Method for synthesizing thiosulfonate compound through aerobic oxidative coupling

Abstract

The invention discloses a method for synthesizing a thiosulfonate compound through aerobic oxidative coupling, and relates to the technical field of organic synthesis.The synthesis method comprises the steps that a nitrogen-doped carbon-loaded cobalt-based catalyst is adopted, and in the oxygen or air atmosphere, a sulfydryl-containing compound and sulfonyl hydrazide are catalyzed to be subjected to an oxidative coupling reaction; the preparation process of the catalyst comprises the following steps: reacting cobalt salt with sodium dicyandiamide in a water phase to generate a dicyandiamide cobalt complex; mixing the complex with an ionic liquid containing dicyandiamide anions in proportion, stirring and drying to obtain an ionic liquid precursor of metal cobalt; and carbonizing the obtained precursor at a high temperature of 500-1000 DEG C in an inert atmosphere, etching for 2-10 hours by using a 1-6 mol / L hydrochloric acid solution, washing to be neutral, and drying to obtain the nitrogen-doped carbon-loaded cobalt-based catalyst. The catalyst used in the method is green, economical and recyclable, the reaction process is mild in condition and simple and convenient to operate, the product yield is excellent, and the method has a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for aerobic oxidative coupling to synthesize thiosulfonate compounds. Background Technology

[0002] Organosulfur compounds with sulfonyl groups possess a wide range of biological activities and are an important class of compounds in drug development. Among various organosulfur compounds, thiosulfonates are of particular interest because they exhibit a variety of biological activities, including antiviral, antibacterial, and bactericidal effects. They can sulfonate thiol groups in enzymes, thereby blocking the normal metabolism of microorganisms. In addition, thiosulfonates have wide industrial applications in polymer production and photographic processes.

[0003] In the early stages, the synthesis of thiosulfonates commonly used strong oxidants to auto-oxidize thiols or disulfides. However, this method had drawbacks such as limited substrate adaptability, insufficiently mild reactions, or high toxicity. Palani et al. used disulfide compounds as substrates and an oxidation system consisting of ozone (O3) and MX salts (MX = KBr, KCl, NaBr, NaCl) to carry out the reaction in an acetonitrile-water mixed solvent at room temperature, thus constructing a synthetic pathway for symmetrical thiosulfonates (Tetrahedron Lett., 2015, 56, 4131-4134). In recent years, the synthesis of thiosulfonates from sulfonyl hydrazides and thiophenols / disulfides has attracted increasing attention. For example, Zhang et al. developed a copper-catalyzed oxidative coupling reaction system based on sulfonyl hydrazides and thiophenols, using a monovalent copper salt as a catalyst, tert-butyl hydroperoxide (TBHP) as an oxidant, and acetonitrile as a reaction solvent. The reaction was carried out at 80°C for 2 h to obtain thiosulfonate products with good yields (J. Org. Chem. 2017, 82, 9801-9807). Peng et al. used 7 equivalents of H2O2 as an oxidant and PEG400 as a solvent. The reaction was carried out at 100°C for 5 h to obtain 78% p-tolylphenyl thiosulfonate (Green Chem., 2018, 20, 1760-1764).

[0004] With the development of green chemistry, the research and development of environmentally friendly synthetic methods has become particularly important. Molecular oxygen is an environmentally friendly oxidant, which is inexpensive, readily available, and produces only water as a byproduct. Developing reaction systems that use molecular oxygen as an oxidant to prepare thiosulfonates aligns with the requirements of green chemistry, can reduce environmental pollution from chemical synthesis, lower energy consumption, and thus achieve sustainable development. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for the aerobic oxidative coupling synthesis of thiosulfonate compounds. This method has mild reaction conditions, is easy to operate, has high reactivity, and the catalyst is stable and can be recycled.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides a thiosulfonate compound having the following structural formula: Formula (I); Among them, R 1 It is an aliphatic group, aromatic group, or heterocyclic group containing a thiol group; R 2 It can be halogen, nitro, alkyl or aromatic.

[0007] In a second aspect, the present invention provides a method for aerobic oxidative coupling to synthesize thiosulfonate compounds, comprising the following steps: using a nitrogen-doped carbon-supported cobalt-based catalyst, in an oxygen or air atmosphere, a mercapto-containing compound and a sulfonyl hydrazine in a molar ratio of 1:1 to 2:1 undergo an oxidative coupling reaction to generate the thiosulfonate compound of formula (I) as described above. The nitrogen-doped carbon-supported cobalt-based catalyst is prepared by the following steps: a. Reacting cobalt salt with sodium dicyandiamide in an aqueous solution to generate a cobalt dicyandiamide complex; b. Mix the dicyandiamide cobalt complex obtained in step a with an ionic liquid containing dicyandiamide anions in a certain proportion, stir and dry to obtain an ionic liquid precursor of metallic cobalt; c. Under an inert atmosphere, the precursor obtained in step b is subjected to high-temperature carbonization at 500–1000°C; d. The carbonized product is etched with 1-6 mol / L hydrochloric acid solution for 2-10 hours, then washed until neutral and dried to obtain the nitrogen-doped carbon-supported cobalt-based catalyst.

