Preparation method of aryl sulfide compound

Abstract

The invention discloses a preparation method of an aryl sulfide compound, which comprises the following steps: by taking a diaryl disulfide compound and halogenated hydrocarbon as raw materials, carrying out free radical chain transfer reaction in a mechanical grinding manner under the action of a polymer and a liquid auxiliary grinding reagent, and after the reaction is finished, separating and purifying the mixture to obtain the aryl sulfide compound. According to the invention, the characteristic that a polymer is subjected to force-induced fracture to generate free radicals in the mechanical grinding process is utilized for the first time, the chain transfer reaction with diaryl disulfide is triggered, and the efficient and safe preparation method of the aryl sulfide compound is realized. The process has the advantages of stable reaction system, simplicity in operation, high yield and environmental friendliness, and a novel technical route is provided for synthesis of the aryl sulfide compound.

Description

Technical Field

[0001] The present invention relates to the technical field of the preparation of organic compounds, and particularly relates to a method for preparing aryl sulfide compounds. Background Art

[0002] Sulfide compounds are present in many drugs and natural products and are often used as precursors for sulfoxide and sulfone drugs. As an electronic isostere of ether molecules, replacing the oxygen atom with a sulfur atom can effectively improve the hydrolysis stability and biological activity of drug molecules.

[0003] There are usually two methods for the preparation of sulfide compounds, including classical synthesis methods (nucleophilic substitution method, Chan–Lam sulfidization, Ullmann sulfidization) and reductive coupling method. Although the classical synthesis method has strong substrate generality, the starting materials thiophenol / thiol required by it are highly toxic, unstable in nature, and have a strong pungent and stinking odor. The reductive coupling method developed in recent years uses thiosulfonate or disulfide as the starting material. Compared with thiophenol or thiol, disulfide and thiosulfonate are more stable and are more ideal organic synthesis raw materials.

[0004] At present, there are few reports on the preparation of sulfide compounds by the reductive coupling strategy, and chemical reducing reagents need to be introduced, such as triethylsilane (literature: Synlett, 2011, 13, 1905−1911); tris(trimethylsilyl)silanol (literature: Chem. Sci., 2020, 11, 13079−13084); sodium borohydride (literature: J. Med. Chem., 2015, 58,3329−3339); nickel or manganese metal (literature: Nat. Commun. 2018, 9, 2240; Chem. Eur. J., 2021,27, 4883–4887). In addition, a large amount of toxic and harmful solvents need to be used in the above preparation methods.

[0005] Therefore, a better preparation of aryl sulfide compounds should have the following characteristics: 1) the reaction raw materials are stable in nature; 2) the use of organic reducing agents is reduced or avoided; 3) the use of organic solvents is minimized to the greatest extent.

[0006] In recent years, mechanochemical grinding technology has significantly enhanced the efficiency and selectivity of organic reactions through solvent-free solid-phase synthesis, while reducing the demand for environmentally harmful solvents and enabling chemical transformations that are difficult to achieve under traditional solution conditions. Under the action of mechanical stress, polymers undergo force-induced fracture, generating macromolecular free radicals. These free radicals induced by mechanical force are called mechanoradicals. Recent studies have shown that mechanoradicals exhibit similar reactivity to small-molecule free radicals in specific chemical transformations (J. Am. Chem. Soc. 2024, 146, 1062). However, to date, there have been no reports of mechanoradicals directly participating in small-molecule chemical reactions. Summary of the Invention

[0007] In view of the problems existing in the prior art, the purpose of the present invention is to provide a method for preparing aryl sulfide compounds that is solvent-free, easy to operate, environmentally friendly, and highly efficient.

[0008] To achieve the above purpose, the technical solution of the present invention is as follows: A method for preparing an aryl sulfide compound, comprising the following steps: Using the diaryl disulfide compound shown in formula (1) and the halogenated hydrocarbon shown in formula (2) as raw materials, under the action of a polymer and a liquid-assisted grinding reagent, a radical chain transfer reaction is carried out by mechanical grinding. After the reaction is completed, the mixture is separated and purified to obtain the aryl sulfide compound shown in formula (3); The specific reaction process is as follows: .

[0009] Further, the molar ratio of the diaryl disulfide compound shown in formula (1) to the halogenated hydrocarbon shown in formula (2) is 1:2 to 6.7; the mass ratio of the polymer to the volume of the liquid-assisted grinding reagent is 500 to 1500:0 to 1000, with the mass unit being mg and the volume unit being m L.

[0010] Further, the diaryl disulfide compound shown in formula (1) is one of diphenyl disulfide, 2,2'-dimethyl diphenyl disulfide, 3,3'-dimethyl diphenyl disulfide, bis(4-hydroxyphenyl) disulfide, 4,4'-dichlorodiphenyl disulfide, bis(naphthalen-2-yl) disulfide, bis(2-methyl-3-furyl) disulfide, dibenzothiazole disulfide, 4,4'-dimethoxydiphenyl disulfide, p-tolyl disulfide, or bis(2,6-dichlorophenyl) disulfide.

[0011] Further, the halogenated hydrocarbon shown in the formula (2) is (2-bromoethyl)benzene, (2-chloroethyl)benzene, 2-(3-bromopropyl)isoindole-1,3-dione, bromoethyltrimethylsilane, 1-[4-(4-chlorophenyl)-2-chloron-butyl]imidazole, benzyl bromide, (3-bromopropyl)benzene, (4-bromobutyl)benzene, 2-bromomethylnaphthalene, 2-phenoxyethyl bromide, bromoacetic acid, methyl bromoacetate, ethyl 7-bromoheptanoate, bromocyclopentane, ethyl 2-bromopropionate, diphenylbromomethane, 3-bromocyclohexene, 1-bromoadamantane, triphenylbromomethane, ethyl 2-bromo-2-methylpropionate, cholesterol chloride, 3'-azido-5'-bromo-3',5'-dideoxythymidine, 5-methyl-2-(propan-2-yl)cyclohexyl bromoacetate, acetyl bromo-α- D -glucose or 2-iodopyridine.

[0012] Further, the polymer is polyethylene powder, polytetrafluoroethylene powder, polyvinyl acetate particles or cellulose powder.

[0013] Further, the liquid-assisted grinding reagent is acetonitrile, ethyl acetate, tetrahydrofuran or n-hexane.

[0014] Further, the mechanical grinding method is as follows: The reactants and stainless steel balls with a diameter of 8 - 14 mm are respectively added into a stainless steel grinding jar, and then the grinding jar is sealed. The sealed grinding jar is placed in a swing-type grinding instrument, and the grinding jar is heated to control the temperature in the jar body at 70 - 130 °C, and mechanical grinding is carried out at a frequency of 20 - 30 Hz until the reaction is completed.

