Method for rapidly preparing aza-aryl thioether compound through mechanical piezoelectric catalysis C-S coupling reaction

Abstract

The invention discloses a method for rapidly preparing aza-aryl thioether compounds through mechanical piezoelectric catalysis C-S coupling reaction. According to the technical scheme, a chlorinated aza-aryl compound and a disulfide compound are used as raw materials, and a C-S coupling reaction is carried out under the conditions of normal temperature, normal pressure and air in a Ni catalysis and trace liquid auxiliary mechanical grinding mode to prepare a series of aza-aryl sulfide coupling products in a green and safe mode. According to the invention, a mechanical force method is adopted to rapidly and simply carry out C-S coupling reaction to prepare an organic sulfide intermediate or carry out thioetherification modification on molecules, the operation and treatment method is simple, the reaction mode is green and safe and is environment-friendly, BaTiO3 / Zn / Ni concerted catalysis is adopted, the reaction condition is mild, and the reaction can be completed in 100 minutes.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis catalysis technology, specifically relating to a novel method for the rapid preparation of nitrogen-containing aromatic thioether compounds via mechanical grinding catalysis CS coupling reaction without inert gas protection or prolonged high-temperature reflux, and with the assistance of trace amounts of liquid. Background Technology

[0002] Azaaryl thioethers, due to their unique nitrogen heterocyclic and thioether group structures, have demonstrated significant research and application value in multiple fields. These compounds have attracted widespread attention due to their remarkable electron-donating or accepting capabilities; their excellent bioactivity makes them an important framework in anticancer drug design. In optoelectronics, they are used as luminescent materials in organic optoelectronic devices, exhibiting excellent luminescent performance. Simultaneously, in environmental science, the special chemical properties of azaaryl thioethers make them ideal markers for environmental pollutant detection, used in environmental monitoring and pollutant analysis. These diverse applications highlight the wide applicability and strategic value of azaaryl thioethers in contemporary science and industry. With the continuous advancement of chemical synthesis technology and the discovery of new applications, developing green, efficient, and simple synthetic methods for azaaryl thioethers has always been a research hotspot and a challenging issue in the field of organic synthesis.

[0003] In traditional organic synthetic chemistry, hot solvent metal coupling reactions have long been considered one of the most important methods for constructing CS bonds, and are widely used to synthesize bioactive and functional molecules with thioether skeletons. However, the successful implementation of this type of reaction usually requires the use of large amounts of organic solvents as a medium, including but not limited to 1,4-dioxane, toluene, and tetrahydrofuran. These organic solvents are volatile and toxic, posing a significant threat to the environment. Furthermore, such metal-catalyzed systems suffer from drawbacks such as precious metal leaching and environmental harm, high ligand costs, and the necessity of high temperatures. (See below.)

[0004] Chemists have been working to develop more efficient alternatives. Paolo Melchiorre developed a photocatalytic protocol that can prepare various alkyl-aryl sulfides without the need for thiols or transition metals. However, this reaction system suffers from excessively long reaction times. (See below:)

[0005] Therefore, how to construct a novel green and environmentally friendly CS coupling reaction catalytic system, develop new catalytic systems, and reduce the use of organic solvents has become a research hotspot and an urgent problem to be solved in this field. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides a method for preparing nitrogen-containing aromatic sulfide compounds by synergistic catalytic CS coupling reaction of piezoelectric materials and Zn / Ni reduction system under mechanical force. This method has a short reaction time, uses a suitable catalyst, and effectively reduces production costs.

[0007] The technical solution adopted in this invention is: A method for rapidly preparing aza-aryl sulfide compounds via a mechanical piezoelectric catalytic CS coupling reaction, wherein the aza-aryl sulfide compounds are prepared from chlorinated aza-aryl hydrocarbon compounds and disulfide compounds under ambient temperature and pressure and air conditions by a CS coupling reaction using BaTiO3 / Zn / Ni synergistic catalysis and micro-liquid-assisted mechanical grinding.

[0008] Furthermore, the above-mentioned method for rapidly preparing aza-aryl sulfide compounds by mechanical piezoelectric catalytic CS coupling reaction includes the following steps: under normal temperature and pressure and air conditions, using chloro-aza-aryl hydrocarbon compounds with structural formula (Ⅰ) and disulfide compounds with structural formula (Ⅱ) as raw materials, zinc powder, nickel bromide, barium titanate, 2,2'-bipyridine, iodine and trace amounts of auxiliary grinding solvent are added and placed in a grinding steel jar. Steel balls are added, the steel jar is sealed, and the steel jar is placed in a Retsch mixed ball mill and ground at 30 Hz for 60-120 min. The crude product obtained is separated and purified to obtain aza-aryl sulfide compounds with structural formula (Ⅲ).

[0009] Wherein, when (Ⅰ) is a pyridine compound, R is -Me, -OMe, -NH2, -CN, -CH2COOMe, -C(CH3)3, -CH2OH, -COOMe, -CF3, -F, -CH(OCH2CH2O), -OCOCH3 or -H; when (Ⅰ) is a quinoline compound, R is -Me or -H; when (Ⅰ) is a pyrimidine compound, R is -Me, -OMe or -H; disulfide compounds are aromatic disulfides or aliphatic disulfides.

[0010] Furthermore, in the above-mentioned method for the rapid preparation of chloro-aromatic sulfides via a mechanical piezoelectric catalytic CS coupling reaction, the chloro-aromatic compound is 4-chlorothieno[3,2-d]pyrimidine, 5-chloropyrazolo[1,5-a]pyrimidine, 6-chloro-9-H-purine, 6-chloro-9-beta-D-(2,3-isopropylidene)furanose ribosylpurine, or 6-chloropurine ribonucleotide; Disulfide compounds are those with structural formulas (Ⅳ), (Ⅴ), (Ⅵ), (Ⅶ), (Ⅷ), (Ⅸ) or (Ⅹ):

[0011] In compound (Ⅳ), R is 4-Me, 4-OMe, 4-NH2, -OH, -Cl, or 2-NH2.

[0012] Furthermore, in the above-mentioned method for the rapid preparation of aza-aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction, the molar ratio is: disulfide compound: chloro-aza-aryl compound: zinc powder: barium titanate: nickel bromide: 2,2'-bipyridine: iodine = 1: (2-3): (4-8): 2: 0.15: 0.4:2.

[0013] Preferably, the ratio of disulfide compounds: chloroaziridine compounds: zinc powder: barium titanate: nickel bromide: 2,2'-bipyridine: iodine is 1: 3: 6: 2: 0.15: 0.4: 2.

[0014] Furthermore, in the above-mentioned method for the rapid preparation of azaaryl sulfide compounds via a mechanical piezoelectric catalytic CS coupling reaction, the trace auxiliary grinding solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and water.

[0015] Preferably, the trace auxiliary grinding solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

[0016] More preferably, the trace auxiliary grinding solvent is N,N-dimethylformamide.

[0017] Furthermore, in the above-mentioned method for the rapid preparation of azaaryl thioether compounds via a mechanopiezo-piezo-catalyzed CS coupling reaction, the amount of the trace auxiliary grinding solvent is: (0.19 μL mg) -1 η = V (liquid; μL) / m (disulfide compounds, mg).

