CN110423239B - 1, 3-oxazine 1,2, 3-triazole derivative and synthetic method and application thereof - Google Patents
1, 3-oxazine 1,2, 3-triazole derivative and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1, 3-oxazine 1,2, 3-triazole derivative, a synthetic method and application thereof, and belongs to the technical field of pesticides and organic synthesis. The structural formula of the 1, 3-oxazine 1,2, 3-triazole derivative is shown in the specification
Or
Wherein R is1H, Me or Cl, R2Is Cl, Br, F or Me, R3Is pyridyl or thienyl; the invention takes 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole as a raw material, and the selective carbon-oxygen coupling reaction is carried out under the catalysis of a transition metal/oxidant system to selectively generate the 1, 3-oxazine 1,2, 3-triazole derivative. The 1, 3-oxazine-1, 2, 3-triazole derivative simultaneously contains oxazine and 1,2, 3-triazole ring structural units, and has a good inhibition effect on pathogenic bacteria of panax notoginseng root rot.
Description
Technical Field
The invention relates to a 1, 3-oxazine 1,2, 3-triazole derivative, a synthetic method and application thereof, and belongs to the technical field of pesticides and organic synthesis.
Background
Triazole compounds have been widely used in the fields of medicines, pesticides, materials and the like, and have been paid attention by chemists all the time. Especially after Sharpless finds the click reaction of organic azide and terminal alkyne, the design, synthesis and application of 1,2, 3-triazole compounds are particularly rapid and widely applied to the aspects of antibiosis, anti-influenza, anti-epilepsy, immunity and treatment of tumor, arthritis, chondropathy and the like (Kanthenti S., Narayan R., Raju K.V.S.N.RSC adv.,2015,5, 3687; Schulze B., Schubert U.S.Chem.Soc.Rev.,2014,43, 2522). Pseudo-ginseng (Panax notoginsen (Burk.) F.H.Chen) has the effects of removing blood stasis, stopping bleeding, relieving swelling and pain, and the like, and is a unique rare medicinal plant for cultivation in China. Pseudo-ginseng is a perennial plant, is warm in nature and moist in yin, and is easy to induce various diseases in the unique ecological environment, wherein the root rot is the most serious, the annual loss is 5-20 percent, the serious loss is up to 70 percent, and the loss accounts for 70-85 percent of various diseases, so that the pseudo-ginseng is a main obstacle in pseudo-ginseng production. Because the varieties of the existing antibacterial agents on the market are deficient, and because the resistance of pathogenic bacteria is easily increased by singly using one or more pesticides, the search for a novel antibacterial agent with better effect for preventing and treating the root rot of the panax notoginseng is urgent.
The sources of the functionalized triazole mainly comprise the following ways: (1) the alkyne and the azide compound undergo cycloaddition reaction to selectively obtain 1, 4-disubstituted-1, 2, 3-triazole derivative under the catalysis of cuprous, and obtain 1, 5-disubstituted-1, 2, 3-triazole derivative under the catalysis of ruthenium or quaternary ammonium base (Luciani, L., et al. Green chem.,2018,20, 183; Liu, P., et al. J. Org. chem.,2018,83, 5092.); (2) an organocatalytic cycloaddition reaction occurs using an organic azide and an olefin as substrates (rohila, s., et al eur.j.org.chem.,2016,847; Li, w., et al rsc adv.,2015,5, 88816.); (3) the 1,2, 3-triazole derivative is directly modified (Ma, X.; et al. Synthesis,2018,50, 2567; Zhao F., et al. org. chem. front.,2017,4, 1112; Zhao S., et al. org. Lett.,2015,17,2828.) to obtain a functionalized 1,2, 3-triazole structure.
Although the synthesis of the functionalized 1,2, 3-triazole is greatly developed, the obtained product is basically single non-fused ring type 1,2, 3-triazole, the structural type of the product cannot meet the requirement of the increasing diversity of the application, and particularly, a fused ring type functionalized triazole construction method is rarely reported.