[0015] Further, the volume of the grinding jar in the swing-type grinding instrument is 15 mL, 25 mL or 50 mL, and the number of stainless steel balls is 1 - 2.

[0016] Further, the reaction time is 20 - 120 min.

[0017] Further, the specific process of separating and purifying the reaction mixture is as follows: The reaction mixture is transferred out of the grinding jar and the stainless steel balls are taken out; then it is dissolved with ethyl acetate, and the insoluble substances are filtered off; the filtrate is concentrated under reduced pressure, and column chromatography separation is carried out using petroleum ether and ethyl acetate as eluents, and the obtained eluate is evaporated to remove the solvent to obtain the target aryl thioether compound shown in the formula (3).

[0018] The reaction mechanism of the present invention is as follows: The present invention utilizes the polymer mechanochemical fracture mechanism during mechanical grinding to generate free radicals, which then undergo a halogen atom transfer reaction with halogenated hydrocarbons to directly initiate the formation of alkyl free radicals. Subsequently, these free radicals experience a chain transfer step with diaryl disulfides, thereby achieving the direct thioetherification of various alkanes and synthesizing aryl thioether compounds.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) The present invention utilizes the property of generating free radicals through polymer force-induced fracture during mechanical grinding to trigger a chain transfer reaction with diaryl disulfides, achieving an efficient and safe preparation method for aryl thioether compounds. This process has the advantages of a stable reaction system, simple operation, high yield, and environmental friendliness, providing a novel technical route for the synthesis of aryl thioether compounds. 2) Through mechanical grinding technology, the present invention does not require the use of various unstable, toxic, and harmful chemicals and large amounts of organic solvents, such as thiophenol, potassium carbonate, manganese powder, etc., thus simplifying the reaction system and reducing the impact on the environment, meeting the requirements of green chemistry. 3) The present invention can complete the reaction within a short time (within 0.5 - 2 hours), significantly shortening the long-time stirring treatment (5 - 24 hours) required by traditional methods, and achieving high yield and selectivity by effectively utilizing mechanical force, heat energy, and specific additives. In addition, the polymer used can be directly recycled and reused without affecting the reaction efficiency. 4) The preparation method of the present invention adopts mechanical grinding technology, does not require complex equipment and steps, and the entire preparation process is more economical and efficient. Specific Embodiments

[0020] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0021] Example 1 Preparation of Phenyl(2-phenylethyl) Sulfane In a 15 mL stainless steel grinding jar, add diphenyl disulfide (131 mg, 0.6 mmol), (2-bromoethyl)benzene (555 mg, 3 mmol), polytetrafluoroethylene powder (900 mg), acetonitrile (500 mL), and then add 2 stainless steel balls with a diameter of 8 mm. Tighten the grinding jar and place it in a swing grinder. Heat the grinding jar and control the temperature inside the jar to 100 °C. Grind at a frequency of 30 Hz for 60 min. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 20 mL of ethyl acetate, filter, concentrate the filtrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain phenyl(2-phenylethyl)sulfane, a pale yellow oily liquid, 227 mg, with a yield of 99%. Thoroughly dry the filter cake in a vacuum drying oven to obtain 1024 mg of filter residue. 1 H NMR(600 MHz,CDCl3) δ: 7.40 – 7.36 (m, 2H), 7.34 – 7.29 (m, 4H), 7.25 – 7.19 (m, 4H), 3.20– 3.17 (m, 2H), 2.97 – 2.93 (m, 2H). 13 C NMR(150 MHz, CDCl3) δ 140.2, 136.4,129.2, 128.9, 128.5, 128.5, 126.4, 126.0, 35.6, 35.1. Polymer recycling: Directly use the dried filter residue above for the next reaction to obtain phenyl(2-phenylethyl)sulfane product, 226 mg, with a yield of 99%. After the polymer is reused 5 times, the product yield does not decrease significantly. The specific data are shown in the following table:

