A method for preparing a sulfur-containing ether compound

Abstract

This invention discloses a method for preparing sulfur-containing ether compounds, comprising the following steps: in the presence of sodium hydride and lithium iodide, o-iodoaryl ether undergoes a coupling reaction with thiophenol or thiol to prepare the sulfur-containing ether compound. This invention prepares aryl sulfides from o-iodoaryl ether and thiophenol / thiol under NaH and LiI conditions. Compared with other conventional methods, this method does not require transition metal catalysis, has mild reaction conditions, and is simple to operate, providing a novel method for synthesizing sulfur-containing ether compounds with broad application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for preparing sulfur-containing ether compounds. Background Technology

[0002] Sulfur-containing organic compounds, especially thioethers, are ubiquitous in natural products, pharmaceuticals, pesticides, and functional materials, and are also widely used as catalysts and intermediates in organic synthesis. Some pharmaceuticals or bioactive substances containing aryl thioethers include noratrexate (Thymitaq), azathioprine, and vortioxetine.

[0003] Because thioethers have significant value in multiple fields, their preparation methods have attracted widespread attention. Transition metal-catalyzed cross-coupling reactions of CS bonds and direct C-H bond functionalization are common techniques for obtaining thioethers. Traditionally, aryl sulfides are obtained by cross-coupling reactions of prefunctionalized aromatic hydrocarbons (such as aryl halides) with thiols or disulfides via transition metal catalysis (mainly palladium, copper, iron, nickel, cobalt, and rhodium, etc.), which is a highly efficient method for CS bond construction. However, transition metal coupling methods have many drawbacks. The most significant is that organosulfur reagents tend to over-coordinate with metal catalysts, causing catalyst poisoning and deactivation. Moreover, most known transition metal-catalyzed CS bond formation methods have relatively harsh reaction conditions, such as requiring strong bases, anhydrous and oxygen-free conditions, expensive ligands, and high temperatures (80-140℃), resulting in poor practicality. Therefore, it is necessary to find better alternatives for CS bond formation.

[0004] Examples of transition metal-free catalysis include a method reported by Sanford for the synthesis of aryl sulfides from RSH (or RSR) and diaryl iodonium salts without metal catalysis. Compared to base / transition metal-catalyzed conversions, this novel method is highly compatible with ambient air and moisture, and has a wider substrate range and functional group tolerance, but requires the prior preparation of various functional group-substituted diphenyliodonium salts and a relatively high reaction temperature.

[0005] For example, the Cuny group reported the photocatalytic preparation of sulfides from aniline in the presence of tert-butyl nitrite; however, this reaction system required the addition of an expensive ruthenium metal photocatalyst. Subsequently, the Lee group, building on Cuny's work, developed a new method for synthesizing sulfides at room temperature without a photocatalyst.

[0006] 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

[0007] This invention discloses a method for synthesizing sulfur-containing ether compounds by coupling o-iodoaryl ethers with thiophene or thiols. The method uses inexpensive and readily available raw materials, is simple to operate, operates under mild reaction conditions, and does not require transition metal catalysis. The method involves the coupling reaction of aryl ethers with thiophene or thiols in the presence of sodium hydride (60% NaH mineral oil dispersion) and lithium iodide to generate aryl sulfides. This invention solves the problems of harsh reaction conditions and heavy metal residues associated with the preparation of such products using traditional methods.

[0008] The present invention adopts the following technical solution:

[0009] A method for preparing a sulfur-containing ether compound includes the following steps: in the presence of sodium hydride and lithium iodide, o-iodoaryl ether is coupled with thiophenol or thiol to prepare the sulfur-containing ether compound.

[0010] A method for preparing a sulfur-containing ether compound includes the following steps: in the presence of sodium hydride, lithium iodide and 2,2,6,6-tetramethylpiperidine oxide, a halogen-substituted o-iodoaryl ether is coupled with thiophenol or thiol to prepare the sulfur-containing ether compound.

[0011] In this invention, the molar ratio of o-iodoaryl ether, thiophenol or thiol, sodium hydride and lithium iodide is 1:(1-3):(2-6):(1-3), preferably 1:2:5:2.

[0012] In this invention, the molar ratio of halogen-substituted o-iodoaryl ether, thiophenol or thiol, sodium hydride, lithium iodide, and 2,2,6,6-tetramethylpiperidine oxide is 1:(1-3):(2-6):(1-3):(1-3), preferably 1:2:5:2:2.

[0013] In this invention, the reaction temperature is 10–60 °C and the reaction time is 5–20 hours; preferably, the reaction temperature is 40 °C and the reaction time is 6 hours.

[0014] 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.

