A method for synthesizing a hydroxyl sulfide compound

Abstract

The application discloses a synthesis method of a hydroxyl sulfide compound and belongs to the field of organic synthesis. The application uses a sulfonium salt and H2O shown in formula I as raw materials, and under the action of alkali and a catalyst CF3COOAg, a hydroxyl sulfide compound shown in formula II is obtained through reaction. The method has the advantages of cheap and easily obtained raw materials, mild reaction conditions, high atomic economy, wide substrate range, high yield, simple operation, easy separation and purification of products and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing hydroxythioether compounds. Background Technology

[0002] Hydroxythioethers are important raw materials for the synthesis of heterocyclic compounds, natural products, and pharmaceuticals, often serving as key target molecules or backbones in organic synthesis. They play a variety of important roles and applications in chemistry and biology. For example, in organic synthesis, hydroxythioethers can act as reducing agents, protecting groups, and intermediates in reactions; in medicinal chemistry, hydroxythioether drugs can improve efficacy and properties by altering solubility, stability, and activity; in materials chemistry, hydroxythioethers help enhance material properties, such as improving adhesion and corrosion resistance, and are commonly used in the preparation of polymers, gels, and coatings; in pharmacology, hydroxythioethers can be used as bioactive molecular markers and enzyme activity modifiers; and in environmental science, hydroxythioethers can be used as reagents for pollutant detection and analysis, for the extraction, separation, and quantitative study of organic substances, and for monitoring pollutants in water, soil, and the atmosphere. In short, hydroxythioethers have wide applications in many areas and are indispensable organic compounds in industrial production and consumer markets.

[0003] Currently, the main methods for synthesizing hydroxy sulfides include ring-opening reactions of epoxides and thiols, as well as the co-oxidation reaction of olefins and thiols (TOCO). However, these methods often involve the use of highly toxic or malodorous chemicals and have problems such as high production costs, low reaction efficiency, unsuitability for scale-up, the need for high-temperature and high-pressure reaction conditions, or the generation of byproducts that pollute the environment.

[0004] Therefore, developing a sustainable, environmentally friendly, and highly selective hydroxy sulfide synthesis technology is a very forward-looking and important task. Summary of the Invention

[0005] This invention provides a method for generating hydroxy sulfides through ring-opening. The reaction method is simple and convenient, and the generated hydroxy sulfides have good stability and can be applied to industrial production. It also has the advantages of a wide range of applicable substrates, high yield, and easy product separation.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for synthesizing hydroxy sulfide compounds, using sulfonium salt of formula I and H2O as raw materials, reacts under the action of alkali and catalyst CF3COOAg to obtain hydroxy sulfide compounds of formula II.

[0008]

[0009] R can be independently selected from: Aryl;

[0010] R1 and R1' are mono- to tri-substituted, with substituents selected from: H, C1-4 alkyl, halogen (F, Cl, Br), C1-4 alkoxy, aryl; R2, R2', and R3 are independently selected from: H, C1-4 alkyl, aryl; Z is selected from: O, S, -CH2CH2-;

[0011] The aryl group can be substituted or unsubstituted phenyl or naphthyl; the substituents on the aryl group are selected from: C1-4 alkyl, C1-4 alkoxy, halogen (F, Cl, Br).

[0012] In one embodiment of the present invention, R is selected from: styrene, p-fluorostyrene, p-bromostyrene, p-sulfonyl styrene, m-chlorostyrene, o-bromostyrene, 2,4-dichlorostyrene, 2,4,6-trimethylstyrene, α-methylstyrene, α-methyl-4-phenylstyrene, α-methyl-3,4-methylenedioxystyrene, α-isopropylstyrene, α-phenylstyrene, benzocyclohexene, benzofuran, benzothiophene, β-phenylstyrene, 2,5-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 2,4,6-trimethylphenyl, and 1-methylnaphthalene.

[0013] In one embodiment of the present invention, R is specifically selected from:

[0014] In one embodiment of the present invention, the catalyst includes one or more of the following: silver trifluoroacetate, silver acetate, and silver carbonate.

[0015] In one embodiment of the present invention, the alkali includes one or more of potassium tert-butoxide, potassium carbonate, and potassium hydroxide.

[0016] In one embodiment of the present invention, the reaction is carried out in an organic solvent, specifically one or more of 1,4-dioxane, ethylene glycol dimethyl ether, tetrahydrofuran, and toluene.