[0022] Example 2 Preparation of (2-methylphenyl)(2-phenylethyl)sulfane In a 25 mL stainless steel grinding jar, add 2,2'-dimethyl diphenyl disulfide (148 mg, 0.6 mmol), (2-bromoethyl)benzene (555 mg, 3.0 mmol), polytetrafluoroethylene powder (900 mg), tetrahydrofuran (400 mL), and then add 2 stainless steel balls with a diameter of 13 mm. Tighten the grinding jar and place it in a swing-type grinding instrument. Heat the grinding jar and control the temperature inside the jar to 80 °C. Grind for 70 min at a frequency of 25 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve them with 20 mL of ethyl acetate, filter, and concentrate under reduced pressure. Then, perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain (2-methylphenyl)(2-phenylethyl) sulfide, a colorless oily liquid, 243 mg, with a yield of 96%. 1 H NMR(600 MHz, CDCl3) δ: 7.37 – 7.31 (m,3H), 7.28 – 7.23 (m, 3H), 7.20 (t, J J = 8.0 Hz, 2H), 7.14 (t, J J = 7.4 Hz, 1H),3.21 – 3.17 (m, 2H), 3.00 – 2.96 (m, 2H), 2.41 (s, 3H). 13 C NMR(150 MHz, CDCl3)δ 140.3, 137.6, 135.7, 130.1, 128.5, 128.5, 127.8, 126.4, 126.4, 125.7, 35.5,34.3, 20.4. Example 3 Preparation of (3-methylphenyl)(2-phenylethyl) sulfide Add 3,3'-dimethyldiphenyldisulfide (148 mg, 0.6 mmol), (2-bromoethyl)benzene (555 mg, 3.0 mmol), polytetrafluoroethylene powder (800 mg), and acetonitrile (300 m L) into a 15 mL stainless steel grinding jar. Then add 1 stainless steel ball with a diameter of 14 mm. Tighten the grinding jar and place it in a swing-type grinding instrument. Heat the grinding jar and control the temperature inside the jar to 70 °C. Grind for 30 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve them with 20 mL of ethyl acetate, filter, and concentrate under reduced pressure. Then, perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain (3-methylphenyl)(2-phenylethyl) sulfide, a colorless oily liquid, 249 mg, with a yield of 91%. 11H NMR (600 MHz, CDCl3) δ: 7.32 – 7.29 (m, 2H), 7.24 – 7.15 (m, 6H), 7.02 – 6.99 (m, 1H), 3.18 – 3.15 (m, 2H), 2.95 – 2.91 (m, 2H), 2.33 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 140.3, 138.7, 136.1, 129.9, 128.8, 128.5, 126.9, 126.4, 126.2, 35.7, 35.1, 21.3. Example 4 Preparation of 4-[(2-phenylethyl)thio]phenol In a 15 mL stainless steel grinding jar, bis(4-hydroxyphenyl) disulfide (150 mg, 0.6 mmol), (2-bromoethyl)benzene (740 mg, 4 mmol), polytetrafluoroethylene powder (1000 mg), and n-hexane (200 m L) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing-type grinder. The grinding jar was heated and the temperature inside the jar was controlled at 90 °C. It was ground at a frequency of 20 Hz for 90 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 40 mL of ethyl acetate, filtered, concentrated under reduced pressure, and subjected to column chromatography separation using petroleum ether and ethyl acetate (volume ratio 5:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain 4-[(2-phenylethyl)thio]phenol, a colorless oily liquid, 220 mg, with a yield of 80%. 1 1H NMR (600 MHz, CDCl3) δ: 7.35 – 7.31 (m, 2H), 7.30 – 7.27 (m, 2H), 7.23 – 7.19 (m, 1H), 7.17 (d, J = 7.0 Hz, 2H), 6.81 – 6.77 (m, 2H), 3.09 – 3.04 (m, 2H), 2.89 – 2.85 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 154.9, 140.3, 133.5, 128.5, 128.5, 126.5, 126.3, 116.1, 37.2, 35.9. Example 5 Preparation of [2-(4-chlorophenyl)ethyl]phenylsulfane In a 50 mL stainless steel grinding jar, 4,4'-dichlorodiphenyl disulfide (172 mg, 0.6 mmol), (2-bromoethyl)benzene (340 mg, 2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (100 m mL) were added. Then, 2 stainless steel balls with a diameter of 14 mm were added. The grinding jar was tightened and placed in a swing-type grinder. The grinding jar was heated and the temperature inside the jar was controlled at 90 °C. It was ground at a frequency of 30 Hz for 90 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 20 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 80:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain [2-(4-chlorophenyl)ethyl]phenyl sulfide, a light yellow oily liquid, 244 mg, with a yield of 82%. 1 1H NMR(600 MHz, CDCl3) δ 7.33 – 7.26 (m, 6H), 7.25– 7.22 (m, 1H), 7.21 – 7.17 (m, 2H), 3.18 – 3.13 (m, 2H), 2.94 – 2.90 (m,2H). 13 13C NMR(150 MHz, CDCl3) δ 139.9, 134.9, 132.0, 130.6, 129.0, 128.5, 128.5,126.5, 35.5, 35.4. Example 6 Preparation of (naphthalen-2-yl)(2-phenylethyl) sulfide In a 25 mL stainless steel grinding jar, bis(naphthalen-2-yl) disulfide (191 mg, 0.6 mmol), (2-bromoethyl)benzene (370 mg, 2 mmol), cellulose powder (1200 mg), and acetonitrile (500 m mL) were added. Then, 2 stainless steel balls with a diameter of 14 mm were added. The grinding jar was tightened and placed in a swing-type grinder. The grinding jar was heated and the temperature inside the jar was controlled at 100 °C. It was ground at a frequency of 30 Hz for 120 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 25 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain (naphthalen-2-yl)(2-phenylethyl) sulfide, a light yellow oily liquid, 156 mg, with a yield of 49%. 11H NMR (600 MHz, CDCl3) δ 7.83 – 7.73 (m, 4H), 7.52 – 7.43 (m, 3H), 7.33 (t, J J = 7.6 Hz, 2H), 7.27 – 7.23 (m, 3H), 3.32 – 3.27 (m, 2H), 3.02 – 2.98 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 140.2, 133.9, 133.8, 131.7, 128.5, 128.4, 127.7, 127.3, 127.0, 126.9, 126.5, 126.5, 125.6, 35.6, 35.0. Example 7 Preparation of 2-Methyl-3-[(2-phenylethyl)thio]furan In a 50 mL stainless steel grinding jar, bis(2-methyl-3-furyl) disulfide (135 mg, 0.6 mmol), (2-bromoethyl)benzene (666 mg, 3.6 mmol), polytetrafluoroethylene powder (1500 mg), and acetonitrile (600 m mL) were added. Then, two stainless steel balls with a diameter of 14 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 80 °C. Grinding was carried out at a frequency of 30 Hz for 80 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatography separation was carried out using petroleum ether and ethyl acetate (volume ratio 30:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain 2-methyl-3-[(2-phenylethyl)thio]furan, a yellow oily liquid, 175 mg, with a yield of 67%. 1 1H NMR (600 MHz, CDCl3) δ: 7.31 – 7.26 (m, 3H), 7.22 – 7.19 (m, 1H), 7.16 (d, J J = 7.4 Hz, 2H), 6.35 (d, J J = 1.9 Hz, 1H), 2.89 – 2.81 (m, 4H), 2.34 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 154.8, 140.6, 140.3, 128.5, 128.4, 126.3, 114.8, 110.2, 37.1, 36.3, 11.8. Example 8 Preparation of 2-[(2-phenylethyl)thio]benzo d [1,3]thiazole Add dibenzothiazole disulfide (199 mg, 0.6 mmol), (2-bromoethyl)benzene (370 mg, 2 mmol), polytetrafluoroethylene powder (600 mg), and acetonitrile (500 m L) into a 15 mL stainless steel grinding jar. Then add 2 stainless steel balls with a diameter of 11 mm, tighten the grinding jar, and place it in a swing grinder. Heat the grinding jar and control the temperature inside the jar to 80 °C. Grind at a frequency of 30 Hz for 30 min. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve it with 35 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 6:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain 2-[(2-phenylethyl)thio]benzo d [1,3]thiazole, a colorless oily liquid, 198 mg, yield 61%. 1 H NMR(600 MHz, CDCl3) δ: 7.90 (d, J =8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.33 (s, 5H),7.26 (s, 2H), 3.60 (t, J = 7.7 Hz, 2H), 3.15 (t, J = 7.7 Hz, 2H). 