[0008] As a preferred embodiment, in step a, the cobalt salt is any one of cobalt nitrate, cobalt chloride, cobalt acetate, or cobalt acetylacetonate; in step b, the cationic portion of the ionic liquid containing dicyandiamide anions is any one of imidazole or pyridine cations, and the molar ratio of the cobalt dicyandiamide complex to the ionic liquid is 1:2 to 1:4.

[0009] As a preferred embodiment, the sulfonyl hydrazine compound is any one of 4-methylbenzenesulfonyl hydrazine, benzenesulfonyl hydrazine, 4-methoxybenzenesulfonyl hydrazine, 4-isopropylbenzenesulfonyl hydrazine, 4-fluorobenzenesulfonyl hydrazine, 4-chlorobenzenesulfonyl hydrazine, 4-bromobenzenesulfonyl hydrazine, 4-nitrobenzenesulfonyl hydrazine, 2-chlorobenzenesulfonyl hydrazine, 3-chlorobenzenesulfonyl hydrazine, 2-methylbenzenesulfonyl hydrazine, methanesulfonyl hydrazine, 2,4,6-trimethylbenzenesulfonyl hydrazine, and 2,4,6-triisopropylbenzenesulfonyl hydrazine.

[0010] As a preferred embodiment, the thiol compound includes 4-methylbenzylthiophenol, 4-hydroxybenzylthiophenol, 4-fluorobenzylthiophenol, 4-chlorobenzylthiophenol, 4-bromobenzylthiophenol, 4-methoxybenzylthiophenol, 4-nitrobenzylthiophenol, 4-aminobenzylthiophenol, 4-isopropylbenzylthiophenol, 4-tert-butylbenzylthiophenol, 2-methoxybenzylthiophenol, 2-fluorobenzylthiophenol, 2-chlorobenzylthiophenol, 2-bromobenzylthiophenol, and 2-methylbenzylthiophenol. Any one of the following: 3-methylbenzylthiophenol, 3-bromobenzylthiophenol, 2-aminobenzylthiophenol, 3-aminobenzylthiophenol, 2,6-dimethylbenzylthiophenol, 2,4-dichlorobenzylthiophenol, 2,5-dichlorobenzylthiophenol, 2,4,6-trimethylbenzylthiophenol, benzylthiol, 2-mercaptobenzothiazole, 2-pyrimidinethiol, 2-mercaptopyridine, 2-naphthiophenol, 2-phenylethylthiol, cyclohexylthiol, 1-octylthiol, and butylthiol.

[0011] As a preferred embodiment, the oxidative coupling reaction is carried out at a pressure of 0.1–1.0 MPa, a reaction temperature of 20–100 °C, and a reaction time of 1–12 hours.

[0012] As a preferred embodiment, the oxidative coupling reaction is carried out at a pressure of 0.1–0.3 MPa, a reaction temperature of 60–80 °C, and a reaction time of 2–5 hours.

[0013] As a preferred embodiment, an alkaline additive is also added to the oxidative coupling reaction, wherein the alkaline additive is Na2CO3 or K2CO3.

[0014] As a preferred embodiment, the oxidative coupling reaction is carried out in a solvent, which is any one of methanol, ethanol, acetone, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, eutectic solvent or ionic liquid.

[0015] As a preferred embodiment, the method further includes a post-reaction processing step: after the reaction is completed, the target product of thiosulfonate compound is obtained by solid-liquid phase separation, extraction, washing, drying and column chromatography.

[0016] According to the above technical solution, the beneficial effects of the present invention are: 1. The present invention provides a method for the aerobic oxidative coupling synthesis of thiosulfonate compounds. This method uses oxygen, which is widely available and inexpensive, as a green oxidant, replacing expensive, toxic, or highly polluting oxidants in traditional processes, such as TBHP and excess H2O2. The reaction byproduct is only water, which has high atom economy and reduces environmental burden, production costs, and safety risks at the source, thus meeting the requirements of sustainable development.

[0017] 2. The method provided by this invention can efficiently catalyze reactions under mild conditions, with low energy consumption, simple operation, and good safety. The nitrogen-doped carbon-supported cobalt-based catalyst used in this invention has high activity and excellent stability, achieving a maximum yield of 96%, and can be recovered and recycled multiple times.