[0018] Furthermore, in the above-mentioned method for rapid preparation of azaaryl sulfide compounds via a mechanical piezoelectric catalytic CS coupling reaction, the steel ball has a diameter of 16 mm and a weight of 17 g.

[0019] Furthermore, in the above-mentioned method for rapid preparation of azaaryl sulfide compounds via mechanical piezoelectric catalytic CS coupling reaction, the grinding time is 100 min.

[0020] Furthermore, the method for rapidly preparing azaaryl sulfide compounds by the above-mentioned mechanical piezoelectric catalytic CS coupling reaction includes the following separation and purification steps: passing the mixture through a short silica gel column and eluting with CH2Cl2 / MeOH (100:0-10:1); washing the eluent with water, drying and concentrating to obtain the crude product; and performing silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate as the eluent to obtain the azaaryl sulfide compounds.

[0021] The beneficial effects of this invention are: 1. The method provided by this invention uses mechanical grinding, replacing traditional thermal energy to drive the reaction, which greatly shortens the reaction time, simplifies the experimental process, and improves the reaction yield.

[0022] 2. By using mechanical force to induce a polarized electric field in piezoelectric materials, the valence state of nickel catalysts (Ni(I) / Ni(III) cycle) is controlled, overcoming the reaction inertia of chlorinated compounds and their dependence on noble metals.

[0023] 3. The method provided by this invention uses inexpensive Ni compounds instead of Pd metal catalysts, which greatly reduces costs while achieving a maximum reaction yield of 98% for the substrate.

[0024] 4. The method provided by the present invention generates an organozinc sulfur reagent (RS-Zn-I) by in-situ reduction of disulfide with Zn / I2, thereby enhancing the nucleophilicity of sulfur and suppressing side reactions.

[0025] 5. The method provided by this invention uses only trace amounts of liquid to assist grinding, eliminating the use of large amounts of organic solvents, reducing reaction costs, and minimizing environmental harm. It is a green, mild, and environmentally friendly organic synthesis method that conforms to the concept of green chemistry.

[0026] 6. The method provided by this invention allows all reactions to be carried out under conventional conditions, without the need for high temperature, high pressure or inert gas protection, thus simplifying the experimental steps. Attached Figure Description

[0027] Figure 1 It is the 2-(phenylthio)pyridine prepared in Example 1. 1 H NMR spectrum.

[0028] Figure 2 It is the 2-(phenylthio)pyridine prepared in Example 1. 13 C NMR spectrum.

[0029] Figure 3 It is the 4-(phenylthio)thiopheno[3,2-d]pyrimidine prepared in Example 13. 1 H NMR spectrum.

[0030] Figure 4 It is the 4-(phenylthio)thiopheno[3,2-d]pyrimidine prepared in Example 13. 13 C NMR spectrum.

[0031] Figure 5 It is the 5-(phenylthio)pyrazolo[1,5-a]pyrimidine prepared in Example 14. 1 H NMR spectrum.

[0032] Figure 6 It is the 5-(phenylthio)pyrazolo[1,5-a]pyrimidine prepared in Example 14. 13 C NMR spectrum.

[0033] Figure 7 It is the 6-(phenylthio)-9H-purine prepared in Example 15 1 H NMR spectrum.

[0034] Figure 8 It is the 6-(phenylthio)-9H-purine prepared in Example 15 13 C NMR spectrum.

[0035] Figure 9 It is the (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol prepared in Example 16. 1 H NMR spectrum.

[0036] Figure 10 It is the (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol prepared in Example 16. 13 C NMR spectrum.

[0037] Figure 11 It is the ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purine-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl)methanol prepared in Example 17. 1 H NMR spectrum.

[0038] Figure 12 It is the ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purine-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl)methanol prepared in Example 17. 13 C NMR spectrum.

[0039] Figure 13 A schematic diagram illustrating the rapid preparation of nitrogen-containing aryl thioether compounds via a mechanical piezoelectric catalytic CS coupling reaction. Detailed Implementation

[0040] The technical solution of the present invention is described clearly and completely below. Obviously, the embodiments described herein are only a part of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0041] Example 1: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0042] The reaction formula is as follows:

[0043] The method is as follows: Under normal temperature, pressure, and air conditions, diphenyl disulfide (0.25 mmol), 2-chloropyridine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 79.5 mg of a yellow oil, namely 2-(phenylthio)pyridine, in 85% yield.

[0044] The structure of the prepared 2-(phenylthio)pyridine is characterized as follows: 1H NMR (600 MHz, Chloroform-d) δ8.41 (d, J = 5.0 Hz, 1H), 7.60 – 7.57 (m, 2H), 7.45 – 7.40 (m, 4H), 6.98 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 6.86 (dt, J = 8.1, 1.0 Hz, 1H). 13 C NMR (151MHz, Chloroform-d) δ 161.67, 149.65, 136.86, 135.09, 131.10, 129.76, 129.23,121.43, 119.98. HRMS (ESI): m / z calculated for C 11 H9NS+H + : 188.0528, [M+H] + Found: 188.0525.

[0045] The preparation of 2-(phenylthio)pyridine 1 H NMR image as follows Figure 1 .

[0046] The preparation of 2-(phenylthio)pyridine 13 C NMR spectrum as shown Figure 2 .

[0047] Example 2: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0048] Under normal temperature, pressure, and air conditions, diphenyl disulfide sulfur (0.25 mmol), 2-chloropyridine (0.5 mmol, 2.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 57.05 mg of a yellow oil, namely 2-(phenylthio)pyridine, in a yield of 61%.

[0049] Example 3: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0050] Under normal temperature, pressure, and air conditions, diphenyl disulfide sulfur (0.25 mmol), 2-chloropyridine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.0 mmol, 4.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 4.46 mg of a yellow oil, namely 2-(phenylthio)pyridine, in a yield of 4.8%.

[0051] Example 4: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0052] Under normal temperature, pressure, and air conditions, diphenyl disulfide sulfur (0.25 mmol), 2-chloropyridine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (2.0 mmol, 8.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 51.43 mg of a yellow oil, namely 2-(phenylthio)pyridine, in 55% yield.

[0053] Example 5: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0054] Under normal temperature, pressure, and air conditions, diphenyl disulfide (0.25 mmol), 2-chloropyridine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 60 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 65.45 mg of a yellow oil, namely 2-(phenylthio)pyridine, in 70% yield.

[0055] Example 6: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0056] Under normal temperature, pressure, and air conditions, diphenyl disulfide (0.25 mmol), 2-chloropyridine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 80 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 72.94 mg of a yellow oil, namely 2-(phenylthio)pyridine, in 78% yield.

[0057] Example 7: Preparation of 2-(phenylthio)pyridine by mechanical piezoelectric catalytic CS coupling reaction

[0058] Under normal temperature, pressure, and air conditions, diphenyl disulfide (0.25 mmol), 2-chloropyridine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 120 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 73.87 mg of a yellow oil, namely 2-(phenylthio)pyridine, in 79% yield.

