A method for preparing a sulfonium ylide compound

Abstract

The present invention provides a new method for synthesizing a class of dimethylsulfonium ylide compounds. Specifically, dimethyl sulfide and chloroacetate are used as raw materials, and in the presence of a catalyst, a chlorosulfonium salt is synthesized, and then hydrogen chloride is removed by an alkali to generate the target compound sulfonium ylide. The method has the advantages that the raw materials are easily obtained, the conditions are mild, the production safety is high, the yield is high, the reaction cost is reduced, it is easy to scale up, and it has high industrial application value.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a dimethylsulfonium ylide compound and its application. Background Art

[0002] In the field of organic synthesis, sulfonium ylide is an important and widely used reagent. It has a carbanion structure stabilized by an adjacent positive sulfur ion. The carbanion is a strong nucleophile and has the conditions to act as a reactive nucleophilic reagent. Using this sulfonium ylide, cyclopropane compounds can be prepared, and ethylene oxide compounds can also be prepared. The dimethylsulfonium ylide compound mentioned in this article has the following structure:

[0003]

[0004] Currently, the methods reported at home and abroad for synthesizing the dimethylsulfonium ylide compound I are to react dimethyl sulfide with bromoacetate to form a bromide salt, and then use a base to remove hydrogen bromide to obtain the target sulfonium ylide compound I [(a) Luo Yu, CN 104744377 A. (b) Frydman, Benjamin, WO 2003050072. (c) Nambu, Hisanori; Chemical Communications 2019, 55(46), 6539 - 6542. (d) Huang Hailan, CN 102177138 A. (e) Zheng Jianyu, CN 1966546 A]. The synthesis route is as follows:

[0005]

[0006] Since this route uses expensive bromoacetate as the raw material, it has a low atom utilization rate and high production cost, which greatly limits the industrial application value of the ylide compound I; and the reaction time for preparing compound VI is long, generally two to three days, and the production efficiency is low. Due to the low reactivity of chloroacetate, the ylide compound I cannot be prepared by the above method, and there is no literature report on the preparation of the ylide compound I using chloroacetate as the raw material. Since chloroacetate is widely available and inexpensive, the present invention uses chloroacetate as the raw material and synthesizes the ylide compound I at low cost and high efficiency through a catalytic activation method. Summary of the Invention

[0007] The object of the present invention is to provide a new method for synthesizing the dimethylsulfonium ylide compound I. Specifically, dimethyl sulfide and chloroacetate are used as raw materials, and under the action of a catalyst, a chlorosulfonium salt compound is synthesized, and then hydrogen chloride is removed by a base to generate the target dimethylsulfonium ylide compound. This method has the advantages of inexpensive and easily available raw materials, mild reaction conditions, easy purification of the product, high yield, high synthesis safety, low preparation cost, and wide application of the product, and has high industrial value.

[0008] Specifically, the technical solution of the present invention is as follows: Using dimethyl sulfide II and chloroacetate III as raw materials, under the action of a catalyst, a chlorosulfonium salt compound IV is synthesized, and then hydrogen chloride is removed by an alkali to generate the target dimethylsulfonium ylide compound I. The specific synthesis route is as follows:

[0009]

[0010] Among them, R is one of C1-C40 alkyl, phenyl, and substituted phenyl, etc. The substituents on the substituted phenyl are one or more of C1-C40 alkyl, C1-C40 alkoxy, nitro, cyano, and halogen (F, Cl, Br, I), and the number of substituents is 1-5;

[0011] According to the above synthesis route:

[0012] The molar ratio of the dimethyl sulfide II to the chloroacetate III is 1-10:1, preferably 1-3:1, and more preferably 1-1.5:1;

[0013] In the reaction of preparing the chlorosulfonium salt compound IV from the dimethyl sulfide II and the chloroacetate III, the catalyst is selected from one or more of iodine, sodium iodide, potassium iodide, zinc iodide, N-iodosuccinimide, tetrabutylammonium iodide, etc., preferably potassium iodide and sodium iodide. The molar ratio of the catalyst to the chloroacetate III is 0.001-0.5:1, preferably 0.01-0.05:1;

