CN110016019B - Oxadiazole derivative based on furan phenol and preparation method and application thereof - Google Patents

Oxadiazole derivative based on furan phenol and preparation method and application thereof Download PDF

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CN110016019B
CN110016019B CN201910360331.9A CN201910360331A CN110016019B CN 110016019 B CN110016019 B CN 110016019B CN 201910360331 A CN201910360331 A CN 201910360331A CN 110016019 B CN110016019 B CN 110016019B
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dihydrobenzofuran
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李婉
李胜男
武世杰
朱华结
田胜尼
冯珂
曹飞
李龙飞
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Hebei University
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The invention provides an oxadiazole derivative based on furan phenol shown in formula (I), and a preparation method and application thereof, wherein R is selected from 4-CN-C6H4、4‑F‑C6H4，4‑Cl‑C6H4、4‑Br‑C6H4、3‑F‑C6H4、3‑Br‑C6H4、4‑NO2‑C6H4、3‑NO2‑C6H4、2‑Br‑C6H4、3‑CH3‑C6H4、4‑CH3‑C6H4、4‑OMe‑C6H4、3‑OMe‑C6H4、2‑OMe‑C6H4Phenyl, isopropyl, cyclohexyl, styryl, furyl, thienyl or naphthyl. The compound and the pharmaceutically acceptable salt thereof have higher inhibition activity on weeds such as barnyard grass and the like, do not cause damage to crops, and provide a new choice for eliminating the weeds.

Description

Oxadiazole derivative based on furan phenol and preparation method and application thereof
Technical Field
The invention relates to a compound, a preparation method and application thereof, and particularly relates to an oxadiazole derivative based on furan phenol and a preparation method and application thereof.
Background
China is a world with large grain production and consumption, and improving the yield per unit of grain is a very important way to ensure the grain safety of China. Weeds are one of the main factors causing the yield reduction of crops, and the development and large-scale application of organic chemical herbicides can greatly reduce the agricultural economic loss caused by the weeds. There are over five hundred varieties of existing herbicides, but many weeds have developed resistance to various types and varieties of herbicides in recent years due to long-term repeated use, and therefore, development of new herbicides is imperative.
The 1,3,4-oxadiazole is a five-membered heterocycle containing O and N atoms, and has wide medicinal and pesticide activities, such as anti-inflammatory, antibacterial and plant growth regulating activities. 1,3,4-oxadiazole compounds are more researched in the aspect of herbicides, for example, dehydroabietic acid is used as a raw material in the aspects of populus torrential flood and the like, 2-substituted thioether-5-dehydroabietyl-, 3,4-oxadiazole compounds are obtained through esterification, hydrazinolysis, ring closing and nucleophilic substitution reaction, the activity is tested by adopting a small cup method, and the result shows that part of compounds have certain inhibition activity on barnyard grass rhizome; 2-substituted-5-pyrazolyl-1, 3,4-oxadiazole compounds are synthesized by chen han song and the like, and have certain inhibitory activity on barnyard grass and rape; the 3- (pyrimidinyl-2) -1,3, 4-oxadiazole-2 (3H) -ketone derivatives reported by Zhuyou quan et al are tested by a rape plate method and a barnyard grass cup method, and part of the compounds show certain herbicidal activity. However, the above 1,3,4-oxadiazole compounds are either complicated in preparation process or low in herbicidal activity, and therefore, it is necessary to develop new 1,3,4-oxadiazole compounds for use in the field of weeding.
Disclosure of Invention
The invention aims to provide an oxadiazole derivative based on furan phenol, which has inhibitory activity on barnyard grass at low dose and provides a new choice for the development of herbicides.
The purpose of the invention is realized as follows:
a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure BDA0002046630990000011
wherein R is selected from 4-CN-C6H4、4-F-C6H4，4-Cl-C6H4、4-Br-C6H4、3-F-C6H4、3-Br-C6H4、4-NO2-C6H4、3-NO2-C6H4、2-Br-C6H4、3-CH3-C6H4、4-CH3-C6H4、4-OMe-C6H4、3-OMe-C6H4、2-OMe-C6H4Phenyl, isopropyl, cyclohexyl, styryl, furyl, thienyl or naphthyl.
Preferably, the compound is selected from:
Figure BDA0002046630990000021
the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:
(1) dissolving compound A (furan phenol) in anhydrous DMF, adding K2CO3Stirring at room temperature until the mixture is dissolved, observing the color of the solution, gradually changing from light green to dark greenish black, finally changing to black, adding ethyl chloroacetate and catalytic amount KI, stirring and heating at 60 ℃ for 6-8h, and detecting by TLC. After the reaction is finished, adding a small amount of water, stirring for 5min, extracting with ethyl acetate, and using anhydrous NaSO for an organic phase4And (5) drying and spin-drying. And (4) carrying out column chromatography with petroleum ether and ethyl acetate of 40: 1 to obtain a pure intermediate product B which is a dark yellow viscous liquid. The mol ratio of the compound A to the ethyl chloroacetate is 1: 1.5;
(2) and dissolving the intermediate product B in absolute ethyl alcohol, dropwise adding hydrazine hydrate (80 mass percent) under an ice bath condition, and stirring for 5min under the ice bath condition. The mixture was heated at 60 ℃ for 2h with stirring and monitored by TLC. After the reaction is finished, extracting by dichloromethane, spin-drying the solvent, adding water, separating out crystals, and performing suction filtration. Recrystallizing with ethanol to obtain pure intermediate product C as white crystal. The mol ratio of the intermediate product B to the hydrazine hydrate is 1: 2.5;
(3) dissolving the intermediate product C in absolute ethyl alcohol, adding aldehyde after stirring and dissolving, stirring and heating at 60 ℃ for 6-8h, and monitoring by TLC. After the reaction is completed, suction filtration and spin drying are carried out to obtain light yellowA viscous solid. By column chromatography (V)Methylene dichloride∶VMethanolAnd (6) performing rotary evaporation at the ratio of 160: 1 to obtain an intermediate product D. The molar ratio of the intermediate product C to the aldehyde is 1: 1.2;
(4) and dissolving the intermediate product D in absolute ethyl alcohol, stirring at 40 ℃ until the intermediate product D is completely dissolved, adding diethyl iodobenzene, stirring and refluxing for 0.5h, and monitoring by TLC. After the reaction is completed, cooling, filtering, rotary evaporating, and respectively using dichloromethane and methanol (V: V) whose ratio is 150: 1 and dichloromethane and methanol (V: V) whose ratio is 60: 1 to make column chromatography to obtain white crystal, namely the invented target product.