Disclosure of Invention
The invention provides a 1, 3-oxazine 1,2, 3-triazole derivative and a synthesis method and application thereof, aiming at the problem of functionalized triazole in the prior art, the invention takes 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole as a raw material, and selective carbon-oxygen coupling reaction is carried out under the catalysis of a transition metal/oxidant system to selectively generate the 1, 3-oxazine 1,2, 3-triazole derivative.
The structural formula of the 1, 3-oxazine 1,2, 3-triazole derivative is shown as the formula (I) or the formula (II):
wherein the content of the first and second substances,
R1is H, Me or Cl, and has the following properties,
R2is Cl, Br, F or Me,
R3is pyridyl or thienyl.
The synthesis method of the 1, 3-oxazine 1,2, 3-triazole derivative comprises the following specific steps:
adding 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole, a catalyst, an oxidant, alkali and an additive into a solvent to obtain a reaction system, reacting for 5-60 hours at 70-50 ℃ in a protective gas atmosphere, adding deionized water for dilution, extracting with ethyl acetate to obtain an extract liquid, washing and drying the extractant, distilling under reduced pressure to remove the solvent to obtain a crude product, and performing column chromatography on the crude product to obtain the 1, 3-oxazine-1, 2, 3-triazole derivative.
The molar ratio of the 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole, the catalyst, the oxidant, the alkali, the additive and the solvent in the reaction system is 1 (0.01-0.2): 1-3): 1-5): 0.02-0.4): 10-100.
The catalyst is palladium chloride, cuprous iodide, cuprous bromide, cuprous chloride or copper acetylacetonate.
The oxidant is tert-butyl hydroperoxide, iodobenzene diacetic acid, potassium peroxodisulfate or di-tert-butyl peroxide.
The additive is iodine, potassium iodide or tetrabutylammonium iodide.
The solvent is 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, benzotrifluoride or toluene.
The 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole is 1-o-hydroxymethyl phenyl-4-phenyl-1, 2, 3-triazole, 1- (3-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, 1- (4-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, 1- (5-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, 1- (6-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, triazole, 1- (3-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1- (4-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1- (5-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1- (6-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-chlorophenyl) -1,2, 3-triazole or 1-o-hydroxymethylphenyl-4- (3-chlorophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-chlorphenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-bromophenyl) -1,2, 3-triazole or 1-o-hydroxymethylphenyl-4- (3-bromophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-bromophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-fluorophenyl) -1,2, 3-triazole or 1-o-hydroxymethylphenyl-4- (3-fluorophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-fluorophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-methylphenyl) -1,2, 3-triazole or, 1-o-hydroxymethylphenyl-4- (3-methylphenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-methylphenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-pyridyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (3-pyridyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-thienyl) -1,2, 3-triazole or 1-o-hydroxymethyl phenyl-4- (3-thienyl) -1,2, 3-triazole.
The protective gas is nitrogen or helium.
The 1, 3-oxazine 1,2, 3-triazole derivative is applied to inhibiting pathogenic bacteria of panax notoginseng root rot.
Furthermore, the 1, 3-oxazine 1,2, 3-triazole derivative can be used for preparing medicines for preventing pathogenic bacteria of panax notoginseng root rot.
The invention has the beneficial effects that:
the method takes 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole as an initial raw material, and generates a carbon-oxygen coupling reaction under the catalysis of a transition metal/oxidant system to selectively generate the 1, 3-oxazine-1, 2, 3-triazole derivative; the synthesized compound simultaneously contains oxazine and 1,2, 3-triazole ring structural units, has good inhibition effect on pathogenic bacteria of the panax notoginseng root rot, and can also provide a new method for synthesis and modification of functional molecules.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but the scope of the present invention is not limited to the description. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available by purchase.
