Preparation method of cyclopropane compound and application of nematicidal activity

Abstract

The invention discloses a preparation method of a cyclopropane compound and application of nematicidal activity. According to the invention, cheap and easily available thioether is used by an electrochemical method, so that the methylene compound is subjected to rapid cyclopropanation. 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 used for large-scale preparation and better research, activity tests show that the cyclopropane compound has relatively high pine wood nematode disease resistance activity, and related research provides a good foundation for the strong biological activity, anti-cancer activity, antibacterial activity and anti-inflammatory activity of the cyclopropane compound.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and specifically relates to a cyclopropane compound, a preparation method thereof and an application of nematicidal activity. Background Art

[0002] Pine wood nematode disease, also known as the "cancer of pine trees", is caused by the pine wood nematode and can cause huge economic losses. Since it was first discovered in the last century, pine wood nematode disease has developed into a global crisis for pine trees. Therefore, it is of great value to develop new drugs to control nematodes.

[0003] Cyclopropane compounds have important application value in medicinal chemistry and organic synthesis due to their unique ring strain and reactivity. The strategies for synthesizing cyclopropane are as follows:

[0004] Simmons-Smith cyclopropanation. It uses Zn-Cu alloy as a catalyst, has a slow reaction rate, is not very reproducible, and may require the use of different alloy surface features to optimize the reaction conditions.

[0005] Catalytic diazo transfer. Usually requires higher temperature and higher catalyst loading, and the product yield needs to be improved. In addition, heterogeneous reaction conditions may limit the efficiency and selectivity of the reaction.

[0006] Kulinkovich cyclopropanation. Although suitable for the synthesis of oxygen- or nitrogen-substituted cyclopropanes, it may require specific titanium catalysts and Gringard reagents, which can be relatively complicated to handle and process.

[0007] Corey - Chaykovsky cyclopropane method. It involves the in situ generation of a nucleophilic sulfonyl radical and may require specific Alkaline conditions and thiophylline reagents, the selection of these reagents and the optimization of reaction conditions can be challenges in the synthesis

[0008] These methods all have the defects of cyclopropanation to varying degrees. Therefore, exploring simpler synthesis methods has become a research topic that needs to be solved urgently. To this end, we introduce a preparation method and use of a class of cyclopropane compounds. Summary of the invention

[0009] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

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

[0011] One of the purposes of the present invention is to provide a cyclopropane compound, introduce a cyclopropane functional group, promote the research of new reactions, and develop diversified derivatives.

[0012] In order to solve the above technical problems, the present invention provides the following technical solution: a cyclopropane compound, whose structure 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, 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 compound of the present invention, the structure thereof is:

[0016]

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

[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.

[0022] As a preferred embodiment of the preparation method of the cyclopropane compound of the present invention, wherein: the compound of formula III is prepared from the carbonyl compound by a one-step reaction. For example, benzaldehyde reacts with bis[(pinacol)boryl]methane at -78°C for 4 hours, then warms to room temperature and reacts for another 4 hours, and the reaction is quenched with a saturated NH4Cl solution; washed with brine, extracted with EtOAC, the organic phase is collected and dried with anhydrous magnesium sulfate, the organic solvent is vacuum concentrated, and purified with a chromatography column to obtain 4,4,5,5-tetramethyl-2-phenylvinyl-1,3,2-dioxaborolane. 4,4,5,5-tetramethyl-2-phenylvinyl-1,3,2-dioxaborolane is dissolved in methanol, potassium bifluoride is added, and stirred at room temperature for one hour; after the system is concentrated, it is dissolved and filtered with acetone, the organic phase is collected, concentrated, and washed with ether to obtain a solid boron salt.

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

[0024] As 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, tetra-tert-butylammonium hexafluorophosphate, tetra-tert-butylammonium tetrafluoroborate, lithium chloride, lithium perchlorate, and lithium trifluoromethanesulfonate; the amount of the electrolyte added is 0.15M; the reaction voltage of the electrochemical reaction is 0.1 to 20V, the reaction temperature is -20 to 40°C, and the reaction current is 1 to 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 the mixture to react, thereby synthesizing the cyclopropane compounds.

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

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

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

[0029] Another object of the present invention is to provide the use of the cyclopropane compounds as described above in preventing and controlling forest pests and diseases, especially in preventing and controlling nematode diseases.

