Ether-substituted alpha-methylene-gamma-butyrolactone compound as well as preparation method and application thereof

Abstract

The invention discloses a benzyl ether and phenyl ether substituted alpha-methylene-gamma-butyrolactone compound as well as a preparation method and application of the benzyl ether and phenyl ether substituted alpha-methylene-gamma-butyrolactone compound. According to the invention, benzyl ether and phenyl ether groups containing different substituents are introduced into the gamma site of alpha-methylene-gamma-butyrolactone, so that a compound with a novel structure is obtained; the structure of the compound is shown as a formula I. The compound disclosed by the invention has broad-spectrum bactericidal activity, and particularly has an obvious inhibition effect on rhizoctonia solani, valsa mali, botrytis cinerea, gaeumania graminis, fusarium graminearum, Colletotrichum orbiculare and Phytophthora capsici, so that the compound disclosed by the invention has the advantages that the compound can be used for preparing medicines for preventing and treating diseases, and the compound can be used for preparing medicines for preventing and treating the diseases caused by the diseases such as the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases caused by the diseases. The compound can be used as a bactericide for preventing and treating agricultural diseases.

Description

Technical Field

[0001] This invention belongs to the field of pathogen control technology, specifically relating to an ether-substituted α-methylene-γ-butyrolactone compound, its preparation method, and its application. Background Technology

[0002] Diseases caused by fungi and oomycetes account for over 80% of total grain losses. Common diseases include rice blast, wheat scab, potato late blight, and apple rot. The primary control method for these diseases is chemical fungicides. Finding new lead compounds is crucial for fungicide development. Sesquiterpene lactones with the α-methylene-γ-butyrolactone skeleton possess rich biological activities, such as antibacterial, anticancer, antiviral, anti-inflammatory, hypotensive, insecticidal, herbicidal, and plant growth-regulating activities. These compounds also exhibit high efficiency, low toxicity, and low residue, making them widely used in the pharmaceutical field, but research in agricultural applications is limited.

[0003] Diaryl ethers are functional group fragments widely found in natural products and synthetic organic compounds. They are a class of compounds with two aromatic ring systems and a flexible oxygen bridge. Due to their strong hydrophobicity, sufficient molecular flexibility, excellent lipophilicity, cell membrane penetration, and metabolic stability, they have become important structural units in many synthetic drug molecules. According to statistics from the ChEMBL 20 database, aryl ethers are among the most popular and durable scaffolds, fully demonstrating their crucial position in the field of medicinal chemistry. Due to their unique physicochemical properties and potential biological activities, diaryl ethers are considered fundamental elements in drugs and agrochemicals targeting various biological targets. Derivatives possessing this structure exhibit biological properties such as anticancer, anti-inflammatory, antiviral, antibacterial, antimalarial, herbicidal, fungicidal, and insecticidal effects. Summary of the Invention

[0004] The purpose of this invention is to provide an ether-substituted α-methylene-γ-butyrolactone compound, its preparation method, and its application. By introducing different substituted benzyl ether and phenyl ether groups into α-methylene-γ-butyrolactone, a series of novel compounds are obtained, and they have been found to have good control effects against plant pathogens.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] An ether-substituted α-methylene-γ-butyrolactone compound, wherein the compound is the compound represented by Formula I;

[0007]

[0008] Wherein: R is selected from at least one of halogen, trifluoromethyl, methyl, nitro, phenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 1-naphthyl and 2-naphthyl, and R is substituted by monosubstitution.

[0009] Optionally, the compound shown in Formula I may be a compound shown in Formula II, Formula III or Formula IV, depending on the position of the ether substitution.

[0010]

[0011] In the compounds represented by formulas II, III and IV, R is selected from at least one of halogen, trifluoromethyl, methyl, nitro, phenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 1-naphthyl and 2-naphthyl, and R is substituted by monosubstitution.

[0012] Optionally, the R in the compounds are specifically shown in the table below:

[0013]

[0014]

[0015]

[0016] The preparation method of any of the ether-substituted α-methylene-γ-butyrolactone compounds according to the present invention is as follows:

[0017]

[0018] Step 1: Bromomethacrylic acid and 2-hydroxy or 3-hydroxy-substituted benzaldehyde are dissolved in a mixed solution of tetrahydrofuran and water, and then indium catalyst powder is added. The mixture is stirred at room temperature for 12 hours. After the reaction is completed, 6M hydrochloric acid is added directly and the reaction is continued for 12 hours. The post-treatment is performed by extraction with ethyl acetate, extraction with saturated brine, drying with anhydrous magnesium sulfate, removing the solvent, and separating by column chromatography.

[0019] Step 2: Add intermediate 2a or 2b, benzyl chloride or benzyl bromide with different substitutions, N,N-dimethylformamide, and finally add potassium carbonate and potassium iodide. After the reaction is complete, add water, extract with ethyl acetate, and separate by column chromatography with petroleum ether / ethyl acetate = 4:1 to 6:1 to obtain compounds II-1-II-23 and III-1-III-23.

[0020] Step 3, the synthetic route of compound IV-1-IV-2, the synthetic method is the same as the preparation of intermediates 2a and 2b in step 1.

[0021] Optionally, in step 1, the molar ratio of the 2-hydroxy or 3-hydroxy substituted benzaldehyde, bromomethacrylic acid and indium powder is 1:1.2:1.2.

[0022] Optionally, in step 1, the ratio of tetrahydrofuran to water is v / v = 1:1.

[0023] Optionally, in step 1, the column chromatography separation conditions are as follows: for ortho-substituted intermediate 2a, eluent: dichloromethane / methanol = 0:1; for meta-substituted intermediate 2b, eluent: petroleum ether / ethyl acetate = 4:1.

[0024] Optionally, in step 2, the molar ratio of potassium iodide, intermediate 2a or 2b, benzyl chloride or benzyl bromide and potassium carbonate is 1:16:20:33, the reaction temperature is 80℃, and the reaction time is 8 to 12 hours.

[0025] The ether-substituted α-methylene-γ-butyrolactone compounds described in any one of the present invention are used in the preparation of agricultural fungicides.

[0026] Optionally, the agricultural fungicide is used for the prevention and control of rice sheath blight, apple rot, tomato gray mold, wheat take-all, wheat scab, cucumber anthracnose, and / or pepper blight.

[0027] The beneficial effects of this invention are as follows:

[0028] This invention introduces different substituted benzyl ether and phenyl ether groups into α-methylene-γ-butyrolactone to obtain a series of novel compounds. The obtained α-methylene-γ-butyrolactone compounds containing benzyl ether and phenyl ether have good bactericidal activity, especially showing significant inhibitory effects on rice sheath blight, apple rot, tomato gray mold, wheat take-all, wheat scab, cucumber anthracnose, and pepper blight. Detailed Implementation

[0029] The present invention will be further illustrated below with specific examples, but the present invention is not limited to these embodiments. Unless otherwise specified, the methods described are conventional methods. Unless otherwise specified, the materials described are all available from publicly available commercial sources.

[0030] To discover novel agricultural fungicides, the inventors introduced benzyl ether and phenyl ether groups with different substitutions into α-methylene-γ-butyrolactone, obtaining a series of novel compounds and discovering that they have good control effects against plant pathogens. Currently, there are no patents for benzyl ether and phenyl ether-substituted α-methylene-γ-butyrolactone compounds as described in this invention. Therefore, this invention discloses the application of a series of structurally novel α-methylene-γ-butyrolactone compounds as agricultural fungicides.

[0031] The benzyl ether and phenyl ether-substituted α-methylene-γ-butyrolactone compounds disclosed in this invention have the general structural formula of Formula I;

[0032]

[0033] Wherein: when n=1, R is selected from at least one of halogen, trifluoromethyl, methyl, nitro, phenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 1-naphthyl and 2-naphthyl, and R is substituted by monosubstitution;

[0034] The compound represented by Formula I may be represented by Formula II, Formula III or Formula IV, depending on the position of the ether substitution.