[0017] In one embodiment of the present invention, the molar ratio of the aryl sulfonium salt represented by Formula I to H2O is 1.0:10-20.

[0018] In one embodiment of the present invention, the amount of catalyst added is 10 mol% to 40 mol% based on the amount of aryl sulfonate shown in Formula I.

[0019] In one embodiment of the present invention, the molar ratio of the aryl sulfonium salt represented by Formula I to the base is 1.0:1.0 to 2.0.

[0020] In one embodiment of the present invention, the amount of organic solvent added is 2 to 10 mL / mmol, calculated as the amount of aryl sulfonate salt represented by Formula I.

[0021] In one embodiment of the present invention, the reaction temperature is 60°C to 100°C, and the reaction time is 12 to 24 hours. Specifically, a reaction at 80°C for 16 hours can be selected.

[0022] In one embodiment of the present invention, the product is purified by silica gel column chromatography after the reaction.

[0023] The purification method is as follows: after the reaction is completed, silica gel for column chromatography is added, the solvent is removed by vacuum distillation, the product adsorbed on silica gel is dried to powder, and then the sample is loaded onto a column and eluted with petroleum ether: ethyl acetate = 2:1. The product is collected and concentrated by evaporation to obtain alkyl alcohol compounds.

[0024] The hydroxythioether compounds synthesized in this invention have excellent application prospects in the preparation of active molecules, specifically for example:

[0025] RS-(CH2) n -OH can be derived to R-SO2-(CH2) through a simple oxidation process. n -OH, R-SO2-(CH2) n -OH is an important intermediate raw material for SphK1 inhibitors (see J. Med. Chem. 2022, 65, 7697-7716). The synthetic method of this invention can yield a series of hydroxythioether compounds, which will help to expand and improve this class of SphK1 inhibitors.

[0026] Furthermore, when R is substituted with a naphthyl group, the corresponding hydroxythioether compound products only require conventional benzene ring substitution expansion and naphthyl ring oxidation to naphthoquinone processes to obtain a series of small drug molecules with inhibitory activities against multiple types of cancer cells.

[0027] Beneficial effects:

[0028] The purpose of this invention is to provide a novel method for synthesizing hydroxy sulfide compounds. This method is low-cost, highly atom-economical, does not require high temperature or high pressure conditions, and can obtain hydroxy sulfide compounds in relatively high yields. Detailed Implementation

[0029] Synthesis of sulfonium salts: Under argon or nitrogen atmosphere, 25 mL of dichloromethane and tetramethylene sulfoxide (11.0 mmol, 1.1 g) were added to a 100 mL reaction flask, and the mixture was stirred at -40 °C for 5 minutes. Then, the corresponding alkene (10.0 mmol) and trifluoromethanesulfonic anhydride (11.0 mmol, 3.1 g) were added to the reaction system, and the reaction was continued at -40 °C for 30 minutes. The temperature was then raised to 0 °C, and the reaction was monitored by TLC. After the reaction was complete, the solvent was removed under vacuum. Recrystallization from dichloromethane and diethyl ether yielded a white solid, which was the corresponding sulfonium salt.

[0030] The synthetic route (gram-level) is as follows:

[0031]

[0032] Example 1:

[0033] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0034]

[0035] Preparation method: Under air conditions, styrene sulfonium salt (0.3 mmol, 102 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, and the eluents were combined and concentrated by evaporation to obtain the compound shown, with a yield of 91%. This substance is a colorless oily liquid.

[0036] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ7.30-7.27(m,4H),7.21-7.17(m,1H),6.72(d,J=15.6Hz,1H),6.49(d,J=15.6 Hz,1H),3.68(t,J=6.2Hz,2H),2.84(t,J=7.0Hz,2H),1.83-1.76(m,2H),1.75-1.70(m,2H),1.61(brs,1H). 13 C NMR (101MHz, Chloroform-d) δ137.0,128.6,127.1,126.8,125.4,124.9,62.3,32.4,31.6,25.8.

[0037] Example 2:

[0038] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0039]

[0040] Preparation method: Under air conditions, p-fluorostyrene sulfonium salt (0.3 mmol, 107.5 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, and the eluents were combined and concentrated by evaporation to obtain the compound shown, with a yield of 70%. This substance is a colorless oily liquid.

