Electrochemical synthesis method of thioether derivative

Abstract

The invention provides an electrochemical synthesis method of thioether derivatives, and belongs to the technical field of pharmaceutical chemical intermediate synthesis, and the electrochemical synthesis method comprises the following steps: mixing a thiol compound, an ether compound, an electrolyte and a solvent to obtain a reaction solution; performing constant-current electrolysis on the reaction solution in a non-discrete electrolytic bath; and performing column chromatography on the electrolyzed solution to obtain the thioether derivative. According to the electrochemical synthesis method of the thioether derivative, the raw materials are easy to obtain, and the method is simple, efficient, safe, environmentally friendly and high in selectivity.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical and chemical intermediate synthesis, and in particular to an electrochemical synthesis method of thioether derivatives. Background Art

[0002] As important functional molecules, sulfide compounds have a wide range of applications in medicinal chemistry, agricultural chemistry, and materials science. They serve as the core building blocks of many natural products and bioactive molecules and are also used in the synthesis of a variety of pharmaceuticals, pesticides, and functional materials. For example, sulfide compounds are used in the synthesis of antibiotics, anticancer drugs, and materials with unique optical properties.

[0003] Traditionally, thioether synthesis methods include reacting alcohols with sulfiding agents and utilizing disulfide rearrangement reactions. However, these methods still face challenges in controlling thioether selectivity and stereochemistry, as well as extending the synthesis to include diverse substituents. Therefore, developing more efficient, flexible, and environmentally friendly methods for synthesizing thioethers has become a key area of current chemical research.

[0004] Over the past few decades, significant progress has been made in the synthesis of sulfide compounds, especially in methods for directly constructing C-S bonds. Traditionally, the synthesis of sulfide compounds relies primarily on the reaction of alcohols with sulfiding agents, but these methods often require multiple steps and face difficulties in controlling selectivity and extending to different substituents. In recent years, methods for synthesizing sulfide compounds by directly constructing C-S bonds have gradually gained attention. However, these methods still face problems such as the high cost of metal catalysts, the large amount of oxidants used, and the difficulty in obtaining substrates. Therefore, the development of more efficient, environmentally friendly, and widely applicable methods for synthesizing sulfide compounds remains an important direction of current chemical research.

[0005] Therefore, it is particularly necessary to develop a synthetic method for sulfide derivatives that has readily available raw materials, simple operation, high selectivity, safety and rapidity. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide an electrochemical synthesis method for thioether derivatives with readily available raw materials, simple and efficient method, safety, environmental protection and high selectivity.

[0007] To solve the above technical problems, the present invention provides an electrochemical synthesis method of sulfide derivatives, comprising the following steps: mixing a thiol compound, an ether compound, an electrolyte and a solvent to obtain a reaction solution; electrolyzing the reaction solution at a constant current in a non-separate electrolytic cell; The electrolyzed solution is subjected to column chromatography to obtain sulfide derivatives; The general structural formula of the thiol compound is: ; The general structural formula of the ether compound is: ; The general structural formula of the thioether derivative is: ; Wherein, Ar is a C5-C8 aryl or heterocyclic aryl group; R 1 is a C1-C4 alkyl group, R 2 is a C3-C6 cycloalkyl group, R 3 It is a C5-C8 aryl group or a heterocyclic aryl group.

[0008] Furthermore, the molar concentration of the thiol compound in the reaction solution is 0.1-0.5 mol / L.

[0009] Furthermore, the amount of the electrolyte is 80-150 mol% of the amount of the thiol compound.

[0010] Furthermore, the electrolyte is at least one of lithium perchlorate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium iodide, tetrabutylammonium bromide, and tetrabutylammonium fluoride.

[0011] Furthermore, the volume ratio of the ether compound to the solvent is 0.5:1-2:1.

[0012] Furthermore, the solvent is methanol, ethanol, isopropanol, trifluoroethanol, hexafluoroisopropanol, mercaptan, chlorobenzene, acetonitrile, dimethyl sulfoxide, N , N -dimethylformamide, N , N - one or more of dimethylacetamide, dioxane, dichloromethane, 1,2-dichloroethane, acetone, tetrahydrofuran, ethyl acetate, and n-hexane.