[0035]

[0036] In the compounds represented by formulas II, III and IV: R is selected from at least one of halogen, trifluoromethyl, methyl, nitro, phenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 1-naphthyl and 2-naphthyl, and R is substituted by monosubstitution;

[0037] For more detailed information, please see the data listed in Table 1:

[0038] Table 1

[0039]

[0040]

[0041] The synthetic route is as follows:

[0042]

[0043] Step 1: Bromomethacrylic acid and 2-hydroxy or 3-hydroxy-substituted benzaldehyde are dissolved in a mixed solution of tetrahydrofuran and water, and then indium catalyst powder is added. The mixture is stirred at room temperature for 12 hours. After the reaction is completed, 6M hydrochloric acid is added directly and the reaction is continued for 12 hours. The post-treatment is performed by extraction with ethyl acetate, extraction with saturated brine, drying with anhydrous magnesium sulfate, removing the solvent, and separating by column chromatography.

[0044] Step 2: Add intermediate 2a or 2b, benzyl chloride or benzyl bromide with different substitutions, N,N-dimethylformamide, and finally add potassium carbonate and potassium iodide. After the reaction is complete, add water, extract with ethyl acetate, and separate by column chromatography with petroleum ether / ethyl acetate = 4:1 to 6:1 to obtain compounds II-1-II-23 and III-1-III-23.

[0045] Step 3, the synthetic route of compound IV-1-IV-2, the synthetic method is the same as the preparation of intermediates 2a and 2b in step 1.

[0046] In step 1, the molar ratio of the 2-hydroxy or 3-hydroxy substituted benzaldehyde, bromomethacrylic acid and indium powder is 1:1.2:1.2.

[0047] In step 1, the ratio of tetrahydrofuran to water is v / v = 1:1.

[0048] In step 1, the column chromatography separation conditions are as follows: for ortho-substituted intermediate 2a, the eluent is dichloromethane / methanol = 0:1; for meta-substituted intermediate 2b, the eluent is petroleum ether / ethyl acetate = 4:1.

[0049] In step 2, the molar ratio of potassium iodide, intermediate 2a or 2b, benzyl chloride or benzyl bromide and potassium carbonate is 1:16:20:33, the reaction temperature is 80℃, and the reaction time is 8 to 12 hours.

[0050] The ether-substituted α-methylene-γ-butyrolactone compounds described in any of the present invention are used in the preparation of agricultural fungicides. These agricultural fungicides are used for the control of rice sheath blight, apple rot, tomato gray mold, wheat take-all, wheat scab, cucumber anthracnose, and / or pepper blight.

[0051] Unless otherwise specified, all reagent ratios used below are volume ratios.

[0052] Example 1: Preparation of compound II-4

[0053]

[0054] To a 150 mL round-bottom flask, bromomethacrylic acid (7.92 g, 48 mmol), 2-hydroxybenzaldehyde (4.93 g, 40 mmol), and a mixed solution of tetrahydrofuran and water (v / v = 1:1) were added sequentially. The mixture was stirred for a period of time until the starting materials were completely dissolved. Then, indium catalyst powder (5.5 g, 48 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, 20 mL of 6M hydrochloric acid was added directly, and the reaction was continued for another 12 h. The reaction was then post-processed by extraction three times with ethyl acetate, and the combined organic phases were extracted twice more with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation. The intermediate was obtained by column chromatography using dichloromethane / methanol (40:1). Add the intermediate (0.5 mmol), 4-chlorobenzyl chloride (0.6 mmol), and 4 mL of N,N-dimethylformamide to a 10 mL round-bottom flask. Finally, add potassium carbonate (1.0 mmol) and 5 mg of potassium iodide. Stir at 80 °C for 8–12 h. After the reaction is complete as monitored by TLC, add deionized water, extract with ethyl acetate, and separate by column chromatography using petroleum ether / ethyl acetate at a ratio of 4:1 to 6:1 to obtain a white solid, II-4. Yield: 74.2%, melting point: 78.8–79.7 °C. 1H NMR(500MHz,Chloroform-d)δ7.42-7.32(m,5H),7.32-7.28(m,1H),7.01(t,J=7.5Hz,1H),6.95(d,J=8.2Hz,1H),6.22(t,J=2.9Hz ,1H),5.78(dd,J=8.5,5.8Hz,1H),5.59(t,J=2.6Hz,1H),5.12-5.02(m,2H),3.39(ddt,J=17.4,8.5,2.7Hz,1H),2.93-2.84(m,1H). 13 C NMR (126MHz, CDCl3) δ170.56,155.12,134.98,134.53,134.02,129.53,128.89, 126.31,122.08,121.15,111.75,77.35,77.10,76.84,74.90,69.42,34.96.HRMS Calcd.for C 18 H 16 ClO3[M+H] + :315.7650,Found:315.7644.

[0055] Example 2: Preparation of compound II-19

[0056]

[0057] In a 150 mL round-bottom flask, bromomethacrylic acid (7.92 g, 48 mmol), 2-hydroxybenzaldehyde (4.93 g, 40 mmol), and a 100 mL mixture of tetrahydrofuran and water (v / v = 1:1) were added sequentially. The mixture was stirred for a period of time until the starting materials were completely dissolved. Then, indium catalyst powder (5.5 g, 48 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, 20 mL of 6M hydrochloric acid was added directly, and the reaction continued for another 12 h. The reaction was then post-processed by extraction three times with ethyl acetate, and the combined organic phases were extracted twice with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation. The intermediate was obtained by column chromatography using dichloromethane / methanol (40:1). In a 10 mL round-bottom flask, the intermediate (0.5 mmol), benzyl chloride (0.6 mmol), and 4 mL of N,N-dimethylformamide were added. Finally, potassium carbonate (1.0 mmol) and 5 mg of potassium iodide were added, and the mixture was stirred at 80 °C for 8–12 h. After the reaction was completed as monitored by TLC, deionized water was added, followed by extraction with ethyl acetate and separation by column chromatography. The eluent was petroleum ether / ethyl acetate at a ratio of 4:1 to 6:1, yielding a yellow oily liquid, II-19. Yield: 73.5%. 1H NMR(400MHz,Chloroform-d)δ7.44-7.23(m,7H),7.02-6.91(m,2H),6.20(t,J=2.9Hz,1H),5.79(dd,J=8.5,5.8Hz,1 H),5.56(t,J=2.6Hz,1H),5.15-5.03(m,2H),3.39(ddt,J=17.4,8.4,2.7Hz,1H),2.85(ddt,J=17.4,5.8,2.9Hz,1H). 13 CNMR (126MHz, CDCl3) δ170.57,155.32,136.57,134.63,129.42,128.82,128.70,128.18,127. 48,126.05,121.97,121.01,111.85,77.32,77.07,76.81,74.81,70.25,35.14.HRMSCalcd.for C 18 H 17 O3[M+H] + :280.1099,Found:280.1098.

[0058] Example 3: Preparation of compound III-4

[0059]

[0060] In a 150 mL round-bottom flask, bromomethacrylic acid (7.92 g, 48 mmol), 3-hydroxybenzaldehyde (4.93 g, 40 mmol), and a 100 mL mixture of tetrahydrofuran and water (v / v = 1:1) were added sequentially. The mixture was stirred until the reactants were completely dissolved, then indium catalyst powder (5.5 g, 48 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, 20 mL of 6M hydrochloric acid was added directly, and the reaction was continued for another 12 h. The reaction was then post-processed by extraction three times with ethyl acetate, and the combined organic phases were extracted twice with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation. The intermediate was obtained by column chromatography using petroleum ether / ethyl acetate at a ratio of 4:1. In a 10 mL round-bottom flask, the intermediate (0.5 mmol), 4-chlorobenzyl chloride (0.6 mmol), and 4 mL of N,N-dimethylformamide were added. Finally, potassium carbonate (1.0 mmol) and 5 mg of potassium iodide were added, and the mixture was stirred at 80 °C for 8–12 h. After the reaction was completed by TLC monitoring, deionized water was added, and the mixture was extracted with ethyl acetate and separated by column chromatography with petroleum ether / ethyl acetate as the eluent (4:1 to 6:1). The resulting white solid was 4, with a yield of 66.1% and a melting point of 49.3-51.4℃. 1H NMR(500MHz,Chloroform-d)δ7.37(s,4H),7.36-7.27(m,2H),6.97-6.90(m,3H),6.31(t,J=2.9Hz,1H),5.70(t,J=2.5H z,1H),5.50(dd,J=8.1,6.4Hz,1H),5.04(s,2H),3.40(ddt,J=17.1,8.2,2.5Hz,1H),2.89(dtd,J=12.0,6.1,2.9Hz,1H). 13 C NMR (126MHz, CDCl3) δ170.13,158.92,141.64,135.24,134.05,133.83,130.11,128.85,128 .80,122.62,118.02,114.75,111.90,77.70,77.40,77.14,76.89,69.27,36.49,36.23.HRMS Calcd.for C 18 H 16 ClO3[M+H] + :315.7650,Found:315.7650.

