Use of a cyclopropane compound for preventing and treating forestry pests

Abstract

The application discloses a preparation method of a cyclopropane compound and application of the cyclopropane compound in nematode killing activity. The application uses an electrochemical method to quickly cyclopropanate a methylene compound by using a cheap and easily available sulfide. The synthesis method is simple, clean, efficient, short in reaction time, low in energy consumption, and cheap and easily available in raw materials, and is suitable for mass production and better research. Through activity testing, the cyclopropane compound has strong activity against pine wood nematode disease, and relevant research provides a good basis for strong biological activity, anticancer activity, antibacterial activity and anti-inflammatory activity.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a cyclopropane compound, its preparation method, and its application in killing nematicides. Background Technology

[0002] Pine nematode disease, also known as "the cancer of pine trees," is caused by pine nematodes and can result in enormous economic losses. Since its initial discovery in the last century, pine nematode disease has developed into a global crisis for pine trees. Therefore, the development of new drugs to control nematodes is of great value.

[0003] Cyclopropanes, due to their unique ring strain and reactivity, have important applications in medicinal chemistry and organic synthesis. The strategies for synthesizing cyclopropanes include the following methods:

[0004] Simmons-Smith cyclopropanation uses a Zn-Cu alloy as a catalyst, but the reaction rate is slow, reproducibility is low, and different alloy surface features may be needed to optimize the reaction conditions.

[0005] Catalytic diazo transfer typically requires high temperatures and high catalyst loadings, and product yields need improvement. Furthermore, heterogeneous reaction conditions may limit the efficiency and selectivity of the reaction.

[0006] The Kulinkovich cyclopropanization process is applicable to the synthesis of oxygen- or nitrogen-substituted cyclopropanes, but may require specific titanium catalysts and Gringard reagents, the operation and handling of which can be relatively complex.

[0007] Corey - The Chaykovsky cyclopropane process. Involving in-situ generation of nucleophilic thioyl groups, which may require specific [methods / methods]. Alkaline conditions and thiocyanate reagents, along with the optimization of reaction conditions, can be challenging aspects of the synthesis.

[0008] These methods all suffer from drawbacks related to cyclopropanation to varying degrees. Therefore, exploring simpler synthetic methods has become an urgent research topic. To this end, we present a method for preparing and using a class of cyclopropane compounds. Summary of the Invention

[0009] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0010] In view of the problems existing in the above and / or prior art, the present invention is proposed.

[0011] One objective of this invention is to provide a cyclopropane compound that introduces a cyclopropane functional group, thereby promoting the research of new reactions and developing diverse derivatives.

[0012] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a cyclopropane compound, the structure of which is shown in Formula I:

[0013]

[0014] In Formula I, EWG is an electron-withdrawing group, such as pyridyl, aryl, substituted aryl, naphthalene, benzocycloalkyl; R1 and R2 are H, methyl, or substituted aryl; R3 is cyano, p-toluenesulfonyl, nitro, ester, carbonyl, or sulfonyl fluoride.

[0015] As a preferred embodiment of the cyclopropane compounds of the present invention, the structure is as follows:

[0016]

[0017] Another object of the present invention is to provide a method for preparing cyclopropane compounds as described above, comprising, under electrochemical conditions in a solvent, adding a compound of formula II or a compound of formula III to a reaction system to synthesize cyclopropane compounds and their applications;

[0018]

[0019] In Formula II, EWG is an electron-withdrawing group, such as pyridyl, aryl, substituted aryl, naphthalene, benzocycloalkyl; R3 is cyano, p-toluenesulfonyl, nitro, ester, carbonyl, sulfonyl fluoride.

[0020]

[0021] In Formula III, R1 and R2 are H, methyl, or substituted aryl groups.

[0022] In a preferred embodiment of the method for preparing cyclopropane compounds of the present invention, the compound of formula III is prepared from a carbonyl compound through a one-step reaction. For example, benzaldehyde reacts with bis[(pinacol)boryl]methane at -78°C for 4 hours, then the temperature is raised to room temperature and the reaction is continued for another 4 hours. The reaction is quenched with saturated NH4Cl solution. After washing with brine, the mixture is extracted with EtOAC, the organic phase is collected and dried over anhydrous magnesium sulfate, the organic solvent is concentrated under vacuum, and purified by column chromatography to obtain 4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxoborhexacyclopentane. Alternatively, 4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxoborhexacyclopentane is dissolved in methanol, potassium hydrogen fluoride is added, and the mixture is stirred at room temperature for one hour. After concentration, the system is dissolved in acetone, filtered, the organic phase is collected, concentrated, and washed with diethyl ether to obtain a solid boron salt.

