A malonic acid dithioester compound, a preparation method and use thereof

Abstract

This invention relates to the field of chemical synthesis, specifically to a malonate dithioester compound, its preparation method, and its uses. The structural formula of the malonate dithioester derivative of this invention is shown in Formula I. The malonate dithioester compound of this invention is more stable than malonyl chloride and has the advantage of higher reactivity than ordinary malonate ester derivatives, and can be used as an excellent intermediate for the synthesis of pyrido[1,2-α]pyrimidinone mesoionic compounds.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a malondithioester compound, its preparation method, and its uses. Background Technology

[0002] Food security is a strategic issue of global importance, affecting economic development, social stability, and national security. In recent years, rice pests, primarily rice planthoppers and rice stem borers, have shown rapidly increasing resistance to pesticides, making it difficult to achieve ideal control even with increased dosage and frequency of application of existing pesticides. Therefore, the development of novel, highly effective insecticides is of paramount importance. Pyrido[1,2-α]pyrimidinone metronidazoles are a new type of insecticide, with the chemical structure shown in Formula V below. In 2009, DuPont first disclosed the insecticidal activity of this class of compounds (WO2009099929). Pyrido[1,2-α]pyrimidinone metronidazoles primarily act on nicotinic acetylcholine receptors (nAChRs), but their mechanism of action differs from traditional neonicotinoid insecticides, exhibiting excellent insecticidal activity and effectively controlling lepidopteran and homoptera pests.

[0003]

[0004] Triflumezopyrim and Dicloromezotiaz are pyrido[1,2-α]pyrimidinone metronidazole insecticides developed by DuPont. Triflumezopyrim, with the chemical structure shown in formula (V1), is a novel insecticide for controlling rice planthoppers and is currently marketed. Dicloromezotiaz, with the chemical structure shown in formula (V2), exhibits excellent control effects against lepidopteran pests and is likely to become a highly effective agent for controlling lepidopteran pests such as the rice stem borer.

[0005]

[0006] Currently, the synthesis of pyrido[1,2-α]pyrimidinone metronidazoles is achieved through the heating condensation of an active α-aryl-substituted malonic acid derivative (VI) with an aminopyridine intermediate (IV) in an inert solvent. The active α-aryl-substituted malonic acid derivative can be either α-aryl-substituted malonyl chloride or an active α-aryl-substituted malonic acid ester. Its synthesis requires first obtaining the α-aryl-substituted malonic acid ester through a metal coupling reaction of the malonic acid ester with a haloaryl hydrocarbon or a Claisen condensation reaction of an aryl acetate ester, followed by hydrolysis to obtain α-aryl-substituted malonic acid as a starting material. The synthetic route is shown below:

[0007]

[0008] The existing synthesis of pyrido[1,2-α]pyrimidinone mesonotropic compounds involves cumbersome steps such as metal-catalyzed coupling, ester hydrolysis, and preparation of active esters or acyl chlorides, resulting in low overall reaction yields and harsh reaction conditions. Furthermore, the process of removing solvent water in the hydrolysis preparation of α-aryl substituted malonate is difficult and time-consuming, which is not conducive to industrial production.

[0009] In view of this, the present invention is proposed. Summary of the Invention

[0010] The primary objective of this invention is to provide a malondithioester compound.

[0011] A second objective of this invention is to provide a method for preparing the compound.

[0012] A third objective of this invention is to provide uses for the compound.

[0013] The fourth objective of this invention is to provide a method for preparing metronid insecticides using this compound.

[0014] To achieve the objective of this invention, the technical solution adopted is as follows:

[0015] The first aspect of this invention provides a malonate dithioester derivative, the structural formula of which is shown in Formula I:

[0016]

[0017] Among them, R 1 Selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, unsubstituted or (R 4 ) m Substituted aryl, aryloxy, aryl C1-C6 alkyl, or heteroaryl; m is selected from 1, 2, 3, 4, or 5, and when m > 1, R 4 They can be the same or different;

[0018] R 2 R 3 Each is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, unsubstituted or (R) 5 ) r Substituted aryl, aryl C1-C6 alkyl, or heteroaryl; r is selected from 1, 2, 3, 4, or 5, and when r > 1, R 5 They can be the same or different;

[0019] R 4 R 5Each group is independently selected from halogen, cyano, amino, nitro, hydroxy, carboxyl, ester, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, and C1-C6 haloalkylthio.

[0020] However, when R1 is methyl, R2 and R3 are not simultaneously ethyl, phenyl, benzyl, p-methylphenyl, or 4-chlorophenyl; or, when R1 is ethyl, R2 and R3 are not simultaneously phenyl, 4-bromophenyl, or 3,4-dichlorophenyl; or, when R1 is propyl or butyl, R2 and R3 are not simultaneously ethyl; or, when R1 is isopropyl, R2 and R3 are not simultaneously phenyl; or, when R1 is phenyl, R2 and R3 are not simultaneously phenyl or p-tolyl.

[0021] A second aspect of this invention provides a method for preparing the malondithioester derivative, the method comprising a coupling reaction of a compound as shown in Formula II with a compound as shown in Formula III to prepare a compound as shown in Formula I, the chemical reaction equation being shown in Formula A:

[0022]

[0023] Where LG represents the leaving group;

[0024] The leaving group is selected from p-nitrophenol, halogen, acyloxy, thioacyloxy, p-toluenesulfonyloxy, imidazolyl, pyridinyl, or pyrimidinyl.

[0025] A third aspect of this invention proposes the application of this malonate dithioester derivative in the synthesis of metronidicides.

[0026] The fourth aspect of this invention provides a method for synthesizing metronidicides from the malonate dithioester derivative, using a compound shown in Formula I as an intermediate, and reacting it with an aminopyridine intermediate shown in Formula IV to synthesize a pyrido[1,2-α]pyrimidinone metronid compound as shown in Formula V, with the chemical reaction equation shown in Formula B:

[0027] .

[0028] The present invention has at least the following beneficial effects:

[0029] The malonate dithioester compounds of this invention are more stable than malonyl chloride and have higher reactivity than ordinary malonate derivatives, making them excellent intermediates for the synthesis of pyrido[1,2-α]pyrimidinone mesoionic compounds.

[0030] The method for synthesizing malonate dithioester compounds of the present invention uses simple and low-cost compounds as starting materials, and can obtain the malonate dithioester compounds of the present invention in a one-step process with high yield.

[0031] The preparation of pyrido[1,2-α]pyrimidinone mesoionic compounds using the malonate dithioester compounds of the present invention has advantages over existing methods, such as simple steps, mild conditions, and high yield. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. In addition, to better illustrate the present invention, numerous specific details are given in the following detailed embodiments. Those skilled in the art should understand that the present invention can be implemented without certain specific details. In some embodiments, raw materials, elements, methods, means, etc., well known to those skilled in the art, are not described in detail in order to highlight the spirit of the present invention.

[0033] This invention provides a malonate dithioester derivative that can be used for a simpler, milder, and more efficient synthesis of pyrido[1,2-α]pyrimidinone metronidazole compounds, the structural formula of which is shown in Formula I:

[0034]

[0035] Among them, R 1 Selected from C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, unsubstituted or (R 4 ) m Substituted aryl, aryloxy, aryl C1-C6 alkyl, or heteroaryl; m is selected from 1, 2, 3, 4, or 5, and when m > 1, R 4 They can be the same or different;

[0036] R 2 R 3 Each is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, unsubstituted or (R) 5 ) r Substituted aryl, aryl C1-C6 alkyl, or heteroaryl; r is selected from 1, 2, 3, 4, or 5, and when r > 1, R 5 They can be the same or different;

[0037] R4 R 5 Each group is independently selected from halogen, cyano, amino, nitro, hydroxy, carboxyl, ester, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, and C1-C6 haloalkylthio.

[0038] However, when R1 is methyl, R2 and R3 are not simultaneously ethyl, phenyl, benzyl, p-methylphenyl, or 4-chlorophenyl; or, when R1 is ethyl, R2 and R3 are not simultaneously phenyl, 4-bromophenyl, or 3,4-dichlorophenyl; or, when R1 is propyl or butyl, R2 and R3 are not simultaneously ethyl; or, when R1 is isopropyl, R2 and R3 are not simultaneously phenyl; or, when R1 is phenyl, R2 and R3 are not simultaneously phenyl or p-tolyl.

[0039] Wherein, C1-C6 alkyl groups can be selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, and hexyl; C1-C6 haloalkyl groups can be selected from monofluoromethyl, difluoromethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, and heptafluoroisopropyl; C3-C8 cycloalkyl groups can be selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; aryl groups can be selected from phenyl and naphthyl; arylmethyl groups can be selected from benzyl and naphthylmethyl; C1-C6 alkoxy groups can be selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and hexoxy; C1-C6 alkylthio groups can be selected from methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentthio, and hexthio; C1-C6 haloalkylthio groups can be selected from difluoromethylthio, difluoroethylthio, trifluoromethylthio, trifluoroethylthio, trifluoropropylthio, and heptafluoroisopropyl; C6-C 10 The aryloxy group can be selected from phenoxy or naphthoxy groups, C3-C 10 The heteroatom in the aromatic heterogroup can be selected from nitrogen, sulfur, or oxygen atoms, C3-C 10 The aromatic heteroyl group can be selected from furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline, pteridine, acridine, etc.; the aromatic C1-C6 alkyl group can be selected from benzyl, phenethyl, phenylpropyl, phenylisopropyl, phenylbutyl, phenyltert-butyl, phenylpentyl, phenylhexyl; the halogen is selected from fluorine, chlorine, bromine, iodine.