[0061] Example 4: Preparation of compound III-19

[0062]

[0063] In a 150 mL round-bottom flask, bromomethacrylic acid (7.92 g, 48 mmol), 3-hydroxybenzaldehyde (4.93 g, 40 mmol), and a 100 mL mixture of tetrahydrofuran and water (v / v = 1:1) were added sequentially. The mixture was stirred for a period of time until the starting materials were completely dissolved. Then, indium catalyst powder (5.5 g, 48 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete as monitored by TLC, 20 mL of 6M hydrochloric acid was added directly, and the reaction continued for another 12 h. The reaction was then post-processed by extraction three times with ethyl acetate, and the combined organic phases were extracted twice with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation. The intermediate was obtained by column chromatography with petroleum ether / ethyl acetate at a ratio of 4:1. In a 10 mL round-bottom flask, the intermediate (0.5 mmol), benzyl chloride (0.6 mmol), and 4 mL of N,N-dimethylformamide were added. Finally, potassium carbonate (1.0 mmol) and 5 mg of potassium iodide were added, and the mixture was stirred at 80 °C for 8–12 h. After the reaction was completed as monitored by TLC, deionized water was added, followed by extraction with ethyl acetate and separation by column chromatography. The eluent was petroleum ether / ethyl acetate at a ratio of 4:1 to 6:1, yielding a yellow oily liquid, Ⅲ-19, with a yield of 80.3%. 1H NMR(400MHz,Chloroform-d)δ7.45-7.35(m,4H),7.35-7.31(m,1H),7.31-7.20(m,1H),7.02-6.81(m,3H),6.29(t,J=2.9Hz,1H),5.6 6(t,J=2.5Hz,1H),5.47(dd,J=8.1,6.4Hz,1H),5.05(s,2H),3.36(ddt,J=17.1,8.1,2.5Hz,1H),2.87(ddt,J=17.1,6.1,2.9Hz,1H). 13 C NMR (126MHz, CDCl3) δ170.10,159.24,141.59,136.75,134.17,130.06,128.65,128.09,127.97,127.54, 127.14,122.48,117.85,115.23,114.87,112.04,77.76,77.37,77.11,76.86,70.16,36.25,29.73.HRMS Calcd.for C 18 H 17 O3[M+H] + :280.1099,Found:280.1098.

[0064] Following the same method as described above for preparing the compounds, R was replaced with various substituted phenyl, 1-naphthyl, 2-naphthyl, 2-phenoxy, and 3-phenoxy compounds to obtain the corresponding products II-1 to II-3, II-5 to II-18, II-19 to II-23, III-1 to III-3, III-5 to III-18, III-19 to III-23, and IV-1 to IV-2. The appearance, melting point, yield, and other properties of the compounds were then compared. 1 The HNMR spectral data are shown below.

[0065] 5-(2-((4-fluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-1)

[0066] Bright yellow solid, yield 55.7%, melting point: 47.1-52.1℃. 1H NMR(500MHz,Chloroform-d)δ7.34(dd,J=7.5,1.7Hz,1H),7.32-7.25(m,3H),7.20(d,J=7.8Hz,2H),7.04-6.92(m,2H),6.21(t,J=2.9Hz,1H),5.78( dd,J=8.4,5.9Hz,1H),5.57(t,J=2.6Hz,1H),5.10-4.99(m,2H),3.39(ddt ,J=17.5,8.5,2.7Hz,1H),2.84(ddt,J=17.4,5.8,2.9Hz,1H),2.37(s,3H).

[0067] 5-(2-((3-fluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-2)

[0068] Yellow solid, yield 47.6%, melting point: 134.5-138.0℃. 1 H NMR(500MHz,Chloroform-d)δ7.45-7.29(m,3H),7.22(d,J=7.6Hz,1H),7.18-7.08(m,1H),7.12-7.00(m,2H),6.97(d,J=8.2Hz,1H),6.27(t,J=3.0H z,1H),5.84(dd,J=8.5,5.8Hz,1H),5.64(t,J=2.6Hz,1H),5.21-5.08(m,2 H), 3.46 (ddt, J=17.4, 8.5, 2.7Hz, 1H), 2.92 (ddt, J=17.6, 5.8, 2.8Hz, 1H).

[0069] 5-(2-((2-fluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-3)

[0070] Bright yellow solid, yield 55.7%, melting point: 47.1-52.1℃. 1H NMR(500MHz,Chloroform-d)δ7.48(td,J=7.5,1.8Hz,1H),7.44-7.37(m,2H),7.37 -7.28(m,1H),7.23(td,J=7.5,1.1Hz,1H),7.19-7.09(m,1H),7.04(t,J=7.2Hz,2H) ,6.23(t,J=2.9Hz,1H),5.80(dd,J=8.5,5.8Hz,1H),5.61(t,J=2.6Hz,1H),5.24-5 .12(m,2H),3.43(ddt,J=17.4,8.5,2.7Hz,1H),2.91(ddt,J=17.4,5.8,2.9Hz,1H).

[0071] 5-(3-((4-chlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-4)

[0072] White solid, yield 74.2%, melting point: 78.8-79.7℃. 1 H NMR(500MHz,Chloroform-d)δ7.42-7.32(m,5H),7.32-7.28(m,1H),7.01(t,J=7.5Hz,1H),6.95(d,J=8.2Hz,1H),6.22(t,J=2.9Hz ,1H),5.78(dd,J=8.5,5.8Hz,1H),5.59(t,J=2.6Hz,1H),5.12-5.02(m,2H),3.39(ddt,J=17.4,8.5,2.7Hz,1H),2.93-2.84(m,1H).

[0073] 5-(3-((3-chlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-5)

[0074] Yellow solid, yield 57.6%, melting point: 65.7-67.0℃. 1H NMR(500MHz,Chloroform-d)δ7.40(s,1H),7.38-7.29(m,5H),7.29-7.25(m,1H),7.01(t,J=7.5Hz,1H),6.95(d,J=8.2Hz,1H),6.23(t,J=2 .9Hz,1H),5.79(dd,J=8.5,5.8Hz,1H),5.61(t,J=2.6Hz,1H),5.08(d,J=4.3Hz,2H),3.42(ddt,J=17.3,8.5,2.7Hz,1H),2.94-2.85(m,1H).

[0075] 5-(3-((2-chlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-6)

[0076] White solid, yield 59.6%, melting point: 69.5-70.8℃. 1 H NMR(500MHz,Chloroform-d)δ7.49-7.40(m,2H),7.40-7.33(m,2H),7.33-7.21(m,3H),7.06-6.96(m,2H),6.21(t,J=3.0Hz,1H ),5.82(dd,J=8.5,5.7Hz,1H),5.59(t,J=2.6Hz,1H),5.25-5.16(m,2H),3.43(ddt,J=17.4,8.5,2.7Hz,1H),2.99-2.87(m,1H).