[0015] In this invention, the chemical structural formula of the o-iodoaryl ether is as follows:

[0016] ;

[0017] The chemical structural formula of thiophenol is as follows:

[0018] ;

[0019] The chemical structural formula of thiols is as follows:

[0020] ;

[0021] The structural formula of the product, a sulfur-containing ether compound, is as follows:

[0022] , ;

[0023] In the above structural formula, R 1 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl, halogen, etc.; R 2 It includes various straight-chain alkanes, branched-chain alkanes, and cycloalkanes, such as methyl, ethyl, propyl, benzyl, cyclopentyl, etc.; R 3 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl, etc.

[0024] In the above structural formula, R 1 When it is halogenated, o-iodoaryl ether is a halogen-substituted o-iodoaryl ether.

[0025] Previous studies have shown that the preparation of aryl sulfides from aryl halides and thiophenols or thiols requires catalysis by transition metals such as palladium, copper, iron, nickel, and cobalt. These reactions are typically carried out at high temperatures, resulting in poor functional group tolerance and a risk of heavy metal residues. This invention uses sodium hydride and lithium iodide as activators to react o-iodoaryl ethers, thiophenols, or thiols, thereby yielding sulfur-containing aryl sulfide 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

[0026] This invention uses o-iodoaryl ether and thiophenol or thiol as raw materials to react and obtain sulfur-containing ether compounds in the presence of sodium hydride (60% NaH mineral oil dispersion) and lithium iodide. Specifically, NaH is weighed into a reaction flask, anhydrous THF is added, and under stirring, a THF solution of thiophenol or thiol and o-iodoaryl ether is added sequentially. The reaction is carried out at 40°C to obtain the aryl sulfide product, a sulfur-containing ether compound.

[0027] 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).

[0028] Example 1

[0029] 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 o-iodoanisole 1a (70.2 mg, 0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) were added dropwise. The reaction was carried out at 40 °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 at 0 °C. 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.

[0030] Table 1 Results under different reaction conditions

[0031]

[0032]

[0033] Example 2

[0034] 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 thiophenol 2a (0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and o-iodoaryl halide 1 (0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) dropwise. React at 40 °C for 6 hours. After the reaction is complete, quench with saturated NH4Cl solution at 0 °C. Transfer the reaction solution to a separatory funnel, extract three times with ethyl acetate, back-extract twice with water, and finally combine the organic phases. Wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, add silica gel powder to the filtrate, and separate by rapid column chromatography (pure petroleum ether) to the corresponding products (3b-3l).

[0035] Table 2 shows the different reaction substrates (substituted o-iodoaryl ether 1 and p-toluenethiophenol 2a) and the resulting aryl thioether products. The substituents of the starting material substituted o-iodoaryl ether 1 are the same as those of the corresponding product 3.

[0036] Table 2. Reaction of substituted o-iodoaryl ethers with p-toluenethiophenol 2a

[0037]

[0038] The above product data are characterized as follows:

[0039] (2-methoxyphenyl)(p-tolyl)sulfane (3a): 1 H NMR (400 MHz, CDCl3): δ7.31 (d, J = 8.0 Hz, 2H), 7.17 – 7.13 (m, 3H), 6.94 (d, J = 7.6 Hz, 1H), 6.89– 6.83 (m, 2H), 3.89 (s, 3H), 2.35 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 156.60(s), 137.74 (s), 132.97 (s), 130.13 (s), 129.97 (s), 129.90 (s), 127.48 (s), 125.74 (s), 121.25 (s), 110.68 (s), 55.90 (s), 21.20 (s). HRMS (ESI):calculated for [C 14 H15 OS (M+H)] + : 231.0838, found: 231.0846.

[0040] (2,5-dimethoxyphenyl)(p-tolyl)sulfane (3b): 1 H NMR (400 MHz, CDCl3):δ 7.35 (d, J = 8.1 Hz, 2H), 7.17 (d, J =8.0, 3H), 6.80 (d, J = 8.8, 1.6 Hz,1H), 6.66 (dd, J= 8.8, 3.0 Hz, 1H), 6.46 (d, J= 3.0 Hz, 1H),3.85(s, 3H), 3.65(s, 3H), 2.37 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 154.06 (s), 150.76 (s),138.12 (s), 133.48 (s), 130.22 (s), 129.18 (s), 127.50 (s), 115.63 (s),111.59 (s), 111.31 (s), 56.55 (s), 55.66 (s), 21.21 (s). HRMS (ESI):calculated for [C 15 H 17 O2S (M+H)] + : 261.0944, found: 261.0952.