The reaction equation is as follows:
Figure BDA0002046630990000031
on the other hand, the invention provides the application of the compound or the pharmaceutically acceptable salt thereof in herbicide medicaments, and the medicaments have strong inhibition activity on weeds such as barnyard grass and the like.
In still another aspect, the present invention provides a pesticide composition, which comprises the compound described in the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable adjuvants.
The pesticide composition provided by the invention contains the compound and pharmaceutically acceptable salts thereof, pharmaceutically acceptable carriers or a combination of the compound as an active ingredient and a pharmaceutical excipient or a diluent.
The various formulations of the pesticidal composition provided by the present invention may be prepared according to conventional production methods in the field of pesticides, for example, by mixing the active ingredient with one or more carriers and then making it into a desired formulation.
The compound and the pharmaceutically acceptable salt thereof have higher inhibition activity on weeds such as barnyard grass and the like, do not cause damage to crops, and provide a new choice for eliminating the weeds. Meanwhile, the compound of the invention has the advantages of simple preparation method, high yield, lower cost and convenient popularization and application.
Detailed Description
The present invention is further illustrated by the following examples in which the procedures and methods not described in detail are conventional and well known in the art, and the starting materials or reagents used in the examples are commercially available, unless otherwise specified, and are commercially available.
Example 1
Synthesis of ethyl-2- ((2,2-dimethyl-2, 3-2, 3-dihydrobenzofuran-7-yl) oxy) acetate (compound B):
Figure BDA0002046630990000032
dissolving compound A in anhydrous DMF, adding K2CO3Stirring at room temperature until the mixture is dissolved, adding ethyl chloroacetate and KI with a catalytic amount, stirring and heating at 60 ℃ for 6-8h, and detecting by TLC. After the reaction is finished, adding a small amount of water, stirring for 5min, extracting with ethyl acetate, and using anhydrous NaSO for an organic phase4And (5) drying and spin-drying. And (4) carrying out column chromatography with petroleum ether and ethyl acetate of 40: 1 to obtain a pure intermediate product B which is yellow viscous liquid and has the yield of 90%. The mol ratio of the compound A to the ethyl chloroacetate is 1: 1.5; MS-ESI, M/z 273.28[ M + Na ]]+.HR-MS-EI m/z calcd for C14H18O4[M+H]+250.2925，found 250.2940；1H NMR(600MHz,CDCl3)δ6.80(d,J＝7.1Hz,1H),6.75–6.68(m,2H),4.71(s,2H),4.24(q,J＝7.1Hz,2H),3.01(s,2H),1.50(s,6H),1.28(t,J＝7.1Hz,3H)；13C NHR(150MHz,CDCl3)δ169.34,147.66,142.65,129.02,120.30,118.79,114.46,87.61,66.72,61.11,43.14,28.19,14.17。
Example 2
Synthesis of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acetohydrazide (Compound C):
Figure BDA0002046630990000041
dissolving the intermediate product B in absolute ethyl alcohol, dropwise adding hydrazine hydrate (80% mass fraction) under the ice-bath condition,stirring for 5min under ice bath condition. The mixture was heated at 60 ℃ for 2h with stirring and monitored by TLC. After the reaction is finished, extracting by dichloromethane, spin-drying the solvent, adding water, separating out crystals, and performing suction filtration. Ethanol recrystallization gave intermediate C as white crystals in 93% yield. The mol ratio of the intermediate product B to the hydrazine hydrate is 1: 2.5; MS-ESI, M/z 259.26[ M + Na ]]+.HR-MS-EI m/z calcd for C12H16N2O3[M+H]+236.2695,found236.2710；1H NMR(600MHz,CDCl3)δ8.13(s,1H),6.86(d,J＝7.2Hz,1H),6.77(t,J＝7.7Hz,1H),6.73(d,J＝8.0Hz,1H),4.65(s,2H),3.90(s,2H),3.05(s,2H),1.52(s,6H)。
Example 3
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorophenylmethylene) acetohydrazide:
Figure BDA0002046630990000042
dissolving 2.4mmol 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide in 50ml ethanol, stirring for dissolving, adding 2.88mmol p-fluorobenzaldehyde, heating in an oil bath kettle at 60 ℃, stirring for 6-8h, monitoring by TLC, performing suction filtration after complete reaction, and spin-drying to obtain a light yellow sticky solid crude product 0.74g, and performing column chromatography (V)Methylene dichloride∶VMethanol160: 1) to yield 0.54g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorobenzylidene) acetohydrazide. m.p.145.9-146.5 deg.C, yield 90.1%,1H NMR(600MHz,CDCl3)δ9.92(s,1H),8.13(s,1H),7.63(d,J＝8.4Hz,2H),7.30(d,J＝8.4Hz,2H),6.84–6.79(m,1H),6.73(d,J＝6.3Hz,2H),4.67(s,2H),2.99(s,2H),1.46(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (4-fluorophenyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000051