[0059] Example 8: Preparation of 2-(phenylthio)pyridine derivatives by mechanical piezoelectric catalytic CS coupling reaction

[0060] The reaction formula is as follows:

[0061] Based on the reaction conditions of the aforementioned general synthetic formula, by changing the chloroaziridine substrate, the following 2-(phenylthio)pyridine derivatives can be obtained: 5-Methyl-2-(phenylthio)pyridine (yellow oil, 79.5 mg, 0.43 mmol, 85% yield).

[0062] 1 H NMR (600 MHz, Chloroform- d ) δ 8.27 (d, J =2.3 Hz, 1H), 7.54 (dd, J = 7.7, 1.8 Hz, 2H), 7.40–7.35 (m, 3H), 7.27 (dd, J= 8.2, 2.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 2.25 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 157.71, 150.06, 137.68, 134.42, 132.10, 129.83, 129.61, 128.78, 121.84, 17.96. HRMS (ESI): m / z calculated for C 12 H 11 NS + H + : 202.0685, [M + H] + found: 202.0692。

[0063] 5-Methoxy-2-(phenylthio)pyridine (pale yellow oil, 66.2 mg, 0.31 mmol, 61 % yield).

[0064] 1 H NMR (600 MHz, Chloroform- d ) δ 8.19 (d, J = 3.0 Hz, 1H), 7.49–7.46 (m, 2H), 7.36 – 7.30 (m, 3H), 7.06 (dd, J = 8.7, 3.0 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 3.81 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 154.10, 150.62, 137.16, 133.49, 133.23, 129.50, 128.23, 124.42, 122.60, 55.87. HRMS (ESI): m / z calculated for C 12 H 11 NOS + H + : 218.0634, [M + H] + found: 218.0638。

[0065] 3-Amino-6-(phenylthio)pyridin-3-amine (white solid, 65.7 mg, 0.33 mmol, 65% yield).

[0066] 1 H NMR (600 MHz, Chloroform- d ) δ 8.02 (d, J =2.9 Hz, 1H), 7.42–7.37 (m, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.25–7.22 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 8.4, 3.0 Hz, 1H), 3.53 (s, 2H). 13 CNMR (151 MHz, Chloroform- d ) δ 146.63, 141.08, 137.58, 134.87, 131.93, 129.31,127.51, 126.04, 123.25. HRMS (ESI): m / z calculated for C 11 H 10 N2S+H + 203.0637, [M+H] + Found: 203.0629.

[0067] 2-[6-(phenylthio)pyridin-3-yl]acetate (pale yellow oil, 93.5 mg, 0.37 mmol, 73% yield).

[0068] 1 H NMR (600 MHz, Chloroform- d ) δ 8.31 (d, J =2.4 Hz, 1H), 7.59–7.55 (m, 2H), 7.42–7.37 (m, 4H), 6.84 (d, J= 8.3 Hz, 1H), 3.67 (s, 3H), 3.54 (s, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 171.25, 160.42, 150.04, 137.82, 135.02, 131.10, 129.75, 129.23, 126.03, 121.30, 52.37, 37.72. HRMS (ESI): m / z calculated for C 14 H 13 NO2S+H + : 260.0740, [M+H] + found: 260.0730。

[0069] 5-Trifluoromethyl-2-(phenylthio)pyridine (2-(phenylthio)-5-(trifluoromethyl)pyridine) (white oil, 40.7 mg, 0.16 mmol, 31 % yield).

[0070] 1 H NMR (600 MHz, Chloroform- d ) δ 8.64 (s, 1H), 7.64–7.58 (m, 3H), 7.47 (dd, J = 5.2, 1.9 Hz, 3H), 6.90 (d, J = 8.5 Hz, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 167.00, 146.48, 146.45, 135.66, 133.58, 133.55, 130.08, 129.32, 124.61, 122.76, 122.54, 120.13. HRMS (ESI): m / z calculated for C 12 H8F3NS +H + : 256.0402, [M+H] + found: 202.0692。

[0071] Methyl 6-(phenylthio)nicotinate (yellow oil, 28.5 mg, 0.12 mmol, 23% yield).

[0072] 1 H NMR (600 MHz, Chloroform- d ) δ 8.98 (dd, J = 2.2, 0.9 Hz, 1H), 7.99 (dd, J = 8.5, 2.2 Hz, 1H), 7.62–7.60 (m, 2H), 7.46(dd, J = 5.1, 1.9 Hz, 3H), 6.84 (dd, J = 8.5, 0.9 Hz, 1H), 3.89 (s, 3H). 13 CNMR (151 MHz, Chloroform- d ) δ 167.78, 165.78, 150.85, 137.45, 135.61, 130.05,129.98, 129.51, 122.03, 119.83, 52.39. HRMS (ESI): m / z calculated forC 13 H 11 NO2S + Na + : 268.0403, [M+Na] + Found: 268.0395.

[0073] 5-fluoro-2-(phenylthio)pyridine (pale yellowoil, 16.5 mg, 0.08 mmol, 16% yield).

[0074] 1 H NMR (600 MHz, Chloroform- d ) δ 8.31 (d, J =3.0 Hz, 1H), 7.57–7.54 (m, 2H), 7.43–7.39 (m, 3H), 7.21 (ddd, J= 8.8, 8.0, 3.0 Hz, 1H), 6.92 (dd, J = 8.8, 4.1 Hz, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ158.53, 156.85, 156.28, 137.92, 137.76, 134.67, 131.57, 129.81, 129.22, 124.29, 124.16, 122.92, 122.90. HRMS (ESI): m / z calculated for C 11 H8FNS+H + : 206.0434, [M+H] + found: 206.0433。

[0075] 4-Methyl-2-(phenylthio)pyridine (pale yellow oil, 52.3 mg, 0.26 mmol, 52 % yield).

[0076] 1 H NMR (600 MHz, Chloroform- d ) δ 8.27 (d, J = 5.0Hz, 1H), 7.57 (dd, J = 7.5, 2.1 Hz, 2H), 7.43–7.39 (m, 3H), 6.81 (d, J = 5.0Hz, 1H), 6.71 (s, 1H), 2.19 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 161.08, 149.38, 148.18, 134.87, 131.40, 129.67, 129.03, 122.20, 121.40, 21.13. HRMS(ESI): m / z calculated for C 12 H 11 NS+H + : 202.0685, [M+H] + found: 202.0693。

[0077] (2-(phenylthio)pyridin-4-yl)methanol (solid, 106.4 mg, 0.49 mmol, 98% yield).

[0078] The melting point is 38.0-38.5 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 8.32 (d, J = 5.0 Hz, 1H), 7.55 (dd, J = 6.5, 3.0 Hz, 2H), 7.40 (q, J = 3.1, 2.5 Hz, 3H), 6.99 (d, J = 5.1 Hz, 1H), 6.88 (s, 1H), 4.57 (s, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 161.62, 151.32, 149.52, 134.97,130.94, 129.77, 129.26, 118.73, 117.80, 63.34. HRMS (ESI): m / z calculated forC 12 H 11 NOS+H + 218.0634, [M+H] + Found: 218.0642.