[0041] (2-methoxynaphthalen-1-yl)(p-tolyl)sulfane (3c): 1 H NMR (400 MHz,CDCl3): δ 7.67 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.41 (d, J =8.4 Hz, 2H), 7.33 – 7.35 (m, 1H), 7.26-7.24 (m, 2H), 7.20(d, 2H), 7.11(s,1H), 3.98 (s, 3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 154.62 (s),138.40 (s), 133.89 (s), 133.01 (s), 130.37 (s), 129.14 (s), 128.92 (s),127.33 (s), 126.80 (s), 126.41 (s), 125.87 (s), 124.02 (s), 105.28 (s), 55.96(s), 21.29 (s). HRMS (ESI): calculated for [C 18 H 17 OS (M+H)] + : 281.0995, found:281.0899.

[0042] 2-methoxy-3-(p-tolylthio)pyridine (3d) 1 H NMR (400 MHz, CDCl3): δ 7.91(d, J = 5.5 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 6.58(dd, J = 5.5, 1.6 Hz, 1H), 6.29 (d, J = 1.4 Hz, 1H), 3.86 (s, 3H), 2.38 (d, J= 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 164.44 (s), 153.03 (s), 146.29 (s),140.01 (s), 135.43 (s), 130.65 (s), 125.74 (s), 114.52 (s), 106.76 (s), 53.40(s), 21.33 (s). HRMS (ESI): calculated for C 13 H 14 NOS (M+H)] + : 232.0791, found:232.0795.

[0043] (5-(tert-butyl)-2-methoxyphenyl)(p-tolyl)sulfane (3e) 1H NMR (400MHz, CDCl3): δ 7.23 – 7.25 (m, 2H), 7.21 (d, J = 2.5 Hz, 1H), 7.11 – 7.13 (m,J = 10.0Hz, 5.2 Hz, 3H), 6.82 (d, 1H), 3.82 (s, 3H), 2.33 (s, 3H), 1.20 (s,9H). 13 C NMR (101 MHz, CDCl3): δ 155.25 (s), 144.00 (s), 136.89 (s), 131.38(s), 131.15 (s), 129.86 (s), 129.00 (s), 124.93 (s), 123.52 (s), 110.43 (s),55.99 (s), 34.19 (s), 31.39 (s), 21.14 (s). HRMS (ESI): calculated for[C 18 H 23 S (M+H)] + : 287.1464, found: 287.1470.

[0044] (2-methoxy-5-(trifluoromethyl)phenyl)(p-tolyl)sulfane (3f) 1 H NMR(400 MHz, CDCl3): δ 7.40 (d, J = 8.5, 1.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H),7.20 (d, J = 7.9 Hz, 2H), 7.09 (s, 1H), 6.90 (d, J = 8.5 Hz, 1H), 3.94 (s,3H), 2.39 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 158.27 (s), 138.84 (s), 133.85(s), 130.48 (s), 128.06 (s), 127.83 (s), 125.53(q, J = 3.7 Hz), 124.22(q, J =3.7 Hz 1H) 123.47(q, J = 32.8 Hz, 1H), 122.06(q, J = 272.7, 1H), 109.98(s),56.14 (s), 21.24 (s).19 F NMR (377 MHz, CDCl3): δ -61.65 (s). HRMS (ESI):calculated for [C 15 H 14 F3OS (M+H)] + : 299.0712, found: 299.0708.

[0045] (2-methoxy-4-methylphenyl)(p-tolyl)sulfane (3g) 1 H NMR (400 MHz,CDCl 3 ): δ 7.31 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 7.01 (dd, J =8.2, 1.4 Hz, 1H), 6.86 (d, J = 1.6 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 3.86(s, 3H), 2.35 (d, J = 15.7 Hz, 3H), 2.21 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ154.97 (s), 137.34 (s), 132.26 (s), 131.24 (s), 130.61 (s), 130.49 (s),130.03 (s), 128.27 (s), 124.70 (s), 110.79 (s), 56.06 (s), 21.18 (s), 20.50(s). HRMS (ESI): calculated for [C 15 H 17 OS (M+H)] + : 245.0995, found: 245.0987.

[0046] (2-ethoxyphenyl)(p-tolyl)sulfane (3h) 1H NMR (400 MHz, CDCl3): δ 7.36(d, 2H), 7.14 – 7.18 (m, 3H), 6.95 (dd, J = 7.7, 1.6 Hz, 1H), 6.86 (d, J =8.2, 0.9 Hz, 1H), 6.82 (td, J = 7.6, 1.2 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H),2.37 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 155.87(s), 137.74 (s), 133.26 (s), 130.05 (s), 129.95 (s) 129.61 (s), 127.22 (s),126.32 (s), 121.07 (s), 111.81 (s), 64.35 (s), 21.21 (s), 14.74 (s). HRMS(ESI): calculated for [C 15 H 17 OS (M+H)] + : 245.0995, found: 245.0987.