[0040] Preferred, R 1 Selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenoxy.

[0041] Specifically, the structural formula of the malondithioester derivative is shown in Formula IA:

[0042]

[0043] (IA)

[0044] R 2 R 3 Each of the following is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, trifluoroethyl, or 2-pyridyl; preferably methyl, ethyl, n-propyl, phenyl, benzyl, p-tolyl, or p-methoxyphenyl.

[0045] X 1 X 2 X 3 X 4 X 5 Each is independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy; preferably hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, heptafluoroisopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy or tert-butoxy.

[0046] Specifically selected from the following compounds:

[0047]

[0048]

[0049] Alternatively, compounds as shown in Table 1 can be selected:

[0050] Table 1

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081] Malonate dithioester derivatives may also be selected from compounds represented by formulas IB, IC, ID, IE, IF, IG, or IH:

[0082]

[0083] Among them, R 2 R 3 Each is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, trifluoroethyl or 2-pyridyl; preferably ethyl or p-tolyl.

[0084] Compounds can be selected from those shown in the following structural formulas:

[0085] The preferred compounds are shown in Table 2:

[0086] Table 2

[0087]

[0088] Alternatively, compounds can be selected from those shown in Table 3:

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] This invention also relates to a method for preparing the malondithioester derivative, the method comprising a coupling reaction of a compound as shown in Formula II with a compound as shown in Formula III to prepare a compound as shown in Formula I, the chemical reaction equation being shown in Formula A:

[0096]

[0097] Where LG represents the leaving group; R 1 R 2 R 3 It has the same meaning as in Equation I.

[0098] The leaving group is selected from p-nitrophenol (-OC6H4NO2), halogen (-X), acyloxy (-OCOR), thioacyloxy (-SCOR), p-toluenesulfonyloxy (-OTs), imidazole (-C3H3N2), pyridinyl (-C5H4N), pyrimidinyl (-C4H3N2), etc.

[0099] The reaction conditions for the coupling reaction include either condition i or condition ii:

[0100] Condition i: The compound shown in Formula II is used as an acylation reagent to directly couple with Formula III to obtain the compound shown in Formula I. This involves the enolization of the compound shown in Formula III under the action of a weak base, and the reaction process is as follows.

[0101]

[0102] The mechanism may be as follows: First, a Lewis acid activates the thioester compound of formula III, causing it to undergo enolization under the action of a weak base. Then, it attacks the carbonyl carbon atom of formula II, completing the thiocarbonylation reaction through electron transfer and the departure of the leaving group to obtain the compound of formula I. Due to the activation effect of the Lewis acid, the thioester compound of formula III can generate a metal enolide to participate in the reaction under mild conditions, without the need for a strong base, and the reaction conditions are mild.

[0103]

[0104] The alkali can be organic or inorganic, particularly potassium carbonate, potassium acetate, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium acetate, silver carbonate, silver acetate, cesium carbonate, cesium fluoride, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, tetramethylguanidine, diazabicyclo(DBU), 4-dimethylaminopyridine (DMAP), imidazole, triethylamine, diethylamine, triethylenediamine (DABCO), etc. Lewis acids are selected from those centered around boron, magnesium, titanium, and tin, with boron trifluoride, titanium tetrachloride, stannous chloride, stannous tetrachloride, magnesium chloride, magnesium perchlorate, magnesium iodide, magnesium bromide, magnesium bromide ether, etc., being preferred.

[0105] Specifically, the coupling reaction time is 0.5 h to 48 h, preferably 12 h to 36 h; the coupling reaction temperature is -78℃ to 150℃, preferably 0℃ to 100℃, and more preferably 20℃ to 25℃.

[0106] After the coupling reaction was completed, dilute acid was added to neutralize the excess base, followed by extraction, washing, drying, and separation by silica gel column chromatography to obtain the compound shown in Formula I.

[0107] Condition ii: The compound shown in Formula II is used as an acylation reagent to directly couple with Formula III to form the compound shown in Formula I, wherein the compound shown in Formula III is involved in the complete enolization of the compound under the action of a strong base.

[0108]

[0109] The mechanism may be as follows: Under the action of a strong base, the compound of formula III is completely enolized, and then attacks the carbonyl carbon atom of formula II. Through electron transfer and the departure of the leaving group, the sulfur carbonylation reaction is completed to obtain the compound of formula I.

[0110]

[0111] Strong bases include organic and inorganic bases, especially sodium hydride (NaH), lithium diisopropylamino (LDA), n-butyllithium (n-BuLi), lithium bis(trimethylsilyl)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), etc.

[0112] Specifically, the coupling reaction time is 0.5 h to 48 h, preferably 12 h to 36 h; the coupling reaction temperature is -78℃ to 150℃, preferably 0℃ to 100℃, and more preferably 20℃ to 25℃.

[0113] After the coupling reaction was completed, a saturated ammonium chloride solution was added to quench the reaction. Then, the mixture was extracted, washed, dried, and separated by silica gel column chromatography to obtain the compound shown in Formula I.

[0114] The coupling reaction is carried out in an organic solvent, which is selected from one or more of the following: hydrocarbon organic solvents, halogenated hydrocarbon organic solvents, alcohol organic solvents, ether organic solvents, ester organic solvents, ketone organic solvents, heterocyclic organic solvents, or nitrile organic solvents; the hydrocarbon organic solvent is selected from one or more of toluene, xylene, trimethylbenzene, phenol, pentane, hexane, octane, and cyclohexane; the halogenated hydrocarbon organic solvent is preferably one or more of chlorobenzene, dichlorobenzene, and dichloromethane; the alcohol organic solvent is selected from one or more of methanol, ethanol, and isopropanol. The ether organic solvent is selected from one or more of diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and diethylene glycol dimethyl ether; the ester organic solvent is selected from one or more of methyl acetate, ethyl acetate, and propyl acetate; the ketone organic solvent is selected from one or more of acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, and toluenecyclohexanone; the heterocyclic organic solvent is selected from one or two of oxypropane and pyridine; the nitrile organic solvent is selected from acetonitrile; the preferred organic solvents are ethyl acetate, toluene, tetrahydrofuran, dichloromethane, acetonitrile, and chlorobenzene.

[0115] Specifically, the coupling reaction time is 0.5 h to 48 h, preferably 12 h to 36 h;

[0116] And / or, the coupling reaction temperature is -78℃ to 150℃, preferably 0℃ to 100℃, more preferably 20℃ to 25℃.

[0117] After the coupling reaction was completed, dilute acid was added to neutralize the excess base, followed by extraction, drying, and separation by silica gel column chromatography to obtain the compound shown in Formula I.

[0118] This invention also relates to the application of the above-mentioned malonate dithioester derivatives in the synthesis of metronidazole insecticides. A method for synthesizing metronidazole insecticides from malonate dithioester derivatives is as follows: using the compound shown in Formula I as an intermediate, a condensation reaction is carried out with the aminopyridine intermediate shown in Formula IV to synthesize a pyrido[1,2-α]pyrimidinone metronidazole compound as shown in Formula V. The chemical reaction equation is shown in Formula B.

[0119]

[0120] Among them, R 6 Selected from C1-C 15 Alkyl, C6-C 10 Aryl or C3-C 10 Aromatic compounds;

[0121] R 7 Selected from C1-C 15 Alkyl, C6-C 10 Aryl or C3-C 10 Aromatic compounds, especially methyl, ethyl, propyl, phenyl, and benzyl;

[0122] And / or, the condensation reaction is carried out in an organic solvent, which is selected from one or more of the following: hydrocarbon organic solvents, halogenated hydrocarbon organic solvents, alcohol organic solvents, ether organic solvents, ester organic solvents, ketone organic solvents, heterocyclic organic solvents, or nitrile organic solvents; the hydrocarbon organic solvent is preferably one or more of toluene, xylene, trimethylbenzene, phenol, pentane, hexane, octane, and cyclohexane; the halogenated hydrocarbon organic solvent is preferably one or more of chlorobenzene, dichlorobenzene, and dichloromethane; the alcohol organic solvent is preferably methanol, ethanol, or isocyanate. One or more of propanol; ether organic solvents preferably include one or more of diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and diethylene glycol dimethyl ether; ester organic solvents preferably include one or more of methyl acetate, ethyl acetate, and propyl acetate; ketone organic solvents preferably include one or more of acetone, methyl butyl ketone, methyl isobutyl ketone, cyclohexanone, and toluenecyclohexanone; heterocyclic organic solvents preferably include one or two of oxypropane and pyridine; nitrile organic solvents preferably include acetonitrile; and more preferably, xylene, trimethylbenzene, and chlorobenzene.