Example 1: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative of this example is shown as (4-o-tolyl-1, 2, 3-triazolo-1, 3-oxazine 2 a):
the method for synthesizing 4-o-tolyl-1, 2, 3-triazole 1, 3-oxazine 2a comprises the following steps:
sequentially adding 1mmol of 1-o-hydroxymethylphenyl-4-o-tolyl-1, 2, 3-triazole (1a), cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, 0.01mmol of cuprous bromide, 1mmol of tert-butyl hydroperoxide, 1mmol of lithium tert-butoxide, 0.02mmol of tetrabutylammonium iodide and 10mmol of 1, 2-dichloroethane into a reactor according to the molar ratio of 1:0.01:1:1:0.02:10 of 1-o-hydroxymethylphenyl-4-o-tolyl-1, 2, 3-triazole, 0.01mmol of cuprous bromide, 1mmol of tert-butyl hydroperoxide, 1mmol of lithium tert-butoxide, 0.02mmol of tetrabutylammonium iodide and 10mmol of 1, 2-dichloroethane, filling nitrogen, and reacting at the temperature of 70 ℃ for 5 hours; adding 40mL of deionized water for dilution, extracting for 3 times by using 130mL of ethyl acetate to obtain an extraction solution, washing the extraction agent by water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 253mg of 1, 3-oxazine 1,2, 3-triazole derivative (4-o-tolyl-1, 2, 3-triazole 1, 3-oxazine 2a), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.05(d,J＝8.0Hz,1H),7.57–7.55(m,1H),7.53(t,J＝7.8Hz,1H),7.38(td,J＝7.6,0.8Hz,1H),7.28(ddd,J＝5.6,4.8,3.0Hz,4H),5.39(s,2H),2.50(s,3H)；13C NMR(150MHz,CDCl3)δ144.22,136.81,131.40,130.79,130.00,129.37,128.92,128.59,128.19,127.79,125.80,125.03,120.14,115.53,69.12,20.71.
the yield of 4-o-tolyl-1, 2, 3-triazolo-1, 3-oxazine 2a in this example was 96%.
Example 2: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-o-methoxyphenyl-1, 2, 3-triazolo-1, 3-oxazine 2b) in this example is shown as follows:
the method for synthesizing the 4-o-methoxyphenyl-1, 2, 3-triazole 1, 3-oxazine 2b comprises the following steps:
sequentially adding 1mmol 1-o-hydroxymethylphenyl-4-o-methoxyphenyl-1, 2, 3-triazole, 0.02:1.2:1.3:0.05:20, 1.05 mmol of cuprous bromide, 1.2mmol of tert-butyl hydroperoxide, 1.3mmol of tert-butyl lithium butoxide, 0.05mmol of tetrabutylammonium iodide and 20mmol of 1, 2-dichloroethane according to the molar ratio of 1:0.02:1.2:1.3:0.05 to 1-o-hydroxymethyltolyl-4-o-methoxyphenyl-1, 2, 3-triazole to the reactor, charging nitrogen, and reacting at 75 ℃ for 10 hours; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 245mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4-o-methoxyphenyl-1, 2, 3-triazole-1, 3-oxazine-2 b), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.04(d,J＝8.0Hz,1H),7.67(dd,J＝7.5,1.4Hz,1H),7.52(t,J＝7.7Hz,1H),7.37(t,J＝7.6Hz,2H),7.28(d,J＝7.5Hz,1H),7.06(t,J＝7.5Hz,1H),7.00(d,J＝8.3Hz,1H),5.37(s,2H),3.88(s,3H)；13C NMR(150MHz,CDCl3)δ156.74,144.69,131.54,130.23,129.89,129.62,128.67,127.66,124.95,120.84,120.41,118.80,115.58,111.43,69.04,55.89.
the yield of 4-o-methoxyphenyl-1, 2, 3-triazolo-1, 3-oxazine 2b of this example was 93%.