[0047] (2-(cyclopropylmethoxy)phenyl)(p-tolyl)sulfane (3i) 1 H NMR (400 MHz,CDCl3): δ 7.36 (d, J = 8.1 Hz, 2H), 7.14 – 7.16 (m, 3H), 6.97 (dd, J = 7.7,1.5 Hz, 1H), 6.82 – 6.84 (m, 2H), 3.89 (d, J = 6.7 Hz, 2H), 2.36 (d, J = 9.5Hz, 3H), 1.33 – 1.21 (m, 1H), 0.60 (q, J = 6.0 Hz, 2H), 0.33 (q, J = 4.8 Hz,2H). 13C NMR (101 MHz, CDCl3): δ 156.01 (s), 137.67 (s), 133.21 (s), 130.07(s), 130.07(s), 129.75 (s), 127.24 (s), 126.62 (s), 121.19 (s), 112.32 (s),73.30 (s), 21.21 (s), 10.23 (s), 3.15 (s). HRMS (ESI): calculated for[C 17 H 19 OS (M+H)] + :271.1151, found: 271.1148.

[0048] (2-(cyclopentylmethoxy)phenyl)(p-tolyl)sulfane (3j) 1 H NMR (400 MHz,CDCl3): δ 7.34 (d, J = 8.0 Hz, 2H), 7.13 – 7.17 (m, 3H), 6.96 (dd, J = 7.7,1.6 Hz, 1H), 6.86 (dd, J = 8.2, 0.9 Hz, 1H), 6.82 (td, J = 7.6, 1.2 Hz, 1H),3.91 (d, J = 6.7 Hz, 2H), 2.37 (s, 3H), 1.79 – 1.83 (m, 2H), 1.73 – 1.50 (m,5H), 1.43 – 1.33 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 156.19 (s), 137.58 (s),133.03 (s), 130.16 (s), 130.27 (s), 129.69 (s), 127.24 (s), 126.30 (s),120.94 (s), 111.73 (s), 72.77 (s), 39.10 (s), 29.42 (s), 25.53 (s), 21.20(s). HRMS (ESI): calculated for [C 19 H 23 OS (M+H)] + : 299.1464, found: 299.1458.

[0049] (2-(2,2-dimethoxyethoxy)phenyl)(p-tolyl)sulfane (3k) 1 H NMR (400 MHz,CDCl3): δ 7.31 (d, J = 8.0 Hz, 2H), 7.17 – 7.12 (m, 3H), 6.95 (dd, J = 7.7,1.6 Hz, 1H), 6.86 (dd, J = 4.2, 2.9 Hz, 1H), 6.85 – 6.81 (td, J = 7.6 Hz,1H), 4.65 (t, J = 5.2 Hz, 1H), 4.04 (d, J = 5.2 Hz, 2H), 3.45 (s, 6H), 2.35(s, 3H). 13 C NMR (101 MHz, CDCl3): δ 155.60 (s), 137.66 (s), 132.96 (s),130.08 (s), 130.06 (s), 130.02 (s), 127.38 (s), 126.52 (s), 121.73 (s),112.21 (s), 102.77 (s), 69.22 (s), 54.86 (s), 21.18 (s). HRMS (ESI):calculated for [C 17 H 21 O3S (M+H)] + : 305.1206, found: 305.1211.

[0050] (2-(pentan-3-yloxy)phenyl)(p-tolyl)sulfane (3l) 1 H NMR (400 MHz,CDCl3): δ 7.33 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.12 – 7.07 (m,1H), 6.90 (dd, J = 7.8, 1.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.79 – 6.74(td, J = 7.6 Hz, 1H), 4.26 – 4.10 (q, J = 4.8 Hz, 2H), 2.34 (s, 3H), 1.75 –1.63 (m, 4H), 0.95 (t, J = 7.2, 6H).13 C NMR (101 MHz, CDCl3): δ 155.47 (s), 137.63 (s), 133.39 (s), 130.25 (s), 130.00 (s), 129.55 (s), 127.46 (s), 126.90 (s), 120.70 (s), 116.04 (s), 113.10 (s), 81.12 (s), 26.00 (s), 21.18(s). HRMS (ESI): calculated for [C 18 H 23 OS (M+H)] + : 287.1464, found: 287.1459.

[0051] Example 3

[0052] When a halogen is added to the o-iodoaryl ether and used as a starting material, the reaction products become more mixed. However, the addition of TEMPO (2,2,6,6-tetramethylpiperidine oxide) can better achieve selective substitution of thiophenol.

[0053] Take NaH (60% in oil, 60 mg, 1.5 mmol, 5.0 equiv), TEMPO (93.7 mg, 0.6 mmol, 2 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 thiophenol 2a (0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and aryl halide 1m-1t (0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) dropwise. React at 40 °C for 6 hours. After the reaction was completed, saturated NH4Cl solution was added at 0℃ 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 product (3m-3t) was obtained by rapid column chromatography (pure petroleum ether).