[0013] Furthermore, the positive electrode of the non-discrete electrolytic cell is one of a platinum electrode, a nickel electrode, a magnesium electrode, a stainless steel electrode, a zinc electrode, a mesh glassy carbon electrode, and a graphite felt electrode; the negative electrode of the non-discrete electrolytic cell is one of a platinum electrode, a nickel electrode, a magnesium electrode, a stainless steel electrode, a zinc electrode, a mesh glassy carbon electrode, and a graphite felt electrode.

[0014] Furthermore, the constant current is 5-40 mA.

[0015] Furthermore, the electrolysis temperature is 25-75°C.

[0016] Furthermore, the column chromatography adopts silica gel column chromatography, and the eluent is a mixed solution of n-hexane and ethyl acetate in a volume ratio of 10:1.

[0017] The present invention provides an electrochemical synthesis method for thioether derivatives. A reaction solution formed by mixing a thiol compound with an ether compound, an electrolyte, and a solvent is subjected to constant current electrolysis in a non-separate electrolytic cell. During the constant current electrolysis of the reaction solution, the thiol compound undergoes a free radical reaction to form a thioether derivative. The electrolyzed solution is then subjected to column chromatography to separate the thioether derivative. This method is not only simple and efficient, but also uses inexpensive and readily available raw materials. This method for synthesizing thioether derivatives offers low production costs, high economic benefits, and promising production prospects, making it worthy of application and promotion.

[0018] Furthermore, the present invention provides an electrochemical synthesis method for sulfide derivatives, wherein the reaction raw materials are non-toxic and pollution-free, and the synthesis process does not require the use of any metal catalysts and oxidants. The target product can be finally obtained through electrocatalytic oxidation, and the by-product is only hydrogen. No toxic substances that affect the environment and human health are produced during the reaction process. Therefore, the production process is not only simple to operate, but also safer and more environmentally friendly. It is an environmentally friendly, simple and efficient green electrochemical synthesis method.

[0019] At the same time, the present invention provides an electrochemical synthesis method for sulfide derivatives. Since the sulfide derivatives are synthesized based on thiol compounds and ether compounds, the construction of the C-S bond during the synthesis process is located at the ortho position of the O of the ether compound, and no other products are generated. The reaction has high chemical selectivity, and the synthesis method is simple and efficient. Therefore, the obtained sulfide derivatives are of high purity, have great implementation value and social and economic benefits, and are in line with the development of green chemistry and society. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 A flow chart of an electrochemical synthesis method for thioether derivatives provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0021] See also Figure 1 The present invention provides an electrochemical synthesis method of sulfide derivatives, comprising the following steps: Step 1) Mixing a thiol compound, an ether compound, an electrolyte and a solvent to obtain a reaction solution.

[0022] Wherein, the general structural formula of the thiol compound is: ; Wherein, the general structural formula of the ether compound is: ; The obtained thioether derivative has the following general structural formula: ; Wherein, Ar is a C5-C8 aryl or heterocyclic aryl group; R 1 is a C1-C4 alkyl group, R 2 is a C3-C6 cycloalkyl group, R 3 It is a C5-C8 aryl group or a heterocyclic aryl group.

[0023] electrolyzing the reaction solution at a constant current in a non-separate electrolytic cell; Wherein, the molar concentration of the thiol compound in the reaction solution is 0.1-0.5 mol / L.

[0024] Wherein, the amount of the electrolyte is 80-150 mol% of the amount of the thiol compound.

[0025] Wherein, the electrolyte is at least one of lithium perchlorate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium iodide, tetrabutylammonium bromide, and tetrabutylammonium fluoride.

[0026] Wherein, the volume ratio of the ether compound to the solvent is 0.5:1-2:1.

[0027] Wherein, the solvent is methanol, ethanol, isopropanol, trifluoroethanol, hexafluoroisopropanol, mercaptan, chlorobenzene, acetonitrile, dimethyl sulfoxide, N , N -dimethylformamide, N , N - one or more of dimethylacetamide, dioxane, dichloromethane, 1,2-dichloroethane, acetone, tetrahydrofuran, ethyl acetate, and n-hexane.

[0028] Step 2) electrolyzing the reaction solution with a constant current in a non-separate electrolytic cell.