[0014] In the reaction of preparing the chlorosulfonium salt compound IV from the dimethyl sulfide II and the chloroacetate III, the solvent is selected from at least one of water, toluene, benzene, methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide, or N,N-dimethylformamide, preferably alcohols, toluene, and acetone;

[0015] In the reaction of preparing the compound IV from the dimethyl sulfide II and the chloroacetate III, the reaction temperature is 0-200°C, preferably 40-90°C. The reaction time is 1-24 h, preferably 1-12 h.

[0016] In the reaction of preparing the target dimethylsulfonium ylide compound I from the chlorosulfonium salt compound IV, the alkali is selected from: KOH, NaOH, Na2CO3, Cs2CO3, K2CO3, NaHCO3, i Pr2NEt, i PrNMe2, NEt3, t BuOK, t BuONa, tAt least one of BuOLi, MeONa, MeOK or K3PO4, preferably KOH, K2CO3, NEt3, t The molar ratio of the base such as BuOK to compound IV is 1-10:1, preferably 1-5:1;

[0017] In the reaction for preparing the target dimethylsulfonium ylide compound I from the chlorosulfonium salt compound IV, the solvent is selected from at least one of water, toluene, benzene, methanol, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, diethyl ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide, preferably dichloromethane, dichloroethane, water, acetonitrile, N,N-dimethylformamide.

[0018] In the reaction for preparing the target dimethylsulfonium ylide compound I from the chlorosulfonium salt compound IV, the reaction temperature is -40 - 90 °C, preferably -10 - 50 °C.

[0019] Specifically, the reaction steps of the present invention are as follows:

[0020] In an autoclave, add dimethyl sulfide II and chloroacetate III, add a solvent and a catalyst, react at a certain temperature for several hours. After the reaction is complete, distill off the solvent under reduced pressure to obtain compound IV. Then dissolve it in a solvent, add a base, react at a certain temperature for several hours, restore to room temperature, filter to remove the generated solid salt, add water for liquid separation, extract the aqueous layer with an organic solvent again, combine the organic layers, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain the product compound I.

[0021] The compound I can be used as a nucleophile to react with an alkene or a benzaldehyde compound containing an electron-withdrawing group to form a cyclized product (such as a cyclopropane compound), and can also undergo a cycloaddition reaction with a 1,3-dipole.

[0022]

[0023] Wherein X is O or CHR 3 one of, R 3 electron-withdrawing groups such as a carbonyl group, an ester group or a cyano group, R 1 and, R 2 are the same or different groups, and are one of H, an alkyl group, a phenyl group or a substituted phenyl group, etc.

[0024] The present invention has the following advantages:

[0025] 1. The reagents and catalysts used are inexpensive and easily available.

[0026] 2. High reaction activity, mild reaction conditions and high yield.

[0027] 3. Compared with the traditional method, this method greatly reduces the reaction cost, has a short reaction time, and improves the preparation efficiency. Description of the Drawings

[0028] Figure 1 1H NMR spectrum of compound I-1 prepared in Example 1;

[0029] Figure 2 1H NMR spectrum of compound I-2 prepared in Example 2. Detailed Description of the Invention

[0030] The following examples will further illustrate the present invention, but the present invention is not limited thereto. Nuclear magnetic resonance was measured by a Bruker 700 nuclear magnetic resonance spectrometer, and gas chromatography (GC) was measured by an Agilent 7820 chromatograph.

[0031] Example 1

[0032]

[0033] 1) In a 250 mL autoclave, 10.8 g (0.1 mol) of methyl chloroacetate, 7.4 g (0.12 mol) of dimethyl sulfide, 0.166 g (0.001 mol) of potassium iodide, and 30 mL of toluene were added. The autoclave was sealed, and the reaction was carried out at 50 °C for three hours. The reaction was stopped, and GC was used to monitor that the methyl chloroacetate reaction was complete. Dimethyl sulfide and toluene were removed by rotary evaporation under reduced pressure to obtain 17 g (0.1 mol) of an oily viscous substance IV-1.

