A method for low temperature preparation of bis-sulfides
By coupling m-dihalobenzene with mercapto compounds in the presence of sodium hydride and lithium iodide, the problems of harsh reaction conditions and heavy metal pollution in existing thioether synthesis methods are solved, realizing low-cost and simple thioether synthesis that is suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SUZHOU UNIV
- Filing Date
- 2024-10-10
- Publication Date
- 2026-04-17
AI Technical Summary
Existing methods for synthesizing sulfides suffer from harsh reaction conditions, complex operations, high costs, and heavy metal contamination in the products, which limit their industrial application and large-scale production.
The coupling reaction of m-dihalobenzene with mercapto compounds was carried out in the presence of sodium hydride and lithium iodide at a temperature of 10–60 °C, using THF, DMA or 1,4-dioxane as solvent, thus avoiding transition metal catalysis.
This method enables the efficient synthesis of sulfides under mild reaction conditions. The raw materials are inexpensive and readily available, the operation is simple, and heavy metal pollution is avoided, making it suitable for industrial applications.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis and relates to a method for preparing sulfides, specifically a method for preparing disulfides at low temperatures. Background Technology
[0002] Sulfides, as well-known sulfur-containing compounds, are an important class of organic compounds and intermediates in organic synthesis, with wide applications in medicine, agriculture, dye industry, and materials. For example, arylthioindole is a novel microtubule inhibitor; cefazolin exhibits strong activity against Staphylococcus, Streptococcus pneumoniae, and Escherichia coli; and omeprazole sulfide is an important intermediate for synthesizing drugs to treat gastroesophageal reflux disease. Meanwhile, the synthesis of chiral sulfoxide compounds, aryl sulfides, through oxidation has been found to possess excellent pharmaceutical activity and industrial applications.
[0003] Thioethers are important organic compounds and intermediates in organic synthesis, making it essential to explore efficient synthetic methods. While synthetic techniques using transition metal catalysts are well-established, these methods suffer from harsh reaction conditions, complex operations, high costs, and heavy metal contamination in the products, hindering the development, application, and large-scale production of transition metal catalysis.
[0004] Shotaro's existing technology discloses the preparation of disulfides from m-dibromobenzene and thiophene at 150°C with a yield of 55%, but this reaction requires high temperature. Lin uses 2-iodophenyldiaryl sulfone with... i -PrMgCl generates a benzyne intermediate in tetrahydrofuran, then RSMgCl is added and the reaction continues for 10 min. The reaction is quenched by an electrophilic reagent (such as I2, DMF, acyl chloride, etc.) to obtain an aryl sulfide compound. This synthetic method requires a temperature of -78℃, which limits its industrial application.
[0005] In summary, existing methods for synthesizing thioethers all have some problems to varying degrees. Some require expensive metal catalysis, leading to high costs and the risk of heavy metal residues in the product; others involve complex and cumbersome reaction operations with harsh reaction conditions. Therefore, there is a need to develop a new method that can synthesize thioethers simply and effectively using inexpensive and readily available raw materials and inexpensive initiating reagents under mild reaction conditions, meeting the needs of both research and practical production. Summary of the Invention
[0006] This invention discloses a method for synthesizing sulfur-containing organic compounds by coupling m-dihalobenzene with mercapto compounds, with mild reaction conditions and no need for transition metal catalysis.
[0007] The present invention adopts the following technical solution:
[0008] A method for preparing disulfides at low temperature includes the following steps: in the presence of sodium hydride and lithium iodide, m-dihalobenzene undergoes a coupling reaction with a mercapto compound to prepare disulfides.
[0009] In this invention, the molar ratio of m-dihalobenzene, mercapto compound, sodium hydride, and lithium iodide is 1:(1-3):(2-6):(1-3), preferably 1:2:5:2.
[0010] In this invention, the reaction temperature is 10–60 °C and the reaction time is 5–20 hours; preferably, the reaction temperature is 20–40 °C and the reaction time is 5–10 hours; more preferably, the reaction temperature is 30 °C and the reaction time is 6 hours.
[0011] In this invention, the reaction is carried out in a solvent, which is THF (tetrahydrofuran), DMA (dimethylacetamide), or 1,4-dioxane (1,4-dioxane), preferably THF.