[0041] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ7.26-7.21(m,2H),7.00-6.95(m,2H),6.61(d,J=15.5Hz,1H),6.44(d,J=15.5 Hz,1H),3.67(t,J=6.3Hz,2H),2.82(t,J=7.1Hz,2H),1.82-1.75(m,2H),1.73-1.68(m,2H),1.67(brs,1H). 13 C NMR(126MHz,Chloroform-d)δ161.8(d,J=246.2Hz),133.2(d,J=3.1Hz),126.9(d,J =7.7Hz), 126.0, 124.59 (d, J = 2.3Hz), 115.5 (d, J = 21.5Hz), 62.2, 32.4, 31.6, 25.8. 19 F NMR(471MHz,Chloroform-d)δ-115.33.

[0042] Example 3:

[0043] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0044]

[0045] Preparation method: Under air conditions, p-bromostyrene sulfonium salt (0.3 mmol, 125.8 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 83%. This substance is a colorless oily liquid.

[0046] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.39(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.71(d,J=15.4Hz ,1H),6.37(d,J=15.5Hz,1H),3.67(t,J=6.2Hz,2H),2.82(t,J=7.0Hz,2H),1.81-1.66(m,5H). 13 C NMR (101MHz, Chloroform-d) δ135.9,131.6,126.9,126.1,125.4,120.3,62.2,32.3,31.5,25.7.

[0047] Example 4:

[0048] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0049]

[0050] Preparation method: Under air conditions, p-sulfonium methylstyrene sulfonium salt (0.3 mmol, 115.8 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 89%. This substance is a colorless oily liquid.

[0051] Characterization data:1 H NMR(400MHz,Chloroform-d)δ7.21-7.15(m,4H),6.66(d,J=15.6Hz,1H),6.42(d,J=15.5Hz,1H ),3.66(t,J=6.2Hz,2H),2.81(t,J=7.0Hz,2H),2.46(s,3H),1.86(brs,1H),1.81-1.65(m,4H). 13 C NMR (101MHz, Chloroform-d) δ136.7,134.1,126.9,126.5,125.8,124.4,61.6,32.4,31.6,25.8,15.9.

[0052] Example 5:

[0053] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0054]

[0055] Preparation method: Under air conditions, 0.3 mmol (112.2 mg) of m-chlorostyrene sulfonium salt, 0.1 mmol (6.6 mg) of silver trifluoroacetate, 0.6 mmol (82.92 mg) of potassium carbonate, 3 mmol (54 μL) of water, and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, and the eluents containing the target product were combined and concentrated by evaporation to obtain the compound shown, with a yield of 70%. The substance is a colorless oily liquid.

[0056] Characterization data: ¹H NMR (500MHz, Chloroform-d) δ 7.30 (t, J = 1.9Hz, ¹H), 7.24 (d, J = 7.8Hz, ¹H), 7.19–7.16 (m, 2H), 6.79 (d, J = 15.6Hz, ¹H), 6.42 (d, J = 15.6Hz, ¹H), 3.73 (t, J = 6.2Hz, 2H), 2.88 (t, J = 7.2Hz, 2H), 1.86–1.80 (m, 2H), 1.78–1.72 (m, 2H), 1.61 (brs, ¹H). ¹³C NMR (126MHz, Chloroform-d) δ138.8,134.5,129.8,127.1,126.6,125.2,125.0,123.6,61.6,33.1,31.5,25.6.

[0057] Example 6:

[0058] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0059]

[0060] Preparation method: Under air conditions, o-bromostyrene sulfonium salt (0.3 mmol, 125.8 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 73%. This substance is a colorless oily liquid.

[0061] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ7.52(dd,J=8.0,1.3Hz,1H),7.42(dd,J=7.9,1.7Hz,1H),7.23(td,J=7.6,1.3Hz,1H),7.04(td,J=7.6 ,1.7Hz,1H),6.78-6.69(m,2H),3.70(t,J=6.3Hz,2H),2.88(t,J=7.2Hz,2H),1.84-1.80(m,2H),1.76-1.70(m,2H),1.52(brs,1H). 13C NMR (126MHz, Chloroform-d) δ136.7,132.9,128.2,127.9,127.5,126.1,124.6,122.5,62.3,32.1,31.7,25.5.

[0062] Example 7:

[0063] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0064]

[0065] Preparation method: Under air conditions, 2,4-dichlorostyrene sulfonium salt (0.3 mmol, 122.8 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 89%. This substance is a colorless oily liquid.