Example 3: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-phenyl-1, 2, 3-triazolo-1, 3-oxazine 2c) in this example is as follows:
the method for synthesizing the 4-phenyl-1, 2, 3-triazole 1, 3-oxazine 2c comprises the following specific steps:
sequentially adding 1mmol of 1-o-hydroxy tolyl-4-phenyl-1, 2, 3-triazole (1c), cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, tetrabutylammonium iodide and 1, 2-dichloroethane according to the molar ratio of 1:0.04:1.7:2:0.09:40, adding 1mmol of 1-o-hydroxymethyl phenyl-4-phenyl-1, 2, 3-triazole, 0.04mmol of cuprous bromide, 1.7mmol of tert-butyl hydroperoxide, 2mmol of lithium tert-butoxide, 0.09mmol of tetrabutylammonium iodide and 40mmol of 1, 2-dichloroethane into a reactor, filling nitrogen, and reacting at 80 ℃ for 15 hours; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 224mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4-phenyl-1, 2, 3-triazole-1, 3-oxazine-2 c), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.02(d,J＝8.0Hz,1H),7.98(d,J＝7.7Hz,2H),7.52(t,J＝7.8Hz,1H),7.45(t,J＝7.6Hz,2H),7.38(t,J＝7.5Hz,1H),7.31(dd,J＝11.6,4.1Hz,2H),5.46(s,2H)；13C NMR(150MHz,CDCl3)δ144.04,131.24,130.01,129.94,128.70,128.12,127.82,127.38,125.15,125.01,119.92,115.52,69.25；
the yield of 4-phenyl-1, 2, 3-triazole 1, 3-oxazine 2c in this example was 85%.
Example 4: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-p-fluorophenyl-1, 2, 3-triazolo-1, 3-oxazine-2 d) in this example is shown as follows:
the method for synthesizing the 4-phenyl-1, 2, 3-triazole 1, 3-oxazine 2c comprises the following specific steps:
sequentially adding 1mmol 1-o-hydroxymethylphenyl-4- (4-fluorophenyl) -1,2, 3-triazole, cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, tetrabutylammonium iodide and 1, 2-dichloroethane according to the molar ratio of 1:0.07:1.8:2.4:0.1:50, 0.07mmol cuprous bromide, 1.8mmol tert-butyl hydroperoxide, 2.4mmol tert-butoxide lithium, 0.1mmol tetrabutylammonium iodide and 50mmol 1, 2-dichloroethane into a reactor, filling nitrogen, and reacting at 90 ℃ for 20 hours; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 238mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4-p-fluorophenyl-1, 2, 3-triazole-1, 3-oxazine-2 d), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ7.99(d,J＝8.0Hz,1H),7.95(t,J＝1.7Hz,1H),7.88–7.85(m,1H),7.51(t,J＝7.7Hz,1H),7.40–7.33(m,2H),7.30(d,J＝7.5Hz,1H),7.27–7.24(m,1H),5.47(s,2H)；13C NMR(150MHz,CDCl3)δ144.26,134.65,131.70,131.02,130.02(d,J＝10.7Hz),127.99,127.30,126.87,125.01(d,J＝7.0Hz),123.07,119.71,115.48,69.36.
this example gives 84% yield of 4-p-fluorophenyl-1, 2, 3-triazolo-1, 3-oxazine 2 d.