[0012] In this invention, the chemical structural formula of m-dihalobenzene is as follows:
[0013] ;
[0014] The chemical structural formula of the thiol compound is as follows:
[0015] , ;
[0016] The structural formula of the product disulfide is as follows:
[0017] , ;
[0018] In the above structural formula, R 1 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, etc.; R 2 It includes thiophene rings, benzene rings, and various straight-chain alkanes and branched-chain alkanes, such as methyl, ethyl, propyl, benzyl, etc.
[0019] Early thioethers were synthesized by reacting halides with reagents such as sodium thiophene. This classic method involved high reaction temperatures, long reaction times, and low yields, limiting its application in practical production. This invention uses sodium hydride and lithium iodide as activators to react with m-dihalobenzenes and mercapto compounds to obtain sulfur-containing organic compounds. The method of this invention uses inexpensive and readily available raw materials, is simple to operate, operates under mild reaction conditions, and does not require (transition) metal catalysis. Detailed Implementation
[0020] This invention uses m-dihalobenzene and a mercapto compound as raw materials to react and obtain disulfides in the presence of sodium hydride (60% NaH mineral oil dispersion) and lithium iodide. Specifically, NaH and lithium iodide are weighed into a reaction flask, anhydrous THF is added, and under stirring, a THF solution of the mercapto compound and m-dihalobenzene is added sequentially. The reaction is carried out at 30°C to obtain the disulfides.
[0021] To better understand the technical content of this invention, the following embodiments are provided for detailed explanation. All raw materials are commercially available products or prepared according to literature methods, and the specific operations and testing methods are conventional techniques. (NMR spectrum) 1 HNMR and 13 All C NMR measurements were performed using an Agilent 400 MHz and a Bruker 400 MHz instrument, with CDCl3 as the sample solvent. NMR data reports include chemical shift, peak area integral, coupling constant, and peak shape. TLC plates were manufactured by Yantai Huanghai Chemical Plant, and visualization was performed at wavelengths of 254 nm and 365 nm. 200-300 mesh silica gel was used for rapid column chromatography. Reactions were conducted in air, and products were separated using conventional purification methods after the reaction. All reagents used were commercially available analytical grade or chemically pure, and were used directly unless otherwise specified. Anhydrous solvents were redistilled solvents or commercially available drying solvents (such as Bailingwei). Example 1
[0022] Weigh NaH (60% in oil, 60 mg, 1.5 mmol, 5.0 equiv) and LiI (79.8 mg, 0.6 mmol, 2 equiv) into a sealing tube, and add 1 mL of anhydrous THF. After stirring at room temperature for 5 min, p-toluenethiophenol 2a (74.4 mg, 0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and m-bromoiodobenzene 1a (84.6 mg, 0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) were added dropwise. The reaction was carried out at 30 °C for 6 hours (the reaction was monitored by TLC using a 254 nm UV lamp). The reaction was then quenched by adding saturated NH4Cl solution in an ice bath. The mixture was extracted three times with ethyl acetate and back-extracted twice with water. The organic phases were combined, washed with saturated NaCl solution, dried with anhydrous Na2SO4, filtered, and silica gel powder was added to the filtrate. The mixture was concentrated under reduced pressure and separated by rapid column chromatography (pure petroleum ether) to obtain product 3a. The reaction results under different operating conditions are shown in Table 1.
[0023] Table 1 Results under different reaction conditions
[0024]
[0025]
[0026] Referring to Example 1, the reaction of other halogenated m-dihalobenzenes with thiophenol at 30°C was investigated, and the results are shown in the table below:
[0027]
[0028] It is evident that, under conditions of 30°C, the m-bromoiodobenzene disclosed in Example 1 exhibits better reactivity than other m-dihalobenzenes. Example 2
[0029] Take NaH (60% in oil, 60 mg, 1.5 mmol, 5.0 equiv) and LiI (79.8 mg, 0.6 mmol, 2 equiv) into a sealed tube, and add 1 mL of anhydrous THF. After stirring at room temperature for 5 min, add p-toluene 2a (74.4 mg, 0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and substituted m-bromoiodobenzene 1b-1c (0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) dropwise. React at 30 °C for 6 hours. After the reaction was completed, saturated NH4Cl solution was added under ice bath to quench the reaction mixture. The reaction solution was then transferred to a separatory funnel and extracted three times with ethyl acetate and back-extracted twice with water. Finally, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and silica gel powder was added to the filtrate for mixing. The products (3b-3c) were separated by rapid column chromatography (pure petroleum ether). Table 2 shows the corresponding products of different reaction substrates (substituted m-bromoiodobenzene 1b-1c), p-toluenethiophenol 2a, and the obtained sulfur-containing organic compounds 3b-3c. Example 3
[0030] Take NaH (60% in oil, 60 mg, 1.5 mmol, 5.0 equiv) and LiI (79.8 mg, 0.6 mmol, 2 equiv) into a sealed tube, and add 1 mL of anhydrous THF. After stirring at room temperature for 5 min, add mercapto compounds 2b-2d (0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and m-bromoiodobenzene 1a (84.6 mg, 0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) dropwise. React at 30 °C for 6 hours. After the reaction was completed, saturated NH4Cl solution was added under ice bath to quench the reaction. The reaction solution was then transferred to a separatory funnel and extracted three times with ethyl acetate and back-extracted twice with water. Finally, the organic phases were combined, washed with saturated NaCl solution, dried with anhydrous Na2SO4, filtered, and silica gel powder was added to the filtrate for mixing. The products (3d-3f) were separated by rapid column chromatography (pure petroleum ether). The corresponding products (3d-3f) are shown in Table 2: m-bromoiodobenzene 1a with different substituted benzenethiophenols or thiols 2b-2d and the obtained aryl thioether derivatives 3d-3f. The substituents of the starting materials 1a-1c and 2a-2d correspond to the products 3a-3f.