[0018] 3. The method provided by this invention exhibits excellent substrate versatility, applicable to structurally diverse sulfonyl hydrazides and thiophenols. Systematic experiments show that this method is compatible with various substituents and aliphatic, aromatic, and heterocyclic skeletal structures, successfully synthesizing a series of structurally diverse thiosulfonate compounds. It shows promising application prospects in constructing libraries of structurally diverse thiosulfonate compounds with potential biological activities (such as antiviral and antibacterial activity). Attached Figure Description

[0019] Figure 1 This is the NMR spectrum of the p-toluenethiosulfonic acid-4-methoxyphenyl ester product in Example 1 of the present invention. Detailed Implementation

[0020] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0021] The general reaction formula for the preparation of thiosulfonate compounds in Examples 1-13 is as follows: The preparation steps of the above thiosulfonate compounds are as follows: Cobalt salts are reacted with sodium dicyandiamide in water to form a dicyandiamide-cobalt complex. The resulting dicyandiamide-cobalt complex is then mixed with an ionic liquid containing dicyandiamide anions at a ratio of 1:2 to 1:4, stirred, and dried to obtain an ionic liquid precursor of metallic cobalt. Under an inert atmosphere (nitrogen or argon), the precursor is heated at a certain rate (e.g., 5 °C / min). -1 The temperature is raised to 500-1000℃ for high-temperature carbonization; after cooling, the carbonization product is etched with 1-6 mol / L hydrochloric acid solution at room temperature for 2-10 hours, then centrifuged, washed until neutral and dried at 80-110℃ to obtain the nitrogen-doped carbon-supported cobalt-based catalyst.

[0022] In a closed reaction apparatus, sulfonyl hydrazide compounds, mercapto compounds, a base additive, and a nitrogen-doped carbon-supported cobalt-based catalyst are added. The system is then evacuated and purged with oxygen (or air) to replace the atmosphere with oxygen at an operating pressure of 0.1–0.3 MPa. Subsequently, an organic solvent is added, and the reaction is stirred at 20–100°C for 1–12 hours to obtain the thiosulfonate compound shown in formula (I): Formula (I); Among them, R1 It is an aliphatic group, aromatic group, or heterocyclic group containing a thiol group; R 2 It can be halogen, nitro, alkyl or aromatic.

[0023] After the set reaction time was reached, the reaction system was allowed to cool to room temperature. The reaction apparatus was then removed, and solid-liquid phase separation was performed using an organic phase filter membrane and a syringe. The solid was washed with an organic solvent, and the resulting filtrate was placed in a separatory funnel with 10 mL of saturated NaHCO3 solution added. Extraction was then performed with ethyl acetate. The oil phase was collected, washed, dried, and allowed to stand. The filtrate was obtained by vacuum filtration and rotary evaporation. Column separation was then performed to obtain purified thiosulfonate compounds as shown in structural formula (I).

[0024] Several representative compounds of the thiosulfonate compounds of the present invention were prepared in Examples 1-13, and their structures and yields are shown in the following examples: Example 1 The target product in this embodiment is p-toluenethiosulfonate-4-methoxyphenyl ester, the structure of which is shown below: (1) Dissolve 20 mmol of cobalt nitrate hexahydrate in 20 mL of deionized water to prepare a cobalt nitrate solution, obtaining solution ①. Separately, dissolve 40 mmol of sodium dicyandiamide in 20 mL of deionized water to obtain a sodium dicyandiamide solution, obtaining solution ②. Under stirring conditions, solution ② is added dropwise to solution ①, and the reaction is maintained at room temperature for 12 h. After the reaction is completed, the solid powder is obtained by filtration, washed with ethanol to remove unreacted reagents, and the solid powder is collected and then transferred to a vacuum drying oven and dried under vacuum at 80 ℃ for 8 h to obtain the cobalt dicyandiamide complex (Co(DCA)2). According to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to cobalt dicyandiamide of 1:2, the corresponding mass of the substances are weighed and placed in a round-bottom flask, and magnetically stirred in an oil bath at 75 ℃ for 3 h. The reaction solution is dried in a vacuum oven at 80 ℃ for 12 h to obtain the ionic liquid precursor.

[0025] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1 The temperature was raised to 800 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 2 mol·L⁻¹ -1The reaction solution was etched at room temperature for 5 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 10 min, and then repeatedly washed with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 ℃ for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0026] (3) Take a clean reaction apparatus and add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.05 mmol of Na2CO3, and 0.25 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 1 mmol of 4-methoxybenzenethiophenol and 4 mL of EtOH, and charge with 1 atm of O2. Seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 60 °C for 7 h. The yield is tested by product purification.

[0027] According to the measurements, the yield of thiosulfonates was 96% when synthesized using the method of this embodiment.

[0028] The NMR data for p-toluenethiosulfonic acid-4-methoxyphenyl ester are shown below: 1 H NMR (400 MHz, CDCl3)δ 7.49 – 7.43 (m, 2H), 7.29 – 7.25 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.88 –6.81 (m, 2H), 3.83 (s, 3H), 2.43 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 162.3, 144.7, 140.3, 138.3, 129.4, 127.6, 118.7, 115.0, 55.5, 21.7. See attached NMR spectrum. Figure 1 .