[0123] Specifically, the condensation reaction time is 0.5 h to 48 h, preferably 3 h to 36 h, and the condensation reaction temperature is -78℃ to 300℃, preferably 0℃ to 200℃, and more preferably the reflux temperature of the organic solvent. After the reaction is completed, the mixture is cooled to room temperature, petroleum ether is added to precipitate the solid, and the solid is filtered and dried to obtain the pyrido[1,2-α]pyrimidinone mesonotropic compound.

[0124] This invention utilizes simple and low-cost compounds of formulas II and III as starting materials to obtain a novel formula I malonate dithioester compound in a one-step, high-yield process. This formula I malonate dithioester compound exhibits greater stability than malonyl chloride and higher reactivity than common malonate derivatives, making it an excellent intermediate for the synthesis of pyrido[1,2-α]pyrimidinone mesoionic compounds. Compared to existing methods, it offers advantages such as simple steps, mild conditions, and high yield.

[0125] The following examples illustrate the invention but do not limit it in any way.

[0126] To properly validate the reaction route, the synthetic intermediates and some mesoionic pyrido[1,2-α]pyrimidinone compounds were isolated and characterized. The structures of the compounds were confirmed by conventional spectroscopic techniques: proton NMR (s=single; d=doublet; dd=doublet; t=triplet; q=quadruplet); carbon NMR (s=single; d=doublet; dd=doublet; t=triplet; q=quadruplet).

[0127] Example 1 Preparation of diethyl thioester of 2-phenylmalonate 1

[0128]

[0129] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 20 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 50 mg of a yellow oily substance, with a yield of 93%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.5 – 7.4 (m, 2H), 7.4 (dd, J = 5.11, 2.07 Hz, 3H), 4.9 (s,1H), 2.9 (qd, J = 7.45, 1.36 Hz, 4H), 1.2 (t, J = 7.46 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 193.0, 132.2, 129.4, 128.7, 128.7, 72.6, 24.3, 14.2ppm; ESI-MS, m / z:291.03[M+Na] + ; IR (KBr): v = 3062, 2969, 2930, 2874, 1700,1600, 1452, 1377, 869, 725 cm -1 Rf = 0.52 (petroleum ether: ethyl acetate = 10:1).

[0130] Example 2 Preparation of diethyl thioester of 2-phenylmalonate

[0131]

[0132] Ethyl phenylacetate (36 mg, 0.2 mmol), toluene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), and bis(trimethylsilyl)aminolithium (LiHMDS) (0.3 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 39 mg of a yellow oily substance, with a yield of 72%. The characterization data are as in Example 1.

[0133] Example 3 Preparation of diethyl thioester of 2-phenylmalonate 3

[0134]

[0135] Ethyl phenylacetate (36 mg, 0.2 mmol), tetrahydrofuran (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 20 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 41 mg of a yellow oily substance, with a yield of 76%. Its characterization data are as shown in Example 1.

[0136] Example 4 Preparation of diethyl thioester of 2-phenylmalonate 4

[0137]

[0138] Ethyl phenylacetate (36 mg, 0.2 mmol), dichloromethane (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·ethyl ether (129 mg, 0.5 mmol), and N,N-dimethylethanolamine (DABCO) (67 mg, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 20 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 13 mg of a yellow oily substance, with a yield of 24%. Its characterization data are as in Example 1.

[0139] Example 5 Preparation of diethyl thioester of 2-phenylmalonate 5

[0140]

[0141] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), dichloromethane (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diisopropylethylamine (DIPEA) (77.4 mg, 0.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 20.5 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 40.2 mg of a yellow oily substance, with a yield of 75%. Its characterization data are as in Example 1.

[0142] Example 6 Preparation of diethyl thioester of 2-phenylmalonate 6

[0143]

[0144] Ethyl phenylacetate (36 mg, 0.2 mmol), dichloromethane (1 mL), S-ethyl 1H-imidazol-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), 4-dimethylaminopyridine (DMAP) (7 mg, 0.6 mmol), and diisopropylethylamine (DIPEA) (77.4 mg, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 22 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 35.5 mg of a yellow oily substance, with a yield of 66%. Its characterization data are as in Example 1.

[0145] Example 7 Preparation of diethyl thioester of 2-phenylmalonate 7

[0146]

[0147] Ethyl phenylacetate (36 mg, 0.2 mmol), dichloromethane (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and triethylamine (DIPEA) (60.6 mg, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 22 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 36 mg of a yellow oily substance, with a yield of 67%. Its characterization data are as shown in Example 1.

[0148] Example 8 Preparation of diethyl thioester of 2-phenylmalonate 8

[0149]

[0150] Ethyl phenylacetate (36 mg, 0.2 mmol), dichloromethane (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 24 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 40.2 mg of a yellow oily substance, with a yield of 80%. Its characterization data are as in Example 1.

[0151] Example 9 Preparation of diethyl thioester of 2-phenylmalonate 9

[0152]

[0153] Ethyl phenylacetate (36 mg, 0.2 mmol), toluene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 19 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 20.3 mg of a yellow oily substance, with a yield of 38%. Its characterization data are as in Example 1.

[0154] Example 10 Preparation of 2-Phenylonmalonic acid diethyl thioester 10

[0155]

[0156] Ethyl phenylacetate (36 mg, 0.2 mmol), tetrahydrofuran (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 20 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 40.9 mg of a yellow oily substance, with a yield of 76%. Its characterization data are as in Example 1.

[0157] Example 11 Preparation of 2-Phenylonmalonic acid diethyl thioester 11

[0158]

[0159] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), acetonitrile (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 20.5 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 44.5 mg of a yellow oily substance, with a yield of 83%. Its characterization data are as in Example 1.

[0160] Example 12 Preparation of diethyl thioester of 2-phenylmalonate 12

[0161]

[0162] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (45 mg, 0.3 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially, and the mixture was stirred at room temperature for 20.5 h. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 45.9 mg of a yellow oily substance, with a yield of 86%.

[0163] Example 13 Preparation of 2-Phenylonmalonic acid diethyl thioester 13

[0164]

[0165] Ethyl phenylacetate (36 mg, 0.2 mmol), tetrahydrofuran (2 mL), S-ethyl 1H-imidazol-1-thioester (60 mg, 0.4 mmol), and sodium bis(trimethylsilyl)amino (NaHMDS) (0.3 mmol) were added sequentially to a single-necked flask, and the mixture was stirred at room temperature for 3 h. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 6 mg of a yellow oily substance, with a yield of 11%. The characterization data are as in Example 1.

[0166] Example 14 Preparation of 2-Phenylonmalonic acid diethyl thioester 14

[0167]

[0168] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), dichloromethane (1 mL), S-ethyl 1H-imidazol-1-thioester (60 mg, 0.4 mmol), and bis(trimethylsilyl)aminolithium (LiHMDS) (0.3 mmol) were added sequentially, and the mixture was stirred at room temperature for 0.5 h. The reaction was quenched by adding saturated ammonium chloride solution. The mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to yield 29 mg of a yellow oily substance, with a yield of 54%. Characterization data are as shown in Example 1.

[0169] Table 4 is a summary table of reaction conditions and yields for Examples 1-14.

[0170]

[0171] Table 4

[0172]

[0173]

[0174] Unless otherwise specified, all the above reactions used 2 equivalents of S-ethyl 1H-imidazol-1-thioester. In Example 6, 3 equivalents of 4-dimethylaminopyridine (DMAP) were added as an additive, and in Example 12, 1.5 equivalents of S-ethyl 1H-imidazol-1-thioester were used.

[0175] Example 15 Preparation of 2-(3-trifluoromethyl)phenylmalonate diethyl thioester 1

[0176]

[0177] To a single-necked flask, 3-trifluoromethylphenylacetic acid ethyl thioester (36 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 6 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 58 mg of colorless oil, with a yield of 87%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.75 – 7.67 (m, 2H), 7.62 (ddt, J =7.77, 1.88, 0.87 Hz, 1H), 7.56 – 7.46 (m, 1H), 5.01 (s, 1H), 2.93 (qd, J =7.44, 1.03 Hz, 4H), 1.25 (t, J = 7.44 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 192.0, 133.0, 132.7, 131.0 (q, J = 32.53 Hz), 129.1, 126.3 (q, J = 3.72 Hz), 125.5 (q, J = 3.80 Hz), 123.9 (q, J =272.58 Hz), 72.0,24.5, 14.2 ppm; ESI-MS, m / z:335.05[MH] - ; IR (KBR):v= 3075, 2932, 2877, 1673,1595, 1450, 1377, 877, 789, 700 cm -1 Rf = 0.4 (petroleum ether: ethyl acetate = 10:1).

[0178] Example 16 Preparation of 2-(3-trifluoromethyl)phenylmalonate diethyl thioester 2

[0179]

[0180] To a single-necked flask, 2.38 g (9.59 mmol) of 3-trifluoromethylphenylacetic acid ethyl thioester, 40 mL of toluene, 3.0 g (19.2 mmol) of S-ethyl 1H-imidazol-1-thioester, and 14.4 mmol of bis(trimethylsilyl)aminolithium (LiHMDS) were added sequentially. The mixture was stirred at room temperature for 2.5 h, and the reaction was monitored by TLC until completion. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 2.4 g of a colorless oily substance, with a yield of 74%. The characterization data are as shown in Example 15.