[0054] Table 3 shows the different reaction substrates (substituted aryl halides 1m-1t and p-toluenethiophenol 2a) and the resulting aryl thioether derivatives 3m-3t. The substituents R of starting material 1 are shown in Table 3. 1 Same as the corresponding product.

[0055] Table 3. Reaction of halogenated o-iodoaryl ethers with p-toluenethiophenol 2a

[0056]

[0057] The above product data are characterized as follows:

[0058] (3-fluoro-2-methoxyphenyl)(p-tolyl)sulfane (3m) 1 H NMR (400 MHz, CDCl3): δ 7.38 (d, J = 6.8 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 6.94 – 6.81 (m,2H), 6.64 – 6.60 (m, 1H), 3.96 (d, J = 1.6 Hz, 3H), 2.38 (s, 3H). 13 C NMR (101MHz, CDCl3): δ 155.50 (d, J = 248.4 Hz), 144.45 (d, J = 12.1 Hz), 138.59 (s), 133.97 (s), 133.82 (d, J = 2.3 Hz), 130.32 (s), 128.81 (s), 124.00 (d, J =3.1 Hz), 123.80 (d, J = 8.1 Hz), 114.33 (d, J = 19.5 Hz), 61.14 (d, J = 5.4Hz), 21.23 (s). 19 F NMR (377 MHz, CDCl3): δ -130.76 (s). HRMS (ESI): calculated for [C 14 H 14 FOS (M+H)] + : 249.0744, found: 249.0452.

[0059] (2-fluoro-6-methoxyphenyl)(p-tolyl)sulfane (3n) 1H NMR (400 MHz,CDCl3): δ 7.33 (td, J = 8.4, 6.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 2H), 7.02 (d,J = 8.1 Hz, 2H), 6.81 – 6.73 (m, 2H), 3.85 (s, 3H), 2.28 (s, 3H). 13 C NMR (101MHz, CDCl3): δ 163.86 (d, J = 246.6 Hz), 161.28 (d, J = 4.3 Hz), 135.63 (s),132.79 (s), 130.97 (d, J = 10.6 Hz), 129.55 (s), 128.07 (s), 109.35 (d, J =20.3 Hz), 108.60 (d, J = 24.2 Hz), 107.03 (d, J = 3.1 Hz), 56.53 (s), 20.97(s). 19 F NMR (377 MHz, CDCl3): δ -103.95 (s). HRMS (ESI): calculated for[C 14 H 14 FOS (M+H)] + : 249.0744, found: 249.0452.

[0060] (4-chloro-2-methoxyphenyl)(p-tolyl)sulfane (3o) 1 H NMR (400 MHz,CDCl3): δ 7.37 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.08 (dd, J =8.7, 2.5 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H) 6.74 (m, 2H), 6.75 (s), 3.88 (s,3H), 2.39 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 154.47 (s), 138.85 (s), 134.16(s), 130.49 (s), 128.97 (s), 127.88 (s), 127.75 (s), 126.33 (s), 126.16 (s),111.34 (s), 56.19 (s), 21.28 (s). HRMS (ESI): calculated for [C 14 H 14 ClOS (M+H)] + : 265.0448, found: 265.0456.

[0061] (5-bromo-2-methoxyphenyl)(p-tolyl)sulfane (3p) 1 H NMR (400 MHz,CDCl3): δ 7.36 (d, J = 8.1 Hz, 2H), 7.25 – 7.17 (m, 3H), 6.91 (d, J = 2.4 Hz,1H), 6.72 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H), 2.38 (s, 3H). 13 C NMR (101 MHz,CDCl3): δ 155.10 (s), 138.76 (s), 133.97 (s), 130.71 (s), 130.47 (s), 129.43(s), 129.27 (s), 128.05 (s), 113.41 (s), 111.94 (s), 56.14 (s), 21.28 (s).HRMS (ESI): calculated for [C 14 H 14 BrOS (M+H)] + : 308.9943, found: 308.9935.

[0062] (4-bromo-2-methoxyphenyl)(p-tolyl)sulfane (3q) 1H NMR (400 MHz,CDCl3): δ 7.31 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.99 (s, 1H),6.95 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H), 2.36 (s,3H). 13 C NMR (101 MHz, CDCl3): δ 156.89 (s), 138.19 (s), 133.21 (s), 130.61(s), 130.26 (s), 129.02 (s), 125.54 (s), 124.17 (s), 120.38 (s), 114.13 (s),56.18 (s), 21.21 (s). HRMS (ESI): calculated for [C 14 H 14 BrOS (M+H)] + : 308.9943,found: 308.9935.