[0029] Example 2 The target product in this embodiment is p-toluenethiosulfonate-2-toluene ester, the structure of which is shown below: (1) The dicyandiamide cobalt complex (Co(DCA)2) was obtained according to the steps in Example 1. The corresponding mass of the substances were weighed according to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to dicyandiamide cobalt at 1:4, and placed in a round-bottom flask. The mixture was magnetically stirred in an oil bath at 75°C for 3 h, and the reaction solution was dried in a vacuum oven at 80°C for 12 h to obtain the ionic liquid precursor.

[0030] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1 The temperature was raised to 900 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 3 mol·L⁻¹ -1 The reaction solution was etched at room temperature for 6 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 15 min, and then washed repeatedly with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 ℃ for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0031] (3) Take a clean reaction apparatus and add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.10 mmol of Na2CO3, and 0.3 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 1 mmol of 2-methylthiophenol and 5 mL of acetone solvent, charge with 2 atm O2, and seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 80 °C for 5 h. The yield is tested by product purification.

[0032] The results showed that the yield of thiosulfonates was 82% when synthesized using the method described in Example 2.

[0033] The NMR data for p-toluenethiosulfonic acid-2-toluene ester are shown below: 1 H NMR (400 MHz, CDCl3) δ7.44 – 7.39 (m, 2H), 7.37 – 7.30 (m, 2H), 7.21 (t, J = 8.1 Hz, 3H), 7.14 (t,J = 7.6 Hz, 1H), 2.41 (s, 3H), 2.14 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 144.8,144.2, 140.7, 138.4, 131.9, 131.0, 129.5, 127.5, 127.3, 126.9, 21.7, 20.7. Example 3 The target product in this embodiment is 4-tert-butylphenyl p-toluenethiosulfonate, and its structure is shown below: (1) Dissolve 20 mmol of cobalt chloride in 20 mL of deionized water to prepare a cobalt chloride solution, resulting in solution ①. Separately, dissolve 40 mmol of sodium dicyandiamide in 20 mL of deionized water to prepare a sodium dicyandiamide solution, resulting in solution ②. Under stirring conditions, add solution ② dropwise to solution ① and maintain the reaction at room temperature for 12 h. After the reaction is complete, separate the solid powder by filtration, wash with ethanol to remove unreacted reagents, collect the solid powder, and then transfer it to a vacuum drying oven and dry it under vacuum at 80 °C for 8 h to obtain the cobalt dicyandiamide complex (Co(DCA)2). Weigh the corresponding mass of the substance according to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to cobalt dicyandiamide of 1:2, place them in a round-bottom flask, stir magnetically in an oil bath at 75 °C for 3 h, and dry the reaction solution in a vacuum oven at 80 °C for 12 h to obtain the ionic liquid precursor.

[0034] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1 The temperature was raised to 920 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 4 mol·L⁻¹ -1 The reaction solution was etched at room temperature for 5 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 10 min, and then repeatedly washed with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 ℃ for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0035] (3) Take a clean reaction apparatus and add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.05 mmol of Na2CO3, and 0.3 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 2 mmol of 4-tert-butylthiophenol and 6 mL of EtOH, and charge with 2 atm O2. Seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 80 °C for 5 h. The yield is tested by product purification.

[0036] According to the measurements, the yield of thiosulfonates was 88% when synthesized using the method of this embodiment.

[0037] The NMR data for p-toluenethiosulfonate-4-tert-butylphenyl ester are shown below: 1H NMR (400 MHz, CDCl3)δ 7.46 – 7.43 (m, 2H), 7.36 – 7.33 (m, 2H), 7.30 – 7.27 (m, 2H), 7.22 – 7.17(m, 2H), 2.42 (s, 3H), 1.31 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 155.2, 144.7,140.6, 136.4, 129.4, 127.7, 126.6, 124.7, 35.1, 31.3, 21.8. Example 4 The target product in this embodiment is p-toluenethiosulfonate-2-chlorophenyl ester, the structure of which is shown below: (1) The dicyandiamide cobalt complex (Co(DCA)2) was obtained according to the steps in Example 3. The corresponding mass of the substances were weighed according to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to dicyandiamide cobalt at 1:4, and placed in a round-bottom flask. The mixture was magnetically stirred in an oil bath at 75 °C for 3 h, and the reaction solution was dried in a vacuum oven at 80 °C for 12 h to obtain the ionic liquid precursor.

[0038] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1 The temperature was raised to 920 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 5 mol·L⁻¹ -1 The reaction solution was etched at room temperature for 6 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 15 min, and then washed repeatedly with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 ℃ for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0039] (3) Take a clean reaction apparatus and add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.05 mmol of Na2CO3, and 0.25 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 1.5 mmol of 2-chlorothiophenol and 4 mL of DMSO, and charge with 3 atm O2. Seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 60 °C for 7 h. The yield is tested by product purification.