[0023] In a preferred embodiment of the method for preparing the cyclopropane compounds of the present invention, the solvent is selected from one or more of diethyl ether, tetrahydrofuran, and 1,4-dioxane; preferably, diethyl ether is used; the concentration of the solvent is 0.4–0.02 M; and the molar ratio of compound II to compound III is 1:1.2–3.

[0024] In a preferred embodiment of the method for preparing cyclopropane compounds of the present invention, the electrolyte used in the electrochemical reaction is one or more of tetraethylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate, tetratert-butylammonium hexafluorophosphate, tetratert-butylammonium tetrafluoroborate, lithium chloride, lithium perchlorate, and lithium trifluoromethanesulfonate; the amount of electrolyte added is 0.15M; the reaction voltage of the electrochemical reaction is 0.1–20V, the reaction temperature is -20–40℃, and the reaction current is 1–20mA.

[0025] Another object of the present invention is to provide another method for preparing cyclopropane compounds, comprising mixing fluorosulfonyl chloride and enol ether in a solvent and stirring to react and synthesize cyclopropane compounds.

[0026] In a preferred embodiment of the method for preparing cyclopropane compounds of the present invention, the solvent is selected from one or more of acetonitrile, diethyl ether, tetrahydrofuran, 1,4-dioxane, and water; the concentration of the solvent is 0.4–0.02 M.

[0027] The molar ratio of compound II to compound III is 1:1.2-3; the reaction time is 2-5 h; the reaction needs to be carried out in an inert gas atmosphere and in an organic solvent.

[0028] The method for preparing the cyclopropane compounds is characterized in that the electrochemical reaction requires catalytic oxidation by thioether compounds.

[0029] Another object of the present invention is to provide the application of cyclopropane compounds as described above in the prevention and control of forest pests and diseases; particularly in the prevention and control of nematode diseases.

[0030] The term "forest pests and diseases" as used in this article refers to the damage caused by insects that harm forests and forest products, resulting in pathological changes in the physiology, tissues, and morphology of trees. Forest pests include root pests, trunk and branch pests (including both boring and piercing-sucking pests), leaf pests, and fruit and seed pests.

[0031] The term "prevention and control of forest pests and diseases" as used in this article refers to preventing or making it more difficult for forest pests to develop or grow, thereby reducing infection pressure, maintaining healthier plants, and reducing damage caused by nematodes.

[0032] The term "nematode" as used in this article refers to plant nematodes, encompassing all nematodes that damage plants. Plant nematodes include both plant-parasitic nematodes and soil-dwelling nematodes. For example, the pine wood nematode (Bursaphelenchus xylophilus) has been effectively controlled using the compounds described herein. However, the use of the compounds described herein is by no means limited to these genera or species, but extends in the same way to other nematodes.

[0033] As a preferred embodiment of the application of the cyclopropane compounds of the present invention in the prevention and control of forest pests and diseases, the contact time between the cyclopropane compounds and pine wood nematodes is 0.5 to 24 hours.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] This invention utilizes electrochemical methods to generate cyclopropane compounds. The synthesis method of this invention is clean, efficient, has a short reaction time, low energy consumption, and uses readily available and inexpensive raw materials. This method facilitates large-scale preparation and further research. Activity tests have shown that cyclopropane compounds exhibit strong activity against pine wilt disease, and related research provides a solid foundation for their potent biological, anticancer, antibacterial, and anti-inflammatory activities. Attached Figure Description

[0036] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. Wherein:

[0037] Figure 1 The hydrogen spectrum of the compound obtained in Example 1 of this invention;

[0038] Figure 2The carbon spectrum of the compound obtained in Example 1 of this invention;

[0039] Figure 3 The hydrogen spectrum of the compound obtained in Example 2 of this invention;

[0040] Figure 4 The carbon spectrum of the compound obtained in Example 2 of this invention;

[0041] Figure 5 The hydrogen spectrum of the compound obtained in Example 3 of this invention;

[0042] Figure 6 The carbon spectrum of the compound obtained in Example 3 of this invention;

[0043] Figure 7 The hydrogen spectrum of the compound obtained in Example 4 of this invention;

[0044] Figure 8 The carbon spectrum of the compound obtained in Example 4 of this invention;

[0045] Figure 9 The hydrogen spectrum of the compound obtained in Example 5 of this invention;

[0046] Figure 10 The carbon spectrum of the compound obtained in Example 5 of this invention; Detailed Implementation

[0047] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0048] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0049] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it a single or selective embodiment that is mutually exclusive with other embodiments.