[0181] Example 17 Preparation of 2-(3-trifluoromethyl)phenylmalonate diethyl thioester 3

[0182]

[0183] To a single-necked flask, ethyl 3-trifluoromethylphenylacetic acid ester (1.15 g, 4.9 mmol), chlorobenzene (50 mL), S-ethyl 1H-imidazolium-1-thioester (1.2 mL, 9.8 mmol), magnesium bromide·diethyl ether (3.2 g, 12 mmol), and diazabicyclo(DBU) (2.19 mL, 14.7 mmol) were added sequentially. The mixture was stirred at room temperature for 11.5 h, and the reaction was monitored by TLC until completion. Acetic acid (1.12 mL, 19.6 mmol) was added, and the mixture was stirred for 5 minutes. Ethyl acetate (40 mL) and water (40 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 1.46 g of colorless oil in 88% yield. The characterization data are as shown in Example 15.

[0184] Example 18 Preparation of 2-Thiazolyl Malonate Diethyl Thioester

[0185]

[0186] To a single-necked flask, 37 mg (0.2 mmol) of 2-thiopheneacetic acid ethyl thioester, 1 mL of chlorobenzene, 60 mg (0.4 mmol) of S-ethyl 1H-imidazol-1-thioester, 129 mg (0.5 mmol) of magnesium bromide·diethyl ether, and 90 μL (0.6 mmol) of diazabicyclohexane (DBU) were added sequentially. The mixture was stirred at room temperature for 23 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 38.3 mg of a yellow oily substance, with a yield of 70%. 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (dd, J = 5.2, 1.3 Hz, 1H), 7.21 –7.09 (m, 1H), 7.02 (dd, J = 5.2, 3.6 Hz, 1H), 5.22 (s, 1H), 2.93 (q, J = 7.4Hz, 4H), 1.26 (t, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 192.7, 132.8,128.6, 127.1, 126.8, 67.3, 24.5, 14.2 ppm; ESI-MS, m / z:296.96[M+Na] + ; IR(KBr): v = 3071, 2931, 2875, 1699, 1664, 1613, 1450, 1376, 897, 760, 687, 522cm -1 Rf = 0.47 (petroleum ether: ethyl acetate = 10:1).

[0187] Example 19 Preparation of diethyl thioester of 2-(1-naphthyl)malonic acid

[0188]

[0189] To a single-necked flask, 46 mg (0.2 mmol) of 1-naphthaleneacetic acid ethyl thioester, 1 mL of chlorobenzene, 60 mg (0.4 mmol) of S-ethyl 1H-imidazolium-1-thioester, 129 mg (0.5 mmol) of magnesium bromide·diethyl ether, and 90 μL (0.6 mmol) of diazabicyclohexane (DBU) were added sequentially. The mixture was stirred at room temperature for 26 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 40 mg of an oily compound, with a yield of 63%. 1 HNMR (400 MHz, Chloroform- d ) δ 8.0 – 8.0 (m, 1H), 7.9 – 7.9 (m, 2H), 7.7 (dd, J = 7.32, 1.22 Hz, 1H), 7.6 – 7.5 (m, 3H), 5.8 (s, 1H), 3.1 – 2.6 (m, 4H), 1.2 (t, J = 7.42 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 193.8, 134.0,131.7, 129.5, 129.2, 128.3, 127.7, 127.0, 126.0, 125.4, 122.7, 68.3, 24.4,14.2 ppm; ESI-MS, m / z:341.06[M+Na] + ; IR (KBr): v = 3050, 1694, 1595, 1508,1448, 1374, 886, 796 cm -1 Rf = 0.42 (petroleum ether: ethyl acetate = 10:1).

[0190] Example 20 Preparation of diethyl thioester of 2-(2-naphthyl)malonic acid

[0191]

[0192] To a single-necked flask, 46 mg (0.2 mmol) of 2-naphthaleneacetic acid ethyl thioester, 1 mL of chlorobenzene, 60 mg (0.4 mmol) of S-ethyl 1H-imidazolium-1-thioester, 129 mg (0.5 mmol) of magnesium bromide·diethyl ether, and 90 μL (0.6 mmol) of diazabicyclohexane (DBU) were added sequentially. The mixture was stirred at room temperature for 27 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 47.8 mg of a pale yellow solid, with a yield of 75%. 1 HNMR (400 MHz, Chloroform- d ) δ 7.96 – 7.78 (m, 4H), 7.65 – 7.45 (m, 3H), 5.11(s, 1H), 2.92 (q, J = 7.4 Hz, 4H), 1.23 (t, J = 7.4 Hz, 6H) ppm; 13 C NMR (101MHz, Chloroform- d ) δ 193.1, 133.2, 129.7, 129.0, 128.5, 128.2, 127.7, 126.7,126.6, 126.4, 72.6, 24.4, 14.3 ppm; ESI-MS, m / z:341.05[M+Na] + ; IR (KBr): v =2966, 2861, 1690, 1500, 1448, 1372, 797, 763 cm -1 Rf = 0.42 (petroleum ether: ethyl acetate = 10:1).

[0193] Example 21 Preparation of diethyl thioester of 2-(4-chlorophenyl)malonate

[0194]

[0195] To a single-necked flask, 4-chlorophenylacetic acid ethyl thioester (43 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 16 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 51 mg of colorless oil, with a yield of 84%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.46 – 7.29 (m, 4H), 4.92 (s, 1H), 2.91(q, J = 7.4 Hz, 4H), 1.24 (t, J = 7.4 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 192.5, 134.9, 130.7, 130.6, 128.9, 71.7, 24.4, 14.2 ppm;ESI-MS, m / z: 325.00 [M+Na] + ; IR (KBr): v = 2930, 2873, 1665, 1452, 1376, 874,830, 693 cm -1 Rf = 0.47 (petroleum ether: ethyl acetate = 10:1).

[0196] Example 22 Preparation of diethyl thioester of 2-(4-methylphenyl)malonate

[0197]

[0198] To a single-necked flask, ethyl 4-methylphenylacetic acid 38.8 mg (0.2 mmol), chlorobenzene 1 mL, S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 16 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 45.2 mg of a colorless oily substance, with a yield of 80%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.34 (d, J = 8.14 Hz, 2H), 7.23 – 7.15(m, 2H), 4.90 (s, 1H), 2.97 – 2.85 (m, 4H), 2.35 (s, 3H), 1.23 (t, J = 7.44Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 193.3, 138.7, 129.5, 129.3,129.3, 72.2, 24.3, 21.2, 14.3 ppm; ESI-MS, m / z: 281.05 [MH] - ; IR (KBr): v =2969, 2929, 2873, 1693, 1512, 1453, 1376, 873, 758, 693 cm -1 Rf = 0.57 (petroleum ether: ethyl acetate = 10:1).

[0199] Example 23 Preparation of 2-(4-methoxyphenyl)malonate diethyl thioester

[0200]

[0201] To a single-necked flask, 4-methoxyphenylacetic acid ethyl thioester (42 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 17 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 50.2 mg of a colorless oil, with a yield of 84%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.37 (d, J = 8.80 Hz, 2H), 6.90 (d, J =8.76 Hz, 2H), 4.88 (s, 1H), 3.81 (s, 3H), 2.90 (q, J = 7.33 Hz, 4H), 1.23 (t, J = 7.46 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 193.6, 160.0, 130.7,124.3, 114.1, 71.7, 55.3, 24.3, 14.3 ppm; ESI-MS, m / z: 297.06 [MH] - ; IR(KBr): v = 2967, 2836, 1663, 1608, 1452, 1376, 1303, 1249, 876, 70 cm -1 Rf = 0.36 (petroleum ether: ethyl acetate = 10:1).

[0202] Example 24 Preparation of diethyl thioester of 2-(2-fluorophenyl)malonate

[0203]

[0204] To a single-necked flask, ethyl 2-fluorophenylacetate (39.4 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 19 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 47.6 mg of a colorless oil, with a yield of 83%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.37 – 7.29 (m, 1H), 7.22 (d, J = 1.10Hz, 2H), 7.11 – 7.00 (m, 1H), 4.94 (s, 1H), 2.92 (q, J = 7.44 Hz, 4H), 1.25(t, J = 7.44 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 192.3, 162.7 (d,J = 246.90 Hz), 134.2 (d, J = 7.93 Hz), 130.1 (d, J = 8.22 Hz), 125.2 (d, J =3.09 Hz), 116.5 (d, J = 22.81 Hz), 115.7 (d, J = 20.95 Hz), 72.0 (d, J = 1.87Hz), 24.4, 14.2 ppm; ESI-MS, m / z: 209.02 [M+Na] + ; IR (KBR): v = 2964, 2927,2874, 1695, 1660, 1447, 1375, 1260, 1136, 967, 871, 758, 686 cm -1 Rf = 0.50 (petroleum ether: ethyl acetate = 10:1).