[0040] Measurements showed that the synthesis of thiosulfonates using the method described in this embodiment yielded a thiosulfonate yield of 80%.

[0041] The NMR data for p-toluenethiosulfonate-2-chlorophenyl ester are shown below: 1 H NMR (400 MHz, CDCl3) δ7.67 – 7.57 (m, 1H), 7.49 – 7.43 (m, 2H), 7.43 – 7.35 (m, 2H), 7.34 – 7.27(m, 1H), 7.21 (d, J = 8.3 Hz, 2H), 2.42 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ145.2, 140.9, 140.4, 139.6, 133.0, 130.4, 129.7, 127.7, 127.7, 127.6, 127.3,21.8. Example 5 The target product in this embodiment is p-toluenethiosulfonate-4-methoxyphenyl ester, the structure of which is shown below: (1) The dicyandiamide cobalt complex (Co(DCA)2) was obtained according to the steps in Example 1. The corresponding mass of the substances were weighed according to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to dicyandiamide cobalt at 1:3, and placed in a round-bottom flask. The mixture was magnetically stirred in an oil bath at 75 °C for 3 h, and the reaction solution was dried in a vacuum oven at 80 °C for 12 h to obtain the ionic liquid precursor.

[0042] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1 The temperature was raised to 500 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 4 mol·L⁻¹ -1 The reaction solution was etched at room temperature for 5 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 15 min, and then repeatedly washed with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 ℃ for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0043] (3) Take a clean reaction apparatus and add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.10 mmol of K2CO3, and 0.3 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 1 mmol of 4-methoxybenzenethiophenol and 6 mL of ACN, and charge with 2 atm O2. Seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 80 °C for 4 h. The yield is tested by product purification.

[0044] According to the measurements, the yield of thiosulfonates was 83% when synthesized using the method of this embodiment.

[0045] The NMR data of the product are the same as those in Example 1.

[0046] Example 6 The target product in this embodiment is p-toluenethiosulfonate-2-toluene ester, the structure of which is shown below: (1) Dissolve 40 mmol of cobalt chloride in 40 mL of deionized water to prepare a cobalt chloride solution, resulting in solution ①. Separately, dissolve 80 mmol of sodium dicyandiamide in 40 mL of deionized water to prepare a sodium dicyandiamide solution, resulting in solution ②. Under stirring conditions, add solution ② dropwise to solution ① and maintain the reaction at room temperature for 12 h. After the reaction is complete, separate the solid powder by filtration, wash with ethanol to remove unreacted reagents, collect the solid powder, and then transfer it to a vacuum drying oven and dry it under vacuum at 80 °C for 8 h to obtain the cobalt dicyandiamide complex (Co(DCA)2). Weigh the corresponding mass of the substances according to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to cobalt dicyandiamide of 1:2, place them in a round-bottom flask, stir magnetically in an oil bath at 75 °C for 3 h, and dry the reaction solution in a vacuum oven at 80 °C for 12 h to obtain the ionic liquid precursor.

[0047] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1 The temperature was raised to 600 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 6 mol·L⁻¹ -1The reaction solution was etched at room temperature for 6 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 15 min, and then washed repeatedly with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 ℃ for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0048] (3) Take a clean reaction apparatus and add 4.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.10 mmol of Na2CO3, and 0.3 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 2 mmol of 2-methylthiophenol and 5 mL of methanol solvent, and charge with 3 atm O2. Seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 80 °C for 5 h. The yield is tested by product purification.

[0049] Measurements showed that the synthesis of thiosulfonates using the method described in this embodiment yielded a thiosulfonate yield of 71%.

[0050] The NMR data of the product are the same as those in Example 2.

[0051] Example 7 The target product in this embodiment is 4-tert-butylphenyl p-toluenethiosulfonate, and its structure is shown below: (1) Dissolve 20 mmol of cobalt acetate in 20 mL of deionized water to prepare a cobalt acetate solution, resulting in solution ①. Separately, dissolve 80 mmol of sodium dicyandiamide in 40 mL of deionized water to prepare a sodium dicyandiamide solution, resulting in solution ②. Under stirring conditions, add solution ② dropwise to solution ① and maintain the reaction at room temperature for 12 h. After the reaction is complete, separate the solid powder by filtration, wash with ethanol to remove unreacted reagents, collect the solid powder, and then transfer it to a vacuum drying oven and dry it under vacuum at 80 °C for 8 h to obtain the cobalt dicyandiamide complex (Co(DCA)2). Weigh the corresponding mass of the substances according to the molar ratio of 1-ethyl-3-methylimidazolium dicyandiamide salt ([EMIM]DCA) to cobalt dicyandiamide of 1:4, place them in a round-bottom flask, stir magnetically in an oil bath at 75 °C for 3 h, and dry the reaction solution in a vacuum oven at 80 °C for 12 h to obtain the ionic liquid precursor.