[0066] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.35-7.33(m,2H),7.16(dd,J=8.4,2.2Hz,1H),6.77-6.67(m,2H),3 .69(t,J=6.2Hz,2H),2.87(t,J=7.1Hz,2H),1.83-1.78(m,2H),1.75-1.70(m,2H),1.59(brs,1H). 13 C NMR (101MHz, Chloroform-d) δ133.7,132.5,132.3,129.4,129.0,127.2,126.6,120.9,62.2,32.2,31.7,25.6.

[0067] Example 8:

[0068] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0069]

[0070] Preparation method: Under air conditions, 2,4,6-trimethylstyrene sulfonium salt (0.3 mmol, 114.6 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for spot detection. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 82%. This substance is a colorless oily liquid.

[0071] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ6.88(s,2H),6.50(d,J=15.8Hz,1H),6.18(d,J=15.9Hz,1H),3.70(t,J =6.3Hz,2H),2.83(t,J=7.1Hz,2H),2.29(s,6H),2.28(s,3H),1.83-1.78(m,2H),1.76-1.71(m,3H). 13 C NMR (126MHz, Chloroform-d) δ136.0,135.7,133.6,128.6,128.0,125.9,62.2,32.3,31.6,25.8,20.9,20.8.

[0072] Example 9:

[0073] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0074]

[0075] Preparation method: Under air conditions, α-methylstyrene sulfonium salt (0.3 mmol, 106.2 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 88%. This substance is a colorless oily liquid.

[0076] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.37-7.35(m,2H),7.33-7.30(m,2H),7.24-7.21(m,1H),6.31(d,J=1.1Hz,1H ),3.67(t,J=6.3Hz,2H),2.82(t,J=7.1Hz,2H),2.14(d,J=1.1Hz,3H),1.83-1.74(m,3H),1.73-1.67(m,2H). 13 C NMR (101MHz, Chloroform-d) δ141.9,133.5,128.2,126.6,125.0,123.4,62.2,33.9,31.4,26.7,17.5.

[0077] Example 10:

[0078] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0079]

[0080] Preparation method: Under air conditions, α-methyl-4-phenylstyrene sulfonium salt (0.3 mmol, 129.15 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 68%. This substance is a colorless oily liquid.

[0081] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.63-7.60(m,2H),7.59-7.56(m,2H),7.48-7.44(m,4H),7.38-7.34 (m,1H),6.41(s,1H),3.69(t,J=6.2Hz,2H),2.85(t,J=7.1Hz,2H),2.19(s,3H),1.85-1.69(m,5H). 13C NMR (101MHz, Chloroform-d) δ140.8,140.6,139.3,133.0,128.7,127.1,126.9,126.8,125.4,123.6,62.3,34.0,31.5,26.8,17.5.

[0082] Example 11:

[0083] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0084]

[0085] Preparation method: Under air conditions, 0.3 mmol (119.5 mg) of 3,4-methylenedioxystyrene sulfonium salt, 0.1 mmol (6.6 mg) of silver trifluoroacetate, 0.6 mmol (82.9 mg) of potassium carbonate, 3.0 mmol (54 μL) of water, and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 54%. This substance is a colorless oily liquid.

[0086] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ6.84(d,J=1.9Hz,1H),6.80(dd,J=8.1,1.8Hz,1H),6.74(d,J=8.1Hz,1H),6.17(d,J=1.2Hz,1H),5.9 3(s,2H),3.67(t,J=6.2Hz,2H),2.78(t,J=7.1Hz,2H),2.07(d,J=1.1Hz,3H),1.79-1.73(m,2H),1.72-1.66(m,2H),1.62(brs,1H). 13 C NMR (126MHz, Chloroform-d) δ147.6,146.3,136.5,133.4,122.2,118.5,108.0,105.7,100.9,62.3,33.9,31.5,26.7.

[0087] Example 12:

[0088] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0089]

[0090] Preparation method: Under air conditions, α-isopropylstyrene sulfonium salt (0.3 mmol, 114.6 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 67%. This substance is a colorless oily liquid.

[0091] Characterization data: ¹H NMR (400MHz, Chloroform-d) δ 7.37–7.32 (m, 2H), 7.28–7.24 (m, 1H), 7.19–7.16 (m, 2H), 5.91 (d, J = 1.1 Hz, 1H), 3.61 (t, J = 6.1 Hz, 2H), 2.69–2.63 (m, 3H), 1.69–1.58 (m, 5H), 1.04 (d, J = 6.8 Hz, 6H). ¹³C NMR (101MHz, Chloroform-d) δ 146.7, 140.1, 128.4, 128.0, 126.9, 120.0, 62.3, 35.9, 34.1, 31.5, 25.7, 21.8.