[0205] Example 25 Preparation of diethyl thioester of 2-(4-bromophenyl)malonate

[0206]

[0207] To a single-necked flask, ethyl 4-bromophenylacetate (51.8 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 20 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 55.2 mg of a colorless oily substance, with a yield of 80%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.50 (d, J = 8.50 Hz, 2H), 7.34 (d, J =8.50 Hz, 2H), 4.90 (s, 1H), 2.91 (q, J = 7.44 Hz, 4H), 1.24 (t, J = 7.44 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 192.4, 131.9, 131.1, 131.0, 123.1,71.8, 24.4, 14.2 ppm; ESI-MS, m / z: 368.97 [M+Na] + ; IR (KBr): v = 2969, 2929,2872, 1665, 1588, 1486, 1451, 1375, 1260, 985, 871, 768, 689 cm -1 Rf = 0.56 (petroleum ether: ethyl acetate = 10:1).

[0208] Example 26 Preparation of 2-Cyclopropylmalonic acid diethyl thioester

[0209]

[0210] Cyclopropyl ethyl thioester (22.8 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially to a single-necked flask. The mixture was stirred at room temperature for 17 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 17.1 mg of colorless oil, with a yield of 37%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.3 (s, 1H), 2.9 (q, J = 7.44 Hz, 4H), 2.9 (d, J = 10.43 Hz, 1H), 1.3 (t, J = 7.43 Hz, 6H), 0.8 – 0.7 (m, 2H), 0.4 –0.3 (m, 2H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 194.6, 72.5, 23.9, 14.4,11.2, 4.8 ppm; ESI-MS, m / z: 255.02 [M+Na] + ; IR (KBr): v = 3082, 2968, 2930,2873, 1670, 1414, 1375, 1078, 971, 830, 761, 720 cm -1 Rf = 0.48 (petroleum ether: ethyl acetate = 10:1).

[0211] Example 27 Preparation of S-ethyl-S'-p-tolyl-2-ethylmalonic acid dithioester

[0212]

[0213] Under argon protection, ethyl butyrate (26.5 mg, 0.2 mmol), toluene (1 mL), lithium bis(methylsilylamino)amine (LiHMDS) (0.3 mmol, 1 M), and ethyl 1H-imidazol-1-thioester (62 mg, 0.4 mmol) were added sequentially to a single-necked flask. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC until completion. The reaction was quenched by adding saturated ammonium chloride solution, and the mixture was extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain 17.5 mg of a colorless oily substance, with a yield of 40%. 1 H NMR (400 MHz, Chloroform-d) δ 3.68 (t, J = 7.42 Hz, 1H), 2.92 (q, J = 7.35 Hz, 4H), 2.00 (p, J = 7.40 Hz, 2H), 1.26 (t, J = 7.48 Hz, 6H), 0.95 (t, J = 7.43 Hz, 3H)ppm; 13 C NMR (101 MHz, Chloroform-d) δ 194.2, 70.0, 53.4, 23.9, 14.4, 11.7ppm; IR: (KBr) v= 2969, 2931,2875, 1698, 1670, 1455, 1377, 1262, 970, 874,796cm -1 ESI-MS, m / Z: 243.03 [M+Na] + R f = 0.81 (petroleum ether: ethyl acetate = 10:1).

[0214] Example 28 Preparation of diethyl thioester of 2-(4-fluorophenyl)malonate

[0215]

[0216] To a single-necked flask, ethyl 4-fluorophenylacetate (39.4 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 20 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 46 mg of colorless oil, with a yield of 80%. 1 H NMR (400 MHz, Chloroform-d) δ 7.44 (dd, J = 8.80, 5.25 Hz, 2H), 7.06(t, J = 8.67 Hz, 2H), 4.93 (s, 1H), 2.91 (q, J = 7.41 Hz, 4H), 1.24 (t, J =7.45 Hz, 6H) ppm; 13 IR (KBr): v = 3075, 1691, 1602, 1540, 1452, 1377, 850, 777, 697 cm -1 ESI-MS, m / z: 285.03 [MH] - Rf = 0.41 (petroleum ether: ethyl acetate = 10:1).

[0217] Example 29 Preparation of diethyl thioester of 2-(4-cyanophenyl)malonate

[0218]

[0219] To a single-necked flask, 41 mg (0.2 mmol) of 4-cyanoacetic acid ethyl thioester, 1 mL of chlorobenzene, 60 mg (0.4 mmol) of S-ethyl 1H-imidazolium-1-thioester, 129 mg (0.5 mmol) of magnesium bromide·diethyl ether, and 90 μL (0.6 mmol) of diazabicyclohexane (DBU) were added sequentially. The mixture was stirred at room temperature for 20.5 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 46 mg of colorless oil, with a yield of 78%. 1 H NMR (400 MHz, Chloroform-d) δ 7.72 – 7.55 (m, 4H), 5.01 (s, 1H), 2.93(q, J = 7.41 Hz, 4H), 1.25 (t, J = 7.43 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform-d) δ 191.4, 137.0, 132.4, 130.2, 118.4, 112.6, 72.2, 24.6, 14.2ppm; ESI-MS, m / z: 292.05 [MH] - ; IR (KBr): v = 3095, 2970, 2228, 1662, 1451,1376, 874, 704 cm -1 Rf = 0.32 (petroleum ether: ethyl acetate = 10:1).

[0220] Example 30 Preparation of S-ethyl-S'-p-tolyl-2-phenylmalonide dithioester

[0221]

[0222] To a single-necked flask, p-toluenethiophene ester (48.5 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 22 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 42 mg of pale yellow solid, with a yield of 64%. 1 H NMR (400 MHz, Chloroform-d) δ 7.5 – 7.4 (m, 2H), 7.4 (dd, J = 4.97,1.88 Hz, 3H), 7.3 (s, 1H), 7.2 – 7.2 (m, 2H), 5.1 (s, 1H), 2.9 (qd, J = 7.43,0.90 Hz,2H), 2.4 (s,3H), 1.2 (t, J = 7.44 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform-d) δ 192.8, 191.6, 140.1, 134.4, 131.9, 130.1, 129.6, 128.8,128.8, 123.5, 72.0, 24.4, 21.4, 14.3 ppm; ESI-MS, m / z: 353.06 [M+Na] + ; IR(KBr): v = 3061, 2926, 2873, 1665, 1601, 1450, 1379, 872, 768, 700 cm -1 Rf = 0.37 (petroleum ether: ethyl acetate = 10:1).

[0223] Example 31 Preparation of S-ethyl-S'-benzyl-2-phenylpropanedithioester

[0224]

[0225] Benzyl phenylacetate thioester (48.4 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially to a single-necked flask. The mixture was stirred at room temperature for 21 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 58 mg of a colorless oily compound, with a yield of 88%. 1 H NMR (400 MHz, Chloroform-d) δ 7.51 – 7.17 (m, 10H), 4.96 (s, 1H), 4.20 –4.08 (m, 2H), 2.90 (qd, J = 7.45, 0.90 Hz, 2H), 1.23 (t, J = 7.45 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform-d) δ 192.9, 192.5, 136.5, 132.0, 129.5, 128.9,128.8, 128.8, 128.7, 127.5, 72.3, 34.2, 24.4, 14.2 ppm; ESI-MS, m / z: 329.11[MH] - ; IR (KBR): v = 3029, 2969, 2929, 1700, 1494, 1453, 1376, 1263, 987,834, 724, 627 cm -1 Rf = 0.40 (petroleum ether: ethyl acetate = 10:1).

[0226] Example 32 Preparation of S-ethyl-S'-propyl-2-phenylpropanedithioester

[0227]

[0228] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), chlorobenzene (1 mL), S-propyl 1H-imidazolium-1-thioester (68 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 21 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 47.8 mg of a colorless oily compound, with a yield of 85%. 1 H NMR (400 MHz, Chloroform-d) δ 7.5 – 7.4 (m, 2H), 7.4 (dd, J = 5.03, 1.90Hz, 3H), 4.96 (s, 1H), 2.9 – 2.8 (m, 4H), 1.6 – 1.5 (m, 2H), 1.2 (t, J = 7.44Hz, 3H), 0.9 (t, J = 7.37 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform-d) δ193.0, 193.0, 132.3, 129.4, 128.7, 128.7, 72.6, 31.7, 24.3, 22.6, 14.2, 13.3ppm; ESI-MS, m / z: 281.06 [MH] - ; IR (KBr): v = 3061, 2967, 2851, 1702, 1665,1493, 1454, 1376, 879, 725 cm -1 Rf = 0.47 (petroleum ether: ethyl acetate = 10:1).

[0229] Example 33 Preparation of S-ethyl-S'-tert-butyl-2-phenylpropanedithioester

[0230]

[0231] To a single-necked flask, ethyl phenylacetate (36 mg, 0.2 mmol), chlorobenzene (1 mL), S-tert-butyl-1H-imidazolium-1-thioester (74 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 24 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 49.5 mg of colorless oily compound I17, with a yield of 90%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.4 (dd, J = 7.61, 2.19 Hz, 2H), 7.4 –7.3 (m, 3H), 4.9 (s, 1H), 2.9 (q, J = 7.45 Hz, 2H), 1.5 (s, 9H), 1.2 (t, J =7.44 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform-d) δ 193.0, 192.9, 132.4,129.5, 129.4, 128.7, 128.6, 128.5, 127.2, 73.0, 51.1, 49.3,48.3; 24.3, 14.2ppm ; ESI-MS, m / z: 295.09 [MH] - ; IR (KBR): v = 3062, 1697, 1599, 1491, 1454,1375, 869, 830, 724 cm -1 Rf = 0.61 (petroleum ether: ethyl acetate = 10:1).