[0052] (2) After the dried precursor is ground evenly, it is placed in a quartz boat and placed in a tube furnace with a nitrogen atmosphere flow rate of 20 mL·min. -1 , at 5 ℃·min -1The temperature was raised to 700 °C and carbonized at that temperature for 3 h. After the furnace body cooled naturally to room temperature, the black powder was collected by grinding, which is the obtained catalyst. The dried catalyst powder was dispersed in 4 mol·L⁻¹ -1 The reaction solution was etched at room temperature for 5 h with magnetic stirring in hydrochloric acid solution. The reaction solution was centrifuged at 10,000 rpm for 10 min, and then repeatedly washed with deionized water until neutral pH ≈ 7. The resulting solid was dried in a vacuum drying oven at 80 °C for 12 h, and then transferred to a vacuum drying oven for further dehydration to obtain the activated porous catalyst.

[0053] (3) Take a clean reaction apparatus and add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.10 mmol of Na2CO3, and 0.2 g of the catalyst obtained in step (2). Then, perform vacuuming and oxygenation operations, repeating three times. During the third oxygenation, add 1 mmol of 4-tert-butylthiophenol and 8 mL of EtOH, and charge with 3 atm O2. Seal the reaction apparatus. Place the reaction apparatus on a reactor and continue the reaction at 80 °C for 5 h. The yield is tested by product purification.

[0054] According to the measurements, the yield of thiosulfonates was 73% when synthesized using the method of this embodiment.

[0055] The NMR data of the product are the same as those in Example 3.

[0056] Example 8 The target product in this embodiment is 4-methylphenyl p-toluenethiosulfonate, and its structure is shown below: The nitrogen-doped carbon-supported cobalt-based catalyst was obtained following the steps in Example 1. A clean reaction apparatus was used to add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.05 mmol of Na₂CO₃, and 0.25 g of the catalyst obtained in Example 1. Vacuuming and oxygen purging were then performed, repeated three times. During the third oxygen purging, 1 mmol of 4-methylbenzenethiophenol and 4 mL of EtOH were added, followed by 1 atm of O₂, and the reaction apparatus was sealed. The reaction apparatus was placed on a reactor, and the reaction system was allowed to react at 60 °C for 7 h. The yield was determined by product purification.

[0057] According to the measurements, the yield of thiosulfonates was 94% when synthesized using the method of this embodiment.

[0058] The NMR data for p-toluenethiosulfonate-4-methylphenyl ester are shown below: 1H NMR (400 MHz, CDCl3) δ7.45 (d, J = 8.4 Hz, 2H), 7.25 – 7.18 (m, 4H), 7.13 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H), 2.37 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 144.71, 142.15, 140.48,136.55, 130.29, 129.46, 127.65, 124.63, 21.74, 21.56. Example 9 The target product in this embodiment is p-toluenethiosulfonate-4-chlorophenyl ester, whose structure is shown below: The nitrogen-doped carbon-supported cobalt-based catalyst was obtained following the steps in Example 1. A clean reaction apparatus was used to add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.05 mmol of Na₂CO₃, and 0.25 g of the catalyst obtained in Example 1. Vacuuming and oxygen purging were then performed, repeated three times. During the third oxygen purging, 1 mmol of 4-chlorothiophenol and 4 mL of EtOH were added, followed by the introduction of 1 atm O₂, and the reaction apparatus was sealed. The reaction apparatus was placed on a reactor, and the reaction system was allowed to react at 60 °C for 7 h. The yield was determined by product purification.

[0059] According to the measurements, the yield of thiosulfonates was 85% when synthesized using the method of this embodiment.

[0060] The NMR data for p-toluenethiosulfonate-4-chlorophenyl ester are shown below: 1 H NMR (400 MHz, CDCl3) δ7.45 (d, J = 8.4 Hz, 2H), 7.33 – 7.26 (m, 4H), 7.22 (d, J = 8.1 Hz, 2H), 2.42 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 145.14, 140.21, 138.25, 137.79, 129.79,129.63, 127.66, 126.60, 21.77. Example 10 The target product in this embodiment is p-toluenethiosulfonate-4-bromophenyl ester, whose structure is shown below: The nitrogen-doped carbon-supported cobalt-based catalyst was obtained following the steps in Example 1. A clean reaction apparatus was used to add 2.0 mmol of 4-methylbenzenesulfonyl hydrazine, 0.05 mmol of Na₂CO₃, and 0.25 g of the catalyst obtained in Example 1. Vacuuming and oxygen purging were then performed, repeated three times. During the third oxygen purging, 1 mmol of 4-bromobenzenethiophenol and 4 mL of EtOH were added, followed by the introduction of 1 atm O₂, and the reaction apparatus was sealed. The reaction apparatus was placed on a reactor, and the reaction system was allowed to react at 60 °C for 7 h. The yield was determined by product purification.