[0077] 5-(2-((4-bromobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-7)

[0078] Yellow solid, yield 58.6%, melting point: 134.5-138.0℃. 1 H NMR(500MHz,Chloroform-d)δ7.50(dd,J=8.7,2.7Hz,2H),7.29(dt,J=7.3,2.4Hz,4H),7.00-6.90(m,2H),6.15(d,J=3.1Hz,1H ),5.74(dd,J=8.6,5.7Hz,1H),5.57(t,J=2.8Hz,1H),5.08-4.98(m,2H),3.41-3.32(m,1H),2.86(ddq,J=16.0,6.2,3.1Hz,1H).

[0079] 5-(2-((3-bromobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-8)

[0080] Bright yellow solid, yield 69.8%, melting point: 93.6-95.5℃. 1 H NMR(500MHz,Chloroform-d)δ7.48(d,J=1.9Hz,1H),7.42(dt,J=8.0,1.5Hz,1H) ,7.30-7.25(m,2H),7.25-7.19(m,2H),6.94(t,J=7.5Hz,1H),6.87(d,J=8.2Hz,1 H),6.16(t,J=2.9Hz,1H),5.72(dd,J=8.5,5.8Hz,1H),5.54(t,J=2.6Hz,1H),5.0 0(s,2H),3.34(ddt,J=17.4,8.5,2.7Hz,1H),2.82(ddt,J=17.4,5.8,2.8Hz,1H).

[0081] 5-(2-((2-bromobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-9)

[0082] Bright yellow solid, yield 52.8%, melting point: 78.7-80.2℃. 1 H NMR(500MHz,Chloroform-d)δ7.65(dd,J=8.0,1.1Hz,1H),7.50(dd,J=7.6,1.7Hz,1H),7.4 3-7.35(m,3H),7.35(dd,J=7.9,1.7Hz,1H),7.33-7.24(m,1H),7.05(t,J=7.5Hz,1H),7.00 (d,J=8.2Hz,1H),6.24(t,J=2.9Hz,1H),5.86(dd,J=8.5,5.8Hz,1H),5.62(t,J=2.6Hz,1H) ,5.25-5.14(m,2H),3.47(ddt,J=17.5,8.5,2.7Hz,1H),2.96(ddt,J=17.4,5.7,2.9Hz,1H).

[0083] 3-methylene-5-(2-((4-(trifluoromethyl)benzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-10)

[0084] White solid, yield 87.1%, melting point: 67.8-69.2℃. 1 H NMR(500MHz,Chloroform-d)δ7.65(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),7.34( dd,J=7.6,1.7Hz,1H),7.29(td,J=7.9,1.8Hz,1H),7.00(t,J=7.5Hz,1H),6.93(d ,J=8.2Hz,1H),6.19(t,J=2.9Hz,1H),5.78(dd,J=8.5,5.8Hz,1H),5.57(t,J=2.6 Hz,1H),5.20-5.10(m,2H),3.39(ddt,J=17.3,8.5,2.7Hz,1H),2.93-2.83(m,1H).

[0085] 3-methylene-5-(2-((3-(trifluoromethyl)benzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-11)

[0086] Yellow oily liquid, yield 73.2%. 1 H NMR(500MHz,Chloroform-d)δ7.66(s,1H),7.60(dd,J=8.0,4.0Hz,2H),7.53(t,J=7.7H z,1H),7.34(dd,J=7.5,1.8Hz,1H),7.33-7.24(m,1H),7.00(t,J=7.5Hz,1H),6.95(d,J= 8.2Hz,1H),6.17(t,J=3.0Hz,1H),5.76(dd,J=8.6,5.8Hz,1H),5.56(t,J=2.6Hz,1H),5. 18-5.08(m,2H),3.38(ddt,J=17.4,8.6,2.7Hz,1H),2.88(ddd,J=14.5,5.8,2.9Hz,1H).

[0087] 3-methylene-5-(2-((2-(trifluoromethyl)benzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-12)

[0088] Bright yellow solid, yield 83.5%, melting point: 66.3-67.8℃. 1 H NMR(500MHz,Chloroform-d)δ7.52(dd,J=7.6,1.9Hz,1H),7.39(td,J=7.7,1.9Hz,1H ),7.32(ddq,J=18.4,8.0,3.1,2.5Hz,4H),7.00(t,J=7.5Hz,1H),6.95(d,J=8.2Hz,1H ),6.18(t,J=3.0Hz,1H),5.77(dd,J=8.5,5.7Hz,1H),5.56(t,J=2.6Hz,1H),5.17(d, J=2.8Hz,2H),3.38(ddt,J=17.4,8.5,2.7Hz,1H),2.87(ddd,J=14.9,5.7,2.9Hz,1H).

[0089] 5-(2-((4-methylbenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-13)

[0090] Yellow oily liquid, yield 74.3%. 1 H NMR(500MHz,Chloroform-d)δ7.34(dd,J=7.5,1.7Hz,1H),7.32-7.25(m,3H),7.20(d,J=7.8Hz,2H),7.04-6.92(m,2H),6.21(t,J=2.9Hz,1H),5.78( dd,J=8.4,5.9Hz,1H),5.57(t,J=2.6Hz,1H),5.10-4.99(m,2H),3.39(ddt ,J=17.5,8.5,2.7Hz,1H),2.84(ddt,J=17.4,5.8,2.9Hz,1H),2.37(s,3H).

[0091] 5-(2-((3-methylbenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-14)

[0092] Yellow oily liquid, yield 85.6%. 1H NMR(500MHz,Chloroform-d)δ7.37(dd,J=7.5,1.7Hz,1H),7.36-7.27(m,2H),7.25-7.11(m,3H),7.05-6.97(m,2H),6.24(t,J=3.0Hz,1H),5.82(dd,J=8 .5,5.8Hz,1H),5.59(t,J=2.6Hz,1H),5.13-5.04(m,2H),3.42(ddt,J=17.4, 8.5, 2.7Hz, 1H), 2.89 (ddt, J=17.4, 5.8, 2.9Hz, 1H), 2.40 (d, J=11.7Hz, 3H).

[0093] 5-(2-((2-methylbenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-15)

[0094] Yellow solid, yield 78.9%, melting point: 47.1-52.1℃. 1 H NMR(500MHz,Chloroform-d)δ7.44-7.24(m,6H),7.06(t,J=7.9Hz,2H),6.22(t,J=2.9Hz,1H),5.82(dd,J=8.4,5.8Hz,1H),5.58(t,J=2.6H z,1H),5.14(d,J=11.3Hz,1H),5.10(d,J=11.3Hz,1H),3.40(ddt,J=17.4,8.5,2.7Hz,1H),2.88(ddt,J=17.4,5.8,2.9Hz,1H),2.43(s,3H).

[0095] 3-methylene-5-(2-((4-nitrobenzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-16)

[0096] Yellow solid, yield 73.6%, melting point: 100.4-101.7℃. 1H NMR(500MHz,Chloroform-d)δ8.33-8.22(m,2H),7.62(d,J=8.5Hz,2H),7.43-7.29(m,2H),7.07(t,J=7.5Hz,1H),6.95(d,J=8.2Hz,1H ),6.27(t,J=2.9Hz,1H),5.84(dd,J=8.5,5.9Hz,1H),5.65(t,J=2.6Hz,1H),5.36-5.15(m,2H),3.49-3.42(m,1H),3.03-2.91(m,1H).

[0097] 3-methylene-5-(2-((3-nitrobenzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-17)

[0098] Yellow solid, yield 48.2%, melting point: 112.6-114.9℃. 1 H NMR(500MHz,Chloroform-d)δ8.32(t,J=2.2Hz,1H),8.26(dd,J=8.3,2.3Hz,1H),7.8 0(d,J=7.6Hz,1H),7.64(t,J=7.9Hz,1H),7.42-7.27(m,2H),7.07(t,J=7.5Hz,1H),6 .99(d,J=8.2Hz,1H),6.24(t,J=3.0Hz,1H),5.82(dd,J=8.5,5.8Hz,1H),5.64(t,J=2 .6Hz,1H),5.28-5.19(m,2H),3.47(ddt,J=17.4,8.6,2.7Hz,1H),3.02-2.91(m,1H).