13 C NMR(150 MHz,CDCl3) δ 166.7, 153.3, 139.6, 135.2, 128.7, 128.6, 126.7, 126.0, 124.2,121.5, 121.0, 35.6, 34.8. Example 9 Preparation of 2-{3-[(4-methoxyphenyl)thio]propyl}isoindoline-1,3-dione Add 4,4'-dimethoxydiphenyl disulfide (167 mg, 0.6 mmol), 2-(3-bromopropyl)isoindoline-1,3-dione (322 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and ethyl acetate (400 mL), add 2 stainless steel balls with a diameter of 9 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 60 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 45 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 10:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain 2-{3-[(4-methoxyphenyl)thio]propyl}isoindoline-1,3-dione, a white solid, 342 mg, with a yield of 87%. 1 H NMR(600MHz, CDCl3) δ:7.83 (dd, J = 5.4, 3.0 Hz, 2H), 7.71 (dd, J = 5.4, 3.0 Hz, 2H),7.37 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 3.82 – 3.78 (m, 5H), 2.83 (t, J = 7.2 Hz, 2H), 1.93 (p, J = 7.2 Hz, 2H). 13 C NMR(150 MHz, CDCl3) δ 168.3, 159.2,134.0, 133.9, 132.1, 125.8, 123.2, 114.6, 55.3, 37.0, 33.6, 28.2. Example 10 Preparation of Trimethyl{[(4-methylphenyl)thio]methyl}silane Add p-tolyl disulfide (148 mg, 0.6 mmol), bromoethyltrimethylsilane (585 mg, 3.5 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (300 m L) to a 15 mL stainless steel grinding jar, add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 50 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 15 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain trimethyl{[(4-methylphenyl)thio]methyl}silane, a colorless oily liquid, 235 mg, with a yield of 93%. 11H NMR (600 MHz, CDCl3) δ: 7.23 – 7.19 (m, 2H), 7.11 – 7.07 (m, 2H), 2.31 (s, 3H), 2.18 (s, 2H), 0.17 (s, 9H). 13 13C NMR (150 MHz, CDCl3) δ 136.6, 134.5, 129.4, 126.6, 20.9, 18.9, -1.6. Example 11 Preparation of 1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]imidazole In a 15 mL stainless steel grinding jar, bis(2,6-dichlorophenyl) disulfide (213 mg, 0.6 mmol), 1-[4-(4-chlorophenyl)-2-chlorobutyl]imidazole (323 mg, 1.2 mmol), polytetrafluoroethylene powder (800 mg), and acetonitrile (300 m mL) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 90 °C. Grinding was carried out at a frequency of 30 Hz for 110 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 40 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 8:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain 1-[4-(4-chlorophenyl)-2-[(2,6-dichlorophenyl)thio]butyl]imidazole, a off-white solid, 349 mg, with a yield of 71%. 1 1H NMR (600 MHz, CDCl3) δ 7.45 (s, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.25 – 7.18 (m, 3H), 7.02 – 6.97 (m, 3H), 6.83 (t, J = 1.3 Hz, 1H), 4.10 – 4.03 (m, 2H), 3.59 – 3.54 (m, 1H), 2.89 – 2.84 (m, 1H), 2.75 – 2.69 (m, 1H), 1.90 – 1.83 (m, 1H), 1.80 – 1.73 (m, 1H). 1313C NMR (150 MHz, CDCl3) δ 141.3, 138.9, 137.4, 131.9, 131.2, 130.5, 129.6, 129.0, 128.6, 119.0, 51.17, 48.5, 33.6, 31.8. Example 12 Preparation of Benzyl Phenyl Sulfide In a 25 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), benzyl bromide (342 mg, 2 mmol), and polytetrafluoroethylene powder (1500 mg) were added. Then, two stainless steel balls with a diameter of 14 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 70 °C. Grinding was carried out for 120 min at a frequency of 30 Hz. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 20 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographed using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. The solvent was evaporated from the obtained eluate to give benzyl phenyl sulfide as a pale yellow oily liquid, 211 mg, with a yield of 88%. 1 1H NMR (600 MHz, CDCl3) δ 7.34 – 7.32 (m, 2H), 7.31 – 7.29 (m, 3H), 7.29 – 7.24 (m, 3H), 7.21 – 7.18 (m, 1H), 4.13 (s, 2H). 13 13C NMR (150 MHz, CDCl3) δ 137.4, 136.4, 129.8, 128.8, 128.8, 128.5, 127.1, 126.3, 39.0. Example 13 Preparation of Phenyl (3 - phenylpropyl) Sulfide In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), (3 - bromopropyl)benzene (398 mg, 2.0 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 mL), add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature inside the jar at 80 °C, and grind for 120 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve them with 20 mL of ethyl acetate, filter, and concentrate under reduced pressure. Then, perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain phenyl(3-phenylpropyl)sulfane, a pale yellow oily liquid, 268 mg, with a yield of 98%. 1 H NMR(400 MHz, CDCl3) δ :7.36 – 7.27 (m, 6H), 7.25 – 7.16 (m,4H), 2.95 (t, J = 7.3 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H), 2.04 – 1.95 (m, 2H). 13 CNMR(150 MHz, CDCl3) δ 141.3, 136.5, 129.1, 128.8, 128.5, 128.4, 125.9, 125.8,34.6, 32.9, 30.6. Example 14 Preparation of phenyl(4-phenylbutyl)sulfane In a 15 mL stainless steel grinding jar, add diphenyl disulfide (131 mg, 0.6 mmol), (4-bromobutyl)benzene (320 mg, 1.5 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (100 m L), add 2 stainless steel balls with a diameter of 10 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature inside the jar at 80 °C, and grind for 30 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve them with 20 mL of ethyl acetate, filter, and concentrate under reduced pressure. Then, perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain phenyl(4-phenylbutyl)sulfane, a pale yellow oily liquid, 217 mg, with a yield of 75%. 1 H NMR(400 MHz, CDCl3) δ: 7.33 – 7.24 (m, 6H), 7.21 – 7.13 (m,4H), 2.94 (t, J = 7.1 Hz, 2H), 2.63 (t, J= 7.4 Hz, 2H), 1.82 – 1.65 (m, 4H). 13 CNMR(150 MHz, CDCl3) δ 142.1, 136.8, 129.1, 128.8, 128.4, 128.3, 125.8, 125.8, 35.4, 33.5, 30.4, 28.7. Example 15 Preparation of (naphthalen-2-ylmethyl)phenylsulfane In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), 2-bromomethylnaphthalene (332 mg, 1.5 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 130 °C. It was ground at a frequency of 30 Hz for 30 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 20 mL of ethyl acetate, filtered, concentrated under reduced pressure, and separated by column chromatography using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain (naphthalen-2-ylmethyl)phenylsulfane, a pale yellow solid, 240 mg, with a yield of 80%. 1 H NMR(600 MHz, CDCl3) δ:7.80 (dd, J = 12.2, 7.1 Hz, 2H), 7.77 – 7.73(m, 1H), 7.68 (s, 1H), 7.49 – 7.44 (m, 3H), 7.35 – 7.31 (m, 2H), 7.27 – 7.23(m, 2H), 7.21 – 7.16 (m, 1H), 4.28 (s, 2H). 13 C NMR(150 MHz, CDCl3) δ 136.2, 134.9, 133.3, 132.6, 130.0, 128.8, 128.3, 127.7, 127.6, 127.4, 127.0, 126.4, 126.1, 125.8, 39.5. Example 16 Preparation of phenyl[2-(phenyloxy)ethyl]sulfane In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), 2-phenoxyethyl bromide (503 mg, 2.5 mmol), polytetrafluoroethylene powder (1300 mg), and acetonitrile (400 mL), add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinder, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 30 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 25 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 60:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain phenyl[2-(phenyloxy)ethyl]sulfane, a white solid, 237 mg, with a yield of 86%. 1 H NMR(600 MHz, CDCl3) δ: 7.46 – 7.42 (m, 2H), 7.35 – 7.31(m, 2H), 7.31 – 7.27 (m, 2H), 7.26 – 7.22 (m, 1H), 6.99 – 6.95 (m, 1H), 6.90– 6.87 (m, 2H), 4.17 (t, J = 7.1 Hz, 2H), 3.32 (t, J = 7.1 Hz, 2H). 