[0034] 2) 50 mL of chloroform was added to 17 g (0.1 mol) of the oily substance, and the mixture was placed at 0 °C. 20 g (0.2 mol) of triethylamine was added dropwise. After the addition was completed, the mixture was returned to room temperature and reacted for one hour. The white solid salt was removed by filtration. 50 mL of water was added to the filtrate, and liquid separation (separating the water layer and the chloroform layer) was carried out. The water layer was extracted with chloroform again, and the organic layers (chloroform layers) were combined, dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure to obtain 11.2 g (0.084 mol) of a yellow liquid product, compound I-1, which was consistent with the description in the literature [(f) J. Org. Chem. 1967, 32, 11, 3351–3355], and the yield was 84%.

[0035] The NMR data are as follows:

[0036] 1 1H NMR (700 MHz, D2O) δ 3.76 (s, 3H), 3.24 (s, 1H), 2.92 (s, 6H).

[0037] Example 2

[0038]

[0039] 1) In a 250 mL autoclave, add 12.2 g (0.1 mol) of ethyl chloroacetate, 7.4 g (0.12 mol) of dimethyl sulfide, 0.149 g (0.001 mol) of sodium iodide, and 30 mL of acetone. Seal the autoclave and react at 50 °C for five hours. Stop the reaction. Monitor by GC until the reaction of methyl chloroacetate is complete. Remove dimethyl sulfide and acetone by rotary evaporation under reduced pressure to obtain 18.4 g (0.1 mol) of an oily viscous substance Ⅳ-2.

[0040] 2) Add 50 mL of toluene to 18.4 g (0.1 mol) of the oily substance and place it in an ice-water bath. Add 13.4 g (0.12 mol) of potassium tert-butoxide in batches. After addition, return to room temperature and react for one hour. Filter to remove the white solid salt. Add 50 mL of water to the filtrate, separate the layers. Extract the aqueous layer with chloroform again. Combine the organic layers, dry over anhydrous sodium sulfate, and remove chloroform under reduced pressure to obtain 9.1 g (0.061 mol) of the product, a yellow liquid compound Ⅰ-2, which is consistent with the description in the literature [(f) J. Org. Chem. 1967, 32, 11, 3351–3355], with a yield of 61%.

[0041] The NMR data are as follows:

[0042] 1 H NMR (700 MHz, CDCl3) δ 4.04 (q, 2H), 2.92 (s, 1H), 2.78 (s, 6H), 1.23 (t, 3H).

[0043] Example 3

[0044] Replace the catalyst in Example 1 with an equimolar amount of sodium iodide, and the remaining procedures and conditions are the same as in Example 1. 11.2 g of compound I-1 is obtained by the reaction, with a yield of 84%.

[0045] Example 4

[0046] Replace the catalyst in Example 1 with an equimolar amount of tetrabutylammonium iodide, and the remaining procedures and conditions are the same as in Example 1. 8.0 g of compound I-1 is obtained by the reaction, with a yield of 60%.

[0047] Example 5

[0048] Increase the amount of dimethyl sulfide in Example 1 to 0.2 mol, and the remaining procedures and conditions are the same as in Example 1. 10.4 g of compound I-1 is obtained by the reaction, with a yield of 78%.

[0049] Example 6

[0050] Reduce the amount of dimethyl sulfide in Example 1 to 0.1 mol, and keep the rest of the process and conditions the same as in Example 1. 9.1 g of Compound I-1 was obtained with a yield of 68%.

[0051] Example 7

[0052] Raise the temperature in Reaction Step 1 of Example 1 to 90 °C, and keep the rest of the process and conditions the same as in Example 1. 9.6 g of Compound I-1 was obtained with a yield of 72%.