[0029] Specifically, the reaction solution prepared in step 1) is added to a non-separate electrolytic cell. The positive and negative electrodes are then inserted into the reaction solution in the non-separate electrolytic cell. The reaction proceeds at a constant current of 5-40 mA and an electrolysis temperature of 25-75°C. During the reaction, the thiol compounds undergo free radical reactions to form thioether derivatives, thereby obtaining an electrolyzed solution containing the thioether derivatives. This reaction not only exhibits high chemical selectivity but also features a simple and efficient synthesis method. The resulting thioether derivatives are of high purity, demonstrating significant practical value and socioeconomic benefits.

[0030] The positive electrode of the non-discrete electrolytic cell is one of a platinum electrode, a nickel electrode, a magnesium electrode, a stainless steel electrode, a zinc electrode, a mesh glassy carbon electrode, and a graphite felt electrode. The negative electrode of the non-discrete electrolytic cell is one of a platinum electrode, a nickel electrode, a magnesium electrode, a stainless steel electrode, a zinc electrode, a mesh glassy carbon electrode, and a graphite felt electrode.

[0031] Step 3) The electrolyzed solution is subjected to column chromatography to obtain sulfide derivatives.

[0032] The column chromatography used was silica gel column chromatography, and the eluent was a mixed solution of n-hexane and ethyl acetate in a volume ratio of 10:1.

[0033] By subjecting the electrolyzed solution to column chromatography, sulfide derivatives with higher purity can be separated.

[0034] The present invention provides an electrochemical synthesis method for sulfide derivatives, which has a simple and efficient process and uses inexpensive and readily available reaction raw materials, resulting in low production costs and high economic benefits. Furthermore, the synthesis method provided by the present invention uses non-toxic and pollution-free reaction raw materials, and the synthesis process does not require the use of any metal catalysts or oxidants. The target product can ultimately be obtained through electrocatalytic oxidation, with the only byproduct being hydrogen. No toxic substances or substances that affect the environment or human health are produced during the reaction. Therefore, the production process is not only simple to operate but also safer and more environmentally friendly. This is an environmentally friendly, simple, and efficient green electrochemical synthesis method with high implementation value and socioeconomic benefits, in line with the development of green chemistry and society.

[0035] The following examples illustrate the electrochemical synthesis method of sulfide derivatives provided by the present invention.

[0036] Example 1: Preparation of 2-(p-tolylthio)tetrahydrofuran (Ia) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 89 mg of colorless liquid 2-(p-tolylthio)tetrahydrofuran (Ia) in a yield of 92%. The structural formula of Ia is:

[0037] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 7.9 Hz,2H), 5.55 (dd, J = 7.3, 3.9 Hz, 1H), 4.00 (q, J= 7.8 Hz, 1H), 3.96 – 3.85 (m,1H), 2.30 (s, 4H), 2.05 – 1.89 (m, 2H), 1.89 – 1.75 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 136.99, 131.88, 131.86, 129.62, 87.61, 67.23, 32.65, 24.89, 21.12.HRMS (ESI-TOF): m / z calcd for C 11 H 15 OS [M+H] + : 195.0838, found 195.0840.

[0038] Example 2: Preparation of 2-(m-methylthio)tetrahydrofuran (Ib) m-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 83 mg of colorless liquid 2-(m-methylthio)tetrahydrofuran (Ib) in an 85% yield. The structural formula of Ib is:

[0039] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.36 – 7.27 (m, 2H), 7.20 – 7.14 (m, 1H),7.03 (d, J = 7.7 Hz, 1H), 5.69 – 5.60 (m, 1H), 4.06 – 3.98 (m, 1H), 3.98 – 3.89(m, 1H), 2.42 – 2.31 (m, 4H), 2.07 – 1.91 (m, 2H), 1.91 – 1.78 (m, 1H). 13C NMR(151 MHz, CDCl3) δ 138.56, 135.45, 131.61, 128.66, 128.07, 127.67, 87.15,67.28, 32.70, 24.89, 21.35. HRMS (ESI-TOF): m / z calcd for C 11 H 15 OS [M+H] + :195.0838, found 195.0836.