13 C NMR(150MHz, CDCl3) δ 158.4, 135.4, 129.9, 129.5, 129.0, 126.5, 121.0, 114.6, 66.6,32.9. Preparation of Phenylthioacetic Acid in Example 17 Add diphenyl disulfide (131 mg, 0.6 mmol), bromoacetic acid (167mg, 1.2 mmol), polytetrafluoroethylene powder (1400 mg), and acetonitrile (1000 m L) to a 15 mL stainless steel grinding jar, add 2 stainless steel balls with a diameter of 10 mm, tighten the grinding jar, place it in a swing-type grinder, heat the grinding jar and control the temperature in the jar to 100 °C, and grind for 120 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 50 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 1:2) as the eluent. Evaporate the solvent from the obtained eluate to obtain phenylthioacetic acid, a white solid, 137 mg, with a yield of 68%. 1 HNMR (600 MHz, CDCl3) δ:7.44 – 7.40 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.27 –7.23 (m, 1H), 3.67 (s, 2H).13 C NMR (150 MHz, CDCl3) δ 175.6, 134.5, 130.1, 129.2, 127.3, 36.6. Example 18 Preparation of Methyl Phenylthioacetate In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), methyl bromoacetate (230 mg, 1.5 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing-type grinding instrument. The grinding jar was heated and the temperature inside the jar was controlled at 80 °C. It was ground at a frequency of 30 Hz for 60 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 40:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain methyl phenylthioacetate, a colorless oily liquid, 176 mg, with a yield of 81%. 1 H NMR (600 MHz, CDCl3) δ: 7.43 – 7.38 (m, 2H), 7.32 – 7.28 (m, 2H), 7.25 – 7.21 (m, 1H), 3.71 (s, 3H), 3.65 (s, 2H). 13 C NMR (150 MHz, CDCl3) δ 170.1, 134.9, 129.9, 129.0, 127.0, 52.5, 36.5. Example 19 Preparation of Ethyl 7-(Phenylthio)heptanoate In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), ethyl 7-bromoheptanoate (283 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (600 m L) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing-type grinding instrument. The grinding jar was heated and the temperature inside the jar was controlled at 110 °C. It was ground at a frequency of 30 Hz for 30 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 30:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain ethyl 7-(phenylthio)heptanoate, a light yellow oily liquid, 252 mg, with a yield of 79%. 11H NMR (400 MHz, CDCl3) δ: 7.34 – 7.23 (m, 4H), 7.19 – 7.12 (m, 1H), 4.11 (q, J J = 7.1 Hz, 2H), 2.93 – 2.88 (m, 2H), 2.28 (t, J J = 7.5 Hz, 2H), 1.68 – 1.57 (m, 4H), 1.48 – 1.40 (m, 2H), 1.37 – 1.30 (m, 2H), 1.24 (t, J J = 7.1 Hz, 3H). 13 13C NMR (150 MHz, CDCl3) δ 173.6, 136.8, 128.9, 128.7, 125.6, 60.1, 34.2, 33.4, 28.9, 28.6, 28.3, 24.7, 14.2. Example 20 Preparation of 5-Methyl-2-(propan-2-yl)cyclohexyl (phenylthio)acetate In a 15 mL stainless steel grinding jar, diphenyldisulfide (131 mg, 0.6 mmol), 5-methyl-2-(propan-2-yl)cyclohexyl bromoacetate (332 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (400 m mL) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 100 °C. Grinding was carried out at a frequency of 30 Hz for 60 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographed using petroleum ether and ethyl acetate (volume ratio 60:1) as the eluent. The solvent was evaporated from the obtained eluate to give 5-Methyl-2-(propan-2-yl)cyclohexyl (phenylthio)acetate as a pale yellow oily liquid, 275 mg, with a yield of 75%. 11H NMR (600 MHz, CDCl3) δ 7.43 – 7.37 (m, 2H), 7.31 – 7.26 (m, 2H), 7.23 – 7.19 (m, 1H), 4.71– 4.66 (m, 1H), 3.63 (s, 2H), 1.95 – 1.91 (m, 1H), 1.78 – 1.73 (m, 1H), 1.68– 1.62 (m, 2H), 1.48 – 1.41 (m, 1H), 1.37 – 1.31 (m, 1H), 1.06 – 0.97 (m,1H), 0.96 – 0.89 (m, 1H), 0.89 – 0.87 (m, 3H), 0.86 – 0.80 (m, 4H), 0.68 (d, J J = 7.0 Hz, 3H). 13 13C NMR (150 MHz, CDCl3) δ 169.2, 135.1, 129.7, 128.9, 126.7,75., 46.84, 40.6, 36.8, 34.1, 31.3, 25.9, 23.2, 21.9, 20.7, 16.0. Example 21 Preparation of Cyclopentylphenyl Sulfide Add diphenyl disulfide (131 mg, 0.6 mmol), cyclopentyl bromide (596 mg, 4 mmol), polytetrafluoroethylene powder (1000 mg), and acetonitrile (200 m mL) into a 15 mL stainless steel grinding jar. Then add 2 stainless steel balls with a diameter of 12 mm. Tighten the grinding jar and place it in a swing mill. Heat the grinding jar and control the temperature inside the jar at 80 °C. Grind at a frequency of 30 Hz for 120 min. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 15 mL of ethyl acetate, filter, and concentrate under reduced pressure. Then perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to get cyclopentylphenyl sulfide, a light yellow oily liquid, 175 mg, with a yield of 82%. 1 1H NMR (600 MHz, CDCl3) δ 7.39 – 7.33 (m, 2H), 7.30 – 7.25 (m, 2H),7.20 – 7.15 (m, 1H), 3.63 – 3.57 (m, 1H), 2.09 – 2.02 (m, 2H), 1.83 – 1.75(m, 2H), 1.66 – 1.58 (m, 4H).13 13C NMR (150 MHz, CDCl3) δ 137.3, 130.0, 128.7, 125.9, 45.9, 33.6, 24.8. Example 22 Preparation of Ethyl 2-(Phenylthio)propionate In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), ethyl 2-bromopropionate (217 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 80 °C. Grinding was carried out at a frequency of 30 Hz for 30 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatography separation was carried out using petroleum ether and ethyl acetate (volume ratio 70:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain ethyl 2-(phenylthio)propionate, a colorless oily liquid, 209 mg, with a yield of 83%. 1 1H NMR (600 MHz, CDCl3) δ: 7.48 – 7.43 (m, 2H), 7.32 – 7.27 (m, 3H), 4.15 – 4.07 (m, 2H), 3.79 (q, J J = 7.1 Hz, 1H), 1.48 (d, J J = 7.1 Hz, 3H), 1.17 (t, J J = 7.1 Hz, 3H). 13 13C NMR (150 MHz, CDCl3) δ 172.6, 133.3, 133.0, 128.9, 127.9, 61.1, 45.3, 17.4, 14.0. Example 23 Preparation of (Diphenylmethyl)phenylsulfane In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), diphenylbromomethane (296 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 mL), add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinder, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 30 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve them with 25 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain (diphenylmethyl)phenylsulfane, a white solid, 274 mg, with a yield of 83%. 1 H NMR(600 MHz, CDCl3) δ:7.43 (d, J J = 7.6 Hz, 4H), 7.30 (t, J J = 7.6 Hz,4H), 7.26 – 7.20 (m, 4H), 7.20 – 7.12 (m, 3H), 5.55 (s, 1H). 13 C NMR (150 MHz,CDCl3) δ 141.0, 136.1, 130.5, 128.7, 128.5, 128.4, 127.2, 126.6, 57.4. Example 24 Preparation of (cyclohex-1-en-3-yl)phenylsulfane Add diphenyldisulfide (131 mg, 0.6 mmol), 3-bromocyclohexene (564 mg, 3.5 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) to a 15 mL stainless steel grinding jar, add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinder, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 60 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve them with 20 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain (cyclohex-1-en-3-yl)phenylsulfane, a white solid, 217 mg, with a yield of 95%. 