[0053] Example 8

[0054] Replace the reaction solvent in Reaction Step 1 of Example 1 with methanol, and keep the rest of the process and conditions the same as in Example 1. 10.1 g of Compound I-1 was obtained with a yield of 75%.

[0055] Example 9

[0056] Replace the reaction solvent in Reaction Step 1 of Example 1 with water, and keep the rest of the process and conditions the same as in Example 1. 10.4 g of Compound I-1 was obtained with a yield of 78%.

[0057] Example 10

[0058] Replace the reaction solvent in Reaction Step 2 of Example 1 with toluene, and keep the rest of the process and conditions the same as in Example 1. 9.6 g of Compound I-1 was obtained with a yield of 72%.

[0059] Example 11

[0060] Replace the base in Reaction Step 2 of Example 1 with a 20% by mass KOH aqueous solution, and keep the rest of the process and conditions the same as in Example 1. 10.5 g of Compound I-1 was obtained with a yield of 78%.

[0061] Example 12

[0062] Replace the base in Reaction Step 2 of Example 1 with a 20% by mass NaOH aqueous solution, and keep the rest of the process and conditions the same as in Example 1. 10.1 g of Compound I-1 was obtained with a yield of 75%.

[0063] Example 13

[0064] Replace the base in Reaction Step 2 of Example 1 with a 20% by mass NaOH aqueous solution and a saturated K2CO3 aqueous solution, and keep the rest the same as in Example 1. 10.9 g of Compound I-1 was obtained with a yield of 81%.

[0065] Example 14

[0066] Change Example 1 to add no catalyst, and keep the rest of the process and conditions the same as in Example 1. 1.2 g of Compound I-1 was obtained with a yield of 0.8%.

[0067] Example 15

[0068] Replace the catalyst in Example 1 with an equimolar amount of sodium bromide, and the remaining processes and conditions are the same as in Example 1. 1.5 g of Compound I-1 was obtained by reaction, with a yield of 0.9%.

[0069] Example 16

[0070] Replace the base in Reaction Step 2 of Example 1 with an aqueous solution of 20% NaOH by mass concentration and a saturated aqueous solution of Na2CO3, and the rest is the same as in Example 1. 10.7 g of Compound I-1 was obtained by reaction, with a yield of 80%.

[0071] Example 17

[0072] Apply the product Ⅰ-2 prepared in Example 2 to the cyclopropanation reaction.

[0073] 5 g (0.033 mol) of Compound Ⅰ-2 was dissolved in 10 mL of toluene and heated to 100 °C. 3.9 g (0.0396 mol) of 4-methyl-3-penten-2-one was dissolved in 10 mL of toluene and added dropwise to the above toluene mixture. After the addition was complete, the reaction was continued at this temperature for 12 h. Toluene and the product were distilled off under reduced pressure to obtain 5.47 g of ethyl 3-acetyl-2,2-dimethylcyclopropane-1-carboxylate, with a yield of 90%.

[0074] Example 18

[0075] Apply the product Ⅰ-2 prepared in Example 2 to the epoxidation reaction.

[0076] 5 g (0.033 mol) of Compound Ⅰ-2 was dissolved in 10 mL of acetonitrile and heated to 60 °C. 3.8 g (0.0396 mol) of benzaldehyde was dissolved in 10 mL of acetonitrile and added dropwise to the above acetonitrile mixture. After the addition was complete, the reaction was continued at this temperature for 12 h. Acetonitrile and the product were distilled off under reduced pressure to obtain 5 g of methyl 3-phenyloxirane-2-carboxylate, with a yield of 85%.