[0031] Table 2. Reaction of substituted m-bromoiodobenzene with substituted p-toluenethiophenol
[0032]
[0033] The above product data are characterized as follows:
[0034] 1,3-bis(p-tolylthio)benzene (3a) 1 H NMR (400 MHz, CDCl3): δ 7.31 (d, J= 8.2 Hz, 4H), 7.18 – 7.10 (m, 6H), 7.05 (s, 1H), 7.03 (t, J = 1.7, 0.8 Hz, 1H), 2.38 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 138.77 (s), 138.05 (s), 132.96 (s), 130.20 (d, J = 4.0 Hz), 129.43 (s), 129.12 (s), 126.73 (s), 21.24 (s).HRMS (ESI): calculated for [C 20 H 18 S2(M+H)] + : 323.0923, found: 323.0935.
[0035] naphthalene-1,3-diylbis(p-tolylsulfane) (3b) 1 H NMR (400 MHz, CDCl3):δ 8.29 (m, 1H), 7.70 (m, 1H), 7.62 (s, 1H), 7.51 – 7.42 (m, 2H), 7.33 – 7.30(m, 2H), 7.30 (s, 1H), 7.15 (dd, J = 15.3, 8.0 Hz, 4H), 7.06 (d, J = 8.0 Hz,2H), 2.38 (s, 3H), 2.33 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 137.95 (s),137.15 (s), 134.95 (s), 134.57 (s), 134.34 (s), 132.71 (s), 131.16 (s),130.81 (s), 130.47 (s), 130.13 (s), 127.88 (s), 127.45 (s), 127.03 (s),126.49 (s), 125.13 (s), 21.25 (s), 21.14 (s). HRMS (ESI): calculated for[C 24 H 20 S2(M+H)] + : 373.1079, found: 373.1088.
[0036] (5-methoxy-1,3-phenylene)bis(p-tolylsulfane) (3c) 1 H NMR (400 MHz,CDCl3): δ 7.33 (d, J = 8.1 Hz, 4H), 7.14 (d, J = 7.9 Hz, 4H), 6.68 – 6.67 (m,1H), 6.58 (d, J = 1.5 Hz, 2H), 3.68 (s, 3H), 2.38 (s, 6H). 13C NMR (101 MHz,CDCl3): δ 160.23 (s), 139.90 (s), 138.22 (s), 133.22 (s), 130.19 (s), 129.78(s), 121.04 (s), 112.04 (s), 55.35 (s), 21.26 (s). HRMS (ESI): calculated for[C 21 H 21 OS2(M+H)] + : 353.1028, found: 353.1022.
[0037] 1,3-bis(tert-butylthio)benzene (3d) 1 H NMR (400 MHz, CDCl3): δ 7.53(t, J = 1.6 Hz, 1H), 7.32 (dd, J = 7.7, 1.7 Hz, 2H), 7.07 (dd, J = 14.4, 6.8Hz, 1H), 1.07 (s, 18H). 13 C NMR (101 MHz, CDCl3): δ 146.11 (s), 137.71 (s),132.96 (s), 128.40 (s), 46.17 (s), 30.98 (s). HRMS (ESI): calculated for[C 14 H 23 S2(M+H)] + : 255.1236, found: 255.1230.