[0079] 4-Amino-2-(phenylthio)pyridin-4-amine (white oil, 32.4 mg, 0.16 mmol, 31% yield).

[0080] 1 H NMR (600 MHz, Chloroform- d ) δ 8.03 (d, J = 5.6Hz, 1H), 7.59–7.56 (m, 2H), 7.41–7.38 (m, 3H), 6.26 (dd, J= 5.6, 2.2 Hz, 1H), 6.07 (d, J = 2.2 Hz, 1H), 4.12 – 4.03 (m, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 161.87, 153.52, 149.86, 135.08, 131.47, 129.64, 129.02, 107.06, 106.45. HRMS (ESI): m / z calculated for C 11 H 10 N2S+H + : 203.0637, [M+H] + found: 203.0629。

[0081] 2-(Phenylthio)isonicotinonitrile (pale yellow oil, 17.1 mg, 0.08 mmol, 16 % yield).

[0082] 1 H NMR (600 MHz, Chloroform- d ) δ 8.55 (d, J = 5.0Hz, 1H), 又 7.63–7.58 (m, 2H), 7.50 (td, J = 5.4, 2.4 Hz, 3H), 7.16 (dd, J =5.0, 1.4 Hz, 1H), 6.95 (s, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 164.72, 150.40, 135.67, 130.39, 130.34, 128.79, 122.00, 121.16, 120.63, 116.40. HRMS(ESI): m / z calculated for C 12 H8N2S +H + : 213.0481, [M+H] + found: :213.0434。

[0083] 3-Methyl-2-(phenylthio)pyridine (pale yellowoil, 61.3 mg, 0.31 mmol, 61% yield).

[0084] 1 H NMR (600 MHz, Chloroform- d ) δ 8.23 ​​(dd, J = 4.5,1.8 Hz, 1H), 7.51 – 7.46 (m, 2H), 7.40–7.32 (m, 4H), 6.97 (dd, J = 7.5, 4.8Hz, 1H), 2.35 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 157.65, 147.41,137.33, 133.96, 132.12, 131.68, 129.14, 128.19, 120.71, 19.24. HRMS (ESI): m / z calculated for C 12 H 11 NS +H + 202.0685, [M+H] + Found: 202.0692.

[0085] 2-(phenylthio)pyridin-3-amine (red solid, 76.8 mg, 0.38 mmol, 76% yield).

[0086] The melting point is 67.4-67.5 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 8.01 (dd, J = 4.5, 1.6 Hz, 1H), 7.27–7.24 (m, 4H), 7.18 (dt, J = 5.1, 3.4 Hz, 1H), 7.07 (dd, J = 8.1, 4.5 Hz, 1H), 7.00 (dd, J= 8.1, 1.6Hz, 1H), 4.31 – 4.09 (m, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 144.37,140.31, 138.95, 134.07, 129.48, 129.24, 126.83, 124.45, 122.31. HRMS (ESI):m / z calculated for C 11 H 10 N2S+H + : 203.0637, [M+H] + found: 203.0629。

[0087] 2-Methyl-6-(phenylthio)pyridine (pale yellow oil, 71.4 mg, 0.36 mmol, 71 % yield).

[0088] 1 H NMR (600 MHz, Chloroform- d ) δ 7.62–7.56 (m,2H), 7.40 (dd, J = 5.1, 2.0 Hz, 3H), 7.31 (t, J = 7.8 Hz, 1H), 6.84 (d, J =7.6 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 2.50 (s, 3H). 13 C NMR (151 MHz,Chloroform- d ) δ 161.22, 158.65, 137.09, 135.10, 131.45, 129.72, 129.13,119.50, 118.19, 24.42. HRMS (ESI): m / z calculated for C 12 H 11 NS+H + : 202.0685, [M+H] + found: 202.0693。

[0089] 2-Amino-6-(phenylthio)pyridine (pale yellowoil, 50.6 mg, 0.25 mmol, 50% yield).

[0090] The melting point is 108.8-108.9 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 7.57 (dd, J = 7.3, 2.3 Hz, 2H), 7.40 – 7.36 (m,3H), 7.19 (t, J = 7.9 Hz, 1H), 6.18 (dd, J = 13.5, 7.9 Hz, 2H), 4.48 (s, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 159.65, 158.07, 140.11, 138.49, 134.93,131.59, 129.54, 128.91, 113.26, 111.44, 104.77, 29.80, 29.42. HRMS (ESI): m / zcalculated for C 11 H 10 N2S+H + 203.0637, [M+H] + Found: 203.0641.

[0091] Methyl 2-methyl-6-(phenylthio)isonicotinate (pale yellow oil, 27.2 mg, 0.11 mmol, 21% yield).

[0092] 1 H NMR (600 MHz, Chloroform- d ) δ 7.59 (dd, J =6.7, 2.9 Hz, 2H), 7.43 (q, J = 2.8 Hz, 3H), 7.38 (d, J= 1.3 Hz, 1H), 7.15(s, 1H), 3.82 (s, 3H), 2.56 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 165.67,162.57, 159.75, 138.54, 135.11, 130.56, 129.89, 129.50, 118.71, 117.40,52.72, 24.42. HRMS (ESI): m / z calculated for C 14 H 13 NO2S+H + : 260.0740, [M+H] + Found: 260.0729.

[0093] Example 9: Preparation of 2-(phenylthio)quinoline and its derivatives by mechanical piezoelectric catalytic CS coupling reaction

[0094] The reaction formula is as follows:

[0095] 2-(phenylthio)quinoline (white solid, 100.9 mg, 0.43 mmol, 85% yield).

[0096] The melting point is 48.5-49.0 ℃. 1 H NMR (600MHz, Chloroform- d ) δ 7.94 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.69(d, J = 8.1 Hz, 1H), 7.65 (td, J = 6.7, 5.9, 2.8 Hz, 3H), 7.46 – 7.42 (m,4H), 6.97 (d, J = 8.7 Hz, 1H). 13 C NMR (151 MHz, Chloroform- d) δ 161.74, 148.14, 136.59, 135.26, 130.96, 130.14, 129.75, 129.34, 128.45, 127.65, 125.94, 125.90, 119.62. HRMS (ESI): m / z calculated for C 15 H 11 NS + H + : 238.0685, [M + H] + found: 238.0693。

[0097] 3-Methyl-2-(phenylthio)quinoline (whitesolid, 111.7 mg, 0.45 mmol, 89 % yield)。

[0098] The melting point is 62.7 - 62.9 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 7.78 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 1H), 7.64–7.60 (m, 2H), 7.52 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.44–7.37 (m, 4H), 2.52 – 2.49 (m, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 159.21, 146.88, 135.29, 134.62, 130.88, 129.83, 128.99, 128.63, 128.40, 126.91, 126.78, 125.70, 19.13. HRMS (ESI): m / z calculated for C 16 H 13 NS + H + : 252.0841, [M + H] + found: 252.0851。

[0099] 4-Methyl-2-(phenylthio)quinoline (whitesolid, 118.1 mg, 0.47 mmol, 94% yield).

