Method for preparing disulfide at low temperature

Abstract

The invention discloses a method for preparing disulfide at low temperature, which comprises the following step: in the presence of sodium hydride and lithium iodide, carrying out coupling reaction on m-dihalobenzene and a sulfhydryl compound to prepare the disulfide. The existing method for synthesizing thioether has more or less problems. Or precious metal catalysis is needed, the cost is high, and the product has the risk of heavy metal residue; or the reaction operation is complex and tedious, and the reaction condition is harsh. According to the novel method disclosed by the invention, the thioether can be simply and effectively synthesized under mild reaction conditions by starting from cheap and easily available raw materials and using a cheap initiating reagent, so that the requirements of research and development and actual production are met.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for preparing sulfide, in particular to a method for preparing disulfide at low temperature. Background Art

[0002] As a well-known sulfur-containing compound, thioether is an important class of organic compounds and organic synthesis intermediates, and has a wide range of application values ​​in the fields of medicine, agriculture, dye industry and materials. For example: Arylthioindole is a new type of microtubule inhibitor; Cefazolin has a strong effect on Staphylococcus, Pneumococcus, Escherichia coli, etc.; Omeprazole thioether (Ufiprzole) is an important intermediate for the synthesis of drugs for the treatment of gastroesophageal reflux disease. At the same time, the synthesis of chiral sulfoxide compounds by oxidation is found to have good pharmaceutical activity and industrial use.

[0003] As an important organic compound and organic synthesis intermediate, it is very necessary to explore its efficient synthesis method. The synthesis technology using transition metal catalysts is very mature, but these methods have the problems of harsh reaction conditions, complicated operation, high cost and heavy metal pollution of products, which hinders the development, application and large-scale production of transition metal catalysis.

[0004] Prior art Shotaro disclosed that dibromobenzene and thiophenol were used as raw materials to prepare disulfide at 150°C with a yield of 55%. This reaction requires high temperature. i -PrMgCl generates a benzyne intermediate in tetrahydrofuran, and then RSMgCl is added to continue the reaction for 10 min. The reaction is quenched with an electrophilic reagent (such as I2, DMF, acyl chloride, etc.) to obtain an aromatic sulfide compound. This synthesis method needs to be carried out at -78°C, which limits its industrial application.

[0005] In short, the existing methods for synthesizing sulfide at this stage all have some problems to a greater or lesser extent. Either they require precious metal catalysis, which is costly and has the risk of heavy metal residues in the product; or the reaction operation is complicated and the reaction conditions are harsh. Therefore, it is necessary to develop a new method that can start from cheap and readily available raw materials, use cheap initiating reagents, and synthesize sulfide simply and effectively under mild reaction conditions to meet the needs of research and development and actual production. Summary of the invention

[0006] The invention discloses a method for synthesizing a sulfur-containing organic compound by coupling meta-dihalobenzene with a mercapto compound. The reaction conditions are mild and no transition metal catalysis is required.

[0007] The present invention adopts the following technical solution: A method for preparing disulfide at low temperature comprises the following steps: in the presence of sodium hydride and lithium iodide, m-dihalobenzene and a mercapto compound undergo a coupling reaction to prepare the disulfide.

[0008] In the present invention, the molar ratio of meta-dihalobenzene, mercapto compound, sodium hydride and lithium iodide is 1:(1-3):(2-6):(1-3), preferably 1:2:5:2.

[0009] In the present 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.

[0010] In the present invention, the reaction is carried out in a solvent, and the solvent is THF (tetrahydrofuran), DMA (dimethylacetamide) or 1,4-dioxane (1,4-dioxane), preferably THF.

[0011] In the present invention, the chemical structural formula of meta-dihalobenzene is as follows: ; The chemical structure of thiol compounds is as follows: , ; The structural formula of the product disulfide is as follows: , ; In the above structural formula, R 1 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, etc.; R 2 It is a thiophene ring, a benzene ring, and various straight-chain alkanes and branched-chain alkanes, such as methyl, ethyl, propyl, benzyl, etc.