Example 5: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-m-chlorophenyl-1, 2, 3-triazolo-1, 3-oxazine-2 e) in this example is shown as follows:
the method for synthesizing 4-m-chlorophenyl-1, 2, 3-triazole 1, 3-oxazine 2e comprises the following steps:
sequentially adding 1mmol 1-o-hydroxymethylphenyl-4- (3-chlorphenyl) -1,2, 3-triazole, cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, tetrabutylammonium iodide and 1, 2-dichloroethane according to the molar ratio of 1:0.08:1.9:2.7:0.13:60 into a reactor, filling nitrogen, and reacting at 100 ℃ for 30 hours, wherein the molar ratio of 1-o-hydroxymethyltolyl-4- (3-chlorphenyl) -1,2, 3-triazole to 1, 2-dichloroethane is 1:0.08 mmol cuprous bromide, 1.9mmol tert-butyl hydroperoxide, 2.7mmol tert-butoxide lithium, 0.13mmol tetrabutylammonium iodide and 60mmol 1, 2-dichloroethane; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 272mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4-m-chlorophenyl-1, 2, 3-triazole-1, 3-oxazine-2 e), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.00(d,J＝8.0Hz,1H),7.96–7.91(m,2H),7.50(d,J＝7.5Hz,1H),7.38(td,J＝7.6,0.9Hz,1H),7.30(d,J＝7.4Hz,1H),7.16–7.09(m,2H),5.45(s,2H)；13C NMR(150MHz,CDCl3)δ162.85,161.21,143.70,131.11,129.99,127.86,127.31,126.78(d,J＝8.0Hz),126.09(d,J＝3.2Hz),125.00,119.80,115.71,115.56,115.44,69.25；
the yield of 4-m-chlorophenyl-1, 2, 3-triazolo-1, 3-oxazine 2e of this example was 96%.
Example 6: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-o-chlorophenyl-1, 2, 3-triazolo-1, 3-oxazine 2f) in this example is shown as follows:
the method for synthesizing 4-o-chlorophenyl-1, 2, 3-triazole 1, 3-oxazine 2f comprises the following steps:
sequentially adding 1mmol of 1-o-hydroxy tolyl-4-o-chlorophenyl-1, 2, 3-triazole (1f), cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, tetrabutyl ammonium iodide and 1, 2-dichloroethane according to the molar ratio of 1:0.12:2.1:3:0.17:70, 0.12mmol of cuprous bromide, 2.1mmol of tert-butyl hydroperoxide, 3mmol of lithium tert-butoxide, 0.17mmol of tetrabutyl ammonium iodide and 70mmol of 1, 2-dichloroethane into a reactor, filling nitrogen, and reacting at 110 ℃ for 35 hours; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 244mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4-o-chlorophenyl-1, 2, 3-triazole-1, 3-oxazine 2f), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.02(d,J＝8.0Hz,1H),7.91(d,J＝8.5Hz,2H),7.53(t,J＝7.7Hz,1H),7.42–7.37(m,3H),7.31(s,1H),5.47(s,2H)；13C NMR(150MHz,CDCl3)δ144.03,132.97,131.10,130.06,129.13,128.88,128.51,128.45,127.93,127.18,126.32,125.01,119.73,115.51,69.32；
the yield of 4-o-chlorophenyl-1, 2, 3-triazolo-1, 3-oxazine 2f of this example was 86%.
Example 7: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-o-bromophenyl-1, 2, 3-triazolo-1, 3-oxazine 2g) in this example is shown as follows:
the method for synthesizing 2g of 4-o-bromophenyl-1, 2, 3-triazole 1, 3-oxazine comprises the following steps:
sequentially adding 1mmol of 1-o-hydroxy tolyl-4-o-bromophenyl-1, 2, 3-triazole, cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, tetrabutylammonium iodide and 1, 2-dichloroethane according to the molar ratio of 1:0.14:2.3:3.5:0.2:75, 0.2mmol of cuprous bromide, 2.3mmol of tert-butyl hydroperoxide, 3.5mmol of lithium tert-butoxide, 0.2mmol of tetrabutylammonium iodide and 75mmol of 1, 2-dichloroethane into a reactor, filling nitrogen, and reacting at 120 ℃ for 40 hours; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 217mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4-o-bromophenyl-1, 2, 3-triazole-1, 3-oxazine-2 g), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.05(d,J＝8.0Hz,1H),7.69(d,J＝8.1Hz,1H),7.61(dd,J＝7.7,1.6Hz,1H),7.54(t,J＝7.8Hz,1H),7.43–7.36(m,2H),7.30(d,J＝7.6Hz,1H),7.28–7.24(m,2H),5.43(s,2H)；13C NMR(150MHz,CDCl3)δ144.27,133.20,131.81,131.29,130.60,129.99,129.87,128.37,127.90,127.44,125.05,122.94,120.16,115.56,68.93；
the yield of 2g of 4-o-bromophenyl-1, 2, 3-triazolo-1, 3-oxazine of this example was 85%.