11H NMR (600 MHz, CDCl3) δ: 7.48 – 7.43 (m, 2H), 7.35 – 7.30 (m, 2H), 7.27 – 7.23 (m, 1H), 5.89 – 5.85 (m, 1H), 5.84 – 5.78 (m, 1H), 3.92 – 3.87 (m, 1H), 2.13 – 2.02 (m, 2H), 2.01 – 1.90 (m, 2H), 1.85 – 1.80 (m, 1H), 1.67 – 1.61 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 135.9, 131.2, 130.4, 128.8, 126.9, 126.5, 43.9, 28.8, 24.9, 19.4. Example 25 Preparation of Phenyl(tricyclo[3.3.1.13,7]dec-3-yl)sulfane In a 15 mL stainless steel grinding jar, diphenyldisulfide (131 mg, 0.6 mmol), 1-bromoadamantane (645 mg, 3 mmol), and polyethylene powder (900 mg) were added. Then, two stainless steel balls with a diameter of 10 mm were added. The grinding jar was tightened and placed in a swing grinder. The grinding jar was heated and the temperature inside the jar was controlled at 110 °C. Grinding was carried out at a frequency of 30 Hz for 60 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 100:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain phenyl(tricyclo[3.3.1.13,7]dec-3-yl)sulfane, a white solid, 260 mg, with a yield of 89%. 1 1H NMR (400 MHz, CDCl3) δ: 7.54 – 7.47 (m, 2H), 7.39 – 7.29 (m, 3H), 2.04 – 1.98 (m, 3H), 1.84 – 1.79 (m, 6H), 1.69 – 1.54 (m, 6H). 13 13C NMR (150 MHz, CDCl3) δ 137.7, 130.6, 128.5, 128.3, 47.8, 43.6, 36.2, 30.0. Example 26 Preparation of Ethyl 2-Methyl-2-(phenylthio)propionate In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), ethyl 2-bromo-2-methylpropionate (234 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m mL) were added. Then, two stainless steel balls with a diameter of 12 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 70 °C. It was ground at a frequency of 30 Hz for 60 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 30 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 80:1) as the eluent. The solvent of the obtained eluate was evaporated to obtain ethyl 2-methyl-2-(phenylthio)propionate, a colorless oily liquid, 236 mg, with a yield of 88%. 1 H NMR(600 MHz, CDCl3) δ 7.48 – 7.43 (m, 2H), 7.32– 7.27 (m, 3H), 4.15 – 4.07 (m, 2H), 3.79 (q, J = 7.1 Hz, 1H), 1.48 (d, J = 7.1Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H). 13 C NMR(150 MHz, CDCl3) δ 173.9, 136.7, 131.5,129.2, 128.5, 61.0, 50.9, 25.9, 14.0. Example 27 Preparation of [9a,11a-dimethyl-1-(6-methylheptan-2-yl)-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]phenyl sulfide In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), cholesterol chloride (486 mg, 1.2 mmol), polytetrafluoroethylene powder (500 mg), and acetonitrile (500 mL), add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 60 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 30 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 80:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain [[9a,11a-dimethyl-1-(6-methylheptan-2-yl)-2,3,3a,3b,4,6,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-cyclopenta[1,2-a]phenanthren-7-yl]phenylsulfane], white solid, 476 mg, yield 83%. 1 H NMR (600 MHz, CDCl3) δ: 7.41 – 7.38 (m, 2H), 7.28 (d, J = 7.8 Hz, 2H), 7.23 – 7.19 (m, 1H), 5.32 – 5.29 (m, 1H), 3.06 – 2.99 (m, 1H), 2.32 (d, J = 7.6 Hz, 2H), 2.03 – 1.94 (m, 2H), 1.92 – 1.87 (m, 2H), 1.86 – 1.79 (m, 1H), 1.65 – 1.22 (m, 13H), 1.20 – 1.02 (m, 8H), 0.99 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.88 – 0.86 (m, 6H), 0.68 (s, 3H). 13 C NMR(150 MHz, CDCl3) δ 141.7, 134.9, 131.8, 128.8, 126.6, 121.1, 56.8, 56.2, 50.3, 47.4, 42.3, 39.8, 39.6, 39.5, 36.9, 36.2, 35.8, 31.8, 31.8, 29.5, 28.2, 28.0, 24.3, 23.8, 22.8, 22.6, 20.9, 19.4, 18.7, 11.9. Example 28 Preparation of 1-{4-azido-5-[(phenylthio)methyl]tetrahydrofuran-2-yl}-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), 3'-azido-5'-bromo-3',5'-dideoxythymidine (395 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) were added. Then, two stainless steel balls with a diameter of 14 mm were added. The grinding jar was tightened and placed in a swing-type grinder. The grinding jar was heated and the temperature inside the jar was controlled at 100 °C. It was ground at a frequency of 30 Hz for 120 min. After grinding, all the reaction mixture was scraped out of the grinding jar, the stainless steel balls were taken out, dissolved with 40 mL of ethyl acetate, filtered, concentrated under reduced pressure, and column chromatographically separated using petroleum ether and ethyl acetate (volume ratio 20:1) as the eluent. The solvent was evaporated from the obtained eluate to obtain 1-{4-azido-5-[(phenylthio)methyl]tetrahydrofuran-2-yl}-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione, a white solid, 323 mg, with a yield of 75%. 1 H NMR(600 MHz, CDCl3) δ: 9.41 (s, 1H), 7.42 – 7.38 (m, 2H), 7.33 – 7.28 (m, 2H), 7.24 – 7.20 (m, 2H), 6.09 (t, J = 6.5 Hz, 1H), 4.26 – 4.22 (m,1H), 4.06 (q, J = 5.1 Hz, 1H), 3.33 – 3.26 (m, 2H), 2.46 – 2.41 (m, 1H), 2.39 – 2.33 (m, 1H), 1.82 (s, 3H). 13 C NMR(150 MHz, CDCl3) δ 163.8, 150.2, 135.5, 134.9, 129.4, 129.2, 126.8, 111.3, 85.1, 82.5, 62.2, 37.3, 36.2, 12.4. Example 29 Preparation of [(2R,3R,4S,5R,6S)-3,4,5-triacetoxy-6-(phenylthio)-3,4,5,6-tetrahydro-2H-pyran-2-yl]methyl acetate In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), acetyl bromide- a - D -glucose (493 mg, 1.2 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 mL), then add 2 stainless steel balls with a diameter of 12 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature in the jar to 90 °C, and grind for 60 min at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 45 mL of ethyl acetate, filter, concentrate under reduced pressure, and perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 4:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain acetic acid - [(2R,3R,4S,5R,6S)-3,4,5-triacetoxy-6-(phenylthio)-3,4,5,6-tetrahydro-2H-pyran-2-yl] methyl ester, a white solid, 454 mg, with a yield of 86%. 1 1H NMR(400 MHz, CDCl3) δ:7.44 (dd, J J = 7.7, 1.9 Hz, 2H), 7.33 – 7.27 (m, 3H),5.92 (d, J J = 5.7 Hz, 1H), 5.48 – 5.40 (m, 1H), 5.14 – 5.04 (m, 2H), 4.60 – 4.53(m, 1H), 4.32 – 4.24 (m, 1H), 4.06 – 4.00 (m, 1H), 2.10 (s, 3H), 2.06 – 2.02(m, 9H). 13 13C NMR(150 MHz, CDCl3) δ 170.5, 169.9, 169.8, 169.6, 132.5, 131.9,129.2, 127.8, 85.0, 70.8, 70.5, 68.6, 68.2, 61.9, 20.7, 20.6, 20.6, 20.6. Example 30 Preparation of 2-(phenylthio)pyridine In a 15 mL stainless steel grinding jar, add diphenyl disulfide (131 mg, 0.6 mmol), 2-iodopyridine (410mg, 2.0 mmol), polytetrafluoroethylene powder (900 mg), acetonitrile (500 mL), add 2 stainless steel balls with a diameter of 14 mm, tighten the grinding jar, place it in a swing-type grinding instrument, heat the grinding jar and control the temperature in the jar to 80 °C, and grind for 120 minutes at a frequency of 30 Hz. After grinding, scrape out all the reaction mixture from the grinding jar, take out the stainless steel balls, dissolve with 35 mL of ethyl acetate, filter, and concentrate under reduced pressure. Then, perform column chromatography separation using petroleum ether and ethyl acetate (volume ratio 20:1) as the eluent. Evaporate the solvent from the obtained eluate to obtain 2-(phenylthio)pyridine, a light yellow oily liquid, 206 mg, with a yield of 92%. 1 H NMR(600 MHz, CDCl3) δ: 8.43 – 8.37 (m, 1H), 7.60 – 7.54 (m,2H), 7.45 – 7.36 (m, 4H), 6.99 – 6.94 (m, 1H), 6.87 (d, J = 8.1 Hz, 1H). 13 C NMR(150 MHz, CDCl3) δ 161.3, 149.4, 136.5, 134.7, 130.9, 129.5, 128.9, 121.2,119.7, 77.2, 77.0, 76.8. Comparative Example 1 Preparation of phenyl(2-phenylethyl)sulfane (stirring treatment) Add diphenyl disulfide (131 mg, 0.6 mmol), (2-bromoethyl)benzene (555mg, 3 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) to a 15 mL pressure-resistant reaction tube and stir at 100 °C for 24 h. No product was formed after stirring.