[0012] Early sulfides were synthesized by reacting halides with reagents such as sodium thiophenolate. This classic method has high reaction temperature, long reaction time and low yield, which limits its application in actual production. The present invention uses sodium hydride and lithium iodide as activators to react with m-dihalobenzene and mercapto compounds to obtain sulfur-containing organic compounds. The method of the present invention has cheap and readily available raw materials, simple operation, mild reaction conditions, and does not require (transition) metal catalysis. DETAILED DESCRIPTION

[0013] The present invention uses m-dihalobenzene and a thiol compound as raw materials, and reacts in the presence of sodium hydride (60% NaH mineral oil dispersion) and lithium iodide to obtain disulfide. The specific method is to weigh NaH and lithium iodide in a reaction bottle, add anhydrous THF, and then add the THF solution of the thiol compound and m-dihalobenzene in sequence under stirring, and react at 30°C to obtain disulfide.

[0014] In order to more clearly understand the technical content of the present invention, the following examples are given in detail. All raw materials are commercially available products or prepared according to literature methods, and the specific operations and testing methods are conventional techniques. 1 HNMR and 13 C NMR was measured using Agilent 400 MHz and Bruker 400 MHz instruments, and the sample solvent was CDCl3. The NMR data report includes: chemical shift, peak area integration, coupling constant, peak shape, etc. TLC thin layer chromatography plates were produced by Yantai Huanghai Chemical Plant, with visual monitoring at 254 nm and 365 nm wavelengths, and the silica gel mesh used for rapid column chromatography was 200-300 mesh. The reaction was carried out in the air, and the conventional purification method was used after the reaction to separate the product. All reagents used were commercially available analytical or chemically pure, and were used directly without special instructions. Anhydrous solvents were all redistilled solvents or commercially available dry solvents (B&K). Embodiment 1

[0015] 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 sealed tube and add 1 mL of anhydrous THF. After stirring at room temperature for 5 min, p-toluene thiophenol 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 in sequence, and the reaction was carried out at 30 °C for 6 h (TLC monitoring of the reaction completion was performed using a 254 nm UV detector lamp). Then, a saturated NH4Cl solution was added to quench the reaction in an ice bath, and the mixture was extracted with ethyl acetate three times and aqueous back-extracted twice. Finally, the organic phases were combined and washed with saturated NaCl solution, and anhydrous Na2SO4 was added to the organic phase for drying, and the mixture was filtered. Silica gel powder was added to the filtrate and the sample was mixed, 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.

[0016] Table 1 Results under different reaction conditions

[0017]

[0018] Referring to Example 1, the reaction of other halogen-substituted m-dihalobenzenes with thiophenol at 30° C. was investigated, and the results are shown in the following table:

[0019] It can be seen that under the condition of 30° C., the m-bromoiodobenzene disclosed in Example 1 has better reactivity than other m-dihalobenzenes. Embodiment 2

[0020] NaH (60% in oil, 60 mg, 1.5 mmol, 5.0 equiv) and LiI (79.8 mg, 0.6 mmol, 2 equiv) were placed in a sealed tube and 1 mL of anhydrous THF was added. After stirring at room temperature for 5 min, p-toluene thiophenol 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) were added dropwise in sequence and reacted at 30 °C for 6 h. After the reaction was completed, saturated NH4Cl solution was added to quench in an ice bath, and the reaction solution was transferred to a separatory funnel, extracted with ethyl acetate 3 times, and aqueous phase was back-extracted 2 times. Finally, the organic phases were combined, washed with saturated NaCl solution, dried by adding anhydrous Na2SO4, filtered, and silica gel powder was added to the filtrate to mix the sample, and the corresponding products (3b-3c) were separated by rapid column chromatography (pure petroleum ether). The corresponding reaction substrates (substituted m-bromoiodobenzene 1b-1c) and p-toluene thiophenol 2a and the obtained sulfur-containing organic compounds 3b-3c are shown in Table 2. Embodiment 3

[0021] NaH (60% in oil, 60 mg, 1.5 mmol, 5.0 equiv) and LiI (79.8 mg, 0.6 mmol, 2 equiv) were placed in a sealed tube and 1 mL of anhydrous THF was added. After stirring at room temperature for 5 min, thiol 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) were added dropwise and reacted at 30 °C for 6 h. After the reaction, saturated NH4Cl solution was added under ice bath to quench, and the reaction solution was transferred to a separatory funnel, extracted with ethyl acetate 3 times, and aqueous back extraction was performed 2 times. Finally, the organic phases were combined, washed with saturated NaCl solution, dried by adding anhydrous Na2SO4, filtered, and silica gel powder was added to the filtrate to mix the sample. The corresponding products (3d-3f) were separated by rapid column chromatography (pure petroleum ether). The corresponding m-bromoiodobenzene 1a and differently substituted thiophenols or thiols 2b-2d and the obtained aromatic thioether derivatives 3d-3f are shown in Table 2; the substituents of the raw materials 1a-1c and 2a-2d correspond to the products 3a-3f.