[0100] The melting point is 78-79 o C. 1 H NMR (600MHz, Chloroform- d ) δ 7.94 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H),7.67-7.62 (m, 3H), 7.45 (ddd, J = 14.8, 6.0, 1.8 Hz, 4H), 6.83 (s, 1H), 2.52(s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 161.16, 147.95, 144.96, 135.09,131.17, 129.81, 129.67, 129.18, 129.02, 126.22, 125.68, 123.82, 120.06,18.87. HRMS (ESI): m / z calculated for C 16 H 13 NS+H + : 252.0841, [M+H] + Found: 252.0851.

[0101] Example 10 Preparation of 2-(phenylthio)isoquinoline by mechanical piezoelectric catalytic CS coupling reaction

[0102] 3-(phenylthio)isoquinoline (pink oil, 56.9 mg, 0.24 mmol, 48% yield).

[0103] 1 H NMR (600 MHz, Chloroform- d ) δ 9.12 (s, 1H), 7.89 (d, J= 8.2 Hz, 1H), 7.60 (ddd, J = 6.6, 4.6, 2.6 Hz, 3H), 7.56 (d, J =8.2 Hz, 1H), 7.49 (ddd, J = 8.1, 6.6, 1.3 Hz, 1H), 7.44–7.37 (m, 3H), 7.28(s, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 154.13, 152.67, 136.92, 134.16,132.48, 130.95, 129.73, 128.77, 127.74, 126.83, 126.76, 125.82, 118.12. HRMS(ESI): m / z calculated for C 15 H 11 NS+H + : 238.0685, [M+H] + ; found 238.0695.

[0104] Example 11 Preparation of 4-(phenylthio)pyrimidine derivatives by mechanical piezoelectric catalytic CS coupling reaction

[0105] The reaction formula is as follows:

[0106] 2-Methyl-4-(phenylthio)pyrimidine (whitesolid, 74.8 mg, 0.37 mmol, 74% yield).

[0107] The melting point is 38.8-39.0 ℃. 1 H NMR (600 MHz, Chloroform- d ) δ 8.20 (d, J = 5.5 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.51–7.43 (m,3H), 6.46 (d, J = 5.5 Hz, 1H), 2.63 (s, 3H). 13 C NMR (151 MHz, Chloroform-d ) δ173.41, 167.59, 156.00, 135.89, 130.30, 130.12, 128.12, 113.91, 25.98. HRMS(ESI): m / z calculated for C 11 H 10 N2S+H + 203.0637, [M+H] + Found: 203.0635.

[0108] 6-Methyl-4-(phenylthio)pyrimidine (whitesolid, 98.98 mg, 0.49 mmol, 98% yield).

[0109] The melting point is 37.2-38.0 ℃. 1 H NMR (600MHz, Chloroform- d ) δ 8.77 (d, J = 1.2 Hz, 1H), 7.59 (dd, J = 7.7, 2.0 Hz,2H), 7.50–7.46 (m, 3H), 6.60 (s, 1H), 2.33 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 172.55, 166.09, 157.74, 135.84, 130.28, 130.08, 127.94,116.35, 24.19. HRMS (ESI): m / z calculated for C 11 H 10 N2S+H + 203.0637, [M+H] + Found: 203.0635.

[0110] 4-Methoxy-6-(phenylthio)pyrimidine (whitesolid, 67.7 mg, 0.31 mmol, 61% yield).

[0111] The melting point is 76.8-77.0 ℃. 1 H NMR (600MHz, Chloroform- d ) δ 8.53 (s, 1H), 7.61–7.55 (m, 2H), 7.51 – 7.42 (m, 3H), 6.08 (s, 1H), 3.87 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 172.74, 169.59,157.63, 135.90, 130.26, 130.10, 128.17, 102.89, 53.89. HRMS (ESI): m / zcalculated for C 11 H 10 N2OS+H + : 219.0587, [M+H] + Found: 219.0595.

[0112] Example 12 Preparation of (2-pyridine)-based thioether derivatives by mechanical piezoelectric-catalyzed CS coupling reaction

[0113] 2-(p-tolylthio)pyridine (pale yellow oil, 60.3 mg, 0.30 mmol, 60% yield).

[0114] 1 H NMR (600 MHz, Chloroform- d ) δ 8.40 (dd, J =5.1, 1.9 Hz, 1H), 7.51–7.46 (m, 2H), 7.41 (td, J = 7.8, 1.9 Hz, 1H), 7.23 (d, J = 7.8 Hz, 2H), 6.95 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 6.84 – 6.80 (m, 1H), 2.38 (s, 3H). 13 C NMR (151 MHz, Chloroform- d) δ 162.33, 149.57, 139.61,136.75, 135.38, 130.60, 127.26, 120.95, 119.71, 21.43. HRMS (ESI): m / zcalculated for C 12 H 11 NS+H + 202.0685, [M+H] + Found: 202.0693.

[0115] 2-((4-methoxyphenyl)thio)pyridine (white solid, 84.62 mg, 0.39 mmol, 78% yield).

[0116] The melting point is 47.3-47.5 ℃. 1 H NMR (600MHz, Chloroform- d ) δ 8.40–8.37 (m, 1H), 7.54 – 7.50 (m, 2H), 7.43 – 7.38 (m,1H), 6.97-6.92 (m, 3H), 6.76 (dt, J = 8.2, 1.0 Hz, 1H), 3.83 (s, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 162.91, 160.76, 149.51, 137.36, 136.72, 121.15,120.47, 119.54, 115.38, 55.48. HRMS (ESI): m / z calculated for C 12 H 11 NOS+H + 218.0634, [M+H] + Found: 218.0634.

[0117] 4-(pyridin-2-ylthio)aniline (white solid, 44.5 mg, 0.22 mmol, 44% yield).

[0118] The melting point is 81.3 - 81.5 °C. 1 H NMR (600MHz, Chloroform - d ) δ 8.38 (dd, J J = 4.9, 1.9 Hz, 1H), 7.42–7.36 (m, 3H), 6.92(dd, J J = 7.4, 4.9 Hz, 1H), 6.76 (d, J J = 8.2 Hz, 1H), 6.71 (d, J J = 8.4 Hz,2H), 3.73 (s, 2H). 13 C NMR (151 MHz, Chloroform - d ) δ 163.78, 149.30, 147.97,137.45, 136.71, 120.21, 119.27, 117.69, 116.09. HRMS (ESI): m / z calculatedfor C 11 H 10 N2S + H + : 203.0637, [M + H] + found: 203.0630; m / z calculated for C 11 H 10 N2S + Na + : 225.0457, [M + H] + found: 225.0459。

[0119] 4 - (pyridin - 2 - ylthio)phenol (white solid, 65.9mg, 0.33 mmol, 65 % yield).

