS.The antifungal activity of compound IV-5 was tested at the concentration of 50 mg/L.The test results showed that the antifungal activity of compound IV-5against the tested strains was less than 50%.5.Using o-azidoaryl formaldehyde V-1,isocyanide V-2 and polysubstituted 2-aminopyridine V-3 as starting materials,imidazole compound V-4 was obtained by GBB reaction;subsequently,the Staudinger/aza-Wittig/addition cascade reaction of imidazole compound V-4 with PPh₃ and isocyanate（R⁴-NCO）occurred successively.When R⁴ is alkyl,pyridine imidazo[1,3]diazepine derivatives V-5were obtained.When R⁴ is aryl,the internal salt V-6 is obtained;when R=H in the internal salt V-6,the ring-opening reaction occurs under the condition of DMF as the reaction solvent at 110 ^oC,and then the pyridine-fused imidazo[1,3]diazepine derivatives V-5 and V-5’are obtained by addition reaction.At the same time,the internal salt V-6 was acidified with HCl to obtain pyridoimidazoquinazoline ammonium chloride derivative V-7.The structures of fourteen pyridoimidazo[1,3]diazepine derivatives V-5 and eleven pyridoimidazoquinazoline ammonium chloride derivatives V-7 were confirmed by ¹H NMR,¹³C NMR and HRMS.At the concentration of50 mg/L,the antifungal activities of the compounds pyridoimidazo[1,3]diazepine derivatives V-5 and pyridoimidazoquinazoline ammonium chloride derivatives V-7 were tested.The test results show that:on the whole,the antibacterial activity of pyridoimidazo[1,3]diazepine derivatives V-5 is better than that of pyridoimidazoquinazoline ammonium chloride derivatives V-7;compounds V-5b,V-5f and V-5j showed 84%,78%and 91%antifungal activity against Pythium aphanidermatum.Compounds V-5b and V-5j showed 89%and 70%antifungal activity against Phytophthora capsici.6.Using arylboronic acid VI-1 and substituted aryl iodide VI-2 as starting materials,methyl biphenyl compound VI-3 was synthesized by Suzuki coupling reaction;bromomethylbiphenyl compound VI-4 was obtained by bromination of methylbiphenyl compound VI-3 with NBS.Subsequently,the bromomethyl biphenyl compound VI-4 and 1-（1H-1,2,4-triazol-1-yl）prop-2-one VI-5 were subjected to nucleophilic substitution/Na BH₄ reduction cascade reaction to obtain sixteen biphenyl triazole sec-butanol compounds VI-7.The structures of the compounds VI-7 were confirmed by ¹H NMR,¹³C NMR and HRMS.The antifungal activity of biphenyl triazole sec-butanol compound VI-7 was tested at the concentration of 50 mg/L.The results showed that when the biphenyl structure was para-substituted（VI-7a-1）,its antibacterial activity was better than that of ortho-and meta-substituted（VI-7a-2 and VI-7a-3）.The antifungal activity of compound VI-7g-1against Pythium aphanidermatum was 70%.The antifungal activity of VI-7g-1 and VI-7k-1 against Fusarium graminearum was 78%and 75%,respectively.The antifungal activity of VI-7g-1 against Phytophthora capsica was 73%.The antifungal activity of compounds VI-7c-1,VI-7g-1,VI-7h-1,VI-7i-1,VI-7j-1 and VI-7k-1 against Colletotrichum gloeosporioides was 70%,84%,85%,80%,79%and 82%,respectively.The antifungal activities of compounds VI-7g-1,VI-7j-1 and VI-7k-1against Magnaporthe grisea were 100%.The results of concentration gradient experiment and calculated EC₅₀ showed that the antifungal activity of compound VI-7g-1 against Pythium aphanidermatum and Phytophthora capsica was better than that of triadimefon and diniconazole.The antifungal activity of compounds VI-7h-1,VI-7i-1 and VI-7k-1 against Colletotrichum gloeosporioides was better than that of the triadimefon,but there was still a certain gap with the diniconazole.