[0099] 3-methylene-5-(2-((2-nitrobenzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-18)

[0100] Yellow solid, yield 62.4%, melting point: 95.2-96.9℃. 1H NMR(500MHz,Chloroform-d)δ8.21(dd,J=8.1,1.2Hz,1H),7.83-7.65(m,2H),7. 61-7.48(m,1H),7.42-7.29(m,2H),7.06(t,J=7.5Hz,1H),6.96(d,J=8.2Hz,1H), 6.30(dt,J=20.8,2.9Hz,1H),5.83(ddd,J=36.1,8.4,6.0Hz,1H),5.73-5.64(m,1 H),5.56(d,J=3.2Hz,2H),3.48(ddt,J=17.4,8.5,2.7Hz,1H),3.03-2.90(m,1H).

[0101] 5-(2-(benzyloxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-19)

[0102] Yellow oily liquid, yield 73.5%. 1 H NMR(400MHz,Chloroform-d)δ7.44-7.23(m,7H),7.02-6.91(m,2H),6.20(t,J=2.9Hz,1H),5.79(dd,J=8.5,5.8Hz,1 H),5.56(t,J=2.6Hz,1H),5.15-5.03(m,2H),3.39(ddt,J=17.4,8.4,2.7Hz,1H),2.85(ddt,J=17.4,5.8,2.9Hz,1H).

[0103] 5-(2-((2,6-difluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-20)

[0104] Yellow solid, yield 57.8%, melting point: 80.2-81.7℃. 1 H NMR(500MHz,Chloroform-d)δ7.32-7.27(m,1H),7.24(s,1H),7.01(d,J=8.0Hz,1H),6.90(dt,J=23.9,7.9Hz,3H),6.05( t,J=2.9Hz,1H),5.64-5.37(m,2H),5.08(s,2H),3.24(ddt,J=17.5,8.5,2.7Hz,1H),2.73(ddt,J=17.5,5.7,2.8Hz,1H).

[0105] 5-(2-((2,6-dichlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅱ-21)

[0106] Yellow solid, yield 59.7%, melting point: 87.2-101.5℃. 1 H NMR(500MHz,Chloroform-d)δ7.45-7.31(m,5H),7.14(d,J=8.2Hz,1H),7.06(t,J=7.5Hz,1H),6.09(t,J=3.0Hz,1H),5.71(dd,J= 8.6,5.7Hz,1H),5.51(t,J=2.6Hz,1H),5.38-5.29(m,2H),3.32(ddt,J=17.5,8.6,2.7Hz,1H),2.87(ddt,J=17.5,5.7,2.8Hz,1H).

[0107] 3-methylene-5-(2-(naphthalen-1-ylmethoxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-22)

[0108] Yellow solid, yield 83.8%, melting point: 54.7-55.3℃. 1 H NMR(500MHz,Chloroform-d)δ8.00-7.93(m,1H),7.92-7.73(m,2H),7.52(td,J=4.4,2.1 Hz,3H),7.47(s,1H),7.46-7.37(m,1H),7.32(t,J=7.7Hz,2H),7.10(d,J=8.1Hz,1H),6.9 9(t,J=7.5Hz,1H),6.01(t,J=3.0Hz,1H),5.66(dd,J=8.5,5.8Hz,1H),5.47(s,2H),5.30 (t,J=2.7Hz,1H),3.15(ddt,J=17.4,8.5,2.7Hz,1H),2.73(ddt,J=17.4,5.8,2.9Hz,1H).

[0109] 3-methylene-5-(2-(naphthalen-2-ylmethoxy)phenyl)dihydrofuran-2(3H)-one(Ⅱ-23)

[0110] Pale yellow solid, yield 70.2%, melting point: 58.7-59.8℃.1 H NMR(500MHz,Chloroform-d)δ7.89-7.75(m,4H),7.53-7.42(m,3H),7.34(dd,J=7.6,1.8Hz, 1H),7.31-7.21(m,1H),7.02-6.94(m,2H),6.16(t,J=2.9Hz,1H),5.79(dd,J=8.4,5.9Hz,1H ),5.51(t,J=2.6Hz,1H),5.27-5.17(m,2H),3.36(ddt,J=17.4,8.4,2.7Hz,1H),2.90-2.82( m,1H).5-(3-((4-fluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-1)

[0111] A bright yellow oily liquid, yield 56.7%. 1 H NMR(500MHz,Chloroform-d)δ7.60-7.49(m,2H),7.52-7.40(m,1H),7.29-7.17(m,2H),7.12-7.04(m,3H),6.47(t,J=2.9Hz,1H),5.8 5(t,J=2.5Hz,1H),5.66(dd,J=8.1,6.4Hz,1H),5.18(s,2H),3.56(ddt,J=17.0,8.0,2.5Hz,1H),3.05(ddt,J=17.1,6.1,2.9Hz,1H).

[0112] 5-(3-((3-fluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-2)

[0113] A bright yellow oily liquid, yield 55.8%. 1 H NMR(500MHz,Chloroform-d)δ7.40-7.05(m,4H),7.01(td,J=8.5,2.6Hz,1H),7.01-6.89(m,3H),6.31(t,J=2.9Hz,1H),5.69(t, J=2.5Hz,1H),5.50(dd,J=8.1,6.4Hz,1H),5.06(s,2H),3.39(ddt,J=17.1,8.2,2.5Hz,1H),2.89(ddt,J=17.1,6.1,2.9Hz,1H).

[0114] 5-(3-((2-fluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-3)

[0115] A bright yellow oily liquid, yield 64.9%. 1 H NMR(500MHz,Chloroform-d)δ7.50(td,J=7.5,1.8Hz,1H),7.38-7.27(m,2H),7 .17(td,J=7.5,1.2Hz,1H),7.09(ddd,J=9.7,8.3,1.2Hz,1H),6.99-6.89(m,3H) ,6.31(t,J=2.9Hz,1H),5.69(t,J=2.6Hz,1H),5.50(dd,J=8.1,6.4Hz,1H),5.13 (s,2H),3.39(ddt,J=17.1,8.1,2.5Hz,1H),2.90(ddt,J=17.1,6.2,2.9Hz,1H). 13 C NMR (126MHz, CDCl3)

[0116] 5-(3-((4-chlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-4)

[0117] White solid, yield 66.1%, melting point: 49.3-51.4℃. 1 H NMR(500MHz,Chloroform-d)δ7.37(s,4H),7.36-7.27(m,2H),6.97-6.90(m,3H),6.31(t,J=2.9Hz,1H),5.70(t,J=2.5H z,1H),5.50(dd,J=8.1,6.4Hz,1H),5.04(s,2H),3.40(ddt,J=17.1,8.2,2.5Hz,1H),2.89(dtd,J=12.0,6.1,2.9Hz,1H).

[0118] 5-(3-((3-chlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-5)

[0119] A pale yellow liquid, yield 72.2%. 1H NMR(500MHz,Chloroform-d)δ7.45(d,J=2.3Hz,1H),7.37-7.27(m,4H),6.98-6.91(m,3H),6.32(t,J=2.9Hz,1H),5. 70(t,J=2.6Hz,1H),5.51(dd,J=8.1,6.3Hz,1H),5.04(s,2H),3.41(ddt,J=17.1,8.2,2.5Hz,1H),2.97-2.85(m,1H).

[0120] 5-(3-((2-chlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-6)

[0121] A pale yellow liquid, with a yield of 62.9%. 1 H NMR(500MHz,Chloroform-d)δ7.57(dd,J=7.2,2.3Hz,1H),7.42(dd,J=7.2,2.1Hz,1 H),7.33(dd,J=9.7,6.5Hz,1H),7.32-7.29(m,1H),7.28(d,J=4.8Hz,1H),6.97(ddd ,J=17.8,6.9,4.6Hz,3H),6.32(t,J=2.9Hz,1H),5.71(t,J=2.6Hz,1H),5.52(dd,J= 8.1, 6.4Hz, 1H), 5.18 (s, 2H), 3.41 (ddt, J=17.1, 8.1, 2.5Hz, 1H), 2.98-2.87 (m, 1H).