[0061] According to the measurements, the yield of thiosulfonates was 86% when synthesized using the method of this embodiment.

[0062] The NMR data for p-toluenethiosulfonate-4-bromophenyl ester are shown below: 1 H NMR (400 MHz, CDCl3) δ7.46 (dd, J = 6.4, 2.0 Hz, 4H), 7.22 (t, J = 7.3 Hz, 4H), 2.42 (s, 3H). 13 CNMR (101 MHz, CDCl3) δ 145.16, 140.25, 137.97, 132.79, 129.65, 127.69,127.22, 126.73, 21.80. Example 11 The target product in this embodiment is 4-methoxyphenyl thiosulfonate, and its structure is shown below: The nitrogen-doped carbon-supported cobalt-based catalyst was obtained following the steps in Example 1. A clean reaction apparatus was used to add 2.0 mmol of benzenesulfonyl hydrazine, 0.05 mmol of Na₂CO₃, and 0.25 g of the catalyst obtained in Example 1. Vacuuming and oxygen purging were then performed, repeated three times. During the third oxygen purging, 1 mmol of 4-methoxybenzylthiophenol and 4 mL of EtOH were added, followed by the introduction of 1 atm O₂, and the reaction apparatus was sealed. The reaction apparatus was placed on a reactor, and the reaction system was allowed to react at 60 °C for 7 h. The yield was determined by product purification.

[0063] Measurements showed that the synthesis of thiosulfonates using the method described in this embodiment yielded a thiosulfonate yield of 90%.

[0064] The NMR data for 4-methoxyphenyl thiosulfonic acid are shown below: 1H NMR (400 MHz, CDCl3) δ7.55 (d, J = 7.1 Hz, 3H), 7.44 – 7.38 (m, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 162.36, 142.90, 138.32, 133.64, 128.87, 127.55, 118.40, 115.03, 55.52. Example 12 The target product in this embodiment is 4-methoxyphenylthiosulfonic acid, and its structure is shown below: The nitrogen-doped carbon-supported cobalt-based catalyst was obtained following the steps in Example 1. A clean reaction apparatus was used to add 2.0 mmol of 4-methoxybenzenesulfonyl hydrazine, 0.05 mmol of Na₂CO₃, and 0.25 g of the catalyst obtained in Example 1. Vacuuming and oxygen purging were then performed, repeated three times. During the third oxygen purging, 1 mmol of 4-methoxybenzenethiophenol and 4 mL of EtOH were added, followed by 1 atm of O₂, and the reaction apparatus was sealed. The apparatus was placed on a reactor, and the reaction system was maintained at 60 °C for 7 h. The yield was determined by product purification.

[0065] According to the measurements, the yield of thiosulfonates was 96% when synthesized using the method of this embodiment.

[0066] The NMR data for 4-methoxyphenylthiosulfonic acid are shown below: 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.83 (dd, J =12.7, 8.9 Hz, 4H), 3.83 (s, 3H), 3.79 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ163.58, 162.24, 138.32, 134.76, 129.85, 118.79, 114.95, 113.89, 55.76, 55.50. Example 13 The target product in this embodiment is p-methoxyphenyl (2,4,6-trimethylphenyl) thiosulfonate, the structure of which is shown below: The nitrogen-doped carbon-supported cobalt-based catalyst was obtained following the steps in Example 1. A clean reaction apparatus was used to add 2.0 mmol of 2,4,6-trimethylbenzenesulfonyl hydrazine, 0.05 mmol of Na₂CO₃, and 0.25 g of the catalyst obtained in Example 1. Vacuuming and oxygen purging were then performed, repeated three times. During the third oxygen purging, 1 mmol of 4-methoxybenzenethiophenol and 4 mmol of LEtOH were added, followed by 1 atm of O₂, and the reaction apparatus was sealed. The reaction apparatus was placed on a reactor, and the reaction system was allowed to react at 60 °C for 7 h. The yield was determined by product purification.

[0067] According to the measurements, the yield of thiosulfonates was 83% when synthesized using the method of this embodiment.

[0068] The NMR data for p-methoxyphenyl (2,4,6-trimethylphenyl) thiosulfonate are shown below: 1 H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.8 Hz, 2H), 6.85 (s, 2H), 6.80 (d, J = 8.9Hz, 2H), 3.80 (s, 3H), 2.33 (s, 6H), 2.29 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ162.34, 143.60, 140.11, 138.70, 137.02, 131.81, 118.83, 114.86, 114.70,55.59, 22.74, 21.16. It should be noted that the above embodiments are only used to illustrate the present invention, but the present invention is not limited to the above embodiments. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A thiosulfonate compound, characterized in that: Its structural formula is: Formula (I); Among them, R 1 It is an aliphatic group, aromatic group, or heterocyclic group containing a thiol group; R 2 It can be halogen, nitro, alkyl or aromatic.