[0030] The term "forest pests and diseases" as used herein refers to the damage caused by insects that harm forests and forest products, which causes pathological changes in the physiology, organization and morphology of trees. Forest pests include root pests, stem and branch pests (including borers and suckers), leaf pests and fruit and seed pests.

[0031] As used herein, "controlling forest pests and diseases" means preventing or making the development or growth of forest pests more difficult, thereby reducing infection pressure, keeping plants healthier, and reducing damage caused by nematodes.

[0032] "Nematodes" as used herein refer to plant nematodes, including all nematodes that damage plants. Plant nematodes include plant parasitic nematodes and soil-dwelling nematodes. For example, pine wood nematodes (Bursaphelenchus xylophilus), this species has been effectively prevented and treated by the compounds described herein. However, the purposes of the compounds described herein are by no means limited to these genera or species, but extend to other nematodes in the same manner.

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

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

[0035] The present invention generates cyclopropane compounds by electrochemical means. The synthesis method of the present invention is clean and efficient, has a short reaction time, low energy consumption, and cheap and readily available raw materials. It is suitable for mass preparation and better research. Through activity tests, cyclopropane compounds have strong anti-pine wood nematode activity. Related research provides a good basis for its strong biological activity, anticancer, antibacterial and anti-inflammatory activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative labor. Among them:

[0037] Figure 1 is the hydrogen spectrum of the compound prepared in Example 1 of the present invention;

[0038] Figure 2is the carbon spectrum of the compound prepared in Example 1 of the present invention;

[0039] Figure 3 is the hydrogen spectrum of the compound prepared in Example 2 of the present invention;

[0040] Figure 4 is the carbon spectrum of the compound prepared in Example 2 of the present invention;

[0041] Figure 5 is the hydrogen spectrum of the compound prepared in Example 3 of the present invention;

[0042] Figure 6 is the carbon spectrum of the compound prepared in Example 3 of the present invention;

[0043] Figure 7 is the hydrogen spectrum of the compound prepared in Example 4 of the present invention;

[0044] Figure 8 is the carbon spectrum of the compound prepared in Example 4 of the present invention;

[0045] Fig. 9 is the hydrogen spectrum of the compound prepared in Example 5 of the present invention;

[0046] Fig.10 is the carbon spectrum of the compound prepared in Example 5 of the present invention; DETAILED DESCRIPTION

[0047] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0048] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present 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 term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0050] Example 1

[0051]

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

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

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

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

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

[0063] Example 3

[0064]

[0065] At room temperature, in a 25mL three-necked round-bottom flask, a carbon electrode and a platinum electrode (20mm×20mm×1mm) were inserted, and electrolyte nBu4NPF6 (77.486mg), thioether (7.45mg, 20mol%), sulfonyl fluoride compound (0.2mmol), boron salt (2eq, 53.58mg) were added. Then acetonitrile and pure water (50:1, 0.04M) were added. The mixture was electrolyzed under constant current conditions (8mA) for 2.5 hours. Subsequently, the electrode was rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to obtain the product cyclopropane compound (22.3mg, 49%).

[0066] The structural characterization data of the product are:

[0067] 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).

[0068] 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 25mL three-necked round-bottom flask, a carbon electrode and a platinum electrode (20mm×20mm×1mm) were inserted, and electrolyte nBu4NPF6 (77.486mg), thioether (7.45mg, 20mol%), formylacetonitrile compound (0.2mmol), boron salt (2eq, 53.58mg) were added. Then acetonitrile and pure water (50:1, 0.04M) were added. The mixture was electrolyzed under constant current conditions (8mA) for 2.5 hours. Subsequently, the electrode was rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to obtain the product cyclopropane compound (22mg, 64%).

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

[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] 13C 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 25mL three-necked round-bottom flask, a carbon electrode and a platinum electrode (20mm×20mm×1mm) were inserted, and electrolyte nBu4NPF6 (77.486mg), thioether (7.45mg, 20mol%), formylacetonitrile compound (0.2mmol), boron salt (2eq, 53.58mg) were added. Then acetonitrile and pure water (50:1, 0.04M) were added. The mixture was electrolyzed under constant current conditions (8mA) for 2.5 hours. Subsequently, the electrode was rinsed with EtOAc. The resulting mixture was extracted with EtOAc, and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to obtain the product cyclopropane compound (20mg, 57%):

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

[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] In order to detect 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 cultured with Botrytis cinerea, which grew well on PDA medium, at a constant temperature of 25° C. in the dark. PDA medium preparation and fungal culture were performed according to conventional methods.

