Synthesis And Bioactivity Study Of Camphene Aldoxime Derivatives

Isoxazoline derivatives and oxime ether derivatives have developed rapidly in the field of organic synthesis due to their excellent biological activities.Isoxazoine derivatives have unique heterocyclic structure and have been widely used in pesticides,pharmaceuticals and materials industries.At the same time,oxime ether derivatives are also important compounds with many biological activities,such as insecticidal,bactericidal,antiviral and so on.They have indispensable application value in the research and development of pesticide chemicals.In this paper,2-(3,3-dimethybicyclo[2.2.1]heptan-2-ylidene)acetaldehyde oxime(camphene aldoxime or product 1)was synthesized by nucleophilic addition reaction with?-formyl camphene,hydroxylamine hydrochloride and sodium acetate trihydrate as raw material.The effects of the type of solvent,alkali type,different type of bases,dosage of base,reaction temperature and reaction time on reaction rate and yield of the product were discussed,and the optimum conditions were obtained by orthogonal tests:75%ethanol as the solvent,sodium acetate trihydrate as the base,n(?-formyl camphene):n(hydroxylamine hydrochloride):n(sodium acetate trihydrate)=1.0:1.2:2.0,the reaction temperature was 70?,the reaction time was 2.5 h.Under these conditions,the yield of camphene aldoxime was 84.14%.The structure of product 1was confirmed by Infrared spectroscopy,gas chromatography-Mass spectroscopy,nuclear magnetic resonance spectroscopy.A series of 3'-(3,3-dimethyl bicyclic[2.2.1]heptane-2-subunit)-5'-(R)-isoxazoline compounds were synthesized by 1,3-dipolar cycloaddition reaction with camphene aldoxime and alkene as raw material.Taking the reaction of camphene aldoxime with styrene as an example,The effects of the solvent type,type and dosage of catalyst,amount of oxidant Oxone,dosage of syrene and reaction time on reaction rate and yield of the product were discussed,and the optimum conditions were obtained by orthogonal tests:50%methanol as solvent,potassium chloride as the catalyst,n(camphene aldoxime):n(potassium chloride):n(Oxone):n(syrene)=1.0:0.5:1.5:2.0 the reaction time was 10 h.Under these conditions,the yield of 3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-phenyl-isoxazoline was 84.14%.At the same time,eight isoxazoline compounds such as 3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-methyl-5'-phenyl-isoxazoline(2b),3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-(tertiary butyl)-isoxazoline(2c),3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-(benzyl)-isoxazoline(2d),3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-(4-bromo phenyl)-isoxazoline(2e),3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-(bromomethyl)-isoxazoline(2f),3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-5'-(butyl)-isoxazoline(2g)and 3'-(3,3-dimethyl bicyclo[2.2.1]hept-2-ylidene)-3'a,4',5',6',7',7'a-hexahydro-4,7-methyl-benzoisoxazoline(2h)were synthesized by extending the substrates.These products(2a?2h)were characterized by Infrared spectroscopy,gas chromatography-Mass spectroscopy,nuclear magnetic resonance spectroscopy.2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-substituted ethers was synthesized by the reaction with camphene aldoxime and halides as raw material.Taking the reaction of camphene aldoxime with benzyl chloride as an example,The effects of solvent type,type and dosage of catalyst,dosage of benzyl chloride,reaction temperature and reaction time on reaction rate and yield of the product were discussed,and the optimum conditions were obtained by orthogonal tests:methylbenzene as solvent,n(camphene aldoxime):n(benzyl chloride):n(tetrabutylammonium bromide)=1.0:1.8:0.08,the reaction temperature was 60?,the reaction time was 20 h.Under these conditions,the yield of 2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-benzyl ether was 84.11%,At the same time,nine oxime ethers compounds such as 2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-butyl ether(3b),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(4-Chlorobutyl)ether(3c),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(3-Brominebenzyl)ether(3d),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(4-tert-butyl benzyl)ether(3e),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(4-Chlorbenzyl)ether(3f),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(4-Cyanobenzyl)ether(3g),2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(2,6-dichlorobenzyl)ether(3h)and2-(3,3-dimethyl bicyclic[2.2.1]hept-2-ylidene)acetaldehyde oxime-O-(Ortho fluorbenzyl)ether(3i)were synthesized by extending the substrates.These products(3a?3i)were characterized by Infrared spectroscopy,gas chromatography-Mass spectroscopy,nuclear magnetic resonance spectroscopy.The inhibitory effects of compounds 1,2a-2h and 3a-3i on Hep G2 cells and MCF7 cells was studied by in vitro antitumor activity tests.The results showed that most compounds had no significant inhibitory effect of Hep G2 cells and MCF7 cells,and compounds 2a,2b,2d,2h and3b have some inhibitory effects on Hep G2 tumor cells,and the effects of compound 2a,2b,2d,2h and 3b on human Hep G2 cells were inhibited.Especially the better inhibition of compound3b,its IC₅₀value is 36.3?M.The effects of compound 3d?3h?3i on human MCF7 cells were inhibited.,especially the better inhibition of compound 3h,its IC₅₀value is 19.2?M.Then,the inhibitoty effects of compounds 1,2a?2h and 3a?3i on Fusarium oxysporum,Rhizoctonia solani,Botrytis cinerea,Fusarium graminearum and Sclerotinia sclerotiorum were studied by in vitro antibacterial activity tests.The results shows that compounds 2e,3a,3d,3c and 3f had better inhibitory effect on Fusarium oxysporum than 125?g/m L.The remaining compounds had no significant inhibitory effect on 5 plant pathogens.