[0040] Example 3: Preparation of 2-(o-methylthio)tetrahydrofuran (Ic) o-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. 2-(o-methylthio)tetrahydrofuran (Ic) was separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) to obtain 75 mg of colorless liquid 2-(o-methylthio)tetrahydrofuran (Ic) in a yield of 77%. The structural formula of Ic is:

[0041] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 1H), 7.21 – 7.08 (m, 3H), 5.68 – 5.59 (m, 1H), 4.02 (q, J = 7.3 Hz, 1H), 3.98 – 3.91 (m, 1H), 2.38 (s, 4H), 2.09 – 1.98 (m, 2H), 1.94 – 1.81 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ138.49, 135.13, 130.94, 130.03, 126.67, 126.48, 86.43, 67.35, 32.82, 24.90,20.73. HRMS (ESI-TOF): m / z calcd for C 11 H 15 OS [M+H] + : 195.0838, found 195.0839.

[0042] Example 4: Preparation of 2-((4-methoxyphenyl)thio)tetrahydrofuran (Id) p-Methoxythiophenol (70 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 91 mg of colorless liquid 2-((4-methoxyphenyl)thio)tetrahydrofuran (Id) in an 87% yield. The structural formula of Id is:

[0043] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz,2H), 5.47 (dd, J = 7.3, 3.9 Hz, 1H), 4.02 (q, J = 7.8 Hz, 1H), 3.98 – 3.88 (m,1H), 3.79 (s, 3H), 2.41 – 2.23 (m, 1H), 2.05 – 1.90 (m, 2H), 1.90 – 1.78 (m,1H). 13 C NMR (151 MHz, CDCl3) δ 159.46, 134.62, 125.59, 114.45, 88.21, 67.19,55.32, 32.50, 24.85. HRMS (ESI-TOF): m / z calcd for C 11 H 15 O2S [M+H] + : 211.0787,found 211.0788.

[0044] Example 5: Preparation of 2-((4-isopropylphenyl)thio)tetrahydrofuran (Ie) p-Isopropylthiophenol (76 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 100 mg of colorless liquid 2-((4-isopropylphenyl)thio)tetrahydrofuran (Ie) with a yield of 90%. The structural formula of Ie is:

[0045] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz,2H), 5.59 (dd, J = 7.2, 4.0 Hz, 1H), 4.03 (q, J = 8.2 Hz, 1H), 3.99 – 3.90 (m,1H), 2.93 – 2.82 (m, 1H), 2.40 – 2.30 (m, 1H), 2.07 – 1.93 (m, 2H), 1.92 –1.81 (m, 1H), 1.23 (d, J = 7.0 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 147.93,132.14, 131.80, 127.00, 87.51, 67.20, 33.76, 32.63, 24.85, 23.90, 23.88. HRMS(ESI-TOF): m / z calcd for C 13 H 19 OS [M+H] + : 223.1151, found 223.1150.

[0046] Example 6: Preparation of 2-(phenylthio)tetrahydrofuran (If) Thiophenol (55 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 81 mg of colorless liquid 2-(phenylthio)tetrahydrofuran (If) with a yield of 90%. The structural formula of If is:

[0047] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.54 – 7.46 (m, 2H), 7.28 (dd, J = 8.5, 6.8Hz, 2H), 7.23 – 7.18 (m, 1H), 5.63 (dd, J = 7.3, 3.9 Hz, 1H), 4.02 (q, J = 7.8Hz, 1H), 3.98 – 3.91 (m, 1H), 2.39 – 2.31 (m, 1H), 2.05 – 1.92 (m, 2H), 1.91 – 1.81 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 135.75, 131.15, 128.79, 126.78,87.18, 67.27, 32.69, 24.85. HRMS (ESI-TOF): m / z calcd for C 10 H 13 OS [M+H] + :181.0682, found 181.0685.