Example 8: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4- (3-thienyl) -1,2, 3-triazole 1, 3-oxazine 2h) in this example is as follows:
the method for synthesizing 4- (3-thienyl) -1,2, 3-triazole 1, 3-oxazine 2h comprises the following steps:
sequentially adding 1mmol 1-o-hydroxymethylphenyl-4- (3-thienyl) -1,2, 3-triazole, 0.17:2.6:4.2:0.28:85 mol of 1-o-hydroxytoluene-4- (3-thienyl) -1,2, 3-triazole, 0.17mmol cuprous bromide, 2.6mmol t-butylhydroperoxide, 4.2mmol t-butyllithium butoxide, 0.28mmol tetrabutylammonium iodide and 85mmol 1, 2-dichloroethane into a reactor according to the mol ratio of 1:0.17:2.6:4.2:0.28:85 of 1-o-hydroxytoluene-4- (3-thienyl) -1,2, 3-triazole, charging nitrogen gas, and reacting at 130 ℃ for 45 h; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 219mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4- (3-thienyl) -1,2, 3-triazole 1, 3-oxazine for 2h), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.02(d,J＝8.0Hz,1H),7.70(dd,J＝3.0,1.1Hz,1H),7.66(dd,J＝5.0,1.1Hz,1H),7.52(q,J＝7.6Hz,1H),7.40(dd,J＝5.0,3.0Hz,1H),7.38(td,J＝7.6,0.9Hz,1H),7.30(d,J＝7.6Hz,1H),5.45(s,2H)；13C NMR(150MHz,CDCl3)δ143.27,131.18,130.53,129.98,127.80,125.94,125.58,125.34,125.00,120.11,119.88,115.48,69.25；
this example gives a yield of 88% of 4- (3-thienyl) -1,2, 3-triazolo-1, 3-oxazine in 2 h.
Example 9: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4- (2-thienyl) -1,2, 3-triazole 1, 3-oxazine 2i) in this example is as follows:
the method for synthesizing 4- (2-thienyl) -1,2, 3-triazole 1, 3-oxazine 2i comprises the following steps:
sequentially adding 1mmol 1-o-hydroxymethylphenyl-4- (2-thiophene) -1,2, 3-triazole, 0.18:2.9:4.7:0.33:90 according to the molar ratio of 1-o-hydroxytoluene-4- (2-thienyl) -1,2, 3-triazole to 1, 2-dichloroethane of 1:0.18:2.9: 4.33: 90 into a reactor, filling nitrogen, and reacting for 50h at the temperature of 140 ℃; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extract, washing the extract with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 233mg of a 1, 3-oxazine-1, 2, 3-triazole derivative (4- (2-thienyl) -1,2, 3-triazole-1, 3-oxazine-2 i), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of ethyl acetate to petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.0Hz,1H),7.51(t,J＝7.8Hz,1H),7.43(dd,J＝3.5,1.1Hz,1H),7.38(td,J＝7.6,0.9Hz,1H),7.32–7.28(m,2H),7.11(dd,J＝5.0,3.6Hz,1H),5.47(s,2H)；13C NMR(150MHz,CDCl3)δ142.71,131.60,131.05,130.00,127.92,127.48,125.02,124.80,124.28,123.47,119.77,115.51,69.35；
this example gives 84% yield of 4- (2-thienyl) -1,2, 3-triazolo-1, 3-oxazine 2 i.