[0120] The melting point is 118.8 - 119.0 °C. 1 H NMR(600 MHz, DMSO - d 6) δ 9.96 (s, 1H), 8.35 - 8.27 (m, 1H), 7.55 (td, J J = 7.8, 1.9Hz, 1H), 7.36 (d, J= 8.5 Hz, 2H), 7.04 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.85(d, J = 8.5 Hz, 2H), 6.71 (dd, J = 8.1, 1.1 Hz, 1H). 13 C NMR (151 MHz, DMSO- d 6) δ 162.57, 159.52, 149.81, 137.93, 137.75, 120.31, 120.19, 118.30, 117.50.HRMS (ESI): m / z calculated for C 11 H9NOS+H + : 204.0478, [M+H] + found: 204.0482。

[0121] 2-((4-chlorophenyl)thio)pyridine (paleyellow oil, 68.51 mg, 0.31 mmol, 62 % yield).

[0122] 1 H NMR (600 MHz, Chloroform- d ) δ 8.44–8.38 (m,1H), 7.53 – 7.49 (m, 2H), 7.47 (td, J = 7.7, 1.9 Hz, 1H), 7.38 (d, J = 8.4Hz, 2H), 7.01 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 160.66, 149.84, 136.95, 136.17, 135.45, 129.91,129.70, 121.69, 120.34. HRMS (ESI): m / z calculated for C 11 H8ClNS+Na +: 243.9958, [M+Na] + found: 243.9962。

[0123] 2-Benzylthio pyridine (2-(benzylthio)pyridine) (yellow oil, 45.2 mg, 0.23 mmol, 45 % yield).

[0124] 1 H NMR (600 MHz, Chloroform- d ) δ 8.45 (dt, J J = 4.9, 1.5 Hz, 1H), 7.46 (td, J J = 7.7, 1.9 Hz, 1H), 7.40 (dd, J J = 7.4, 1.7 Hz, 2H), 7.31–7.27 (m, 2H), 7.24 – 7.20 (m, 1H), 7.15 (d, J J = 8.1 Hz, 1H), 6.98(ddd, J J = 7.5, 5.0, 1.1 Hz, 1H), 4.43 (s, 2H). 13 C NMR (151 MHz, Chloroform- d ) δ 158.89, 149.46, 138.03, 136.11, 129.06, 128.58, 127.19, 122.21, 119.70, 34.53. HRMS (ESI): m / z calculated for C 12 H 11 NS+H + : 202.0685, [M+H] + found: 202.0675。

[0125] 2-Propylthio pyridine (2-(propylthio)pyridine) (yellow oil, 44.4 mg, 0.29 mmol, 58 % yield).

[0126] 1 H NMR (600 MHz, Chloroform- d ) δ 8.40 (ddd, J=5.0, 1.9, 1.0 Hz, 1H), 7.48–7.42 (m, 1H), 7.15 (dt, J = 8.1, 1.0 Hz, 1H),6.95 (ddd, J = 7.3, 4.9, 1.1 Hz, 1H), 3.13 (t, J = 7.3 Hz, 2H), 1.72 (q, J =7.3 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ159.64, 149.48, 135.95, 122.27, 119.28, 32.17, 22.82, 13.64. HRMS (ESI): m / zcalculated for C8H 11 NS+H + : 154.0685, [M+H] + found:154.0691。

[0127] 2-(butylthio)pyridine (yellow oil, 44.4 mg, 0.29 mmol,58 % yield).

[0128] 1 H NMR (600 MHz, Chloroform- d ) δ 8.40 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.45 (td, J = 7.8, 1.9 Hz, 1H), 7.15 (dt, J = 8.1,1.1 Hz, 1H), 6.94 (ddd, J = 7.4, 4.9, 1.1 Hz, 1H), 3.15 (t, J = 7.4 Hz, 2H),1.68 (tt, J = 8.9, 6.8 Hz, 2H), 1.46 (h, J = 7.4 Hz, 2H), 93 (t, J = 7.4Hz, 3H).13 C NMR (151 MHz, Chloroform- d ) δ 159.71, 149.49, 135.94, 122.22, 119.26, 31.48, 29.94, 22.18, 13.81. HRMS (ESI): m / z calculated for C9H 13 NS+H + : 168.0841, [M+H] + found: 168.0850。

[0129] 2-(pentylthio)pyridine (yellow oil, 44.4 mg, 0.29 mmol, 58 % yield).

[0130] 1 H NMR (600 MHz, Chloroform- d ) δ 8.45–8.33 (m, 1H), 7.45 (td, J J = 7.7, 1.9 Hz, 1H), 7.15 (dt, J J = 8.1, 1.0 Hz, 1H), 6.95 (ddd, J J = 7.3, 4.9, 1.1 Hz, 1H), 3.14 (t, J J = 7.4 Hz, 2H), 1.70 (q, J J = 7.4 Hz, 2H), 1.42 (dq, J J = 8.4, 6.8 Hz, 2H), 1.37 – 1.29 (m, 2H), 0.89 (t, J J = 7.3 Hz, 3H). 13 C NMR (151 MHz, Chloroform- d ) δ 159.71, 149.49, 135.94, 122.22, 119.26, 31.22, 30.21, 29.09, 22.38, 14.07. HRMS (ESI): m / z calculated for C 10 H 15 NS+H + : 182.0998, [M+H] +Found: 182.0996.

[0131] 2-(cyclohexylthio)pyridine (yellow oil, 50.3 mg, 0.26 mmol, 52% yield).

[0132] 1 H NMR (600 MHz, Chloroform- d ) δ 8.41 (d, J = 4.9Hz, 1H), 7.44 (td, J = 7.7, 1.9 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.94 (dd, J = 7.3, 4.9 Hz, 1H), 3.79 (td, J = 10.1, 3.8 Hz, 1H), 2.11–2.03 (m, 2H), 1.76 (dd, J = 9.6, 4.5 Hz, 2H), 1.66–1.60 (m, 1H), 1.50 – 1.40 (m, 4H), 1.33– 1.26 (m, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 159.37, 149.62, 135.95,122.97, 119.37, 42.98, 33.36, 26.11, 25.90. HRMS (ESI): m / z calculated forC 11 H 15 NS+H + : 194.0998, [M+H] + Found: 194.0988.

[0133] 2-(thiophen-2-ylthio)pyridine (brown oil, 27.0 mg, 0.14 mmol, 28% yield).

[0134] 1 H NMR (600 MHz, Chloroform- d) δ 8.40 (dd, J J = 4.9, 1.0 Hz, 1H), 7.56 (dd, J J = 5.4, 1.3 Hz, 1H), 7.47 (td, J J = 7.8, 1.9 Hz, 1H),7.35 (dd, J J = 3.5, 1.3 Hz, 1H), 7.13 (dd, J J = 5.4, 3.5 Hz, 1H), 6.99 (ddd, J J = 7.4, 4.8, 1.0 Hz, 1H), 6.85 (dt, J J = 8.1, 1.0 Hz, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 162.20, 149.42, 137.39, 137.06, 132.54, 128.42, 128.33, 120.09, 120.06. HRMS (ESI): m / z calculated for C9H7NS2+H + : 194.0093, [M+H] + found 194.0092。

[0135] 2-((2-methylfuran-3-yl)thio)pyridine (yellow oil, 56.3 mg, 0.30 mmol, 59 % yield)。

[0136] 1 H NMR (600 MHz, Chloroform- d ) δ 8.40 (ddd, J J = 4.9, 1.9, 1.0 Hz, 1H), 7.48–7.40 (m, 2H), 6.97 (ddd, J J = 7.4, 4.9, 1.1 Hz,1H), 6.85 (dt, J J = 8.2, 1.0 Hz, 1H), 6.42 (d, J J = 2.0 Hz, 1H), 2.35 (s, 3H). 13C NMR (151 MHz, Chloroform- d ) δ 161.51, 157.57, 149.61, 141.59, 136.81,119.69, 119.61, 115.62, 106.43, 11.96. HRMS (ESI): m / z calculated for C 10 H9NOS+H + : 192.0478, [M+H] + Found: 192.0477.