[0063] (5-chloro-2-methoxyphenyl)(p-tolyl)sulfane (3r) 1 H NMR (400 MHz,CDCl3): δ 7.37 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 7.9 Hz, 1H), 7.08 (d, J =8.7 Hz, 1H), 6.97 (dd, J = 7.7, 1.6 Hz, 1H), 6.75 (s, 1H), 3.88 (s, 1H), 2.39(s, 1H). 13 C NMR (101 MHz, CDCl3): δ 154.51 (s), 138.84 (s), 134.14 (s),130.48 (s), 128.97 (s), 127.93 (s), 127.80 (s), 126.34 (s), 126.17 (s),111.37 (s), 56.20 (s), 21.27 (s). HRMS (ESI): calculated for [C 14 H 14 ClOS (M+H)] + : 265.0448, found: 265.0456.

[0064] (5-fluoro-2-methoxyphenyl)(p-tolyl)sulfane (3s) 1 H NMR (400 MHz,CDCl3): δ 7.40 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.77 – 6.79(m, 2H), 6.48 – 6.50 (m, 1H), 3.88 (s, 3H), 2.39 (s, 3H). 13 C NMR (101 MHz,CDCl3): δ 157.43 (d, J = 240.0 Hz), 151.81 (s), 139.05 (s), 134.59 (s),130.52 (s), 129.33 (d, J = 7.9 Hz), 127.75 (s), 114.69 (d, J = 26.2 Hz),112.22 (d, J = 23.2 Hz), 111.03 (d, J = 8.4 Hz), 56.46 (s), 21.27 (s). 19 F NMR(377 MHz, CDCl3): δ -122.58 (s). HRMS (ESI): calculated for [C 14 H 14 FOS (M+H)] + : 249.0744, found: 249.0452.

[0065] 5-bromo-2-methoxy-3-(p-tolylthio)pyridine (3t) 1 H NMR (400 MHz,CDCl3): δ 7.92 (d, J = 2.3 Hz, 1H), 7.44 – 7.36 (d, J = 8.4 Hz 2H), 7.24 (d,J = 7.9 Hz, 2H), 6.99 (d, J = 2.3 Hz, 1H), 4.00 (s, 3H), 2.40 (s, 3H). 13C NMR(101 MHz, CDCl3): δ 158.19 (s), 143.27 (s), 139.75 (s), 136.64 (s), 134.88(s), 130.81 (s), 126.12 (s), 125.50 (s), 112.17 (s), 54.26 (s), 21.33 (s).HRMS (ESI): calculated for [C 13 H 13 BrNOS (M+H)] + : 309.9896, found: 309.9888.

[0066] Example 4

[0067] When an additional halogen is added to the o-iodoaryl ether, if TEMPO (2,2,6,6-tetramethylpiperidine oxide) is not added, disubstitution, deiodination, and low yield will occur when it reacts with thiophenol.

[0068] 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 thiophenol 2a (0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and aryl halide 1p or 1q (0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) dropwise. React at 40 °C for 6 hours. After the reaction was completed, saturated NH4Cl solution was added at 0℃ 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 product (3p, 3p1 or 3q1, 3q2) was obtained by rapid column chromatography (pure petroleum ether).

[0069]

[0070] The data representations for 3p1, 3q1, and 3q2 are as follows:

[0071] (4-methoxy-1,3-phenylene)bis(p-tolylsulfane) (3p1) 1H NMR (400 MHz,CDCl3): δ 7.32 – 7.23 (m, 3H), 7.17 (dd, J = 8.3, 1.9 Hz, 1H), 7.14 – 6.99(m, 6H), 6.89 (d, J = 1.9 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.89 (d, J = 9.3Hz, 3H), 2.33 (d, J = 15.8 Hz, 6H). HRMS (ESI): calculated for [C 21 H 21 OS2 (M+H)] + : 353.1028, found: 353.1011.

[0072] (3-methoxyphenyl)(p-tolyl)sulfane (3q1) 1 H NMR (400 MHz, CDCl3): δ7.34 (d, J = 8.1 Hz, 2H), 7.22 – 7.10 (m, 3H), 6.84 (d, J = 7.7 Hz, 1H), 6.82– 6.79 (m, 1H), 6.74 (dd, J = 8.2, 1.8 Hz, 1H), 3.75 (s, 3H), 2.36 (s, 3H).HRMS (ESI): calculated for [C 14 H 15 OS (M+H)]+: 231.0838, found: 231.0830.