Example 10: the structural formula of the 1, 3-oxazine-1, 2, 3-triazole derivative (4-p-tolyl-1, 2, 3-triazolo-1, 3-oxazine-2 j) in this example is shown as follows:
the method for synthesizing 4-p-tolyl-1, 2, 3-triazole 1, 3-oxazine 2j comprises the following steps:
sequentially adding 1mmol1- (2-hydroxymethyl-4-methylphenyl) -4-phenyl-1, 2, 3-triazole, cuprous bromide, tert-butyl hydroperoxide, lithium tert-butoxide, tetrabutylammonium iodide and 1, 2-dichloroethane according to the molar ratio of 1:0.2:3:5:0.4:100 to the 1- (2-hydroxymethyl-4-methylphenyl) -4-phenyl-1, 2, 3-triazole, 0.2mmol cuprous bromide, 3mmol tert-butyl hydroperoxide, 5mmol tert-butoxide lithium, 0.4mmol tetrabutylammonium iodide and 100mmol 1, 2-dichloroethane in a reactor, filling nitrogen, and reacting at 150 ℃ for 60 hours; adding 40mL of deionized water for dilution, extracting with 130mL of ethyl acetate for 4 times to obtain an extraction solution, washing the extraction agent with water, drying, distilling under reduced pressure to remove the solvent to obtain a crude product, performing column chromatography (400-mesh silica gel) on the crude product to obtain 239mg of 1, 3-oxazine 1,2, 3-triazole derivatives (4-p-tolyl-1, 2, 3-triazole 1, 3-oxazine 2j), wherein the eluent of the column chromatography is ethyl acetate/petroleum ether (the volume ratio of the ethyl acetate to the petroleum ether is 1: 4);
the reaction equation is as follows:
the product nuclear magnetic resonance spectrum characterization data are as follows:1H NMR(600MHz,CDCl3)δ7.89(d,J＝8.1Hz,1H),7.86(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,1H),7.27–7.23(m,2H),7.09(s,1H),5.39(s,2H),2.41(s,3H),2.38(s,3H)；13C NMR(150MHz,CDCl3)δ143.54,137.88,137.06,130.39,129.34,128.98,128.15,127.16,125.36,125.03,119.88,115.32,69.22,21.33,21.27；
this example gives 86% yield of 4-p-tolyl-1, 2, 3-triazolo-1, 3-oxazine 2 j.
Example 11: the application of the 1, 3-oxazine 1,2, 3-triazole derivative in inhibiting pathogenic bacteria of panax notoginseng root rot;
activation of pathogenic bacteria
(1) Potato dextrose agar medium (PDA): 200g of potatoes, 20g of glucose, 20g of agar and 1000mL of distilled water;
(2) purifying and identifying pathogenic bacteria separated from the root of pseudo-ginseng into Fusarium oxysporum (Fusarium oxysporum), Fusarium solani (Fusarium solani) and Cylindrocarpon destructor, inoculating the strains on a PDA culture medium for activation, and taking a strain which grows vigorously for later use after 3-4 times of inoculation;
compound Minimum Inhibitory Concentration (MIC) assay;
(1) dissolving the 1, 3-oxazine 1,2, 3-triazole derivatives 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i and 2j synthesized in the embodiments 1-10 and common chemical pesticides hymexazol, flutriafol, ripping agent and propamocarb in the market respectively by using DMSO (dimethyl sulfoxide) to prepare a solution of 6 mg/mL;
(2) the pathogen of example 11, which grew for 7 days, was washed with 20mL 1/4PDA liquid medium (no agar added, potato and glucose in the amount of 1/4 of conventional medium), and then made to have a spore concentration of 1X 104Spore suspension per mL;
(3) adding 4 μ L of the monomeric compound sterilized by filtration through a 0.22 μm microporous membrane and 156 μ L of the spore suspension prepared in the step (2) into a 96-well plate; preparing a plurality of concentration gradient liquids with the compound concentration range of 150 mu g/mL-0.146 mu g/mL in the step (1) by a double dilution method;
(4) blanks were 4. mu.L DMSO and 156. mu.L 1/4PDA broth; the positive control is 4. mu.L DMSO and 156. mu.L spore suspension in step (3);
(5) culturing a 96-well plate at a constant temperature of 28 ℃ for 36h, and then checking the growth condition of fungi in the hole; the absorbance of each well was measured at 595nm using a microplate reader (Thermo 1510), and the results are given in the following table;
the compounds 2a and 2h have stronger broad-spectrum antibacterial activity on three pathogenic strains causing the root rot of panax notoginseng, the antibacterial activity is in the same order of magnitude as that of positive medicines hymexazol and flutriafol, and the antibacterial activity is higher than that of loose soil essence and propamocarb; the tested and synthesized compound has stronger bacteriostatic activity on fusarium oxysporum, and the compound 2j has stronger bacteriostatic activity on the destructive Neurospora.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1, 3-oxazine 1,2, 3-triazole derivative, characterised in that the structural formula is as shown in formula (I) or formula (ii):
wherein the content of the first and second substances,
R1is H, Me or Cl, and has the following properties,
R2is Cl, Br, F or Me,
R3is pyridyl or thienyl.