2.16mmol (E) -2- ((2, 2-bis)Methyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorobenzylidene) acethydrazide is dissolved in absolute ethyl alcohol, stirred at 40 ℃ and completely dissolved, 2.59mmol of iodobenzene diethyl ester is added, and the mixture is stirred and refluxed for 0.5h and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.69g of yellow solid, namely the target product, and the yield is 94.2%. MS-ESI, M/z363.11[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17FN2O3[M+H]+341.1288,found341.1301.m.p.139-141℃；1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.6Hz,2H),7.49(d,J＝8.6Hz,2H),6.92(d,J＝8.1Hz,1H),6.85(d,J＝7.4Hz,1H),6.76(t,J＝7.8Hz,1H),5.41(s,2H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ164.94,162.79,148.09,142.08,138.28,129.48,129.30,128.38,122.13,120.55,119.68,115.16,87.98,61.37,43.10,28.20。
Example 4
Preparation of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - ((1E, 2E) -3-phenyleneinyl) acethydrazide:
Figure BDA0002046630990000052
the preparation was carried out as described in example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of cinnamaldehyde for 6-8h to give 0.77g of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - ((1E, 2E) -3-phenyleneiryl) acethydrazide as a yellow solid in 92.1% yield m.p.142.3-144.2 ℃;1H NMR(600MHz,CDCl3)δ9.87(s,1H),7.86(d,J＝9.2Hz,1H),7.38(d,J＝7.3Hz,2H),7.29(t,J＝7.4Hz,2H),7.25(d,J＝7.2Hz,1H),6.82(dd,J＝10.1,5.6Hz,2H),6.73(d,J＝4.7Hz,2H),4.66(s,2H),2.99(s,2H),1.46(s,6H)。
(E) preparation of-2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5-styryl-1,3, 4-oxadiazole:
Figure BDA0002046630990000061
2.21mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorobenzylidene) acethydrazide are dissolved in absolute ethanol, and after complete dissolution by stirring at 40 ℃, 2.65mmol of iodobenzene diethyl ester are added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring are carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.72g of light yellow powder, namely the target product, and the yield is 94.1%. MS-ESI, M/z 371.14[ M + Na ]]+.HR-MS-EI m/z calcd for C21H20N2O3[M+H]+349.1534,found349.1552.m.p.138-140℃；1H NMR(600MHz,CDCl3)δ1.41(s,6H,2×CH3),2.93(s,2H,CH2),5.33(s,2H,CH2),7.98(d,J＝6Hz,2H,C6H52,5H),7.438(d,J＝7.2Hz,1H,C6H5 4H),7.409(t,2H,C6H5 3,5H),6.840(d,J＝7.8Hz,1H,C6H3 4H),6.753(d,J＝7.8Hz,1H,C6H3,6H),6.669(t,1H,C6H35H)；13C NMR(151MHz,CDCl3)δ165.35,162.05,143.04,139.90,137.40,134.65,129.03,128.59,128.54,127.58,126.53,126.47,120.55,109.68,87.96,61.44,43.12,28.21。
Example 5
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (naphthalen-1-ylmethylene) acetohydrazide:
Figure BDA0002046630990000062
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 1-naphthalene aldehyde to react for 6 to 8 hours, so as to obtain 0.81g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (naphthalene-1-ylmethylene) acethydrazide as a yellow solid, wherein m.p.145.1-146.4 ℃ has the yield of 90.4 percent;1H NMR(600MHz,CDCl3)δ8.91(s,1H),8.58(d,J＝8.5Hz,1H),8.00(d,J＝7.1Hz,1H),7.82(dd,J＝15.4,8.2Hz,2H),7.53(t,J＝7.6Hz,1H),7.44(dd,J＝16.7,8.6Hz,2H),6.81(d,J＝6.9Hz,1H),6.75(dt,J＝18.3,7.0Hz,2H),4.68(s,2H),3.01(s,2H),1.50(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (naphthalen-2-yl) -1,3, 4-oxadizole:
Figure BDA0002046630990000063
2.17mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorobenzylidene) acethydrazide is dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.60mmol of iodobenzene diethyl ester is added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring are carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.77g of yellow solid, namely the target product, and the yield is 95.5%. MS-ESI, M/z 395.14[ M + Na ]]+.HR-MS-EI m/z calcd for C23H20N2O4[M+H]+373.1537,found373.1552。m.p.134-136℃；1H NMR(600MHz,CDCl3)δ9.18(d,J＝8.6Hz,1H),8.21(d,J＝7.2Hz,1H),8.04(d,J＝8.2Hz,1H),7.93(d,J＝8.1Hz,1H),7.67(t,J＝7.7Hz,1H),7.58(dt,J＝12.4,7.8Hz,2H),6.97(d,J＝8.1Hz,1H),6.86(d,J＝7.4Hz,1H),6.77(t,J＝7.8Hz,1H),5.49(s,2H),3.03(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ165.75,162.29,148.17,142.16,133.83,132.81,130.05,129.30,128.21,126.73,126.17,124.85,120.57,120.22,119.66,115.35,87.97,61.48,43.12,28.21。
Example 6
(E) Preparation of (E) -N' - (4-chlorobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide:
Figure BDA0002046630990000071
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of p-fluorobenzaldehyde are reacted for 6 to 8 hours to obtain 0.76g of (E) -N' - (4-chlorobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide as a white solid, m.p.141.7-143.5 ℃ and the yield is 88.3 percent;1H NMR(600MHz,CDCl3)δ10.07(s,1H),8.11(s,1H),7.60(d,J＝8.5Hz,2H),7.27(d,J＝8.4Hz,2H),6.82–6.77(m,1H),6.74–6.71(m,2H),4.65(s,2H),2.98(s,2H),1.45(s,6H)。
preparation of 2- (4-chlorophenylyl) -5- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000072
2.12mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorobenzylidene) acethydrazide are dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.54mmol of iodobenzene diethyl ester are added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring are carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.72g of white powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z 379.08[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17ClN2O3[M+H]+357.0990,found 357.1006。m.p.141-143℃；1H NMR(600MHz,CDCl3)δ8.20(d,J＝8.5Hz,2H),7.82(d,J＝8.5Hz,2H),6.91(d,J＝8.1Hz,1H),6.86(d,J＝6.8Hz,1H),6.76(t,J＝7.8Hz,1H),5.44(s,2H),3.03(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ164.94,162.80,148.09,142.08,138.28,129.48,129.33,128.38,122.13,120.55,119.69,115.17,87.98,61.38,43.10,28.20。