[0137] N-(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(pyridin-2-yl)cysteine ​​(white solid, 84.11 mg, 0.20 mmol, 40% yield).

[0138] The melting point is 47.0-47.4℃. 1 H NMR (600 MHz, DMSO d 6) δ 8.39 (d, J = 5.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 8.2 Hz, 3H), 7.09 (t, J = 6.2 Hz, 1H), 5.28 (t, J = 4.9 Hz, 1H), 4.20 (d, J = 12.0 Hz, 2H), 4.17 (s, 1H), 3.20 (t, J = 11.8 Hz, 2H). 13 CNMR (151 MHz, Chloroform- d) δ 158.63, 156.85, 148.66, 144.00, 143.84, 141.36,141.33, 137.11, 127.75, 127.12, 125.31, 125.26, 123.26, 120.45, 120.02,68.06, 67.19, 47.15, 33.12, 29.80, 25.68. HRMS (ESI): m / z calculated forC 23 H 20 N₂O₄S + H₂ + :421.1217, [M+H] + Found: 421.1217.

[0139] Example 13 Preparation of 4-(phenylthio)thiopheno[3,2-d]pyrimidine by mechanical piezoelectric catalytic CS coupling reaction

[0140] The reaction formula is as follows:

[0141] The method is as follows: Under normal temperature, pressure, and air conditions, diphenyl disulfide sulfide (0.25 mmol), 4-chlorothiophene[3,2-d]pyrimidine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30 Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 80.5 mg of a white solid, namely 4-(phenylthio)thiophene[3,2-d]pyrimidine, in 65% yield.

[0142] The structure of the prepared 4-(phenylthio)thiopheno[3,2-d]pyrimidine is characterized as follows: 1 H NMR (600 MHz, Chloroform- d ) δ 8.88 (s, 1H), 7.85 (d, J = 5.5 Hz, 1H), 7.67 (dt, J = 6.9,1.5 Hz, 2H), 7.53 – 7.43 (m, 4H). 13 C NMR (151 MHz, Chloroform- d ) δ 164.39,159.80, 154.11, 136.04, 134.95, 130.28, 129.58, 128.13, 126.99, 124.55. HRMS(ESI): m / z calculated for C 12 H8N2S2+H + : 245.0202, [M+H] + Found: 245.0206.

[0143] The prepared 4-(phenylthio)thiopheno[3,2-d]pyrimidine 1 H NMR image as follows Figure 3 .

[0144] The prepared 4-(phenylthio)thiopheno[3,2-d]pyrimidine 13 C NMR spectrum as shown Figure 4 .

[0145] Example 14 Preparation of 5-(phenylthio)pyrazolo[1,5-a]pyrimidine by mechanical piezoelectric catalytic CS coupling reaction

[0146] The reaction formula is as follows:

[0147] The method is as follows: Under normal temperature, pressure, and air conditions, diphenyl disulfide sulfide (0.25 mmol), 5-chloropyrazolo[1,5-a]pyrimidine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30 Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 63.6 mg of a white solid, namely 5-(phenylthio)pyrazolo[1,5-a]pyrimidine, in 56% yield.

[0148] The structure of the prepared 5-(phenylthio)pyrazolo[1,5-a]pyrimidine is characterized as follows: 1 H NMR (600 MHz, Chloroform- d ) δ 8.35 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.66–7.60(m, 2H), 7.50–7.43 (m, 3H), 6.44 (d, J = 2.2 Hz, 1H), 6.36 (d, J = 7.3 Hz, 1H). 13 C NMR (151 MHz, Chloroform- d ) δ 162.18, 148.12, 145.50, 135.60, 134.44,130.06, 129.93, 129.03, 106.04, 95.62. HRMS (ESI): m / z calculated for C 12 H9N3S+H+ : 228.0590, [M+H] + Found: 228.0599.

[0149] The prepared 5-(phenylthio)pyrazolo[1,5-a]pyrimidine 1 H NMR image as follows Figure 5 .

[0150] The prepared 5-(phenylthio)pyrazolo[1,5-a]pyrimidine 13 C NMR spectrum as shown Figure 6 .

[0151] Example 15 Preparation of 6-(phenylthio)-9H-purine by mechanical piezoelectric catalytic CS coupling reaction

[0152] The reaction formula is as follows:

[0153] The method is as follows: Under normal temperature, pressure, and air conditions, diphenyl disulfide (0.25 mmol), 6-chloro-9-H-purine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1 η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 58.2 mg of a white solid, namely 6-(phenylthio)-9H-purine, in 51% yield.

[0154] The structure of the prepared 5-(phenylthio)pyrazolo[1,5-a]pyrimidine is characterized as follows: 1H NMR (600 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.48 (s, 1H), 7.60 (dd, J = 6.6, 2.9 Hz, 2H), 7.46 (dd, J = 5.2, 1.9 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 152.18, 136.05,130.02, 129.92, 127.48. HRMS (ESI): m / z calculated for C12H9N3S+H + : 229.0542,[M+H] + Found: 229.0544.

[0155] Preparation of 6-(phenylthio)-9H-purine 1 H NMR image as follows Figure 7 .

[0156] Preparation of 6-(phenylthio)-9H-purine 13 C NMR spectrum as shown Figure 8 .

[0157] Example 16 Preparation of (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol by mechanical piezoelectric catalytic CS coupling reaction

[0158] The reaction formula is as follows:

[0159] The method is as follows: Under normal temperature, pressure, and air conditions, diphenyl disulfide (0.25 mmol), 6-chloropurine ribonucleoside (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 39.6 mg of a white solid, namely (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol, in 21% yield.

[0160] The structure of the prepared (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol is characterized as follows: The melting point is 235.0-235.8 ℃. 1 H NMR (600 MHz, DMSO- d 6) δ 8.74 (s, 1H), 8.55 (s, 1H), 7.62–7.58 (m, 2H), 7.47 (dd, J = 5.1, 1.9 Hz, 3H), 5.96 (d, J = 5.5 Hz, 1H), 5.51 (d, J = 5.9 Hz, 1H), 5.21 (d, J =5.0 Hz, 1H), 5.08 (t, J = 5.6 Hz, 1H), 4.57 (q, J = 5.5 Hz, 1H), 4.15 (q, J =4.6 Hz, 1H), 3.94 (q, J = 3.9 Hz, 1H), 3.65 (dt, J = 12.0, 4.6 Hz, 1H), 3.53(ddd, J = 11.9, 6.0, 4.0 Hz, 1H). 13 C NMR (151 MHz, DMSO- d6) δ 159.60, 152.24,149.17, 144.32, 136.09, 131.10, 130.19, 129.98, 127.16, 88.38, 86.23, 74.31,70.76, 61.73. HRMS (ESI): m / z calculated for C 16 H 16 N4O4S+H + :361.0965, [M+H] + Found: 361.0966.