[0050] Example 1

[0051]

[0052] At room temperature, in a 25 mL three-necked round-bottom flask, carbon and platinum electrodes (20 mm × 20 mm × 1 mm) were inserted, and electrolyte nBu4NPF6 (77.486 mg), sulfide (7.45 mg, 20 mol%), formyl acetonitrile compound (0.2 mmol), and boron salt (2 eq, 53.58 mg) were added. Acetonitrile and pure water (50:1, 0.04 M) were then added. The mixture was electrolyzed at a constant current (8 mA) for 2.5 h. Subsequently, the electrodes were rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give the product cyclopropane compounds (26.2 mg, 59%).

[0053] The structural characterization data of the product are as follows:

[0054] 1 H NMR (600MHz, CDCl3) δ9.05 (dd, J=4.2, 1.5Hz, 1H), 8.68 (s, 1H), 8.34 (dd, J=8.3, 1.4Hz, 1H), 8.26-8.17 (m, 2H), 7.53 (dd, J=8.3, 4.2Hz, 1H), 1.97 (q, J=4.3Hz, 2H), 1.85 (q, J=4.3Hz, 2H).

[0055] 13 C NMR (150MHz, CDCl3) δ192.0, 153.3, 150.3, 137.9, 133.6, 130.6, 130.5, 128.1, 127.4, 122.4, 121.1, 20.9, 18.5.

[0056] HRMS-ESI m / z: [M+H] + Calculated for C 14 H 11 N2O + 223.0866; found 223.0874.

[0057] Example 2

[0058]

[0059] At room temperature, in a 25 mL three-necked round-bottom flask, carbon and platinum electrodes (20 mm × 20 mm × 1 mm) were inserted, and electrolyte nBu4NPF6 (77.486 mg), sulfide (7.45 mg, 20 mol%), sulfonyl fluoride compound (0.2 mmol), and boron salt (2 eq, 53.58 mg) were added. Acetonitrile and pure water (50:1, 0.04 M) were then added. The mixture was electrolyzed at a constant current (8 mA) for 2.5 h. Subsequently, the electrodes were rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give the product, a cyclopropane compound (14.4 mg, 36%).

[0060] The structural characterization data of the product are as follows:

[0061] 1 H NMR (600MHz, CDCl3) δ7.57-7.55(m, 2H), 7.40-7.43(m, 3H), 2.01-1.97(m, 2H), 1.54-1.49(m, 2H).

[0062] 13 C NMR (150MHz, CDCl3) δ131.9, 130.0, 129.1, 43.4 (d, J=24.2Hz), 14.2.

[0063] HRMS-ESI m / z: [M+H] + Calculated for C9H 10 FO2S + 201.0380; found 201.0379.

[0064] Example 3

[0065]

[0066] At room temperature, in a 25 mL three-necked round-bottom flask, carbon and platinum electrodes (20 mm × 20 mm × 1 mm) were inserted, and electrolyte nBu4NPF6 (77.486 mg), sulfide (7.45 mg, 20 mol%), sulfonyl fluoride compound (0.2 mmol), and boron salt (2 eq, 53.58 mg) were added. Acetonitrile and pure water (50:1, 0.04 M) were then added. The mixture was electrolyzed at a constant current (8 mA) for 2.5 h. Subsequently, the electrodes were rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give the product cyclopropane compounds (22.3 mg, 49%).

[0067] The structural characterization data of the product are as follows:

[0068] 1 H NMR (600MHz, CDCl3) δ8.02 (d, J=7.4Hz, 2H), 7.65 (t, J=7.5Hz, 1H), 7.51 (t, J=7.9Hz, 2H), 2.07-2.03 (m, 2H), 1.84-1.79 (m, 2H).

[0069] 13 C NMR (150MHz, CDCl3) δ188.2, 134.7, 134.6, 130.0, 128.8, 44.9 (d, J==23,9Hz) 14.8.

[0070] HRMS-ESI m / z: [M+Na] + Calculated for C 10 H9FNaO3S + 251.0149; found 251.0156.