[0048] Example 7: Preparation of 2-((4-fluorophenyl)thio)tetrahydrofuran (1g) p-Fluorothiophenol (64 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL) and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. After separation by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 10:1, volume ratio), 81 mg of colorless liquid 2-((4-fluorophenyl)thio)tetrahydrofuran (Ig) was obtained with a yield of 82%. The structural formula of Ig is:

[0049] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.49 (dd, J = 8.3, 5.4 Hz, 2H), 6.99 (t, J = 8.7Hz, 2H), 5.53 (dd, J = 7.3, 4.0 Hz, 1H), 4.01 (q, J = 7.8 Hz, 1H), 3.98 – 3.91(m, 1H), 2.40 – 2.29 (m, 1H), 2.06 – 1.91 (m, 2H), 1.91 – 1.81 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 162.37 (d, J = 246.9 Hz), 134.01 (d, J = 8.1 Hz), 130.46 (d, J =3.3 Hz), 115.85 (d, J = 21.7 Hz), 87.82, 67.22, 32.56, 24.82. 19 F NMR (565 MHz, CDCl3) δ -114.84. HRMS (ESI-TOF): m / z calcd for C 10 H 12 FOS [M+H] + : 199.0587,found 199.0588.

[0050] Example 8: Preparation of 2-((4-chlorophenyl)thio)tetrahydrofuran (Ih) p-Chlorothiophenol (72 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 84 mg of colorless liquid 2-((4-chlorophenyl)thio)tetrahydrofuran (Ih) in a yield of 78%. The structural formula of Ih is:

[0051] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.34 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.6 Hz,2H), 5.50 (dd, J = 7.3, 4.1 Hz, 1H), 3.92 (q, J = 7.8 Hz, 1H), 3.89 – 3.83 (m,1H), 2.31 – 2.21 (m, 1H), 1.97 – 1.83 (m, 2H), 1.82 – 1.73 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 133.29, 131.90, 131.39, 127.87, 86.22, 66.26, 31.59,23.78. HRMS (ESI-TOF): m / z calcd for C 10 H 12 ClOS [M+H] + : 215.0292, found215.0294.

[0052] Example 9: Preparation of 2-((4-(trifluoromethyl)phenyl)thio)tetrahydrofuran (Ii) p-Trifluoromethylthiophenol (89 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA, and the reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 89 mg of colorless liquid 2-((4-(trifluoromethyl)phenyl)thio)tetrahydrofuran (Ii) in a yield of 72%. The structural formula of Ii is:

[0053] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.1 Hz,2H), 5.74 (dd, J = 7.2, 4.0 Hz, 1H), 4.06 – 3.96 (m, 2H), 2.47 – 2.35 (m, 1H), 2.10 – 1.96 (m, 2H), 1.96 – 1.84 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 141.48,129.53 (d, J = 2.9 Hz), 128.29 (d, J = 32.8 Hz), 125.54 (q, J = 4.0 Hz), 124.19 (d, J = 271.6 Hz), 86.28, 67.44, 32.61, 24.78. 19 F NMR (565 MHz, CDCl3) δ -62.55.HRMS (ESI-TOF): m / z calcd for C 11 H 12 F3OS [M+H] + : 249.0555, found 239.0556.

[0054] Example 10: Preparation of 2-(naphthalen-1-ylthio)tetrahydrofuran (Ij) 1-Naphthol (80 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL) and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane: ethyl acetate = 10:1, volume ratio) was used to separate 81 mg of colorless liquid (naphthalene-1-ylthio)tetrahydrofuran (Ij) with a yield of 70%. The structural formula of Ij is:

[0055] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 8.44 (d, J = 8.5 Hz, 1H), 7.83 (dd, J = 17.2,7.6 Hz, 2H), 7.75 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.4Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 5.65 (dd, J = 7.2, 3.7 Hz, 1H), 4.05 (q, J = 7.7Hz, 1H), 3.96 – 3.87 (m, 1H), 2.40 – 2.29 (m, 1H), 2.13 – 1.95 (m, 2H), 1.91 – 1.77 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 134.01, 133.79, 132.81, 130.94,128.54, 128.09, 126.40, 126.12, 125.75, 125.54, 87.50, 67.47, 33.01, 24.87.HRMS (ESI-TOF): m / z calcd for C 14 H 15 OS [M+H] + : 231.0838, found 231.0836.