[0073] (2-methoxy-1,4-phenylene)bis(p-tolylsulfane) (3q2) 1 H NMR (400 MHz,CDCl3): δ 7.28 (t, J = 8.3 Hz, 4H), 7.12 (t, J = 7.1 Hz, 4H), 6.86 – 6.77 (m,2H), 6.69 (dd, J= 8.1, 1.7 Hz, 1H), 3.79 (s, 3H), 2.33 (d, J = 3.6 Hz, 6H).HRMS (ESI): calculated for [C 21 H 21 OS2 (M+H)] + : 353.1028, found: 353.1011.

[0074] Example 5

[0075] 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 thiophenol or thiols 2b-2f (0.6 mmol, 2.0 equiv, dissolved in 0.5 mL THF) and o-iodoanisole 1a (70.2 mg, 0.3 mmol, 1.0 equiv, dissolved in 0.5 mL THF) dropwise, and react at 40 °C for 6 hours. After the reaction was completed, saturated NH4Cl solution was added to quench the reaction at 0 °C. The reaction solution was 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 (3u-3y) were separated by rapid column chromatography (pure petroleum ether). The results of o-iodoanisole 1a with different substituted thiophenols or thiols 2b-2f and the obtained aryl thioether derivatives 3u-3y are shown in Table 4. The substituents R of the raw material 2 are also shown. 3 Same as the corresponding product.

[0076] Table 4. Reaction of o-iodoanisole 1a with substituted thiophenols

[0077]

[0078] The above product data are characterized as follows:

[0079] (4-(tert-butyl)phenyl)(2-methoxyphenyl)sulfane (3u) 1H NMR (400 MHz,CDCl3): δ 7.41 – 7.34 (m, 4H), 7.20 (td, J = 8.2, 1.7 Hz, 1H), 7.00 (dd, J =7.7, 1.6 Hz, 1H), 6.89 (dd, J = 5.7, 4.9 Hz, 1H), 6.86 (td, J = 7.6, 1.1 Hz,1H), 3.90 (s, 3H), 1.34 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 156.74 (s),150.82 (s), 132.44 (s), 130.28 (s), 130.05 (s), 127.59 (s), 126.38 (s),125.47 (s), 121.26 (s), 110.71 (s), 55.91 (s), 34.63 (s), 31.33 (s). HRMS(ESI): calculated for [C 17 H 21 OS (M+H)] + : 273.1308, found: 273.1312.

[0080] (2,6-dimethylphenyl)(2-methoxyphenyl)sulfane (3v) 1 H NMR (400 MHz,CDCl3): δ 7.27 – 7.17 (m, 3H), 7.04 (td, J = 8.1, 1.5 Hz, 1H), 6.84 (dd, J =8.0, 0.6 Hz, 1H), 6.71 (td, J = 7.7, 1.1 Hz, 1H), 6.32 (dd, J = 7.8, 1.5 Hz,1H), 3.94 (s, 3H), 2.42 (s, 6H). 13 C NMR (101 MHz, CDCl3): δ 155.47 (s),144.44 (s), 129.47 (s), 129.35 (s), 128.55 (s), 126.34 (s), 125.31 (s),124.61 (s), 121.35 (s), 110.31 (s), 55.94 (s), 21.76 (s). HRMS (ESI):calculated for [C15 H 17 OS (M+H)] + : 245.0995, found: 245.0987.

[0081] bis(2-methoxyphenyl)sulfane (3w) 1 H NMR (400 MHz, CDCl3): δ 7.28 –7.22 (m, 2H), 7.07 (dd, J = 7.7, 1.6 Hz, 2H), 6.93 – 6.90 (dd, J = 8.0, 0.6Hz, 2H), 6.90 – 6.85 (td, J = 7.7, 1.1 Hz, 2H), 3.86 (s, 6H). 13 C NMR (101MHz, CDCl3): δ 157.87 (s), 131.97 (s), 128.39 (s), 122.66 (s), 121.21 (s),110.84 (s), 55.88 (s). HRMS (ESI): calculated for [C 14 H 15 O2S (M+H)] + :247.0787,found: 247.0780.

[0082] 3-((2-methoxyphenyl)thio)-2,4-dimethylfuran (3x) 1 H NMR (400 MHz,CDCl3): δ 7.09 (ddd, J = 8.2, 6.9, 2.2 Hz, 1H), 6.86 – 6.79 (m, 3H), 5.95 (s,1H), 3.92 (s, 3H), 2.30 (d, J = 5.3 Hz, 6H). 13 C NMR (101 MHz, CDCl3): δ155.63 (s), 155.25 (s), 150.83 (s), 126.95 (s), 125.82 (s), 125.66 (s),121.17 (s), 111.24 (s), 110.19 (s), 106.35 (s), 55.82 (s), 13.61 (s), 11.76(s). HRMS (ESI): calculated for [C13 H 14 O2S (M+H)] + : 235.0787, found: 235.0780.