[0092] Example 13:

[0093] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0094]

[0095] Preparation method: Under air conditions, 1,1-stilbene sulfonium salt (0.3 mmol, 124.8 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 89%. This substance is a colorless oily liquid.

[0096] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.39-7.36(m,2H),7.31-7.28(m,3H),7.24-7.19(m,5H),6.57(s,1H) ,3.63(t,J=6.3Hz,2H),2.78(t,J=7.1Hz,2H),1.80-1.73(m,2H),1.68-1.60(m,2H),1.60(brs,1H). 13 C NMR (101MHz, Chloroform-d) δ141.9,139.5,138.7,129.7,128.2,128.2,127.4,127.0,126.8,125.9,62.2,34.6,32.1,26.6.

[0097] Example 14:

[0098] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0099]

[0100] Preparation method: Under air conditions, benzocyclohexene sulfonium salt (0.3 mmol, 109.9 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 86%. This substance is a colorless oily liquid.

[0101] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.15(td,J=7.2,6.7,2.7Hz,1H),7.11-7.05(m,2H),6.98(d,J=6.9Hz,1H) ,6.24(s,1H),3.69(t,J=6.1Hz,2H),2.91-2.83(m,4H),2.41(td,J=7.9,1.2Hz,2H),1.84-1.69(m,5H). 13 C NMR (101MHz, Chloroform-d) δ136.9,134.4,133.5,127.2,126.6,126.0,124.8,119.6,62.2,31.8,30.6,29.1,28.3,24.9.

[0102] Example 15:

[0103] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0104]

[0105] Preparation method: Under air conditions, benzofuran sulfonium salt (0.3 mmol, 106.3 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, and the eluents were combined and concentrated by evaporation to obtain the compound shown, with a yield of 80%. This substance is a colorless oily liquid.

[0106] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.50-7.48(m,1H),7.45-7.42(m,1H),7.28-7.24(m,1H),7.20(td,J=7.4,1.2H z,1H),6.79(d,J=0.9Hz,1H),3.65(t,J=6.1Hz,2H),2.98(t,J=6.9Hz,2H),1.80-1.66(m,4H),1.56(brs,1H). 13C NMR (101MHz, Chloroform-d) δ156.3,150.5,128.6,124.3,122.8,120.3,110.9,110.8,62.2,34.4,31.4,26.1.

[0107] Example 16:

[0108] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0109]

[0110] Preparation method: Under air conditions, benzothiophene sulfonium salt (0.3 mmol, 111.1 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 88%. This substance is a colorless oily liquid.

[0111] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.94(d,J=8.6Hz,1H),7.86(d,J=7.9Hz,1H),7.46-7. 36(m,3H),3.63-3.40(m,2H),2.92-2.89(m,2H),1.74(brs,1H),1.71-1.67(m,4H). 13 C NMR (101MHz, Chloroform-d) δ139.8,139.1,126.9,126.5,124.8,124.4,122.8,122.5,62.2,34.5,31.5,25.8.

[0112] Example 17:

[0113] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0114]

[0115] Preparation method: Under air conditions, β-phenylstyrene sulfonium salt (0.3 mmol, 124.9 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 88%. This substance is a colorless oily liquid.

[0116] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.41-7.28(m,5H),7.12-7.05(m,3H),6.96-6.93(m, 2H),6.79(s,1H),3.60(t,J=6.0Hz,2H),2.56(t,J=6.8Hz,2H),1.71-1.59(m,5H). 13 C NMR (101MHz, Chloroform-d) δ138.0,136.7,129.6,128.8,128.6,128.0,127.9,127.1,126.4,62.2,31.6,31.5,25.5.

[0117] Example 18:

[0118] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0119]

[0120] Preparation method: Under air conditions, 2,5-dimethoxyphenylsulfonium salt (0.3 mmol, 112.2 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 80%. This substance is a colorless oily liquid.

[0121] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ6.82(d,J=2.9Hz,1H),6.75(d,J=8.8Hz,1H),6.66(dd,J=8.8,3.0H z,1H),3.82(s,3H),3.75(s,3H),3.63(t,J=6.0Hz,2H),2.90(t,J=6.9Hz,2H),1.76-1.68(m,5H). 13 C NMR (126MHz, Chloroform-d) δ153.8,151.4,126.1,115.2,111.2,110.5,62.2,56.3,55.7,31.7,31.6,25.1.