[0038] 1,3-bis(thiophen-2-ylthio)benzene (3e) 1 H NMR (400 MHz, CDCl3): δ 7.47(dd, J = 5.4, 1.2 Hz, 2H), 7.25 (dd, J = 3.6, 1.2 Hz, 2H), 7.15 – 7.09 (m,1H), 7.06 (dd, J = 5.4, 3.6 Hz, 2H), 6.96 (d, J = 1.8 Hz, 1H), 6.94 – 6.93(m, 1H), 6.91 (t, J = 1.7 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 140.07 (s),136.62 (s), 131.75 (s), 129.98 (s), 129.26 (s), 128.04 (s), 124.38 (s),124.10 (s). HRMS (ESI): calculated for [C 14 H 11 S4 (M+H)] + : 306.9738, found: 306.9746.
[0039] 1,3-bis((2-chlorophenyl)thio)benzene (3f) 1 H NMR (400 MHz, CDCl3): δ7.40 (d, 2 H, J = 6.0 Hz), 7.33-7.31 (m, 4 H), 7.19-7.14 (m, 6 H). 13 C NMR (101MHz, CDCl3): δ 135.3 (s), 134.8 (s), 134.7 (s), 134.6 (s), 131.7 (s), 131.1(s), 130.3 (s), 130.0 (s), 128.2 (s), 127.4 (s). HRMS (ESI): calculated for[C 18 H 13 Cl2S2 (M+H)] + : 362.9830, found: 362.9838.
[0040] In the embodiments of the present invention, each reaction substrate can be commercially available or prepared according to conventional methods. As an example, the preparation methods of some raw materials are as follows.
[0041]
[0042] Weigh 1.1 g (8.0 mmol, 2.0 equiv.) of K2CO3 and 1.2 g (4 mmol, 1.0 equiv.) of 3-bromo-5-iodophenol into a two-necked reaction flask, protect with N2, add 4 mL of DMF and stir at room temperature, then add 4 mL of DMF solution of haloalkanes (6 mmol, 1.5 equiv.) and react at 30-90 °C for 2 h. After the reaction is complete, quench the reaction with water, transfer the reaction solution to a separatory funnel, extract with ethyl acetate 3 times and back-extract with water 2 times, finally combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, add silica gel powder to the filtrate and mix, and separate by rapid column chromatography (pure petroleum ether) to obtain the derivative of m-bromoiodophenol.
[0043] In the above structure, R 3 It can be straight-chain alkanes or branched-chain alkanes, such as methyl, ethyl, and isobutyl.
[0044] The data representation for 1c is as follows: 1-bromo-3-iodo-5-methoxybenzene (1c) 1 H NMR (400MHz, CDCl3): δ 7.68 (1H, s), 7.49 (1H, s), 7.31 (1H, s), 3.71 (s, 3H), 2.31(3H, s). HRMS (ESI): calculated for [C7H7BrIO (M+H)] + :312.8719, found:312.8723.
[0045] This invention discloses a method for reacting NaH and LiI together with m-bromoiodobenzene, followed by reaction with thiophenol or thiol, to obtain disulfide. Compared with other conventional methods, this method does not require transition metal catalysis, has mild reaction conditions, and is simple to operate, providing a new method for synthesizing sulfur-containing organic compounds with broad application prospects.
Claims
1. A method for preparing disulfide at low temperature, comprising the following steps: in the presence of sodium hydride and lithium iodide, m-dihalobenzene undergoes a coupling reaction with a mercapto compound to prepare disulfide; the reaction is carried out in a solvent, wherein the solvent is THF; The chemical structural formula of m-dihalobenzene is as follows: ； The chemical structural formula of the thiol compound is as follows: ， ； The structural formula of the product disulfide is as follows: ， ； In the above structural formula, R 1 R is one of hydrogen, methoxy, methyl, tert-butyl, and phenyl; R² is one of methyl, ethyl, propyl, benzyl, and cyclopentyl. The molar ratio of m-dihalobenzene, mercapto compound, sodium hydride, and lithium iodide is 1:2:5:
2.
2. The process for the low temperature preparation of bisulfides according to claim 1, characterized in that, The reaction temperature is 10–60℃, and the reaction time is 5–20 hours.
3. The process for the low temperature preparation of bisulfides according to claim 2, characterized in that, The reaction was carried out at a temperature of 30°C for 6 hours.