[0077] The above-described embodiments only represent the implementation modes of the present invention, but should not be construed as limiting the scope of the present invention patent. It should be noted that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing a dimethylsulfonium ylide compound, characterized in that: The dimethylsulfonium ylide compound is a compound of the following chemical formula I: ； wherein R is one of C1-C40 alkyl, phenyl or substituted phenyl, and the substituents on the substituted phenyl are one or more of C1-C40 alkyl, C1-C40 alkoxy, nitro, cyano, halogen F, Cl, Br, I, and the number of substituents is 1-5; Using dimethyl sulfide II and chloroacetate III as raw materials, a chlorosulfonium salt compound IV is synthesized, and then hydrogen chloride is removed to generate the target compound I; The structural formula of dimethyl sulfide II is: The structural formula of chloroacetate III is: , The structural formula of the chloro-sulfate compound Ⅳ is: , In the structural formulas III and IV, the R group is the same group as the R in the structural formula I; The specific reaction route is as follows: Using dimethyl sulfide II and chloroacetate III as raw materials, in the presence of a catalyst, a chlorosulfonium salt compound IV is synthesized, and then hydrogen chloride is removed by an alkali to generate the target compound I; ； In the structural formulas III and IV, the R group is the same group as the R in the structural formula I; The molar ratio of the dimethyl sulfide II to the chloroacetate III is 1-10:1; The reaction of preparing the compound IV from the dimethyl sulfide II and the chloroacetate III is carried out in the presence of a catalyst, and the catalyst is selected from one or two of potassium iodide and sodium iodide; the molar ratio of the catalyst to the chloroacetate III is 0.001-0.5:1; The reaction for preparing Compound I from Compound IV is carried out in the presence of a base, and the base is selected from at least one or two of NEt3 and t BuOK.

2. According to the synthesis method described in claim 1, wherein: The molar ratio of the dimethyl sulfide II to the chloroacetate III is 1-3:1; The molar ratio of the catalyst to the chloroacetate III is 0.01-0.05:

1.

3. According to the synthesis method described in claim 2, wherein: The molar ratio of the dimethyl sulfide II to the chloroacetate III is 1-1.5:

1.

4. The synthesis method according to claim 1, characterized in that: The reaction of preparing the compound IV from the dimethyl sulfide II and the chloroacetate III is carried out in a solvent, and the solvent is selected from at least one or more of toluene, benzene, ethanol, isopropanol, acetone, acetonitrile, water, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

5. The synthesis method according to claim 1, characterized in that: In the reaction for preparing compound Ⅳ from dimethyl sulfide Ⅱ and chloroacetate Ⅲ, the reaction temperature is 0 - 50 o °C; the reaction time is 1 - 24 h.

6. The synthesis method according to claim 5, characterized in that: In the reaction of preparing the compound IV from the dimethyl sulfide II and the chloroacetate III, the reaction time is 1-12 h.

7. The synthesis method according to claim 1, characterized in that: The molar ratio of the alkali to the compound IV is 1-10:

1.

8. The synthesis method according to claim 7, characterized in that: The molar ratio of the alkali to the compound IV is 1-5:

1.

9. The synthesis method according to claim 1, characterized in that: The reaction of preparing the compound I from the compound IV is carried out in a solvent, and the solvent is selected from at least one or more of water, toluene, benzene, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

10. The synthesis method according to claim 1, characterized in that: In the reaction for preparing Compound I from Compound IV, the reaction temperature is -40 - 90 o °C; the reaction time is 0.2 - 24 h.

11. The synthesis method according to claim 10, wherein: In the reaction for preparing Compound I from Compound IV, the temperature for adding the base is -10 - 10 o °C, and after adding the base, the reaction temperature is 10 - 50 °C; the reaction time is 0.2 - 12 h.

12. According to the synthesis method described in any one of claims 1-11, it is characterized in that: The method is specifically as follows: In a pressure vessel, add dimethyl sulfide II and chloroacetate III, add a solvent and a catalyst, react, after the reaction is complete, distill off the solvent under reduced pressure to obtain the compound IV; then dissolve the compound IV in a solvent, add an alkali, react, restore to room temperature after the reaction, filter to remove the generated solid salt, add water for liquid separation, extract the aqueous layer with an organic solvent, combine the organic layers, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain the product compound I; The organic solvent is at least one or more than two of toluene, benzene, ethanol, isopropanol, acetone, acetonitrile, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N, N-dimethylformamide.

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