[0232] Example 34 Preparation of 2-phenoxymalonic acid diethyl thioester

[0233]

[0234] To a single-necked flask, phenoxyacetic acid ethyl thioester (39.2 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazol-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 17 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 40 mg of a colorless oily compound, with a yield of 70%. 1 H NMR (400 MHz, Chloroform-d) δ 7.3 (dd, J = 8.74, 7.40 Hz,2H), 7.1 –7.0 (m,1H), 7.0 (dt, J = 7.77, 1.03 Hz, 2H), 5.2 (s, 1H), 2.9 (q, J = 7.46Hz, 4H), 1.3 (t, J = 7.45 Hz, 6H) ppm; 13 C NMR (101 MHz, CDCl3) δ 193.7,156.7, 129.9, 123.2, 115.8, 88.3, ​​23.3, 14.1 ppm; ESI-MS, m / z: 283.04 [MH] - ; IR (KBR): v = 2969, 2873, 1700, 1454, 1375, 1260, 874, 688 cm -1 Rf = 0.30 (petroleum ether: ethyl acetate = 10:1).

[0235] Example 35 Preparation of 2-methoxymalonic acid diethyl thioester

[0236]

[0237] Ethyl methoxyacetate (50 mg, 0.37 mmol), chlorobenzene (2 mL), S-ethyl 1H-imidazolium-1-thioester (116.4 mg, 0.75 mmol), magnesium bromide·ethyl ether (241 mg, 0.93 mmol), and DBU (191 μL, 1.12 mmol) were added sequentially to a single-necked flask. The mixture was stirred at room temperature for 24 h, and the reaction was monitored by TLC until completion. Acetic acid (1.48 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (4 mL) and water (4 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 46 mg of a yellow oily compound, in 55% yield. 1 HNMR (400 MHz, Chloroform-d) δ 4.34 (s, 1H), 3.59 (s, 3H), 2.91 (qd, J = 7.37,2.83 Hz, 4H), 1.27 (t, J = 7.44 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform-d)δ 194.6, 92.1, 59.8, 23.0, 14.2 ppm; IR (KBr): v = 2967, 2931, 2874, 1700,1453, 1376, 1134, 1080, 991, 803, 634cm -1 ESI-MS, m / Z: 221.11 [MH] - R f =0.32 (petroleum ether: ethyl acetate = 10:1).

[0238] Example 36 Preparation of diethyl thioester of 2-(3,5-dichlorophenyl)malonate

[0239]

[0240] To a single-necked flask, ethyl 3,5-dichlorophenylacetic acid ester (50 mg, 0.2 mmol), chlorobenzene (1 mL), S-ethyl 1H-imidazolium-1-thioester (60 mg, 0.4 mmol), magnesium bromide·diethyl ether (129 mg, 0.5 mmol), and diazabicyclo(DBU) (90 μL, 0.6 mmol) were added sequentially. The mixture was stirred at room temperature for 20 h, and the reaction was monitored by TLC until completion. Acetic acid (0.8 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (2 mL) and water (2 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 46 mg of a yellow oily compound, in 68% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (d, J = 1.90 Hz, 2H), 7.35 (t, J= 1.86 Hz, 1H), 4.87 (s, 1H), 2.93 (dd, J = 7.41, 1.02 Hz, 4H), 1.26 (t, J =7.47 Hz, 6H) ppm; 13 C NMR (101 MHz, Chloroform-d) δ 191.4, 135.1, 135.0,128.9, 127.8, 71.4, 24.5, 14.1 ppm; ESI-MS, m / z: 335.08 [MH] - ; IR (KBr): v= 3078, 1698, 1453, 1377, 860, 796, 695, 580 cm -1 Rf = 0.44 (petroleum ether: ethyl acetate = 10:1).

[0241] Example 37 Preparation of diethyl thioester of 2-(3,5-dichlorophenyl)malonate

[0242]

[0243] To a single-necked flask, ethyl 3,5-dichlorophenylacetic acid 100 mg (0.4 mmol), 2 mL of dried tetrahydrofuran, 72 mg of S-ethyl 1H-imidazolium-1-thioester (0.48 mmol), and 0.48 mmol of bis(trimethylsilyl)aminolithium (LiHMDS) were added sequentially. The reaction was carried out at room temperature for 3 h, and the reaction was monitored by TLC until it ended. The reaction was quenched by adding saturated ammonium chloride solution, extracted twice with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 80 mg of a yellow oily substance, with a yield of 59%. The characterization data are as shown in Example 36.

[0244] Example 38 Preparation of S-ethyl-S'-p-tolyl-2-methylmalonic acid dithioester

[0245]

[0246] To a single-necked flask, p-toluenethioester acetate (70 mg, 0.39 mmol), dichloromethane (2 mL), S-ethyl 1H-imidazolium-1-thioester (116.5 mg, 0.78 mmol), magnesium bromide·diethyl ether (260 mg, 0.97 mmol), and triethylamine (162 μL, 1.17 mmol) were added sequentially. The mixture was stirred at room temperature for 25 h, and the reaction was monitored by TLC until completion. Acetic acid (1.56 mmol) was added, and the mixture was stirred for 5 min. Ethyl acetate (4 mL) and water (4 mL) were added, and the mixture was extracted twice by separation. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to give 33 mg of a colorless oily compound, with a yield of 32%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.3 (d, J = 8.19 Hz, 2H), 7.2 – 7.2 (m,2H), 3.9 (q, J = 7.06 Hz, 1H), 2.9 (q, J = 7.42 Hz, 2H), 1.5 (d, J = 7.03 Hz, 3H), 1.3 (t, J = 7.43 Hz, 3H) ppm; 13 C NMR (101 MHz, Chloroform- d) δ 194.8,193.6, 140.0, 134.4, 130.1, 123.4, 61.7, 23.9, 21.3, 14.7, 14.4 ppm; ESI-MS, m / z: 291.06 [M+Na] + Rf = 0.50 (petroleum ether: ethyl acetate = 10:1).

[0247] Example 39 Preparation of the mesoionic insecticide triflumezopyrim V1 1

[0248]

[0249] To a 10 mL reaction flask, diethyl thioester of 2-(3-trifluoromethyl)phenylmalonate (76 mg, 0.22 mmol), 1 mL of chlorobenzene, and N-(pyrimidin-5-ylmethyl)pyridine-2-amine (21 mg, 0.11 mmol) were added sequentially. The mixture was refluxed and stirred for 3 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to give 39 mg of yellow crystalline solid Triflumezopyrim (yield 87%). 1 H NMR (400 MHz, DMSO- d 6) δ 9.35 (dd, J =6.89, 1.63 Hz, 1H), 9.11 (s, 1H), 8.83 (s, 2H), 8.30 (ddd, J = 8.89, 7.05,1.69 Hz, 1H), 8.19 (d, J = 1.81 Hz, 1H), 8.13 (d, J = 7.74 Hz, 1H), 7.88 (d, J = 8.96 Hz, 1H), 7.71 – 7.38 (m, 3H), 5.62 (s, 2H) ppm; 13 C NMR (151 MHz, DMSO- d 6) δδ 159.1, 157.9, 156.3, 154.2, 146.9, 144.7, 137.1, 134.7, 132.0,130.3, 128.4, 128.3 (q, J = 31.01Hz), 127.1 (q, J = 4.06 Hz), 125.1 (q, J=270Hz), 122.1 (q, J = 3.66 Hz), 117.2, 114.7, 92.6, 42.1, 40.5 ppm.

[0250] Example 40 Preparation of the interionic insecticide triflumezopyrim V1 2

[0251] S-ethyl-S'-p-tolyl-2-(3-trifluoromethyl)malonide dithioester (40 mg, 0.12 mmol), 1 mL of toluene, and N-(pyrimidin-5-ylmethyl)pyridine-2-amine (19 mg, 0.10 mmol) were added sequentially to a 10 mL reaction flask. The mixture was refluxed and stirred for 24 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to give 27 mg of yellow crystalline solid Triflumezopyrim (yield 68%). Its characterization is as described in Example 39.

[0252] Example 41 Preparation of the mesoionic insecticide triflumezopyrim V1 3 (gram-scale reaction)

[0253] Diethyl 2-(3-trifluoromethyl)phenylmalonate (2.837 g, 8.44 mmol), 30 mL of chlorobenzene, and N-(pyrimidin-5-ylmethyl)pyridine-2-amine (0.784 g, 4.215 mmol) were added sequentially to a 100 mL reaction flask. The mixture was refluxed and stirred for 10 hours. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to obtain 1.414 g of yellow crystalline solid Triflumezopyrim (yield 84%). Its characterization data are as shown in Example 39.

