Synthesis And Biological Activity Of 2-aryl-2-methoxyiminophenylacetic Acid Derivatives

Taking kresoxim-mehtyl and trifloxystrobin as the lead compounds and using the intermediate derivatization method to introduce benzofuran ring,pyrimidine ring and 1,3,4-oxadiazole ring and other fragments with broad spectrum biological activities into the side chain position of methyl 2-methoxyiminophenylacetate,(E)-2-[2-(aryloxymethyl)phenyl]-2-(methoxyimino)acetic acid derivatives(A and B)、(E)-2-[2-Pyrimidineoxymethyl-phenyl]-2-(methoxyimino)acetic acid derivatives(C and D)and(E)-2-(methoxyimino)-2-(2-((((5-(aryloxymethyl)-1,3,4-oxadiazol-2-yl)thio)methyl)phenyl)acetate(E)were designed and synthesized,59 compounds in total.At the same time,the insecticidal and antifungicidal activities of compounds A～E were also studied.The specific research contents and results are as follows:(1)Study of synthesis process of kresoxim-methyl and trifloxystrobinA new synthetic route of kresoxim-mehtyl / trifloxystrobin and its key intermediates were designed through five-step reactions of oximation,methylation,hydrolysis,esterification and bromination by using 2-(o-tolyl)acetonitrile as the starting material,with the yield of 52.8%and 43.5% respectly.At the same time,four factors and three levels of orthogonal experiments were used to optimize the methylation reaction,and the optimal conditions of methylation reaction were obtained.After repeated and scaled up experiments,the yield was stable at 90%.Finally,the bromination reaction was carried out in the system of 1,3-dibromohydrin and 1,2-dichloroethane with the yield of 82.5%.(2)Synthesis of 2-aryl-2-methoxyiminophenylacetic acid derivativesOn the basis of the structure of kresoxim-mehtyl and trifloxystrobin,and combined with the guiding idea of "intermediate derivatization method",benzofuran ring、pyrimidine ring and1,3,4-oxadiazole ring with broad-spectrum biological activities were introduced into the molecular framework.And the target compounds A1～A12 and B1～B12,C1～C7 and D1～D7,E1～E20 were obtained with its structures characterized by NMR.At the same time,representative compounds A1 and E9 were selected for single crystal X-ray diffraction.The results showed that compound A1 belonged to the monoclinic crystal system,and the space group was P21/c with 4 molecules in each unit cell.Compound E9 belonged to the triclinic crystal system,and the space group was P-1 with 2 molecules in each unit cell.And the entire crystal was stabilized by van der Waals force.(3)Bactericidal activities of 2-aryl-2-methoxyiminophenylacetic acid derivativesThe bactericidal activities showed that the target compounds had certain inhibitory activity against Phytophthora capsici,Alternaria alternata,Gibberella zeae,Botrytis cinerea and Sclerotinia sclerotiorum at a concentration of 25 mg/L in vitro.Among them,the compounds A10,B10,B12,D3,E12 and E19 showed good inhibitory activity against Phytophthora capsici,which were better than the positive control trifloxystrobin;While compounds A10,B10,B12,E2,E5,E8,E11,E14 and E19 exhibited outstanding inhibitory activity against Gibberella zeae,which were equivalent to the positive control trifloxystrobin;Compounds A9,A10,B1,C3,C4,C5,D4,E3,E8,E16,E17,E19 and E20 were effective against Botrytis cinereal with the inhibitory activity equivalent to that of the positive control trifloxystrobin;Compounds A10,A11,A12,B1,B10,B12,C1,C2,C3,D3,E1,E19 and E20 also showed good performance against Alternaria alternata with the inhibition rate over 40%.The inhibitory activity of target compounds against Sclerotinia sclerotiorum were generally better than that of trifloxystrobin.The in vivo inhibitory activities of some compounds against wheat powdery mildew and corn rust were tested at a concentration of 500 mg/L,and the results showed that the target compounds had excellent prevention effects on wheat powdery mildew and corn rust.Among them,compounds A10,B1,B12 and C1 had a prevention effect of more than 90% against wheat powdery mildew;Compounds A10,B1,B12 and E20 had a prevention effect of more than 95%against corn rust;The preferred compounds A10,B1 and B12 had the value of further research and development.Taking the preferred compounds B12 and C1 as examples,the LUMO and LOMO orbital distributions of the target compounds were analyzed.The results showed that the preferred compounds B12 and C1 had similar energy level orbital distribution,and their LUMO orbitals were concentrated in the part of their pharmacophore methoxyiminophenyl acetate,while the HOMO orbitals were mainly distributed in their side chains.(4)Insecticidal activities of 2-aryl-2-methoxyiminophenylacetic acid derivativesThe killing activities of the target compounds against aphids,armyworms and red spiders were tested at a concentration of 500 mg/L,and the results showed that some target compounds had good killing activities against aphids and armyworms.Among them,the lethality rates of compounds A7,B7 and C1 to Mythimna separata reached 100%;The lethality rates of compounds A10,B10,B12 and C4 to Aphids were all above 98%;Preferred target compounds A7,A10,B7,B10,B12,C1 and C4 had the value of further research.Taking the preferred target compounds A7,B7 and C1 with excellent activity toward aphids as examples,the HOMO and LUMO orbital distributions of the target compounds were analyzed,and their energy level differences were calculated.From the perspective of the energy level orbital distribution,we found that the preferred target compounds A7,B7 and C1 had similar energy level orbital distributions,and their LUMO orbitals were all distributed in the pharmacophore methoxyiminophenyl acetate part,while the HOMO orbitals were all distributed in the side chain benzofuran ring part.