[0122] 5-(3-((4-bromobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-7)

[0123] White solid, yield 78.4%, melting point: 80.8-82.5℃. 1H NMR (500MHz, Chloroform-d) δ7.56-7.46(m,2H),7.36-7.24(m,3H),6.97-6.90(m,3H),6.33(t,J=2.9Hz,1H),5.71(t,J=2. 6Hz,1H),5.52(dd,J=8.1,6.4Hz,1H),5.03(s,2H),3.41(ddt,J=17.2,8.2,2.5Hz,1H),2.90(ddt,J=17.1,6.1,2.9Hz,1H).

[0124] 5-(3-((3-bromobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-8)

[0125] A pale yellow, oily liquid, with a yield of 57.1%. 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=1.9Hz,1H),7.49-7.38(m,1H),7.38-7.20(m,3H),6.92(d,J=9.2Hz,3H),6.31(t,J=2.9 Hz,1H),5.69(t,J=2.5Hz,1H),5.50(dd,J=8.1,6.4Hz,1H),5.03(s,2H),3.40(ddt,J=17.1,8.1,2.5Hz,1H),2.98-2.83(m,1H).

[0126] 5-(3-((2-bromobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-9)

[0127] A pale yellow, oily liquid with a yield of 58.2%. 1 H NMR(400MHz,Chloroform-d)δ7.62-7.45(m,2H),7.37-7.29(m,2H),7.20(td,J=7.7,1.8Hz,1H),6.98-6.90(m,3H),6.31(q,J=5.2, 4.0Hz,1H),5.69(t,J=2.5Hz,1H),5.51(dd,J=8.0,6.4Hz,1H),5.13(s,2H),3.40(ddt,J=17.1,8.1,2.5Hz,1H),2.98-2.85(m,1H).

[0128] 3-methylene-5-(3-((4-(trifluoromethyl)benzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-10)

[0129] A pale yellow, oily liquid with a yield of 59.2%. 1 H NMR(500MHz,Chloroform-d)δ7.66(d,J=8.0Hz,2H),7.57(d,J=8.0Hz,2H),7.33(t,J=7.9Hz,1H),6.96(ddd,J=13.8,5.0,2.4Hz,3H),6.3 2(t,J=2.9Hz,1H),5.70(t,J=2.6Hz,1H),5.52(dd,J=8.1,6.4Hz,1H),5.14(s,2H),3.41(ddt,J=17.1,8.2,2.5Hz,1H),2.98-2.88(m,1H).

[0130] 3-methylene-5-(3-((3-(trifluoromethyl)benzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-11)

[0131] A pale yellow liquid, yield 61.7%. 1 H NMR(500MHz,Chloroform-d)δ7.73(s,1H),7.62(dd,J=13.3,7.8Hz,2H),7.53(t,J=7.7Hz,1H),7.34(t,J=7.8Hz,1H),6.96(ddd,J=14.7,5.6,1.8Hz ,3H),6.32(t,J=2.9Hz,1H),5.71(t,J=2.6Hz,1H),5.52(dd,J=8.1,6.4Hz ,1H),5.12(s,2H),3.42(ddt,J=17.1,8.1,2.5Hz,1H),2.98-2.86(m,1H).

[0132] 3-methylene-5-(3-((2-(trifluoromethyl)benzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-12)

[0133] Pale yellow solid, yield 67.2%, melting point: 39.6-41.2℃. 1H NMR(500MHz,Chloroform-d)δ7.61(dd,J=7.6,1.9Hz,1H),7.38(qd,J=8.8,8.3,1.7Hz,1H),7 .35-7.27(m,3H),7.00-6.93(m,3H),6.32(t,J=2.9Hz,1H),5.70(t,J=2.6Hz,1H),5.51(dd,J= 8.1,6.4Hz,1H),5.17(s,2H),3.41(ddt,J=17.1,8.1,2.5Hz,1H),2.92(ddt,J=17.0,6.2,3.3H z,1H).5-(3-((4-methylbenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-13)

[0134] White solid, yield 62.3%, melting point: 52.4-55.1℃. 1 H NMR(500MHz,Chloroform-d)δ7.40-7.35(m,3H),7.27(d,J=7.9Hz,2H),7.01(dd,J=6.3,2.6Hz,2H),6.97(d,J=7.6Hz,1H),6.38(t,J=2.9Hz,1H),5 .76(t,J=2.6Hz,1H),5.57(dd,J=8.1,6.4Hz,1H),5.09(s,2H),3.46(ddt, J=17.1,8.2,2.5Hz,1H),2.96(ddt,J=17.0,6.1,2.9Hz,1H),2.43(s,3H).

[0135] 5-(3-((3-methylbenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-14)

[0136] White solid, yield 71.6%, melting point: 45.5-46.7℃. 1H NMR(500MHz,Chloroform-d)δ7.36-7.21(m,4H),7.18(d,J=7.5Hz,1H),7.00-6.96(m,2H),6. 93(d,J=7.7Hz,1H),6.33(t,J=2.9Hz,1H),5.71(t,J=2.6Hz,1H),5.52(dd,J=8.1,6.4Hz,1H), 5.05(s,1H),5.05-4.99(m,1H),3.41(ddt,J=17.1,8.1,2.6Hz,1H),2.99-2.87(m,1H),2.41( s,3H).5-(3-((2-methylbenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-15)

[0137] A bright yellow oily liquid, yield 76.6%. 1 H NMR(500MHz,Chloroform-d)δ7.45(dd,J=7.1,2.1Hz,1H),7.40-7.34(m,1H),7 .33-7.21(m,3H),7.04-6.99(m,2H),6.97(dt,J=8.0,1.2Hz,1H),6.36(t,J=2. 9Hz,1H),5.74(t,J=2.6Hz,1H),5.56(dd,J=8.1,6.4Hz,1H),5.09(s,2H),3.44 (ddt,J=17.1,8.0,2.5Hz,1H),2.96(ddt,J=17.1,6.1,2.9Hz,1H),2.43(s,3H).

[0138] 3-methylene-5-(3-((4-nitrobenzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-16)

[0139] Yellow solid, yield 62.6%, melting point: 89.5-91.1℃. 1H NMR(400MHz,Chloroform-d)δ8.31-8.13(m,2H),7.58(dd,J=29.6,8.6Hz,2H),7.3 5-7.19(m,1H),6.98-6.90(m,2H),6.90-6.79(m,1H),6.31(dt,J=8.7,2.9Hz,1H),5 .70(dt,J=6.8,2.5Hz,1H),5.50(ddd,J=19.0,8.0,6.3Hz,1H),5.01(d,J=134.4Hz, 2H), 3.40 (dddt,J=16.9,14.4,8.1,2.5Hz,1H), 2.90(dtd,J=14.4,6.0,2.8Hz,1H).

[0140] 3-methylene-5-(3-((3-nitrobenzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-17)

[0141] Yellow solid, yield 46.4%, melting point: 93.4-94.6℃. 1 H NMR(400MHz,Chloroform-d)δ8.31(t,J=2.0Hz,1H),8.24-8.14(m,1H),7.76(ddd,J=7.7,1.7 ,1.0Hz,1H),7.54(dt,J=24.1,7.9Hz,1H),7.32(td,J=7.7,0.8Hz,1H),6.98-6.89(m,2H),6. 85-6.78(m,1H),6.29(dt,J=11.6,2.8Hz,1H),5.68(dt,J=11.2,2.5Hz,1H),5.48(ddd,J=24. 8,8.1,6.3Hz,1H),5.15(s,2H),3.50-3.36(m,1H),2.89(dddd,J=17.2,9.3,6.2,3.0Hz,1H).