[0161] The preparation of (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol 1 H NMR image as follows Figure 9 .

[0162] The preparation of (2S,3R,4S)-2-(hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol 13 C NMR spectrum as shown Figure 10 .

[0163] Example 17 Preparation of ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl)methanol by mechanical piezoelectric catalytic CS coupling reaction

[0164] The method is as follows: Under normal temperature, pressure, and air conditions, diphenyl disulfide sulfur (0.25 mmol), 6-chloro-9-beta-D-(2,3-isopropylidene)furanoribosylpurine (0.75 mmol, 3.0 equiv), BaTiO3 (0.5 mmol, 2.0 equiv), I2 (0.5 mmol, 2.0 equiv), NiBr2 (0.0375 mmol, 15 mol%), 2,2'-bipyridine (0.1 mmol, 40 mol%), and zinc powder (1.5 mmol, 6.0 equiv) were placed in a ball mill container (stainless steel, 10 mL) containing a grinding ball (stainless steel, diameter: 16 mm, weight: 17 g). Then, N,N-dimethylformamide (DMF) (η = 0.19 μL mg) was added. -1η = V(liquid; μL) / m(disulfide compounds; mg)). After sealing the container in air without purging with an inert gas, the container was placed in a ball mill (Retsch MM400, 30Hz). After reacting for 100 minutes, the mixture was passed through a short silica gel column and eluted with CH2Cl2 / MeOH (100:0-10:1). The eluent was washed with water, dried, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent to give 74.0 mg of a white solid, namely ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxane-4-yl)methanol, in a yield of 37%.

[0165] The structure of the prepared ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purine-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxane-4-yl)methanol is characterized as follows: The melting point is 61.0-61.3℃. 1 H NMR (600 MHz, Chloroform- d ) δ 8.55 (s, 1H), 8.07 (s, 1H), 7.66–7.59(m, 2H), 7.47 (dt, J = 5.1, 2.4 Hz, 3H), 5.91 (d, J = 4.8 Hz, 1H), 5.18 (t, J = 5.4 Hz, 1H), 5.09 (dd, J = 5.9, 1.3 Hz, 1H), 4.53 (d, J = 1.9 Hz, 1H), 3.95 (dd, J = 12.7, 1.6 Hz, 1H), 3.78 (dd, J = 12.7, 2.0 Hz, 1H), 1.64 (s, 3H), 1.36 (s, 3H). 13 C NMR (151 MHz, Chloroform- d) δ 162.64, 151.81, 147.39,142.86, 135.75, 132.37, 129.90, 129.50, 126.72, 114.33, 94.39, 86.21, 83.12,81.70, 63.44, 27.71, 25.31. HRMS (ESI): m / z calculated for C 19 H 20 N4O4S+H + :401.1278, [M+H] + Found: 401.1283.

[0166] The preparation of ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl)methanol 1 H NMR image as follows Figure 11 .

[0167] The preparation of ((4R,6R)-2,2-dimethyl-6-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofurano[3,4-d][1,3]m-dioxacyclopenten-4-yl)methanol 13 C NMR spectrum as shown Figure 12 .

Claims

1. A method for the rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS-coupled reaction, characterized in that, The aforementioned aza-aryl sulfide compounds are a series of aza-aryl sulfide compounds prepared from chlorinated aza-aryl hydrocarbon compounds and disulfide compounds under normal temperature and pressure and air conditions by CS coupling reaction using BaTiO3 / Zn / Ni synergistic catalysis and micro-liquid-assisted mechanical grinding.

2. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 1, characterized in that, The method includes the following steps: Under normal temperature and pressure and air conditions, using chloroazirroary compounds with structural formula (Ⅰ) and disulfide compounds with structural formula (Ⅱ) as raw materials, zinc powder, nickel bromide, barium titanate, 2,2'-bipyridine, iodine and trace amounts of auxiliary grinding solvent are added to a grinding steel jar, steel balls are added, the jar is sealed, and the jar is placed in a Retsch mixed ball mill and ground at 30 Hz for 60-120 min. The crude product obtained is separated and purified to obtain a azirroary sulfide compound with structural formula (Ⅲ). Wherein, when (Ⅰ) is a pyridine compound, R is -Me, -OMe, -NH2, -CN, -CH2COOMe, -C(CH3)3, -CH2OH, -COOMe, -CF3, -F, -CH(OCH2CH2O), -OCOCH3 or -H; when (Ⅰ) is a quinoline compound, R is -Me or -H; when (Ⅰ) is a pyrimidine compound, R is -Me, -OMe or -H; disulfide compounds are aromatic disulfides or aliphatic disulfides.

3. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 2, characterized in that, The chloro-acidic aromatic compounds are 4-chlorothieno[3,2-d]pyrimidine, 5-chloropyrazolo[1,5-a]pyrimidine, 6-chloro-9-H-purine, 6-chloro-9-beta-D-(2,3-isopropylidene)furanosylpurine, and 6-chloropurine ribonucleotide. Disulfide compounds are those with structural formulas (Ⅳ), (Ⅴ), (Ⅵ), (Ⅶ), (Ⅷ), (Ⅸ) or (Ⅹ): ； In compound (Ⅳ), R is 4-Me, 4-OMe, 4-NH2, -OH, -Cl, or 2-NH2.

4. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 2, characterized in that, Molar ratio: disulfide compounds: chloroazirroaro compounds: zinc powder: barium titanate: nickel bromide: 2,2'-bipyridine: iodine = 1: (2~3): (4~8): 2: 0.15: 0.4:

2.

5. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 4, characterized in that, The molar ratio of disulfide compounds: chloroazirroaro compounds: zinc powder: barium titanate: nickel bromide: 2,2'-bipyridine: iodine is 1: 3: 6: 2: 0.15: 0.4:

2.

6. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 2, characterized in that, The trace auxiliary grinding solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide, and water.

7. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanopiezo-piezo-catalyzed CS-coupled reaction according to claim 6, characterized in that, The amount of the trace auxiliary grinding solvent used is 0.19 μL / 1 mg of disulfide compound.

8. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 2, characterized in that, The steel ball has a diameter of 16 mm and a weight of 17 g.

9. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanical piezoelectric catalytic CS coupling reaction according to claim 2, characterized in that, The grinding time is 100 min.

10. The method for rapid preparation of nitrogen-containing aryl sulfides via a mechanopiezo-piezo-catalyzed CS-coupled reaction according to claim 2, characterized in that, The separation and purification steps include: passing the mixture through a short silica gel column and eluting with a gradient of CH2Cl2 / MeOH in the range of 100:0-10:1; washing the eluent with water, drying and concentrating to obtain the crude product; and performing silica gel column chromatography using a mixed solution of petroleum ether and ethyl acetate as the eluent to obtain azaaryl thioether compounds.

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