2. A method for aerobic oxidative coupling to synthesize thiosulfonate compounds, characterized in that: Includes the following steps: Using a nitrogen-doped carbon-supported cobalt-based catalyst, in an oxygen or air atmosphere, a mercapto-containing compound and a sulfonyl hydrazine in a molar ratio of 1:1 to 2:1 undergo an oxidative coupling reaction to generate the thiosulfonate compound of formula (I) as described in claim 1. The nitrogen-doped carbon-supported cobalt-based catalyst is prepared by the following steps: a. Reacting cobalt salt with sodium dicyandiamide in an aqueous solution to generate a cobalt dicyandiamide complex; b. Mix the dicyandiamide cobalt complex obtained in step a with an ionic liquid containing dicyandiamide anions in a certain proportion, stir and dry to obtain an ionic liquid precursor of metallic cobalt; c. Under an inert atmosphere, the precursor obtained in step b is subjected to high-temperature carbonization at 500–1000°C; d. The carbonized product is etched with 1-6 mol / L hydrochloric acid solution for 2-10 hours, then washed until neutral and dried to obtain the nitrogen-doped carbon-supported cobalt-based catalyst.

3. The method according to claim 2, characterized in that: In step a, the cobalt salt is any one of cobalt nitrate, cobalt chloride, cobalt acetate, or cobalt acetylacetone; in step b, the cationic portion of the ionic liquid containing dicyandiamide anion is any one of imidazole or pyridine cations, and the molar ratio of the cobalt dicyandiamide complex to the ionic liquid is 1:2 to 1:

4.

4. The method according to claim 2, characterized in that: The sulfonyl hydrazide compound is any one of 4-methylbenzenesulfonyl hydrazide, benzenesulfonyl hydrazide, 4-methoxybenzenesulfonyl hydrazide, 4-isopropylbenzenesulfonyl hydrazide, 4-fluorobenzenesulfonyl hydrazide, 4-chlorobenzenesulfonyl hydrazide, 4-bromobenzenesulfonyl hydrazide, 4-nitrobenzenesulfonyl hydrazide, 2-chlorobenzenesulfonyl hydrazide, 3-chlorobenzenesulfonyl hydrazide, 2-methylbenzenesulfonyl hydrazide, methanesulfonyl hydrazide, 2,4,6-trimethylbenzenesulfonyl hydrazide, and 2,4,6-triisopropylbenzenesulfonyl hydrazide.

5. The method according to claim 2, characterized in that: The thiols are 4-methylbenzylthiophenol, 4-hydroxybenzylthiophenol, 4-fluorobenzylthiophenol, 4-chlorobenzylthiophenol, 4-bromobenzylthiophenol, 4-methoxybenzylthiophenol, 4-nitrobenzylthiophenol, 4-aminobenzylthiophenol, 4-isopropylbenzylthiophenol, 4-tert-butylbenzylthiophenol, 2-methoxybenzylthiophenol, 2-fluorobenzylthiophenol, 2-chlorobenzylthiophenol, 2-bromobenzylthiophenol, 2-methylbenzylthiophenol, 3-methylbenzylthiophenol, etc. Any one of the following: thiophene, 3-bromothiophene, 2-aminothiophene, 3-aminothiophene, 2,6-dimethylthiophene, 2,4-dichlorothiophene, 2,5-dichlorothiophene, 2,4,6-trimethylthiophene, benzyl thiol, 2-mercaptobenzothiazole, 2-pyrimidine thiol, 2-mercaptopyridine, 2-naphthiophene, 2-phenylethyl thiol, cyclohexyl thiol, 1-octyl thiol, and butyl thiol. According to claim 2, the method is characterized in that: the pressure of the oxidative coupling reaction is 0.1-1.0 MPa, the reaction temperature is 20-100°C, and the reaction time is 1-12 hours.

6. The method according to claim 6, characterized in that: The oxidative coupling reaction is carried out at a pressure of 0.1–0.3 MPa, a temperature of 60–80 °C, and a time of 2–5 hours.

7. The method according to claim 2, characterized in that: The oxidative coupling reaction also includes the addition of an alkaline additive, which is Na2CO3 or K2CO3.

8. The method according to claim 2, characterized in that: The oxidative coupling reaction is carried out in a solvent, which is any one of methanol, ethanol, acetone, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, eutectic solvent or ionic liquid.

9. The method according to claim 2, characterized in that: The method further includes a post-reaction processing step: after the reaction is completed, the target product of thiosulfonate compounds is obtained by solid-liquid phase separation, extraction, washing, drying and column chromatography.

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