[0254] Comparison with existing technologies

[0255]

[0256]

[0257] *Data extracted from Pest Manag Sci 2017, 73 , 796–806.

[0258] Example 42 Preparation of the mesoionic insecticide Dicloromezotiaz (V2) 1

[0259]

[0260] Diethyl thioester 2-(3,5-dichlorophenyl)malonate (58 mg, 0.17 mmol), 1 mL of 1,3,5-trimethylbenzene, and N-(((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (21 mg, 0.09 mmol) were added sequentially to a 10 mL reaction flask. The mixture was refluxed and stirred for 6 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to give 24 mg of yellow crystalline solid Dicloromezotiaz (yield 62%). 1 H NMR (600 MHz, Chloroform- d ) δ 9.75 – 9.05 (m, 1H), 8.02 (d, J = 7.20 Hz, 1H), 7.77 (d, J =1.95 Hz, 2H), 7.45 (s, 1H), 7.40 (t, J = 6.96 Hz, 1H), 7.23 (t, J = 1.93 Hz,1H), 5.59 (s, 2H), 2.82 (s, 3H) ppm; 13 C NMR (101 MHz, Chloroform- d ) δ 160.7,154.1, 153.2, 148.3, 147.3, 140.0, 137.0, 136.4, 134.0, 131.8, 128.8, 126.2,124.0, 116.8, 92.4, 44.3, 23.6 ppm.

[0261] Example 43 Preparation of the mesoionic insecticide Dicloromezotiaz (V2) 2

[0262] Diethyl thioester 2-(3,5-dichlorophenyl)malonate (85 mg, 0.25 mmol), 1 mL of chlorobenzene, and N-(((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (30 mg, 0.13 mmol) were added sequentially to a 10 mL reaction flask. The mixture was refluxed and stirred for 24 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to obtain 27 mg of yellow crystalline solid Dicloromezotiaz (yield 47%). Its characterization data are as shown in Example 42.

[0263] Preparation of the 44-dihydropyridine insecticide Dicloromezotiaz (V2) 3

[0264] S-ethyl-S'-p-tolyl-2-(3,5-dichlorophenyl)malonide dithioester (40 mg, 0.10 mmol), 2 mL of chlorobenzene, and N-(((2-chlorothiazol-5-yl)methyl)-3-methylpyridin-2-amine (24 mg, 0.10 mmol) were added sequentially to a 10 mL reaction flask. The mixture was refluxed and stirred for 8 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to obtain 12 mg of yellow crystalline solid Dicloromezotiaz (yield 27%). Its characterization data are as shown in Example 42.

[0265] Comparison with existing technologies

[0266]

[0267]

[0268] *Data extracted from Pest Manag Sci 2017, 73 , 796–806.

[0269] Example 45 Preparation of metronid insecticide V3

[0270]

[0271] Diethyl thioester of 2-phenylmalonate (73 mg, 0.27 mmol), 2 mL of chlorobenzene, and N-benzylpyridin-2-amine (25 mg, 0.14 mmol) were added sequentially to a 10 mL reaction flask. The mixture was refluxed and stirred for 3 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to give 42 mg of a yellow crystalline solid, 1-benzyl-4-oxo-3-phenyl-4H-pyrido[1,2-α]pyrimidine-1-onium-2-salt (V3) (yield 93%). 1 H NMR (400 MHz, Chloroform-d) δ 9.52 (ddd, J = 6.9, 1.7, 0.6 Hz, 1H), 7.93 (ddd, J = 8.8,7.0, 1.7 Hz, 1H), 7.82 (dd, J = 8.3, 1.3 Hz, 2H), 7.44 – 7.26 (m, 9H), 7.25 (s, 1H), 5.61 (s, 2H) ppm; 13C NMR (101 MHz, Chloroform-d) δ 159.1, 153.5,146.2, 142.1, 135.1, 134.2, 132.3, 130.8, 129.2, 128.0, 127.7, 126.7, 126.4,115.4, 113.4, 95.7, 46.2 ppm; IR (KBr): v = 2919, 2850, 1625, 1494, 1453,1356, 1190, 1059, 934, 834, 756, 699, 535 cm -1 .

[0272] Example 46 Preparation of metronid insecticide V4

[0273]

[0274] To a 10 mL reaction flask, diethyl thioester of 2-trifluorophenylmalonate (134 mg, 0.40 mmol), 1 mL of 1,3,5-trimethylbenzene, and N-(((2-chlorothiazol-5-yl)methyl)pyridine-2-amine (45 mg, 0.20 mmol) were added sequentially. The mixture was stirred at 130 °C for 2 hours, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and petroleum ether was added to precipitate a solid. The solid was filtered and dried to obtain 75 mg of a yellow crystalline solid (yield 85%).

[0275] 1 (400 MHz, Acetone-d6) δ 9.47 (d, J = 6.88 Hz, 1H), 8.49 – 8.39 (m,1H), 8.37 (s, 1H), 8.26 (d, J = 7.91 Hz, 1H), 8.20 (d, J = 8.95 Hz, 1H), 7.96(s, 0H), 7.61 (t, J = 7.00 Hz, 1H), 7.51 (dd, J = 19.12, 7.99 Hz, 2H), 5.78(s, 1H) ppm; 13 C NMR (101 MHz, Acetone-d6) 158.7, 153.6, 152.5, 146.4, 144.1,141.2, 136.8, 135.7, 134.1, 132.1, 128.7 (q, J= 30.3 Hz), 127.0 (q, J = 4.15Hz), 125.0 (q, J = 272.7 Hz), 121.6 (q, J = 3.95 Hz), 116.5, 113.6, 92.1,39.4 ppm.

[0276] Example 47 Preparation of metronid insecticide V5

[0277]

[0278] Diethyl thioester 2-(3,5-dichlorophenyl)malonate (76 mg, 0.23 mmol), 1 mL of 1,3,5-trimethylbenzene, and N-(((2-chlorothiazol-5-yl)methyl)pyridine-2-amine (26 mg, 0.11 mmol) were added sequentially to a 10 mL reaction flask, and the mixture was stirred at 130 °C for 6 hours. After cooling the reaction solution to room temperature, petroleum ether was added to precipitate a solid, which was then filtered and dried to give 23 mg of a yellow solid (yield 46%). 1 H NMR (400 MHz, Chloroform- d ) δ 9.54 (d, J = 6.85 Hz, 2H), 8.20(t, J = 7.98 Hz, 1H), 7.77 (d, J = 1.84 Hz, 2H), 7.67 (s, 1H), 7.60 (d, J =8.95 Hz, 1H), 7.44 (t, J = 7.01 Hz, 1H), 5.59 (s, 2H) ppm; 13 C NMR (151 MHz, Chloroform-d) δ 158.2, 154.6, 153.1, 145.8, 143.5, 140.5, 136.8, 134.0,134.0, 133.0, 128.9, 126.4, 116.3, 112.1, 93.3, 40.0 ppm.

[0279] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A malonic acid dithioester derivative, characterized by, The structural formula of the malonic acid dithioester derivative is shown as formula I: wherein R 1 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylthio, C1-C6haloalkylthio, unsubstituted or substituted aryl, aryloxy, aryl C1-C6alkyl or heteroaryl; m is selected from 1, 2, 3, 4 or 5, and when m > 1, R 4 may be the same or different; m substituted aryl, aryloxy, aryl C1-C6alkyl or heteroaryl; m is selected from 1, 2, 3, 4 or 5, and when m > 1, R 4 may be the same or different; R 2 , R 3 are each independently selected from the group consisting of Ci-C6-alkyl, Ci-C6-haloalkyl, unsubstituted or substituted aryl, aryl Ci-C6-alkyl or heteroaryl; r is selected from 1, 2, 3, 4 or 5, R 5 may be the same or different; r 5 may be the same or different;​ R 4 , R 5 each independently is selected from the group consisting of halogen, cyano, amino, nitro, hydroxy, carboxy, ester, Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C8-cycloalkyl, Ci-C6-alkoxy, Ci-C6-alkylthio, Ci-C6-haloalkoxy, Ci-C6-haloalkylthio; However, when R1 is methyl, R2 and R3 are not simultaneously ethyl, phenyl, benzyl, p-methylphenyl or 4-chlorophenyl; or, when R1 is ethyl, R2 and R3 are not simultaneously phenyl, 4-bromophenyl or 3,4-dichlorophenyl; or, when R1 is propyl or butyl, R2 and R3 are not simultaneously ethyl; or, when R1 is isopropyl, R2 and R3 are not simultaneously phenyl; or, when R1 is phenyl, R2 and R3 are not simultaneously phenyl or p-tolyl; or, when R2 and R3 are ethyl, R1 is not simultaneously benzyl and n-hexyl.