[0142] 3-methylene-5-(3-((2-nitrobenzyl)oxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-18)

[0143] Yellow solid, yield 42.7%, melting point: 89.8-91.6℃. 1H NMR(400MHz,Chloroform-d)δ8.19-8.05(m,1H),7.86(t,J=9.6Hz,1H),7.72-7.42(m,2H),7.35-7.17(m,1H),6.99-6.91(m,2H),6.81(d,J=6.5Hz,1H ),6.29(dt,J=12.1,2.8Hz,1H),5.69(dt,J=11.9,2.5Hz,1H),5.61-5.41( m,2H),3.38(tdt,J=19.8,8.3,2.5Hz,1H),3.00-2.81(m,1H),2.26(s,1H).

[0144] 5-(3-(benzyloxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-19)

[0145] Yellow oily liquid, yield 80.3%. 1 H NMR(400MHz,Chloroform-d)δ7.45-7.35(m,4H),7.35-7.31(m,1H),7.31-7.20(m,1H),7.02-6.81(m,3H),6.29(t,J=2.9Hz,1H),5.6 6(t,J=2.5Hz,1H),5.47(dd,J=8.1,6.4Hz,1H),5.05(s,2H),3.36(ddt,J=17.1,8.1,2.5Hz,1H),2.87(ddt,J=17.1,6.1,2.9Hz,1H).

[0146] 5-(3-((2,6-difluorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-20)

[0147] Yellow oily liquid, yield 79.7%. 1 H NMR(500MHz,Chloroform-d)δ7.35-7.29(m,2H),7.01-6.93(m,3H),6.92(d,J=7.4Hz,2H),6.30(t,J=2.9Hz,1H),5.68(t,J=2.6H z,1H),5.49(dd,J=8.1,6.4Hz,1H),5.12(d,J=1.3Hz,2H),3.39(ddt,J=17.1,8.1,2.5Hz,1H),2.89(ddt,J=17.2,6.1,2.9Hz,1H).

[0148] 5-(3-((2,6-dichlorobenzyl)oxy)phenyl)-3-methylenedihydrofuran-2(3H)-one(Ⅲ-21)

[0149] Yellow oily liquid, yield 65.5%. 1 H NMR(500MHz,Chloroform-d)δ7.39-7.29(m,3H),7.25(dd,J=8.6,7.5Hz,1H),7.03-6.96(m,2H),6.96-6.91(m,1H),6.30(t,J=2.9Hz,1H) ,5.69(t,J=2.5Hz,1H),5.51(dd,J=8.1,6.5Hz,1H),5.27(s,2H),3.40(ddt,J=17.1,8.0,2.5Hz,1H),2.92(ddt,J=17.1,6.3,3.0Hz,1H).

[0150] 3-methylene-5-(3-(naphthalen-1-ylmethoxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-22)

[0151] A pale yellow, oily liquid with a yield of 83.4%. 1 H NMR(500MHz,Chloroform-d)δ8.11-8.05(m,1H),7.96-7.87(m,2H),7.65-7.58(m,1 H),7.58-7.53(m,2H),7.50(t,J=7.6Hz,1H),7.36(dd,J=10.4,6.2Hz,1H),7.06(dd ,J=6.1,2.9Hz,2H),6.96(d,J=7.6Hz,1H),6.33(t,J=2.9Hz,1H),5.69(t,J=2.6Hz, 1H), 5.51 (s, 3H), 3.39 (ddt, J=17.1, 8.1, 2.5Hz, 1H), 2.92 (dt, J=17.0, 3.6Hz, 1H).

[0152] 3-methylene-5-(3-(naphthalen-2-ylmethoxy)phenyl)dihydrofuran-2(3H)-one(Ⅲ-23)

[0153] A pale yellow, oily liquid with a yield of 71.1%. 1H NMR(500MHz,Chloroform-d)δ7.91(d,J=2.6Hz,2H),7.89-7.78(m,3H),7.56(dd,J=8.4,1.8 Hz,1H),7.53(dd,J=6.3,3.2Hz,1H),7.50(d,J=3.7Hz,1H),7.34(t,J=7.8Hz,1H),7.02(d,J= 7.7Hz,2H),6.93(d,J=7.6Hz,1H),6.32(t,J=2.9Hz,1H),5.67(t,J=2.6Hz,1H),5.51(dd,J=8 .1, 6.3Hz, 1H), 5.25 (s, 2H), 3.38 (ddt, J=17.2, 8.2, 2.6Hz, 1H), 2.89 (tq, J=9.3, 2.9Hz, 1H).

[0154] 3-methylene-5-(2-phenoxyphenyl)dihydrofuran-2(3H)-one(IV-1)

[0155] Yellow oily liquid, yield 66.2%. 1 H NMR (400MHz, Chloroform-d) δ7.42(d,J=6.9Hz,1H),7.32(t,J=7.9Hz,1H),7.23(d,J=8.5Hz,1H),7.11(t,J=7.3Hz,2H),6.96(d,J=8. 6Hz,1H),6.85(d,J=8.2Hz,1H),6.24(t,J=2.9Hz,1H),5.82-5.73(m,1H),5.59(t,J=2.6Hz,1H),3.47-3.32(m,1H),2.94-2.82(m,1H).

[0156] 3-methylene-5-(3-phenoxyphenyl)dihydrofuran-2(3H)-one(IV-2)

[0157] Yellow oily liquid, yield 64.5%. 1H NMR(400MHz,Chloroform-d)δ7.34(ddt,J=8.9,7.0,3.2Hz,3H),7.16-7.10(m,1H),7.07-7.04(m,1H),7.03-6.92(m,4H),6.30(t ,J=2.9Hz,1H),5.69(t,J=2.5Hz,1H),5.58-5.45(m,1H),3.39(ddt,J=17.0,8.0,2.5Hz,1H),2.90(ddt,J=17.1,6.2,2.9Hz,1H).

[0158] Example 5: Inhibitory activity of compound I against 7 plant pathogens

[0159] The antibacterial activity of compound I was determined using the mycelial growth rate method. The tested fungal species were *Rhizoctonia solani*, *Pseudomonas aeruginosa*, *Botrytis cinerea*, *Tricholoma materia granatum*, *Fusarium graminearum*, *Anthracnose*, and *Phytophthora capsici*.

[0160] Weigh out each compound of Formula I and prepare a stock solution of 10000 mg / L with dimethyl sulfoxide. Use a pipette to add the prepared 10000 mg / L stock solution to sterilized and cooled potato dextrose agar (PDA) medium. Mix well to prepare a 50 mg / L drug-loaded medium. Pour 15 mL into 9 cm diameter petri dishes, with each agent tested in triplicate. After the drug-loaded medium in the dishes has solidified, prepare drug-loaded PDA plates. Use dimethyl sulfoxide as a solvent blank control. Prepare mycelial discs (0.5 cm in diameter) along the colony edge of the cultured pathogen plates using a punch. Inoculate these discs into drug-loaded and blank control PDA plates, and incubate in the dark at 25°C. After the colonies in the blank control PDA plates have fully grown, measure the colony diameter of each treatment using the cross-sectional method and take the average value.

[0161] Calculate the mycelial growth inhibition rate using the following formula:

[0162]

[0163] The in-vitro antibacterial activity data of the compounds are shown in Table 2.

[0164] Table 2 shows the in-vitro antibacterial activity (inhibition rate %) of compound I.

[0165]

[0166]

[0167] Note: + indicates that the compound has an inhibition rate of 0-40% against pathogens, ++ indicates that the compound has an inhibition rate of 41-79% against pathogens, and +++ indicates that the compound has an inhibition rate of 80%-100% against pathogens.

[0168] As can be seen from the table above, the compound of formula I provided by this invention has certain inhibitory activity against all seven plant pathogens tested at 50 μg / mL.

[0169] Compounds II-6, II-17, II-20, III-12, III-16, III-17, III-18 and IV-2 showed inhibition rates of over 80% against wheat take-all pathogen.

[0170] Compounds III-2, III-3, IV-1, and IV-2 showed inhibition rates of over 80% against rice sheath blight pathogen.

[0171] Compounds II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-10, II-11, II-12, II-13, II-15, II-20, II-21, II-22, III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-10, III-11, III-12, III-13, III-14, III-15, III-17, III-20, III-21, III-22, III-23 and IV-2 showed inhibition rates of over 80% against apple tree rot pathogens.