[0056] Example 11: Preparation of methyl 4-(tetrahydrofuran-2-yl)thio)benzoate (Ik) Methyl p-thiobenzoate (84 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. After separation by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio), 81 mg of colorless liquid methyl 4-(tetrahydrofuran-2-yl)thio)benzoate (Ik) was obtained in a yield of 68%. The structural formula of Ik is:

[0057] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz,2H), 5.78 (dd, J = 7.3, 4.1 Hz, 1H), 4.10 – 3.96 (m, 2H), 3.89 (s, 3H), 2.47 –2.34 (m, 1H), 2.13 – 1.96 (m, 2H), 1.96 – 1.80 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 166.80, 143.14, 129.85, 128.58, 127.63, 85.96, 67.50, 52.00, 32.63,24.82. HRMS (ESI-TOF): m / z calcd for C 12 H 15 O3S [M+H] + : 239.0736, found239.0738.

[0058] Example 12: Preparation of 2-(thiophen-2-ylthio)tetrahydrofuran (Il) 2-Thiophenethiol (58 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 56 mg of colorless liquid 2-(thiophen-2-ylsulfide)tetrahydrofuran (Il) with a yield of 60%. The structural formula of Il is:

[0059] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.36 (dd, J = 5.3, 1.3 Hz, 1H), 7.17 (dd, J =3.5, 1.2 Hz, 1H), 6.99 (dd, J = 5.4, 3.5 Hz, 1H), 5.42 (dd, J = 7.1, 3.0 Hz, 1H),4.03 (q, J = 7.9 Hz, 1H), 3.98 – 3.92 (m, 1H), 2.32 – 2.25 (m, 1H), 2.03 – 1.94(m, 2H), 1.91 – 1.83 (m, 1H). 13 C NMR (151 MHz, CDCl3) δ 134.28, 132.49,129.84, 127.48, 89.51, 67.52, 32.15, 24.63. HRMS (ESI-TOF): m / z calcd forC8H 11 OS2[M+H] + : 187.0246, found 187.0244.

[0060] Example 13: Preparation of 2-methyl-3-((tetrahydrofuran-2-yl)thio)furan (Im) 2-Methyl-3-mercaptofuran (57 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 60 mg of colorless liquid 2-methyl-3-((tetrahydrofuran-2-yl)thio)furan (Im) in a yield of 65%. The structural formula of Im is:

[0061] Example 14: Preparation of 2-(tetrahydrofuran-2-yl)thio)thiazole (In) 2-Mercaptothiazole (59 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 50 mg of colorless liquid 2-(tetrahydrofuran-2-yl)thio)thiazole (In) in a yield of 53%. The structural formula of In is:

[0062] Example 15: Preparation of 2-(tetrahydrofuran-2-yl)thio)pyrimidine (Io) 2-Pyrimidinethiol (56 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 62 mg of colorless liquid 2-(tetrahydrofuran-2-yl)thio)pyrimidine (Io) in a yield of 68%. The structural formula of Io is:

[0063] Example 16: Preparation of 2-(tetrahydrofuran-2-yl)thio)pyridine (Ip) 2-Pyridinethiol (56 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 62 mg of colorless liquid 2-(tetrahydrofuran-2-yl)thio)pyridine (Ip) in a yield of 68%. The structural formula of Ip is:

[0064] Example 17: Preparation of 2-(tetrahydrofuran-2-yl)thio)benzo[d]oxazole (Iq) 2-Mercaptobenzoxazole (76 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 72 mg of colorless liquid 2-(tetrahydrofuran-2-yl)thio)benzo[d]oxazole (Iq) in a yield of 65%. The structural formula of Iq is:

[0065] The characterization information is as follows: 1 H NMR (600 MHz, CDCl3) δ 7.37 – 7.31 (m, 1H), 7.29 – 7.23 (m, 3H), 6.55 – 6.50 (m, 1H), 4.38 – 4.31 (m, 1H), 4.12 – 4.05 (m, 1H), 2.58 – 2.49(m, 1H), 2.35 – 2.27 (m, 1H), 2.21 – 2.14 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ179.01, 147.45, 129.96, 124.77, 124.12, 111.30, 110.39, 89.85, 69.82, 30.64,25.07. HRMS (ESI-TOF): m / z calcd for C 11 H 12 NO2S [M+H] +: 222.0583, found222.0584.