[0023] Comparative Example 2 Preparation of phenyl(2-phenylethyl)sulfane (room temperature grinding treatment) Add diphenyl disulfide (131 mg, 0.6 mmol), (2-bromoethyl)benzene (555 mg, 3 mmol), polytetrafluoroethylene powder (900 mg), and acetonitrile (500 m L) to a 15 mL stainless steel grinding jar, add 2 stainless steel balls with a diameter of 8 mm, tighten the grinding jar, place it in a swing-type grinding instrument, and grind at a frequency of 30 Hz for 30 minutes. No product was formed after grinding.

[0024] Comparative Example 3 Preparation of phenyl(2-phenylethyl)sulfane (without adding polymer) In a 15 mL stainless steel grinding jar, diphenyl disulfide (131 mg, 0.6 mmol), (2-bromoethyl)benzene (555 mg, 3 mmol), and acetonitrile (500 m L) were added. Then, two stainless steel balls with a diameter of 8 mm were added. The grinding jar was tightened and placed in a swing mill. The grinding jar was heated and the temperature inside the jar was controlled at 80 °C, and it was ground at a frequency of 30 Hz for 30 minutes. No product was formed after grinding.

[0025] Comparative Example 4 Preparation of Phenyl(2-phenylethyl)sulfane (Nucleophilic Substitution Method) In a reaction flask, thiophenol (1.1 g, 10 mmol), potassium carbonate (7.0 g, 50 mmol), N , N N,N-dimethylformamide were added, and it was stirred for 5 minutes. Then, (2-bromoethyl)benzene (1.85 g, 10 mmol) was added, and it was stirred overnight at 90 °C. After the reaction was completed, it was extracted with ethyl acetate. Subsequently, the organic phase was washed with water five times and with saturated brine twice. The organic phase was separated and concentrated under reduced pressure, and then column chromatography was carried out using petroleum ether as the eluent. The solvent of the obtained eluate was evaporated to obtain phenyl(2-phenylethyl)sulfane, a pale yellow oily liquid, with a yield of 96%.