Example 7
(E) Preparation of (E) -N' - (4-bromobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide:
Figure BDA0002046630990000081
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of p-bromobenzaldehyde are reacted for 6 to 8 hours to obtain 0.86g of (E) -N' - (4-bromobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide as a white solid, m.p.142.3-144.2 ℃ and the yield is 94.5 percent;1H NMR(600MHz,CDCl3)δ10.02(s,1H),8.11(s,1H),7.55(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),6.81(dd,J＝5.3,3.2Hz,1H),6.74–6.71(m,2H),4.66(s,2H),2.99(s,2H),1.46(s,6H)。
preparation of 2- (4-bromophenyl) -5- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000082
2.13mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-fluorobenzylidene) acethydrazide is dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.56mmol of iodobenzene diethyl ester is added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring is carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.81g of white powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z 423.03[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17BrN2O3[M+H]+401.0484,found401.0510。m.p.143-145℃；1H NMR(600MHz,CDCl3)δ7.94(d,J＝8.6Hz,2H),7.65(d,J＝8.6Hz,2H),6.92(d,J＝8.1Hz,1H),6.85(d,J＝8.1Hz,1H),6.76(t,J＝7.8Hz,1H),5.41(s,2H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ165.04,162.82,148.09,142.08,132.44,129.30,128.51,126.72,122.57,120.55,119.69,115.16,87.99,61.38,43.10,28.20。
Example 8
(E) Preparation of (E) -N' - (2-bromobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide:
Figure BDA0002046630990000091
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 2-bromobenzaldehyde to react for 6 to 8 hours, so as to obtain 0.92g of (E) -N' - (2-bromobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide as a white solid, m.p.141.3-143.2 ℃ and the yield is 95.1 percent;1H NMR(600MHz,CDCl3)δ8.10(d,J＝6.6Hz,1H),7.48(d,J＝7.9Hz,1H),7.25(s,1H),7.21–7.10(m,2H),6.81(d,J＝6.5Hz,1H),6.77–6.67(m,2H),4.68(s,2H),2.98(s,2H),1.47(s,6H)。
preparation of 2- (2-bromophenyl) -5- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -1,3, 4-oxadiazinole:
Figure BDA0002046630990000092
2.28mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (2-bromobenzylidene) acetyl hydrazone was dissolved in absolute ethanol, and after complete dissolution by stirring at 40 ℃, 2.74mmol of iodobenzene diethyl ester was added, and the mixture was refluxed for 0.5h with stirring and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane with the ratio of dichloromethane to methanol (V: V) being 150: 1 and dichloromethane to methanol (V: V) being 60: 1 respectively to obtain 0.87g of white powder, namely the target product, and the yield is 95%. MS-ESI, M/z 423.03[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17BrN2O3[M+H]+401.0484,found 401.0501。m.p.143-145℃；1H NMR(600MHz,CDCl3)δ7.92(d,J＝7.8Hz,1H),7.73(d,J＝8.0Hz,1H),7.44(t,J＝7.6Hz,1H),7.37(t,J＝8.5Hz,1H),6.92(d,J＝8.1Hz,1H),6.84(d,J＝7.3Hz,1H),6.75(t,J＝7.8Hz,1H),5.45(s,2H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ164.56,163.16,148.11,142.09,134.58,132.62,131.72,129.29,127.56,125.06,121.76,120.53,119.63,115.37,87.95,61.36,43.09,28.21。
Example 9
(E) Preparation of (E) -N' - (3-bromobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide:
Figure BDA0002046630990000093
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 3-bromobenzaldehyde to react for 6 to 8 hours, so as to obtain 0.93g of (E) -N' - (3-bromobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide as a white solid, m.p.143.3-145.2 ℃ and the yield is 94.6 percent;1H NMR(600MHz,CDCl3)δ9.99(s,1H),8.10(s,1H),7.87(s,1H),7.57(d,J＝7.7Hz,1H),7.45(d,J＝8.0Hz,1H),7.19(d,J＝2.0Hz,1H),6.82(dd,J＝5.6,1.9Hz,1H),6.75–6.72(m,2H),4.67(s,2H),2.99(s,2H),1.46(s,6H)。
preparation of 2- (3-bromophenyl) -5- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -1,3, 4-oxadiazine (SN-A-1):
Figure BDA0002046630990000101
2.31mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-bromobenzylidene) acetyl hydrazone was dissolved in absolute ethanol, and after complete dissolution by stirring at 40 ℃, 2.77mmol of iodobenzene diethyl ester was added, and the mixture was refluxed for 0.5h with stirring and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.88g of white powder, namely the target product, and the yield is 95%. MS-ESI, M/z 423.03[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17BrN2O3[M+H]+401.0491,found 401.0501。m.p.143-145℃；1H NMR(600MHz,CDCl3)δ1.51(s,6H,2×CH3),3.02(s,2H,CH2),5.42(s,2H,CH2),6.76(t,1H,C6H3 5H),6.85(d,J＝6Hz,1H,C6H3 4H)，6.91(d,J＝6Hz,1H,C6H3 6H)，7.38(t,1H,C6H4 5H)，7.66(d,J＝7.2Hz,1H,C6H4 6H)，8.02(s,1H,C6H4 2H)；13C NMR(151MHz,CDCl3)δ164.44,162.99,148.12,142.04,134.91,130.64,129.98,129.34,125.61,125.47,123.10,120.56,119.74,115.27,88.01,61.41,43.10,28.20。
Example 10
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-fluorobenzylidene) acetohydrazide:
Figure BDA0002046630990000102
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 3-fluorobenzaldehyde to react for 6 to 8 hours, so as to obtain 0.78g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-fluorobenzylidene) acethydrazide as a white solid, wherein m.p.144.9-146.5 ℃ and the yield is 94.6 percent;1H NMR(600MHz,CDCl3)δ10.02(d,J＝32.4Hz,1H),8.13(s,1H),7.88(s,1H),7.58(d,J＝7.7Hz,1H),7.44(t,J＝7.6Hz,1H),6.85–6.78(m,1H),6.74–6.78(m,2H),4.67(s,2H),2.99(s,2H),1.46(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (3-fluorophenyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000111
2.27mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-fluorobenzylidene) acetohydrazide is dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.72mmol of iodobenzene diethyl ester is added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring is carried out. After the reaction is completed, cooling, filtering, rotary evaporating, respectively using dichloromethane and methanol (V: V) whose ratio is 150: 1 and dichloro-methaneChromatography with methane and methanol (V: V) at 60: 1 in dichloromethane to obtain yellowish powder 0.72g, which is the target product with 93% yield. MS-ESI, M/z363.11[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17FN2O3[M+H]+341.1288,found 341.1301.m.p.139-141℃；1H NMR(600MHz,CDCl3)δ7.87(d,J＝7.8Hz,1H),7.77(d,J＝13.0Hz,1H),7.48(t,J＝8.0Hz,1H),7.25(s,1H),6.92(d,J＝8.1Hz,1H),6.85(d,J＝6.8Hz,1H),6.76(t,J＝7.8Hz,1H),5.42(s,2H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ163.65,162.95,162.00,148.12,142.07,129.32,125.56,122.89,122.87,120.55,119.71,115.25,114.26,114.09,87.99,61.40,43.10,28.19。
Example 11
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-nitrobenzylidene) acetohydrazide:
Figure BDA0002046630990000112
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of p-nitrobenzaldehyde to react for 6 to 8 hours, so as to obtain 0.84g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-nitrobenzylidene) acethydrazide as a yellow solid, wherein m.p.138.6-140.7 ℃ and the yield is 95.2 percent;1H NMR(600MHz,CDCl3)δ10.39(s,1H),8.40(s,1H),8.26(d,J＝8.7Hz,2H),7.94(d,J＝8.7Hz,2H),6.90(d,J＝6.0Hz,1H),6.85–6.78(m,2H),4.75(s,2H),3.08(s,2H),1.55(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (4-nitrophenyl) -1,3, 4-oxadiazinole:
Figure BDA0002046630990000121
2.28mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-nitrobenzylidene) acetohydrazide in anhydrous formAfter the mixture was completely dissolved in ethanol at 40 ℃ with stirring, 2.74mmol of diethyliodobenzene was added, and the mixture was refluxed for 0.5 hour with stirring and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then column chromatography is carried out by using dichloromethane and methanol (V: V) of 150: 1 and dichloromethane and methanol (V: V) of 60: 1 respectively to obtain 0.79g of yellow powder, namely the target product, and the yield is 94%. MS-ESI, M/z 390.11[ M + Na ]]+.HR-MS-EI m/z calcd for C19H17N3O5[M+H]+368.1231，found368.1246。m.p.146-148℃；1H NMR(600MHz,CDCl3)δ8.40(d,J＝8.8Hz,2H),8.29(d,J＝8.8Hz,2H),6.94(d,J＝8.1Hz,1H),6.89(d,J＝7.4Hz,1H),6.79(t,J＝7.8Hz,1H),5.47(s,2H),3.05(s,2H),1.51(s,6H)；13C NMR(151MHz,CDCl3)δ163.97,163.68,149.74,148.06,141.96,129.41,129.10,128.05,124.38,120.58,119.84,115.19,88.07,61.35,43.06,28.19。
Example 12
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (thien-2-ylmethylene) acetohydrazide:
Figure BDA0002046630990000122
the preparation method is the same as example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of thiophene 2-formaldehyde to react for 6 to 8 hours, so as to obtain 0.75g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (thiophene-2-ylmethylene) acethydrazide brown solid, m.p.139.5-141.3 ℃, and the yield is 95 percent;1H NMR(600MHz,CDCl3)δ8.52(s,1H),7.30(d,J＝21.6Hz,1H),7.21(d,J＝19.2Hz,1H),6.98–6.95(m,1H),6.82–6.77(m,1H),6.71(d,J＝4.5Hz,2H),4.63(s,2H),2.97(s,2H),1.45(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (thiophen-2-yl) -1,3, 4-oxadizole:
Figure BDA0002046630990000123
2.28mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (thien-2-ylmethylene) acetohydrazide is dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.73mmol of diethyliodobenzene are added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring are carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.72g of yellow solid, namely the target product, and the yield is 95.6%. MS-ESI, M/z 351.08[ M + Na ]]+.HR-MS-EI m/z calcd for C17H16N2O3S[M+H]+329.0445,found329.0960。m.p.129-131℃；1H NMR(600MHz,CDCl3)δ7.78(d,J＝2.7Hz,1H),7.56(d,J＝5.9Hz,1H),7.22–7.11(m,1H),6.92(d,J＝8.1Hz,1H),6.85(d,J＝7.3Hz,1H),6.75(t,J＝7.8Hz,1H),5.39(s,2H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ162.03,161.97,148.11,142.08,130.49,130.28,129.27,128.17,124.89,120.54,119.65,115.24,87.96,61.29,43.10,28.19。
Example 13
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-methylbenzylidene) acethydrazide:
Figure BDA0002046630990000131