[0066] Example 18: Preparation of 3-((Tetrahydrofuran-2-yl)thio)-1H-indole (Ir) 3-Mercaptoindole (75 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. 49 mg of colorless liquid 3-((tetrahydrofuran-2-yl)thio)-1H-indole (Ir) was separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) in a yield of 45%. The structural formula of Ir is:

[0067] Example 19: Preparation of 2-(p-tolylthio)tetrahydro-2H-pyran (IIa) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), tetrahydropyran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 78 mg of colorless liquid 2-(p-tolylthio)tetrahydro-2H-pyran (IIa) with a yield of 75%. The structural formula of IIa is:

[0068] Example 20: Preparation of 2-(p-tolylthio)-1,4-dioxane (IIb) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), 1,4-dioxane (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 61 mg of colorless liquid 2-(p-tolylthio)-1,4-dioxane (IIb) in a yield of 58%. The structural formula of IIb is:

[0069] The characterization information is as follows: 1H NMR (600 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.8 Hz,2H), 5.03 (dd, J = 6.1, 2.9 Hz, 1H), 4.26 – 4.14 (m, 1H), 3.96 (dd, J = 11.8, 3.0Hz, 1H), 3.77 – 3.61 (m, 4H), 2.33 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 137.67,132.38, 129.97, 129.74, 83.53, 69.93, 66.45, 64.07, 21.09. HRMS (ESI-TOF): m / z calcd for C 11 H 15 O2S [M+H] + : 211.0787, found 211.0785.

[0070] Example 21: Preparation of 4-methyl-2-(p-tolylthio)morpholine (IIc) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), N -Methylmorpholine (2.5 mL) and dichloromethane (2.5 mL) were added to the reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA and the reaction was carried out at 25°C for 12 hours. 4-methyl-2-(p-tolylthio)morpholine (IIc) was separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) to obtain 61 mg of colorless liquid 4-methyl-2-(p-tolylthio)morpholine (IIc) with a yield of 55%. The structural formula of IIc is:

[0071] Example 22: Preparation of 2-(p-tolylthio)-1,3-dioxolane (IId) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), 1,3-dioxolane (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 69 mg of colorless liquid 2-(p-tolylthio)-1,3-dioxolane (IId) in a yield of 70%. The structural formula of IId is:

[0072] Example 23: Preparation of ((cyclopentyloxy)methyl)(p-tolyl)sulfone (IIe) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), cyclopentyl methyl ether (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. 48 mg of colorless liquid ((cyclopentyloxy)methyl)(p-tolyl)sulfone (IIe) was separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) to obtain ((cyclopentyloxy)methyl)(p-tolyl)sulfone (IIe) in a yield of 43%. The structural formula of IIe is:

[0073] Example 24: Preparation of (tert-Butoxymethyl)(p-Tolyl)sulfane (IIf) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), methyl tert-butyl ether (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 50 mg of a colorless liquid (tert-butoxymethyl)(p-tolyl)sulfane (IIf) in a yield of 48%. The structural formula of IIf is:

[0074] Example 25: Preparation of (1-ethoxyethyl)(p-tolyl)sulfane (IIg) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), ether (2.5 mL) and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. After separation by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 10:1, volume ratio), 59 mg of colorless liquid (1-ethoxyethyl)(p-tolyl)sulfane (IIg) was obtained with a yield of 60%. The structural formula of IIg is:

[0075] Example 26: Preparation of ((2-methoxyethoxy)methyl)(p-tolyl)sulfane (IIh) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), ethylene glycol dimethyl ether (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 69 mg of a colorless liquid ((2-methoxyethoxy)methyl)(p-tolyl)sulfane (IIh) in a yield of 65%. The structural formula of IIh is:

[0076] Example 27: Preparation of 2-methyl-5-(p-tolylthio)tetrahydrofuran (III) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), 2-methyltetrahydrofuran (2.5 mL) and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane: ethyl acetate = 10:1, volume ratio) was used to separate 54 mg of colorless liquid 2-methyl-5-(p-tolylthio)tetrahydrofuran (IIi) with a yield of 52%. The structural formula of IIi is:

[0077] Example 28: Preparation of 2-methyl-2-(p-tolylthio)tetrahydrofuran (IIj) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), 2-methyltetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. 24 mg of colorless liquid 2-methyl-2-(p-tolylthio)tetrahydrofuran (IIj) was separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) in a yield of 23%. The structural formula of IIj is:

[0078] Example 29: Preparation of 4-methyl-2-(p-tolylthio)tetrahydrofuran (IIk) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), 3-methyltetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. 47 mg of colorless liquid 4-methyl-2-(p-tolylthio)tetrahydrofuran (IIk) was separated by silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) with a yield of 45%. The structural formula of IIk is:

[0079] Example 30: Preparation of 3-methyl-2-(p-tolylthio)tetrahydrofuran (III) p-Methylthiophenol (62 mg, 0.5 mmol), tetrabutylammonium tetrafluoroborate (165 mg, 0.5 mmol), 3-methyltetrahydrofuran (2.5 mL), and dichloromethane (2.5 mL) were added to a reaction flask, and a platinum electrode and a graphite felt electrode were inserted. The current was adjusted to a constant current of 5 mA. The reaction was carried out at 25°C for 12 hours. Silica gel column chromatography (eluent: n-hexane:ethyl acetate = 10:1, volume ratio) was used to separate 21 mg of colorless liquid 3-methyl-2-(p-tolylthio)tetrahydrofuran (IIl) in a yield of 20%. The structural formula of IIl is:

[0080] Finally, it should be noted that the above specific implementation methods are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to examples, those skilled in the art should understand that the technical solutions of the present invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the present invention.

Claims

1. A method for electrochemical synthesis of sulfide derivatives, characterized in that: The steps include: mixing a thiol compound, an ether compound, an electrolyte and a solvent to obtain a reaction solution; electrolyzing the reaction solution at a constant current in a non-separate electrolytic cell; The electrolyzed solution is subjected to column chromatography to obtain sulfide derivatives; The general structural formula of the thiol compound is: ； The general structural formula of the ether compound is: ； The general structural formula of the obtained thioether derivatives is: ； Wherein, Ar is a C5-C8 aryl or heterocyclic aryl group; R 1 is a C1-C4 alkyl group, R 2 is a C3-C6 cycloalkyl group, R 3 It is a C5-C8 aryl group or a heterocyclic aryl group.

2. The electrochemical synthesis method of thioether derivatives according to claim 1, characterized in that: The molar concentration of the thiol compound in the reaction solution is 0.1-0.5 mol / L.

3. The electrochemical synthesis method of thioether derivatives according to claim 2, characterized in that: The amount of the electrolyte used is 80-150 mol% of the amount of the thiol compound used.

4. The electrochemical synthesis method of thioether derivatives according to claim 3, characterized in that: The electrolyte is at least one of lithium perchlorate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium iodide, tetrabutylammonium bromide, and tetrabutylammonium fluoride.

5. The electrochemical synthesis method of thioether derivatives according to claim 3, characterized in that: The volume ratio of the ether compound to the solvent is 0.5:1-2:

1.

6. The electrochemical synthesis method of thioether derivatives according to claim 5, characterized in that: The solvent is methanol, ethanol, isopropanol, trifluoroethanol, hexafluoroisopropanol, mercaptan, chlorobenzene, acetonitrile, dimethyl sulfoxide, N , N -dimethylformamide, N , N - one or more of dimethylacetamide, dioxane, dichloromethane, 1,2-dichloroethane, acetone, tetrahydrofuran, ethyl acetate, and n-hexane.

7. The electrochemical synthesis method of thioether derivatives according to claim 1, characterized in that: The positive electrode of the non-discrete electrolytic cell is one of a platinum electrode, a nickel electrode, a magnesium electrode, a stainless steel electrode, a zinc electrode, a mesh glassy carbon electrode, and a graphite felt electrode; the negative electrode of the non-discrete electrolytic cell is one of a platinum electrode, a nickel electrode, a magnesium electrode, a stainless steel electrode, a zinc electrode, a mesh glassy carbon electrode, and a graphite felt electrode.

8. The electrochemical synthesis method of thioether derivatives according to claim 7, characterized in that: The constant current is 5-40mA.

9. The electrochemical synthesis method of thioether derivatives according to claim 7, characterized in that: The electrolysis temperature is 25-75°C.

10. The electrochemical synthesis method of thioether derivatives according to claim 1, characterized in that: The column chromatography adopts silica gel column chromatography, and the eluent is a mixed solution of n-hexane and ethyl acetate with a volume ratio of 10:1.

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