[0071] Example 4

[0072]

[0073] At room temperature, in a 25 mL three-necked round-bottom flask, with carbon and platinum electrodes (20 mm × 20 mm × 1 mm) inserted, electrolyte nBu4NPF6 (77.486 mg), sulfide (7.45 mg, 20 mol%), formyl acetonitrile compound (0.2 mmol), and boron salt (2 eq, 53.58 mg) were added. Acetonitrile and pure water (50:1, 0.04 M) were then added. The mixture was electrolyzed at a constant current (8 mA) for 2.5 h. Subsequently, the electrodes were rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to give the product, a cyclopropane compound (22 mg, 64%).

[0074] The structural characterization data of the product are as follows:

[0075] 1 H NMR (600MHz, CDCl3) δ 8.78 (m, 1H), 7.91 (m, 1H), 7.86 (m, 1H), 7.53 (m, 1H), 1.95 (dd, J=8.2, 4.3Hz, 2H), 1.80 (dd, J=8.2, 4.3Hz, 2H).

[0076] 13 C NMR (150MHz, CDCl3) δ192.5, 152.1, 148.8, 137.3, 127.9, 123.2, 121.1, 21.6, 18.5.HRMS-ESI m / z: [M+H] + Calculated for C 10 H9N2O + 173.0709; found 173.0706.

[0077] Example 5

[0078]

[0079] At room temperature, in a 25 mL three-necked round-bottom flask, with carbon and platinum electrodes (20 mm × 20 mm × 1 mm) inserted, electrolyte nBu4NPF6 (77.486 mg), sulfide (7.45 mg, 20 mol%), formyl acetonitrile compound (0.2 mmol), and boron salt (2 eq, 53.58 mg) were added. Acetonitrile and pure water (50:1, 0.04 M) were then added. The mixture was electrolyzed at a constant current (8 mA) for 2.5 h. Subsequently, the electrodes were rinsed with EtOAc. The resulting mixture was extracted with EtOAc, the combined organic layers were dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography to give the product cyclopropane compounds (20 mg, 57%).

[0080] The structural characterization data of the product are as follows:

[0081] 1 H NMR (600MHz, CDCl3) δ8.45 (d; J=3.4Hz, 1H), 7.75 (d, J=5.0Hz, 1H), 7.22S20-7.16 (m, 1H), 1.90 (q, J=4.3Hz, 2H), 1.74 (q, J=4.3Hz, 2H).

[0082] 13 C NMR (150MHz, CDCl3) δ183.3, 142.0, 135.8, 134.7, 128.9, 121.4, 21.4, 17.8.HRMS-ESI m / z: [M+H] + Calculated for C9H8NOS + 200.0141; found 200.0140.

[0083] Example 6

[0084] To investigate the effects of cyclopropane compounds on pine wood nematodes, nematodes provided by the Forest Pathology Laboratory of Nanjing Forestry University were used for verification.

[0085] Preparation of nematode culture medium: Pine wood nematodes were fed with *Botrytis cinerea*, which grows well on PDA medium, under constant temperature and darkness at 25°C. PDA medium preparation and fungal culture were performed according to standard methods.

[0086] Prepare the solvent: Mix 2 mL of DMF and 1000 mL of 2.5 wt% OP10 / H2O solution in the specified ratio to prepare the solvent for later use.

[0087] Preparation of mixed sample solution: Take 0.2 mg of the cyclopropane compound prepared in Example 1 and mix it with 1 mL of the above solvent for later use.

[0088] Mix 100 μL of the mixed sample solution with 100 μL of nematode culture medium, let stand for 24 h, and observe the nematode mortality rate; nematode mortality rate = number of dead nematodes / number of tested nematodes * 100%.

[0089] Using the solvent as a blank control, 100 μL of solvent was mixed with 100 μL of nematode culture medium. The number of nematodes in the nematode culture medium of the blank control group was the same as that of the experimental group. After standing for 24 hours, the results were observed. The table below shows the preliminary nematode killing rate:

[0090]

[0091] This invention utilizes an electrochemical method with readily available and inexpensive thioethers to rapidly cyclopropanate methylene compounds. The synthesis method of this invention is simple, clean, efficient, has a short reaction time, low energy consumption, and uses readily available and inexpensive raw materials. This method facilitates large-scale preparation and further research. Activity tests have shown that cyclopropane compounds exhibit strong activity against pine wilt disease, and related research provides a solid foundation for their potent biological, anticancer, antibacterial, and anti-inflammatory activities.

[0092] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. The application of a cyclopropane compound in the control of forest pests and diseases, the structure of which is shown below: The cyclopropane compound for preventing and treating forestry diseases and pests is used to inhibit pine wood nematode.

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