[0083] tert-butyl(2-methoxyphenyl)sulfane (3y) 1 H NMR (400 MHz, CDCl3): δ7.51 (dd, J = 7.8, 1.8 Hz, 1H), 7.35 (dt, J = 1.6, 6.4 Hz, 1H), 6.96 – 6.88(m, 2H), 3.86 (s, 3H), 1.29 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 161.30 (s), 140.34 (s), 130.75 (s), 120.62 (s), 120.43 (s), 111.06 (s), 55.61 (s), 46.89(s), 30.99 (s). HRMS (ESI): calculated for [C 11 H 16 OS (M+H)] + : 197.0995, found: 197.0988.

[0084] This invention discloses a method for preparing sulfur-containing ether compounds by coupling o-iodoaryl ethers with thiophenol or thiols, comprising the following steps: in the presence of sodium hydride and lithium iodide, o-iodoaryl ethers are reacted with thiophenol or thiols as raw materials to prepare aryl sulfides. Specifically, in the presence of sodium hydride and lithium iodide, o-iodoaryl ethers are reacted with thiophenol or thiols in a solvent to obtain the aryl sulfide product.

[0085] 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.

[0086]

[0087] Weigh 1.1 g (8.0 mmol, 2.0 equiv.) of K2CO3 and 880.8 mg (4 mmol, 1.0 equiv.) of o-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 °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 o-iodoanisole, with a yield between 70% and 90%.

[0088] The data for 1k is represented as follows: 1-(2,2-dimethoxyethoxy)-2-iodobenzene (3k) 1 H NMR (400 MHz, CDCl3): δ 7.77 (dd, 1H, J=7.8, 1.5 Hz), 7.28 (ddd, 1H, J=9.8, 7.5,1.8 Hz), 6.82 (dd, 1H, J=8.4, 1.5 Hz), 6.72 (td, 1H, J=7.5, 1.5 Hz), 4.76 (t,1H, J=5.1 Hz), 4.04 (d, 2H, J=5.1 Hz), 3.52 (s, 6H). 13 C NMR (101 MHz, CDCl3): d HRMS (ESI): calculated for [C 10 H 13 IO3 (M+H)] + : 308.9982, found: 308.9984.

[0089] This invention discloses a method for synthesizing aryl sulfides by reacting NaH and LiI with o-iodoaryl ethers to produce meta-benzyne, which is then reacted with thiophenol or thiol. 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 aryl sulfides with broad application prospects.

Claims

1. A method for preparing a sulfur-containing ether compound, comprising the following steps: in the presence of sodium hydride and lithium iodide, o-iodoaryl ether undergoes a coupling reaction with thiophenol or thiol to prepare the sulfur-containing ether compound; the reaction is carried out in THF; the chemical structural formula of o-iodoaryl ether is as follows: ； The chemical structural formulas of thiophenol and thiols are as follows: ， ； The structural formula of the product, a sulfur-containing ether compound, is as follows: 、 ； In the above structural formula, R 1 R is hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl, or halogen. 1 When it is halogenated, o-iodoaryl ether is a halogen-substituted o-iodoaryl ether; R 2 It is methyl, ethyl, propyl, benzyl, or cyclopentyl; R 3 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, or trifluoromethyl.

2. The method for preparing the sulfur-containing ether compound according to claim 1, characterized in that, The molar ratio of o-iodoaryl ether, thiophenol or thiol, sodium hydride and lithium iodide is 1:(1-3):(2-6):(1-3).

3. A method for preparing a sulfur-containing ether compound, comprising the following steps: in the presence of sodium hydride, lithium iodide, and 2,2,6,6-tetramethylpiperidine oxide, a halogen-substituted o-iodoaryl ether undergoes a coupling reaction with benzenethiophenol or thiol to prepare the sulfur-containing ether compound; the reaction is carried out in THF; the chemical structural formula of the o-iodoaryl ether is as follows: ； The chemical structural formulas of thiophenol and thiols are as follows: ， ； The structural formula of the product, a sulfur-containing ether compound, is as follows: 、 ； In the above structural formula, R 1 R is hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl, or halogen. 1 When it is halogenated, o-iodoaryl ether is a halogen-substituted o-iodoaryl ether; R 2 It is methyl, ethyl, propyl, benzyl, or cyclopentyl; R 3 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, or trifluoromethyl.

4. The method for preparing the sulfur-containing ether compound according to claim 3, characterized in that, The molar ratio of halogen-substituted o-iodoaryl ether, thiophenol or thiol, sodium hydride, lithium iodide, and 2,2,6,6-tetramethylpiperidine oxide is 1:(1-3):(2-6):(1-3):(1-3).

5. The method for preparing the sulfur-containing ether compound according to claim 1 or 3, characterized in that, The reaction temperature is 10–60 °C, and the reaction time is 5–20 hours.

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