[0022] Table 2 Reaction of substituted m-bromoiodobenzene with substituted p-toluenethiophenol

[0023] The above product data are characterized as follows: 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. 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. (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. 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. 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. 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. In the embodiments of the present invention, each reaction substrate can be purchased from the market or prepared according to conventional methods. As an example, the preparation method of some raw materials is as follows.

[0024]

[0025] Weigh K2CO3 (1.1 g, 8.0 mmol, 2.0 equiv.) and 3-bromo-5-iodophenol (1.2 g, 4 mmol, 1.0 equiv.) into a two-necked reaction bottle, protect with N2, add DMF (4 mL) and stir at room temperature, then add a DMF solution (4 mL) of a halogenated hydrocarbon (6 mmol, 1.5 equiv.), react at 30-90 ℃ for 2 h. After the reaction is completed, quench the reaction with water, transfer the reaction solution to a separatory funnel, extract with ethyl acetate 3 times, back-extract with water 2 times, finally combine the organic phases, wash with saturated NaCl solution, add anhydrous Na2SO4 to dry, filter, add silica gel powder to the filtrate and mix, separate by rapid column chromatography (pure petroleum ether) to obtain a derivative of m-bromoiodobenzene.

[0026] In the above structure, R 3 It can be a straight-chain alkane or a branched-chain alkane, such as methyl, ethyl, isobutyl, etc.

[0027] The data of 1c are 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. The invention discloses a method for obtaining disulfide by co-acting NaH and LiI on m-bromoiodobenzene and then reacting with thiophenol or mercaptan. Compared with other traditional methods, the method of the invention does not require the use of transition metal catalysis, has mild reaction conditions, and is simple to operate, thus providing a new method for synthesizing sulfur-containing organic compounds and having 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 and a mercapto compound undergo a coupling reaction to prepare disulfide.

2. The method for preparing disulfide at low temperature according to claim 1, characterized in that: The molar ratio of meta-dihalobenzene, mercapto compound, sodium hydride and lithium iodide is 1:(1-3):(2-6):(1-3).

3. The method for preparing disulfide at low temperature according to claim 2, characterized in that: The molar ratio of meta-dihalobenzene, mercapto compound, sodium hydride and lithium iodide is 1:2:5:

2.

4. The method for preparing disulfide at low temperature according to claim 1, characterized in that: The reaction temperature is 10 to 60°C and the reaction time is 5 to 20 hours.

5. The method for preparing disulfide at low temperature according to claim 4, characterized in that: The reaction temperature was 30°C and the reaction time was 6 hours.

6. The method for preparing disulfide at low temperature according to claim 1, characterized in that: The reaction is carried out in a solvent, which is THF, DMA or 1,4-dioxane.

7. The method for preparing disulfide at low temperature according to claim 1, characterized in that: The chemical structure of meta-dihalobenzene is as follows: ； The chemical structure of thiol compounds is as follows: ， ； The structural formula of the product disulfide is as follows: ， ； In the above structural formula, R 1 is one of hydrogen, methoxy, methyl, tert-butyl and phenyl; R 2 It is one of a thiophene ring, a benzene ring, a straight-chain alkane, a branched-chain alkane, and a cycloalkane.

8. The method for preparing disulfide at low temperature according to claim 7, characterized in that: R 2 It is one of methyl, ethyl, propyl, benzyl and cyclopentyl.

9. The disulfide prepared according to the method for preparing disulfide at low temperature according to claim 1.

10. Application of m-dihalobenzene and mercapto compounds in the low-temperature preparation of disulfide in the presence of sodium hydride and lithium iodide.

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