the preparation was carried out as described in example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 3-methylbenzaldehyde for 6-8h to give (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-methylbenzylidene) acethydrazide as a white solid in an amount of 0.77g, m.p.131.9-133.8 ℃ in 95.2% yield;1H NMR(600MHz,CDCl3)δ10.07(s,1H),8.09(s,1H),7.58(s,1H),7.42(d,J＝7.6Hz,1H),7.21–7.18(m,1H),7.14(d,J＝7.5Hz,1H),6.80(dd,J＝5.3,3.1Hz,1H),6.75–6.71(m,2H),4.65(s,2H),2.98(s,2H),2.29(s,3H),1.46(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (m-tolyl) -1,3, 4-oxadiazole:
Figure BDA0002046630990000132
2.28mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-methylbenzylidene) acethydrazide are dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.74mmol of iodobenzene diethyl ester are added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring are carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then column chromatography is carried out by using dichloromethane and methanol (V: V) of 150: 1 and dichloromethane and methanol (V: V) of 60: 1 respectively to obtain 0.73g of yellow powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z359.14[ M + Na ]]+.HR-MS-EI m/z calcd for C20H20N2O3[M+H]+337.1535,found337.1552。m.p.131-139℃；1H NMR(600MHz,CDCl3)δ7.93(s,1H),7.88(d,J＝7.5Hz,1H),7.41(t,J＝7.6Hz,1H),7.37(d,J＝7.6Hz,1H),6.95(d,J＝8.1Hz,1H),6.87(d,J＝7.3Hz,1H),6.78(t,J＝7.7Hz,1H),5.43(s,2H),3.04(s,2H),2.45(s,3H),1.52(s,6H)；13C NMR(151MHz,CDCl3)δ165.89,162.54,148.14,138.94,132.73,129.23,128.94,127.64,124.25,123.50,120.52,119.59,115.19,87.93,61.44,43.11,28.19,21.29。
Example 14
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-methylbenzylidene) acethydrazide:
Figure BDA0002046630990000141
the preparation method is the same as example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 4-methylbenzaldehyde to react for 6 to 8 hours, so as to obtain 0.77g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-methylbenzylidene) acethydrazide with m.p.131.6-133.7 ℃ and the yield of 94.8 percent;1H NMR(600MHz,CDCl3)δ9.90(s,1H),8.08(s,1H),7.58(d,J＝8.0Hz,2H),7.13(d,J＝7.9Hz,2H),6.81(d,J＝6.5Hz,1H),6.74–6.70(m,2H),4.66(s,2H),2.30(s,3H),1.46(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (p-tolyl) -1,3, 4-oxadiazole:
Figure BDA0002046630990000142
2.29mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-methylbenzylidene) acethydrazide are dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.75mmol of iodobenzene diethyl ester are added, and stirring and refluxing are carried out for 0.5h, and TLC monitoring are carried out. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then column chromatography is carried out by using dichloromethane and methanol (V: V) of 150: 1 and dichloromethane and methanol (V: V) of 60: 1 respectively to obtain 0.73g of yellow powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z359.14[ M + Na ]]+.HR-MS-EI m/z calcd for C20H20N2O3[M+H]+337.1537,found337.1552。m.p.137-139℃；1H NMR(600MHz,CDCl3)δ7.86(d,J＝8.2Hz,2H),7.21(d,J＝8.1Hz,2H),6.84(d,J＝8.1Hz,1H),6.75(d,J＝8.0Hz,1H),6.66(t,J＝7.8Hz,1H),5.31(s,2H),2.93(s,2H),2.33(s,3H),1.40(s,6H)；13C NMR(151MHz,CDCl3)δ165.87,162.37,148.11,142.50,142.17,129.75,129.22,127.06,120.89,120.53,119.58,115.19,87.91,61.42,43.11,28.19,21.64。
Example 15
(E) Preparation of (E) -2- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-methoxybenzylidene) acethydrazide:
Figure BDA0002046630990000151
the preparation is carried out as described in example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 4-methoxybenzaldehyde for 6-8h to give (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-methoxybenzylidene) acethydrazideWhite solid 0.81g, m.p.133.5-134.8 deg.C, yield 95.4%;1H NMR(600MHz,CDCl3)δ8.12(s,1H),7.35–7.19(m,2H),7.16(d,J＝7.3Hz,2H),6.91–6.85(m,1H),6.80(s,1H),6.73(s,1H),4.65(s,2H),3.76(s,3H),2.98(s,2H),1.45(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (4-methoxyphenyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000152
2.28mmol of (E) -2- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (4-methoxybenzylidene) acetohydrazide in absolute ethanol, after complete dissolution by stirring at 40 ℃ 2.75mmol of iodobenzene diethyl ester were added and the mixture was refluxed for 0.5h with TLC monitoring. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.76g of yellow powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z375.13[ M + Na ]]+.HR-MS-EI m/z calcd for C20H20N2O4[M+H]+353.1487,found 353.1501。m.p.136-158℃；1H NMR(600MHz,CDCl3)δ7.95(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz,2H),6.93(d,J＝8.1Hz,1H),6.84(d,J＝7.4Hz,1H),6.75(t,J＝7.8Hz,1H),5.40(s,2H),3.02(s,2H),2.42(s,3H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ165.89,162.37,148.11,142.50,142.17,129.75,129.22,127.07,120.89,120.53,119.57,115.18,87.92,61.42,43.12,28.19,21.64。
Example 16
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-methoxybenzylidene) acethydrazide:
Figure BDA0002046630990000153
the preparation method is the same as example 3, 2.4mmol of 2- ((2,2-dimethyl-2, 3-dihydrobenzo)Furan-7-yl) oxy) acethydrazide and 2.88mmol of 3-methoxybenzaldehyde react for 6-8h to obtain 0.81g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-methoxybenzylidene) acethydrazide as a white solid, m.p.132.5-134.7 ℃ with a yield of 95.4%;1H NMR(600MHz,CDCl3)δ8.11(s,1H),7.29(s,1H),7.20(dd,J＝14.3,6.1Hz,2H),7.16(d,J＝7.4Hz,1H),6.87(d,J＝8.2Hz,1H),6.80(d,J＝6.4Hz,1H),6.72–6.67(m,1H),4.66(s,2H),3.75(s,3H),2.97(s,2H),1.45(s,6H)。