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

[0087] Prepare a 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] Take 100 μL of the mixed sample solution and mix it with 100 μL of nematode culture medium, let it stand for 24 hours, and observe the nematode mortality rate; nematode mortality rate = number of dead nematodes / number of tested nematodes*100%.

[0089] The solvent was used as a blank control, that is, 100 μL of solvent was mixed with 100 μL of nematode culture solution. The number of nematodes in the nematode culture solution of the blank control group was the same as that of the experimental group. The solution was left to stand for 24 hours and the results were observed. The following table shows the preliminary nematode killing rate:

[0090]

[0091] The present invention uses cheap and readily available thioether by electrochemical method to rapidly cyclopropanate methylene compounds. The synthesis method of the present invention is simple, clean and efficient, has a short reaction time, low energy consumption, and cheap and readily available raw materials. It is suitable for mass preparation and better research. Through activity tests, cyclopropane compounds have strong anti-pine wood nematode activity. Related research provides a good basis for its strong biological activity, anticancer, antibacterial and anti-inflammatory activity.

[0092] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A cyclopropane compound, characterized in that: Its structure is shown in Formula I: In formula I, EWG is an electron withdrawing group, such as pyridyl, aryl, substituted aryl, naphthalene, benzocycloalkyl; R1, R2 are H, methyl or substituted aryl; R3 is cyano, p-toluenesulfonyl, nitro, ester, carbonyl, or sulfonyl fluoride.

2. The method for preparing cyclopropane compounds according to claim 1, wherein: The method comprises adding a compound of formula II or a compound of formula III into a reaction system under electrochemical conditions in a solvent to synthesize a cyclopropane compound; 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. In formula III, R1 and R2 are H, methyl or substituted aryl.

3. The method for preparing cyclopropane compounds according to claim 1, wherein: The solvent is selected from one or more of acetonitrile, ether, tetrahydrofuran, 1,4-dioxane, and water; the concentration of the solvent is 0.4 to 0.02M; Wherein, the molar ratio of the compound of formula II to the compound of formula III is 1:1.2-3.

4. The method for preparing a cyclopropane compound as claimed in claim 2 or 3, characterized in that: The electrolyte used in the electrochemical reaction is one or more of tetraethylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate, tetra-tert-butylammonium hexafluorophosphate, tetra-tert-butylammonium tetrafluoroborate, lithium chloride, lithium perchlorate, and lithium trifluoromethanesulfonate; the added amount of the electrolyte is 0.15M; the reaction voltage of the electrochemical reaction is 0.1 to 20V, the reaction temperature is -20 to 40°C, and the reaction current is 1 to 20mA.

5. The method for preparing cyclopropane compounds according to claim 1, wherein: A mixture of the compound of formula II and the compound of formula III is stirred and reacted in a solvent to synthesize cyclopropane compounds.

6. The method for preparing cyclopropane compounds according to claim 4, characterized in that: The solvent is selected from one or more of acetonitrile, ether, tetrahydrofuran, 1,4-dioxane, and water; the concentration of the solvent is 0.4-0.02M; the molar ratio of the compound of formula II to the compound of formula III is 1:1.2-3; and the reaction time is 2-5h.

7. Use of the cyclopropane compound as claimed in claim 1 as a cyclopropanation reagent.

8. The use according to claim 7, characterized in that: The substrate is reacted with a boron salt compound; The reaction is carried out at -20 to 40° C., the reaction time is 2 to 5 hours, the reaction needs to be carried out in an inert gas atmosphere, and the reaction is carried out in an organic solvent.

9. The method for preparing cyclopropane compounds as claimed in claim 1, characterized in that The electrochemical reaction requires sulfide compounds to be catalytically oxidized.

10. Use of the cyclopropane compound according to claim 1 or the cyclopropane compound prepared by the method according to any one of claims 2 to 9 in preventing and controlling forest pests and diseases, characterized in that: The cyclopropane compound for preventing and controlling forest pests and diseases is used to inhibit one or more pine wood nematodes.

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