[0026] Comparative Example 5 Preparation of Phenyl(2-phenylethyl)sulfane (Reductive Coupling Method) In a pre-dried 8 mL screw vial, NiCl2(PPh3)2 (16 mg, 0.025 mmol), 6,6'-dimethyl-2,2'-bipyridine (7 mg, 0.0375 mmol), manganese powder (41 mg), and N , N N,N-dimethylformamide (1 mL) were added, and it was stirred at room temperature for ten minutes. Then, (2-bromoethyl)benzene (93 mg, 0.5 mmol) and S phenyl(phenylthio)sulfone (138 mg, 0.55 mmol) were added. Subsequently, N , N N,N-dimethylformamide (1.5 mL) was added dropwise. It was stirred at 30 °C for 5 h. After the reaction was completed, it was diluted with 100 mL of ethyl acetate, and the reaction solution was washed with 20 mL of water three times. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and then column chromatography was carried out using petroleum ether as the eluent. The solvent of the obtained eluate was evaporated to obtain phenyl(2-phenylethyl)sulfane, a pale yellow oily liquid, with a yield of 95%.

[0027] Comparative Example 6 Preparation of 2-(phenylthio)pyridine (Ullmann Thioetherification Method) In a 25 mL round-bottomed reaction flask under nitrogen protection, 2-iodopyridine (205 mg, 1.0 mmol), benzenethiol (121 mg, 1.1 mmol), cesium carbonate (652 mg, 2 mmol), copper(I) iodide (19 mg, 0.1 mmol) and glycerol (4 mL) were added, and the mixture was stirred at 110 °C for 24 h. After the reaction was completed, it was extracted with petroleum ether (40 mL). After concentration under reduced pressure, column chromatography was carried out using petroleum ether as the eluent. The solvent was evaporated from the obtained eluate to obtain 2-(phenylthio)pyridine, a pale yellow oily liquid, with a yield of 82%.

[0028] Through the studies of Comparative Examples 1 to 3, it was found that mechanical force, external heating and polymer additives are the key factors to ensure the smooth progress of such reactions. Compared with the traditional chemical reaction methods in solution, such as nucleophilic substitution and reductive coupling methods, the method proposed in the present invention shows significant advantages. Traditional methods usually require the use of unstable and environmentally unfriendly raw materials, including but not limited to benzenethiol, etc.; base reagents such as potassium carbonate; reducing agents such as manganese powder; metal catalysts such as NiCl2(PPh3)2, CuI; and a large amount of organic solvents, such as N , N -dimethylformamide. These components not only impose a burden on the environment, but also increase the operational complexity and cost. In contrast, the method described in the present invention does not require the above materials, but relies on mechanical force, external heating and polymer additives to achieve efficient conversion of chemical reactions.

Claims

1. A method for preparing an aryl sulfide compound, characterized in that The steps include: Using the diaryl disulfide compound represented by formula (1) and the halogenated hydrocarbon represented by formula (2) as raw materials, a free radical chain transfer reaction is carried out by mechanical grinding under the action of a polymer and a liquid-assisted grinding agent. After the reaction is completed, the mixture is separated and purified to obtain an aryl sulfide compound represented by formula (3); The specific reaction process is as follows: 。 2. The method for preparing an aryl sulfide compound according to claim 1, characterized in that The molar ratio of the diaryl disulfide compound represented by formula (1) to the halogenated hydrocarbon represented by formula (2) is 1:2-6.7; the mass ratio of the polymer to the volume ratio of the liquid auxiliary grinding agent is 500-1500:0-1000, with the mass unit being mg and the volume unit being mL.

3. The method for preparing an aryl sulfide compound according to claim 1 or 2, characterized in that The diaryl disulfide compound represented by the formula (1) is one of diphenyl disulfide, 2,2'-dimethyl diphenyl disulfide, 3,3'-dimethyl diphenyl disulfide, bis(4-hydroxyphenyl) disulfide, 4,4'-dichlorodiphenyl disulfide, di(naphthalene-2-yl) disulfide, bis(2-methyl-3-furyl) disulfide, dibenzothiazole disulfide, 4,4'-dimethoxydiphenyl disulfide, p-toluene disulfide or bis(2,6-dichlorophenyl) disulfide.

4. The method for preparing an aryl sulfide compound according to claim 1 or 2, characterized in that The halogenated hydrocarbon represented by formula (2) is (2-bromoethyl)benzene, (2-chloroethyl)benzene, 2-(3-bromopropyl)isoindole-1,3-dione, bromoethyltrimethylsilane, 1-[4-(4-chlorophenyl)-2-chloro-n-butyl]imidazole, benzyl bromide, (3-bromopropyl)benzene, (4-bromobutyl)benzene, 2-bromomethylnaphthalene, 2-phenoxyethyl bromide, bromoacetic acid, methyl bromoacetate, ethyl 7-bromoheptanoate, bromocyclopentane, ethyl 2-bromopropionate, diphenylmethane, 3-bromocyclohexene, 1-bromoadamantane, triphenylmethane, ethyl 2-bromo-2-methylpropionate, cholesterol chloride, 3'-azido-5'-bromo-3',5'-dideoxythymidine, 5-methyl-2-(propan-2-yl)cyclohexyl bromoacetate, acetyl bromide-α- D -Glucose or 2-iodopyridine.

5. The method for preparing an aryl sulfide compound according to claim 4, characterized in that The polymer is polyethylene powder, polytetrafluoroethylene powder, polyvinyl acetate particles or cellulose powder.

6. The method for preparing an aryl sulfide compound according to claim 5, characterized in that The liquid auxiliary grinding agent is acetonitrile, ethyl acetate, tetrahydrofuran or n-hexane.

7. The method for preparing an aryl sulfide compound according to claim 1, characterized in that The mechanical grinding method comprises the following steps: adding reactants and stainless steel balls with a diameter of 8 to 14 mm into a stainless steel grinding jar respectively, then sealing the grinding jar, placing the sealed grinding jar in a vibrating grinder, heating the grinding jar, controlling the temperature inside the jar to be 70 to 130° C., and performing mechanical grinding at a frequency of 20 to 30 Hz until the reaction is completed.

8. The method for preparing an aryl sulfide compound according to claim 7, characterized in that The grinding jar in the oscillating grinder has a volume of 15 mL, 25 mL or 50 mL, and the number of stainless steel balls is 1 to 2.

9. The method for preparing an aryl sulfide compound according to claim 7, characterized in that The reaction time is 20 to 120 min.

10. The method for preparing an aryl sulfide compound according to claim 1, characterized in that The specific process of separation and purification of the reaction mixture is as follows: The reaction mixture is transferred from the grinding pot and the stainless steel ball is taken out; it is then dissolved with ethyl acetate and the insoluble matter is removed by filtration; the filtrate is concentrated under reduced pressure and separated by column chromatography using petroleum ether and ethyl acetate as eluents, and the solvent is evaporated from the obtained eluate to obtain the target aryl sulfide compound represented by formula (3).

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