preparation of 2- (((2,2-dimethyl-2, 3-dihydrobenzofuranyl-7-yl) oxy) methyl) -5- (3-methoxyphenyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000161
2.28mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (3-methoxybenzylidene) acetohydrazide is dissolved in absolute ethanol, after complete dissolution by stirring at 40 ℃, 2.74mmol of iodobenzene diethyl ester is added, and stirring is carried out at reflux for 0.5h, monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then column chromatography is carried out by using dichloromethane and methanol (V: V) of 150: 1 and dichloromethane and methanol (V: V) of 60: 1 respectively, so as to obtain 0.76g of yellow powder, namely the target product. MS-ESI, M/z375.13[ M + Na ]]+.HR-MS-EI m/z calcd for C20H20N2O4[M+H]+353.1487,found353.1501。m.p.134-158℃；1HNMR(600MHz,CDCl3)δ7.64(d,J＝7.7Hz,1H),7.59(s,1H),7.40(t,J＝8.0Hz,1H),7.08(d,J＝10.8Hz,1H),6.93(d,J＝8.0Hz,1H),6.85(d,J＝6.7Hz,1H),6.75(t,J＝7.8Hz,1H),5.41(s,2H),3.88(s,3H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ165.70,162.66,159.97,148.10,142.13,130.20,129.25,124.74,120.54,119.61,119.54,115.19,111.52,87.95,61.40,55.53,43.11,28.19。
Example 17
(E) Preparation of-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (2-methoxybenzylidene) acethydrazide:
Figure BDA0002046630990000162
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 2-methoxybenzaldehyde to react for 6 to 8 hours, so as to obtain 0.81g of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (2-methoxybenzylidene) acethydrazide as a white solid, m.p.132.4-134.8 ℃ and the yield is 95 percent;1H NMR(600MHz,CDCl3)δ10.09(s,1H),8.46(s,1H),7.97(d,J＝7.7Hz,1H),7.21(t,J＝7.8Hz,1H),6.82(t,J＝7.5Hz,1H),6.75(d,J＝7.7Hz,2H),6.70(d,J＝7.9Hz,1H),6.68–6.65(m,1H),4.62(s,2H),3.69(s,3H),2.91(s,2H),1.41(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5- (2-methoxyphenyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000171
2.28mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (2-methoxybenzylidene) acetohydrazide in absolute ethanol, after complete dissolution by stirring at 40 ℃ 2.74mmol of iodobenzene diethyl ester were added and the mixture was refluxed for 0.5h with stirring and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.76g of yellow powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z375.13[ M + Na ]]+.HR-MS-EI m/z calcd for C20H20N2O4[M+H]+353.1487,found353.1501。m.p.136-158℃；1H NMR(600MHz,CDCl3)δ7.93(d,J＝7.6Hz,1H),7.50(t,J＝7.2Hz,1H),7.13–6.99(m,2H),6.94(d,J＝8.1Hz,1H),6.83(d,J＝7.3Hz,1H),6.75(t,J＝7.8Hz,1H),5.42(s,2H),3.95(s,3H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ164.38,162.35,158.09，157.96,148.05,142.30，142.17,133.23,130.64,129.14,120.70,120.48,119.44,115.14,112.79,111.91,87.87,61.41,55.97,43.13,28.20。
Example 18
(E) Preparation of (E) -N' - (cyclohexylmethylene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide:
Figure BDA0002046630990000172
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of cyclohexane formaldehyde to react for 6 to 8 hours, so as to obtain 0.70g of (E) -N' - (cyclohexylmethylene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide as a white solid, m.p.133.5-134.8 ℃ and the yield is 95.1 percent;1H NMR(600MHz,CDCl3)δ9.54(s,1H),6.84–6.77(m,1H),6.72(d,J＝4.7Hz,2H),4.60(s,2H),2.98(s,2H),2.43–2.27(m,1H),1.77(d,J＝12.1Hz,2H),1.72–1.66(m,2H),1.44(s,6H),1.26–1.14(m,6H)。
preparation of 2-cyclohexoxy-5- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -1,3, 4-oxadizole:
Figure BDA0002046630990000173
2.13mmol of (E) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) -N' - (2-methoxybenzylidene) acetohydrazide in absolute ethanol, after complete dissolution by stirring at 40 ℃ 2.56mmol of iodobenzene diethyl ester were added, and the mixture was refluxed for 0.5h with stirring and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.67g of yellow solid, namely the target product, and the yield is 95.1%. MS-ESI, M/z 351.17[ M + Na ]]+.HR-MS-EI m/z calcd for C19H24N2O3[M+H]+329.1851,found329.1865.m.p.122-124℃；1H NMR(600MHz,CDCl3)δ6.79(d,J＝8.1Hz,1H),6.76(d,J＝6.7Hz,1H),6.66(t,J＝7.8Hz,1H),5.23(s,2H),2.94(s,2H),2.85–2.80(m,1H),2.03–1.97(m,2H),1.78–1.72(m,2H),1.66–1.61(m,1H),1.53(qd,J＝12.4,3.3Hz,2H),1.42(s,6H),1.35–1.26(m,2H),1.26–1.20(m,1H)；13C NMR(151MHz,CDCl3)δ171.12,162.42,148.07,142.20,129.18,120.46,119.49,115.18,87.87,61.39,43.10,35.18,30.00,28.19,25.55,25.33。
Example 19
(E) Preparation of (E) -N' - (4-cyanobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide:
Figure BDA0002046630990000181
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of 4-cyanobenzaldehyde are reacted for 6-8h to obtain 0.80g of (E) -N' - (4-cyanobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide as a yellow solid, m.p.131.9-133.9 ℃ and the yield is 95%;1H NMR(600MHz,CDCl3)δ10.10(s,1H),8.25(s,1H),7.79(d,J＝8.2Hz,2H),7.62(d,J＝8.2Hz,2H),6.82(dd,J＝8.1,4.6Hz,1H),6.77–6.72(m,2H),4.68(s,2H),3.00(s,2H),1.47(s,6H)。