[0172] Compounds III-1, III-3, III-4, III-8, III-14, III-19, III-20, IV-1, and IV-2 showed inhibition rates of over 80% against Phytophthora capsici, the causal agent of the pepper blight.

[0173] Example 6: EC50 of some compounds of Formula I against four plant pathogens 50 Value determination

[0174] Some compounds in Formula I exhibit EC50 activity against four plant pathogens. 50 The mycelial growth rate method was used to determine the value of the fungal strains tested, which were wheat take-all pathogen, rice sheath blight pathogen, apple tree rot pathogen, and pepper phytophthora.

[0175] Table 3 shows the EC50 of some compounds in Formula I against four plant pathogens. 50 value

[0176]

[0177] In Example 6, the EC50 values ​​of compounds II-3, II-6, III-16, III-17, III-18, and IV-2 against *Tricholoma materia granatum* were 16.71, 11.93, 7.27, 7.88, 3.65, and 2.97 μg / mL, respectively; the EC50 values ​​of compounds III-2 and III-3 against *Rhizoctonia solani* were 2.51 and 2.31 μg / mL, respectively; and the EC50 values ​​of compounds II-3 and II-6 against *Tricholoma materia granatum* were 2.51 and 2.31 μg / mL, respectively. The EC50 values ​​of compounds Ⅱ-7, Ⅱ-8, Ⅱ-13, Ⅲ-13, and Ⅲ-20 against *Phytophthora indica* were 19.05, 4.81, 4.89, 17.01, 17.25, and 3.07 μg / mL, respectively; while the EC50 values ​​of compounds Ⅲ-1, Ⅲ-3, Ⅲ-19, and Ⅳ-2 against *Phytophthora capsici* were 13.64, 10.72, 24.60, and 0.74 μg / mL, respectively.

[0178] The results of Example 6 show that the compound of Formula I has good inhibitory effects on wheat take-all, rice sheath blight, apple tree rot, and pepper phytophthora. Among them, compound IV-2 has an EC50 value of less than 1 μg / mL against pepper phytophthora, showing excellent inhibitory effect. To verify its activity, a pot experiment was conducted to further verify the efficacy of compound IV-2 against pepper phytophthora.

[0179] Example 7: Pot efficacy test of compound IV-2 against Phytophthora capsici in peppers

[0180] Pepper plants were grown in pots (9cm×8cm×6cm) filled with a mixture of potting soil (nutrient soil / ordinary loess = 1:1, v / v). After 5 weeks of growth in a greenhouse (8-10 leaf stage), a test was conducted to assess the efficacy against Phytophthora blight. First, the test compound and the positive control agent, oxadiazon, were dissolved in tap water containing 0.1% Tween 80, diluting to concentrations of 100, 50, and 25 mg / L. 1×10 5 Three mL of a suspension of CFU / mL pepper zoospores was inoculated into the roots of pepper plants. Before and after inoculation, the pepper plants were drenched with the prepared solution. 10 mL of the test solution was poured onto the soil around the roots of each plant. 0.1% Tween 80 tap water was used as a control. Each treatment was repeated three times. After 14 days of cultivation in a greenhouse, the pepper plants were investigated according to the disease severity grading standards for Phytophthora capsici. The disease index and control efficacy were calculated using the following formula.

[0181] Level 0: No obvious symptoms of disease;

[0182] Grade 1: Leaves are slightly wilted, and the base of the stem shows brown symptoms;

[0183] Level 2: 30-50% of the plants are diseased;

[0184] Level 3: 50-70% of the plants are diseased;

[0185] Level 4: 70-90% of the plants are diseased;

[0186] Level 5: Plants are dead.

[0187]

[0188] Table 4. Potted plant control efficacy of compound IV-2 against Phytophthora capsici.

[0189]

[0190] In Example 7, at a concentration of 150 mg / L, compound IV-2 showed 95.0% potted protective efficacy and 84.2% potted curative efficacy against Phytophthora capsici.

[0191] The preferred embodiments of this disclosure have been described in detail above. However, this disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this disclosure, various simple modifications can be made to the technical solutions of this disclosure, and these simple modifications all fall within the protection scope of this disclosure.

[0192] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately.

[0193] Furthermore, various different embodiments of this disclosure can be combined in any way, as long as they do not violate the spirit of this disclosure, they should also be regarded as the content disclosed in this disclosure.

Claims

1. An ether-substituted α-methylene-γ-butyrolactone compound, characterized in that, The compound is the compound represented by Formula I; Wherein: R is selected from at least one of halogen, trifluoromethyl, methyl, nitro, phenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 1-naphthyl and 2-naphthyl, and R is substituted by monosubstitution.

2. The ether-substituted α-methylene-γ-butyrolactone compound according to claim 1, characterized in that, The compound represented by Formula I may be represented by Formula II, Formula III or Formula IV, depending on the position of the ether substitution. In the compounds represented by formulas II, III and IV, R is selected from at least one of halogen, trifluoromethyl, methyl, nitro, phenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 1-naphthyl and 2-naphthyl, and R is substituted by monosubstitution.

3. The ether-substituted α-methylene-γ-butyrolactone compound according to claim 1 or 2, characterized in that, The specific R values ​​in the compounds are shown in the table below:

4. A method for preparing the ether-substituted α-methylene-γ-butyrolactone compound according to any one of claims 1-3, characterized in that, Its synthetic route is as follows: Step 1: Bromomethacrylic acid and 2-hydroxy or 3-hydroxy-substituted benzaldehyde are dissolved in a mixed solution of tetrahydrofuran and water, and then indium catalyst powder is added. The mixture is stirred at room temperature for 12 hours. After the reaction is completed, 6M hydrochloric acid is added directly and the reaction is continued for 12 hours. The post-treatment is performed by extraction with ethyl acetate, extraction with saturated brine, drying with anhydrous magnesium sulfate, removing the solvent, and separating by column chromatography. Step 2: Add intermediate 2a or 2b, benzyl chloride or benzyl bromide with different substitutions, N,N-dimethylformamide, and finally add potassium carbonate and potassium iodide. After the reaction is complete, add water, extract with ethyl acetate, and separate by column chromatography with petroleum ether / ethyl acetate = 4:1 to 6:1 to obtain compounds II-1-II-23 and III-1-III-23. Step 3, the synthetic route of compound IV-1-IV-2, the synthetic method is the same as the preparation of intermediates 2a and 2b in step 1.

5. The method for preparing ether-substituted α-methylene-γ-butyrolactone compounds according to claim 4, characterized in that, In step 1, the molar ratio of the 2-hydroxy or 3-hydroxy substituted benzaldehyde, bromomethacrylic acid and indium powder is 1:1.2:1.

2.

6. The method for preparing ether-substituted α-methylene-γ-butyrolactone compounds according to claim 4, characterized in that, In step 1, the ratio of tetrahydrofuran to water is v / v = 1:

1.

7. The method for preparing ether-substituted α-methylene-γ-butyrolactone compounds according to claim 4, characterized in that, In step 1, the column chromatography separation conditions are as follows: eluent for ortho-substituted intermediate 2a: dichloromethane / methanol = 0:1; Meta-2b: Petroleum ether / ethyl acetate = 4:

1.

8. The method for preparing ether-substituted α-methylene-γ-butyrolactone compounds according to claim 4, characterized in that, In step 2, the molar ratio of potassium iodide, intermediate 2a or 2b, benzyl chloride or benzyl bromide and potassium carbonate is 1:16:20:33, the reaction temperature is 80℃, and the reaction time is 8 to 12 hours.

9. The use of the ether-substituted α-methylene-γ-butyrolactone compounds according to any one of claims 1-3 in the preparation of agricultural fungicides.

10. The application according to claim 9, characterized in that, The aforementioned agricultural fungicide is used for the prevention and control of rice sheath blight, apple rot, tomato gray mold, wheat take-all, wheat scab, cucumber anthracnose, and / or pepper blight.

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