2. The synthesis method of the 1, 3-oxazine 1,2, 3-triazole derivative as claimed in claim 1, characterized by comprising the following steps:
adding 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole, a catalyst, an oxidant, alkali and an additive into a solvent to obtain a reaction system, reacting for 5-60 hours at 70-50 ℃ in a protective gas atmosphere, adding deionized water for dilution, extracting with ethyl acetate to obtain an extract liquid, washing and drying the extractant, distilling under reduced pressure to remove the solvent to obtain a crude product, and performing column chromatography on the crude product to obtain a 1, 3-oxazine-1, 2, 3-triazole derivative; the catalyst is palladium chloride, cuprous iodide, cuprous bromide, cuprous chloride or copper acetylacetonate, the oxidant is tert-butyl hydroperoxide, iodobenzene diacetic acid, potassium peroxodisulfate or di-tert-butyl peroxide, and the additive is iodine, potassium iodide or tetrabutylammonium iodide.
3. The method of synthesis according to claim 2, wherein: the molar ratio of the 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole, the catalyst, the oxidant, the alkali, the additive and the solvent in the reaction system is 1 (0.01-0.2): (1-3): 1-5): 0.02-0.4): 10-100.
4. The synthesis method according to claim 2 or 3, characterized in that: the solvent is 1, 2-dichloroethane, tetrahydrofuran, 1, 4-dioxane, benzotrifluoride or toluene.
5. The synthesis method according to claim 2 or 3, characterized in that: the 1-o-hydroxymethyl aryl-4-aryl-1, 2, 3-triazole is 1-o-hydroxymethyl phenyl-4-phenyl-1, 2, 3-triazole, 1- (3-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, 1- (4-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, 1- (5-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, 1- (6-methyl-2-hydroxymethyl phenyl) -4-phenyl-1, 2, 3-triazole, triazole, 1- (3-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1- (4-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1- (5-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1- (6-chloro-2-hydroxymethylphenyl) -4-phenyl-1, 2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-chlorophenyl) -1,2, 3-triazole or 1-o-hydroxymethylphenyl-4- (3-chlorophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-chlorphenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-bromophenyl) -1,2, 3-triazole or 1-o-hydroxymethylphenyl-4- (3-bromophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-bromophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-fluorophenyl) -1,2, 3-triazole or 1-o-hydroxymethylphenyl-4- (3-fluorophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-fluorophenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-methylphenyl) -1,2, 3-triazole or, 1-o-hydroxymethylphenyl-4- (3-methylphenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (4-methylphenyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-pyridyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (3-pyridyl) -1,2, 3-triazole, 1-o-hydroxymethylphenyl-4- (2-thienyl) -1,2, 3-triazole or 1-o-hydroxymethyl phenyl-4- (3-thienyl) -1,2, 3-triazole.
6. The synthesis method according to claim 2 or 3, characterized in that: the protective gas is nitrogen or helium.
7. The use of the 1, 3-oxazine-1, 2, 3-triazole derivatives as claimed in claim 1 for inhibiting pathogenic bacteria of root rot of panax notoginseng.
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