preparation of 4- (5- (((2,2-dimethyl-2, 3-dihydrobenzofuranyl-7-yl) oxy) methyl) -1,3,4-oxadiazol-2-yl) nitrile:
Figure BDA0002046630990000182
2.29mmol of (E) -N' - (4-cyanobenzylidene) -2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide is dissolved in absolute ethanol, and after complete dissolution by stirring at 40 ℃, 2.75mmol of diethyliodobenzene is added, and the mixture is refluxed for 0.5h with stirring and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.76g of yellow powder, namely the target product, and the yield is 95.1%. MS-ESI, M/z 370.12[ M + Na ]]+.HR-MS-EI m/z calcd for C20H17N3O3[M+H]+348.1333,found348.1348。m.p.142-144℃；1H NMR(600MHz,CDCl3)δ8.20(d,J＝8.5Hz,2H),7.82(d,J＝8.5Hz,2H),6.91(d,J＝8.1Hz,1H),6.86(d,J＝6.8Hz,1H),6.76(t,J＝7.8Hz,1H),5.44(s,2H),3.03(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ164.19,163.51,148.08,141.99,132.87,129.97,129.41,127.57,120.58,119.83,117.79,115.51,115.23,88.05,61.37,43.08,28.19。
Example 20
(E) Preparation of-N' -benzyl-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acetohydrazide:
Figure BDA0002046630990000191
the preparation method is the same as that of example 3, 2.4mmol of 2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide and 2.88mmol of benzaldehyde to react for 6-8h, so as to obtain 0.71g of (E) -N' -benzyl-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide white solid, m.p.132.2-134.5 ℃ and the yield is 91%;1H NMR(600MHz,CDCl3)δ8.14(s,1H),7.72–7.64(m,2H),7.33–7.30(m,3H),6.81(d,J＝6.6Hz,1H),6.75–6.70(m,2H),4.66(s,2H),2.98(s,2H),1.46(s,6H)。
preparation of 2- (((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) methyl) -5-phenyl-1,3, 4-oxadiazole:
Figure BDA0002046630990000192
2.18mmol of (E) -N' -benzyl-2- ((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl) oxy) acethydrazide is dissolved in absolute ethanol, and after complete dissolution by stirring at 40 ℃, 2.62mmol of iodobenzene diethyl ester is added, and the mixture is stirred and refluxed for 0.5h and monitored by TLC. After the reaction is completed, the mixture is cooled, filtered and rotary evaporated, and then is subjected to column chromatography by dichloromethane of which the ratio of dichloromethane to methanol (V: V) is 150: 1 and the ratio of dichloromethane to methanol (V: V) is 60: 1 respectively to obtain 0.67g of white solid, namely the target product, and the yield is 95.1%. MS-ESI,m/z 345.12[M+Na]+.HR-MS-EI m/z calcd for C19H18N2O3[M+H]+323.1378,found 323.1396。m.p.131-133℃；1H NMR(600MHz,CDCl3)δ8.07(d,J＝7.1Hz,2H),7.52(dt,J＝24.8,7.2Hz,3H),6.93(d,J＝8.1Hz,1H),6.85(d,J＝7.4Hz,1H),6.76(t,J＝7.8Hz,1H),5.42(s,2H),3.02(s,2H),1.49(s,6H)；13C NMR(151MHz,CDCl3)δ165.74,162.65,148.11,142.14,131.93,129.26,129.05,127.12,123.66,120.54,119.62,115.19,87.95,61.42,43.11,28.19。
Example 21: the herbicidal activity of the products obtained in the embodiments 3 to 20 of the present invention was measured.
The target compound is prepared into liquid medicine with the concentration of 500mg/L, and the prophase growth inhibition activity test is carried out on the barnyard grass by adopting a plate method. 2 pieces of filter paper sheets are flatly paved in a culture dish with the diameter of 9cm, then 10mL of liquid medicine is poured, and 30 cockspur grass seeds are evenly placed to ensure that each seed is evenly soaked. An equal amount of distilled water was used as a blank control. And (3) putting the culture dish into an artificial climate box for culture at the temperature of 25 ℃, illuminating for 8 hours every day after 3 days of culture, investigating the root length, stem length and overall germination condition of the most luxuriant 10 plants after 7 days, and calculating the effect according to the following formula to perform drug administration evaluation.
Effect ═ [ (blank-treatment/blank ] × 100%,
a positive value indicates that the agent has an inhibitory effect, and a negative value indicates that the agent has an accelerating effect. The evaluation standard of the inhibition activity is grade A which is more than or equal to 90 percent; grade B, 70% -89%; grade C, 50% -69%; grade D, < 50%.
The results obtained at a dose of 500mg/L using a common sieve are shown in the following table.
Results of herbicidal Activity test (500mg/L) for the Compound of the present invention
Figure BDA0002046630990000201

Claims (5)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003516258360000011
wherein R is selected from 4-CN-C6H4、4-F-C6H4，4-Cl-C6H4、3-F-C6H4、3-Br-C6H4、4-NO2-C6H4、3-NO2-C6H4。
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from one of the following compounds:
Figure FDA0003516258360000012
3. a process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the reaction comprises:
Figure FDA0003516258360000013
wherein R is as defined in claim 1.
4. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a herbicide medicament.
5. The pesticide composition is characterized by comprising a compound shown as a formula (I) or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable auxiliary materials.
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