2. The malonic acid dithioester derivative according to claim 1, wherein, R 1 selected from C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4haloalkylthio or unsubstituted or substituted phenyl, benzyl, phenoxy, naphthyl, furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, quinolinyl, pteridinyl or acridinyl; m is selected from 1, 2, 3, 4 or 5, and when m > 1, R 4 ) m may be the same or different; and n is 0, 1, 2, 3 or 4. 4 may be the same or different; and n is 0, 1, 2, 3 or 4. R 2 R 3 Each is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, unsubstituted or (R) 5 ) r Substituted phenyl, benzyl, or 2-pyridyl; r is selected from 1, 2, or 3, where R > 1. 5 They can be the same or different; R 4 selected from halogen, cyano, amino, nitro, hydroxy, carboxy, ester, Ci-C4-alkyl, Ci-C4-haloalkyl, C3-C6-cycloalkyl, Ci-C4-alkoxy, Ci-C4-alkylthio, Ci-C4-haloalkoxy, Ci-C4-haloalkylthio; R 5 selected from halogen, nitro or C1-C4alkyl.

3. The malonic acid dithioester derivative according to claim 2, characterized by R 1 selected from C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4haloalkylthio or unsubstituted or substituted phenyl, phenyloxy, naphthyl, 2-pyridyl, furanyl or thienyl; m is selected from 1, 2, 3, 4 or 5, and when m > 1, the R 4 m substituted phenyl, phenyloxy, naphthyl, 2-pyridyl, furanyl or thienyl; m is selected from 1, 2, 3, 4 or 5, and when m > 1, the R 4 may be the same or different;​ R 2 , R 3 each independently is selected from the group consisting of C1-C4 alkyl, unsubstituted or substituted phenyl or benzyl; r is selected from 1 or 2, when r = 2 R 5 ) r substituted phenyl or benzyl; r is selected from 1 or 2, when r = 2 R 5 may be the same or different; R 4 selected from halogen, cyano, amino, nitro, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy or C1-C4-haloalkylthio; R 5 selected from halogen, nitro or methyl.

4. The malonic acid dithioester derivative according to any of claims 1 to 3, characterized in that, The structural formula of the malonic acid dithioester derivative is shown as formula IA: R 2 , R 3 each independently is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, trifluoroethyl or 2-pyridyl; X 1 , X 2 , X 3 , X 4 , X 5 each independently is selected from hydrogen, halogen, cyano, C1-C4alkyl, C1-C4haloalkyl or C1-C4alkoxy.

5. The malonic acid dithioester derivative according to any of claims 1 to 3, characterized in that, The structural formula of the malonic acid dithioester derivative is shown as formula IA: R 2 , R 3 are each independently selected from the group consisting of methyl, ethyl, n-propyl, phenyl, benzyl, p-tolyl, or p-methoxyphenyl; X 1 , X 2 , X 3 , X 4 , X 5 each independently is selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, heptafluoro-i-propyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy or t-butoxy.

6. The malonic acid dithioester derivative according to any of claims 1 to 3, characterized in that, The malonic acid dithioester derivative is selected from the compounds shown as formula IB, formula IC, formula ID, formula IE, formula IF, formula IG or formula IH: R 2 , R 3 each independently is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, trifluoroethyl or 2-pyridyl.

7. The malonic acid dithioester derivative according to any of claims 1 to 3, characterized in that, The malonic acid dithioester derivative is selected from the compounds shown as formula IB, formula IC, formula ID, formula IE, formula IF, formula IG or formula IH: R 2 , R 3 are each independently selected from ethyl or p-tolyl.

8. The malonic acid dithioester derivative according to any one of claims 1 to 3, characterized in that, The malonic acid dithioester derivative is selected from the compounds shown as formula IA: wherein, The malonic acid dithioester derivative is selected from the compounds shown as formula IA: wherein, 9. A method for preparing a malonic acid dithioester derivative according to any one of claims 1 to 8, characterized in that, The preparation method comprises coupling reaction of a compound shown as formula II with a compound shown as formula III to prepare a compound shown as formula I, and the chemical reaction equation is shown as formula A: wherein, LG represents a leaving group; The leaving group is selected from p-nitrophenol group, halogen, acyloxy, thioacyloxy, p-toluenesulfonyloxy, imidazolyl, pyridyl or pyrimidyl.

10. The method of claim 9, wherein, The reaction conditions of the coupling reaction comprise performing under condition i or condition ii: The condition i is to perform the reaction in the presence of a weak base and a Lewis acid, the weak base is selected from potassium carbonate, potassium acetate, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium acetate, silver carbonate, silver acetate, cesium carbonate, cesium fluoride, potassium tert-butoxide, sodium tert-butoxide, diazabicyclo, 4-dimethylamino pyridine, imidazole, triethylamine, diethylamine, triethylenediamine, and the Lewis acid is selected from boron, magnesium, titanium, tin centered Lewis acid; The condition ii is to perform the reaction in the presence of a strong base, the strong base is selected from sodium hydride, lithium diisopropylamide, n-butyllithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide; And / or, the coupling reaction is performed in an organic solvent, the organic solvent is selected from one or more of hydrocarbon organic solvent, halogenated hydrocarbon organic solvent, alcohol organic solvent, ether organic solvent, ester organic solvent, ketone organic solvent, heterocyclic organic solvent or nitrile organic solvent; And / or, the time of the coupling reaction is 0.5h-48h; And / or, the temperature of the coupling reaction is -78℃-150℃.

11. The method of claim 9, wherein, The reaction conditions of the coupling reaction comprise performing under condition i or condition ii: The condition i is that the reaction is carried out in the presence of a weak base selected from potassium carbonate, potassium acetate, potassium phosphate, potassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, sodium acetate, silver carbonate, silver acetate, cesium carbonate, cesium fluoride, potassium tert-butoxide, sodium tert-butoxide, diazabicyclo, 4-dimethylaminopyridine, imidazole, triethylamine, diethylamine, triethylenediamine, and a Lewis acid selected from boron trifluoride, titanium tetrachloride, stannous chloride, tin tetrachloride, magnesium chloride, magnesium perchlorate, magnesium iodide, magnesium bromide or magnesium bromide-diethyl ether; The condition ii is that the reaction is carried out in the presence of a strong base selected from sodium hydride, lithium diisopropylamine, n-butyllithium, bis(trimethylsilyl)amido lithium, bis(trimethylsilyl)amido sodium or bis(trimethylsilyl)amido potassium; And / or, the coupling reaction is carried out in an organic solvent selected from one or more of toluene, xylene, mesitylene, phenol, pentane, hexane, octane, cyclohexane, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, pyridine, acetonitrile; And / or, the coupling reaction time is 12h-36h; And / or, the coupling reaction temperature is 0℃-100℃.

12. Use of the malonic acid dithioester derivative according to any one of claims 1-8 for synthesizing ionophoric insecticides.

13. A method for synthesizing mesoionic insecticides using the malonic acid dithioester derivative according to any one of claims 1 to 8, characterized in that, The compound shown in formula I is used as an intermediate to carry out a condensation reaction with an amino pyridine intermediate shown in formula IV to synthesize a pyrido[1,2-α]pyrimidine ketone ionophoric compound shown in formula V, and the chemical reaction equation is shown in formula B: Among them, R 6 Selected from cyano, C1-C 15 Alkyl, C6-C 10 Aryl or C3-C 10 Mixed aromatics; R 7 selected from C1-C 15 alkyl, C6-C 10 aryl or C3-C 10 heteroaryl; And / or, the condensation reaction is carried out in an organic solvent selected from one or more of a hydrocarbon organic solvent, a halogenated hydrocarbon organic solvent, an alcohol organic solvent, an ether organic solvent, an ester organic solvent, a ketone organic solvent, a heterocyclic organic solvent or a nitrile organic solvent; And / or, the condensation reaction time is 0.5h-48h, And / or, the condensation reaction temperature is -78℃-300℃.

14. A method for synthesizing mesoionic insecticides using the malonic acid dithioester derivative according to any one of claims 1 to 8, characterized in that, The compound shown in formula I is used as an intermediate to carry out a condensation reaction with an amino pyridine intermediate shown in formula IV to synthesize a pyrido[1,2-α]pyrimidine ketone ionophoric compound shown in formula V, and the chemical reaction equation is shown in formula B: Among them, R 6 Selected from cyano, C1-C 15 Alkyl, C6-C 10 Aryl or C3-C 10 Mixed aromatics; R 7 is selected from methyl, ethyl, propyl, phenyl or benzyl; And / or, the condensation reaction is carried out in an organic solvent selected from one or more of toluene, xylene, mesitylene, phenol, pentane, hexane, octane, cyclohexane, chlorobenzene, dichlorobenzene, dichloromethane, methanol, ethanol, isopropanol, diethyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diglyme, methyl acetate, ethyl acetate, propyl acetate, acetone, methyl butanone, methyl isobutyl ketone, cyclohexanone, toluene cyclohexanone, pyridine, acetonitrile, tetrahydrofuran; And / or, the condensation reaction time is 3h-36h, And / or, the condensation reaction temperature is 0℃-200℃.

15. The method for synthesizing metronid insecticides from malonate dithioester derivatives as described in claim 14, characterized in that, The temperature of the condensation reaction is the reflux temperature of the organic solvent.

16. The use of the malonic acid dithioester derivative according to claim 12 for the synthesis of mesoionic insecticides, characterized in that, The mesoionic insecticide is V1, V2, V3, V4 or V5:

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