[0122] Example 19:

[0123] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0124]

[0125] Preparation method: Under air conditions, 0.3 mmol (107.4 mg) of 3,4-methylenedioxyphenylsulfonium salt, 0.1 mmol (6.6 mg) of silver trifluoroacetate, 0.6 mmol (82.9 mg) of potassium carbonate, 3.0 mmol (54 μL) of water, and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, combined, and concentrated by evaporation to obtain the compound shown, with a yield of 88%. The substance is a colorless oily liquid.

[0126] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ6.88-6.86(m,2H),6.73-6.71(m,1H),5.93(s, 2H),3.62-3.60(m,2H),2.85-2.81(m,2H),1.79(brs,1H),1.67-1.63(m,4H). 13 CNMR(126MHz,Chloroform-d)δ147.9,146.8,128.0,125.1,111.8,108.6,101.2,62.2,35.5,31.5,25.5.

[0127] Example 20:

[0128] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0129]

[0130] Preparation method: Under air conditions, 0.3 mmol (106.9 mg) of mesitylene arylsulfonium salt, 0.1 mmol (6.6 mg) of silver trifluoroacetate, 0.6 mmol (82.9 mg) of potassium carbonate, 3 mmol (54 μL) of water, and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered, washed with dichloromethane, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 2:1), and the TLC was used for monitoring. The eluent containing the target product was collected, and the eluents containing the target product were combined and concentrated by evaporation to obtain the compound shown, with a yield of 93%. The substance is a colorless oily liquid.

[0131] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ6.93(s,2H),3.62(t,J=6.2Hz,2H),2.65(t,J=7.0Hz,2H),2.51(s,6H),2.27(s,3H),1.71-1.57(m,5H). 13 C NMR (101MHz, Chloroform-d) δ142.8,137.8,130.3,128.9,62.4,35.3,31.9,26.1,21.9,20.9.

[0132] Example 21:

[0133] The structures of the hydroxythioether compounds prepared in this example are as follows:

[0134]

[0135] Preparation method: Under air conditions, 1-naphthalenesulfonium salt (0.3 mmol, 109.2 mg), silver trifluoroacetate (0.1 mmol, 6.6 mg), potassium carbonate (0.6 mmol, 82.9 mg), water (3.0 mmol, 54 μL), and 2 mL of 1,4-dioxane were added to a 10 mL reaction tube and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, and the eluents were combined and concentrated by evaporation to obtain the compound shown, with a yield of 60%. This substance is a colorless oily liquid.

[0136] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ8.42(d,J=8.3Hz,1H),7.85(d,J=7.9Hz,1H),7.73(d,J=8.2Hz,1H),7.58-7.50( m,3H),7.41(t,J=7.7Hz,1H),3.63(t,J=5.8Hz,2H),3.01(t,J=6.6Hz,2H),1.79-1.67(m,4H).1.59(BRs,1H). 13 C NMR (101MHz, Chloroform-d) δ133.9,133.7,133.0,128.5,127.9,127.1,126.3,126.2,125.5,125.0,61.8,33.4,31.7,25.5.

[0137] Example 22: Effect of Catalyst Type

[0138] Referring to Example 1, only the catalyst was replaced with other catalysts in Table 1, while everything else remained the same. The results of the corresponding reaction are shown in Table 1.

[0139] Table 1 Effect of temperature on the preparation of hydroxythioether compounds

[0140]

[0141] Example 23: The Effect of Temperature

[0142] Referring to Example 1, only the temperature was replaced with other temperatures in Table 2, while everything else remained the same. The results of the corresponding reactions are shown in Table 2.

[0143] Table 2 Effect of temperature on the preparation of hydroxythioether compounds

[0144] temperature Yield of hydroxythioether compounds 80℃ (Example 1) 91％ 60℃ 63％ 100℃ 60％

[0145] Example 24: The Effect of Alkali

[0146] Referring to Example 1, only the potassium carbonate was replaced with other bases shown in Table 3, while everything else remained the same. The results of the corresponding reactions are shown in Table 3.

[0147] Table 3 Effect of base on the preparation of hydroxy thioether compounds

[0148] alkali Yield of hydroxythioether compounds Potassium carbonate (Example 1) 91％ <![CDATA[ t Full]]> 31％ KOH 48％

[0149] Example 25: The Effect of Solvents

[0150] Referring to Example 1, only the solvent was replaced by other solvents shown in Table 4, while everything else remained the same. The results of the corresponding reactions are shown in Table 4.

[0151] Table 4. Effect of solvent selection on the preparation of hydroxythioether compounds

[0152] solvent Yield of hydroxythioether compounds 1,4-Dioxane (Example 1) 91％ THF 65％ DME 52％

[0153] Example 26: Expansion of the Reaction Atmosphere

[0154] Referring to Example 1, the air condition was replaced with oxygen and argon, while other conditions remained unchanged. The results of the corresponding reactions are shown in Table 5.

[0155] Table 5. Effect of reaction atmosphere on the preparation of hydroxythioether compounds

[0156] Reaction Atmosphere Yield of hydroxythioether compounds Air (Example 1) 91％ Ar 60％ <![CDATA[O2]]> 71％

[0157] Example 27: The Effect of Time

[0158] Referring to Example 1, the time 16h was replaced with 24h and 12h respectively, while other things remained the same. The results of the corresponding reactions are shown in Table 6.

[0159] Table 6. Effect of time on the preparation of hydroxythioether compounds

[0160] reaction time Yield of hydroxythioether compounds 16h (Example 1) 91％ 24h 90％ 12h 71％

[0161] Example 28: Scale-up reaction

[0162] Referring to Example 1, under air conditions, styrene sulfonium salt (5.0 mmol, 1.6 g), silver trifluoroacetate (0.5 mmol, 110 mg), potassium carbonate (10 mmol, 1.38 g), water (50.0 mmol, 0.9 mL), and 25 mL of 1,4-dioxane were added to a 100 mL reaction flask and reacted at 80 °C for 16 h. After the reaction, the product was filtered and washed with dichloromethane, followed by vacuum distillation to remove the solvent. The crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1), and detected by TLC. The eluent containing the target product was collected, and the eluents containing the target product were combined and concentrated by evaporation to obtain the compound shown in Example 1, with a yield of 79%. This substance is a colorless oily liquid.

[0163] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing a hydroxy sulfide compound, characterized by, Using the sulfonium salt and H2O shown in Formula I as raw materials, the reaction is carried out under the action of alkali and catalyst CF3COOAg to obtain the hydroxy sulfide compound shown in Formula II; wherein R is selected from: aryl; R1 and R1' are mono- to tri-substituted, with substituents selected from: H, C1-4 alkyl, halogen, C1-4 alkoxy, aryl; R2, R2', and R3 are independently selected from: H, C1-4 alkyl, aryl; Z is selected from: O, S, -CH2CH2-; The aryl group can be substituted or unsubstituted phenyl or naphthyl; the substituents on the aryl group are selected from: C1-4 alkyl, C1-4 alkoxy, and halogen; The base is selected from any one or more of the following: potassium tert-butoxide, potassium carbonate, and potassium hydroxide.

2. The method of claim 1, wherein, The reaction is carried out in an organic solvent; the organic solvent is any one or more of 1,4-dioxane, ethylene glycol dimethyl ether, and tetrahydrofuran.

3. The method of claim 1, wherein, The molar ratio of the aryl sulfonium salt and H2O shown in Formula I is 1.0:10-20.

4. The method of claim 1, wherein, The amount of catalyst added is 10 mol% to 40 mol% based on the amount of aryl sulfonate shown in Formula I.

5. The method of claim 1, wherein, The molar ratio of the aryl sulfonium salt to the base shown in Formula I is 1.0:1.0 to 2.

0.

6. The method of claim 1, wherein, The amount of organic solvent added is 2 to 10 mL / mmol, calculated as the amount of aryl sulfonium salt shown in Formula I.

7. The method according to any one of claims 1 to 6, characterized in that, The reaction temperature is 60℃~100℃, and the time is 12~24h.

8. The method according to any one of claims 1 to 6, characterized in that, After the reaction, the product was purified by silica gel column chromatography. The purification method was as follows: after the reaction was completed, silica gel for column chromatography was added, the solvent was removed by vacuum distillation, the product was dried until it was powdered by silica gel adsorption, and then the sample was loaded onto the column. The product was eluted with petroleum ether and ethyl acetate, collected, and concentrated by evaporation to obtain alkyl alcohol compounds.

Images