Preparation method of sulfur-containing ether compound

Abstract

The invention discloses a preparation method of a sulfur-containing ether compound, which comprises the following step: in the presence of sodium hydride and lithium iodide, performing coupling reaction on o-iodo aryl ether and thiophenol or mercaptan to prepare the sulfur-containing ether compound. According to the method, aryl sulfide is prepared from o-iodo aryl ether and thiophenol / mercaptan under the conditions of NaH and LiI, compared with other traditional methods, transition metal catalysis is not needed, reaction conditions are mild, operation is easy, a new method is provided for synthesizing sulfur-containing ether compounds, and the method has wide application prospects.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a sulfur-containing ether compound. Background Art

[0002] Sulfur-containing organic compounds, especially thioethers, are commonly found in natural products, drugs, pesticides and functional materials, and are also widely used as catalysts and organic synthesis intermediates. Some drugs or bioactive substances containing aryl thioethers, such as Thymitaq, Azathioprine and Vortioxetine, etc.

[0003] Since sulfides are of great value in many fields, their preparation methods have attracted widespread attention. Transition metal-catalyzed CS cross-coupling reactions and direct C−H bond functionalization are common techniques for obtaining sulfides. Traditionally, the cross-coupling reaction of pre-functionalized aromatics (such as aromatic halides) with thiols or disulfides through transition metal catalysis (mainly palladium, copper, iron, nickel, cobalt, and rhodium, etc.) to obtain aromatic sulfides is a very effective CS construction method. However, the transition metal coupling method has many disadvantages. The most significant point is that the organic sulfur reagent is easy to form over-coordination with the metal catalyst, causing the metal catalyst to be poisoned and deactivated; moreover, most of the known transition metal-catalyzed methods for forming CS bonds have relatively harsh reaction conditions, such as strong base, anhydrous and oxygen-free conditions, high-cost ligands, and high temperature conditions (80-140°C), which makes these methods less practical. Therefore, it is necessary to find better alternatives for forming CS bonds.

[0004] Examples of transition metal-free catalysis include a method reported by Sanford for the synthesis of aromatic sulfides from RSH (or RSR) and diaryliodonium salts without metal catalysis. Compared with base / transition metal-catalyzed transformations, this new method has good compatibility with air and moisture in the environment, and has a wider range of substrates and functional group tolerance, but requires the pre-preparation of various functional group-substituted diphenyliodonium salts, and the reaction temperature is relatively high.

[0005] For example, the Cuny group reported the photocatalytic preparation of sulfide using aniline as raw material in the presence of tert-butyl nitrite, but the reaction system required the addition of expensive ruthenium metal photocatalyst. Later, the Lee group developed a new method for synthesizing sulfide at room temperature without photocatalyst based on Cuny's work.

[0006] 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

[0007] The invention discloses a method for synthesizing a sulfur-containing ether compound by coupling an o-iodine aryl ether with thiophenol or thiol. The method of the invention has cheap and readily available raw materials, simple operation, mild reaction conditions, and does not require transition metal catalysis. The method is to couple an aryl ether with thiophenol or thiol in the presence of sodium hydride (60% NaH mineral oil dispersion) and lithium iodide to generate an aryl thioether. The invention solves the problems of harsh reaction conditions and heavy metal residues in the preparation of such products using traditional methods.

[0008] The present invention adopts the following technical solution: A method for preparing a sulfur-containing ether compound comprises the following steps: in the presence of sodium hydride and lithium iodide, o-iodoaryl ether is subjected to coupling reaction with thiophenol or mercaptan to prepare the sulfur-containing ether compound.

[0009] A method for preparing a sulfur-containing ether compound comprises the following steps: in the presence of sodium hydride, lithium iodide and 2,2,6,6-tetramethylpiperidinyl oxide, a halogen-substituted o-iodine aryl ether is subjected to a coupling reaction with thiophenol or mercaptan to prepare the sulfur-containing ether compound.

[0010] In the present invention, the molar ratio of o-iodine aryl ether, thiophenol or thiol, sodium hydride and lithium iodide is 1:(1-3):(2-6):(1-3), preferably 1:2:5:2.

[0011] In the present invention, the molar ratio of halogen-substituted o-iodine aryl ether, thiophenol or thiol, sodium hydride, lithium iodide, and 2,2,6,6-tetramethylpiperidinyl oxide is 1:(1-3):(2-6):(1-3):(1-3), preferably 1:2:5:2:2.

[0012] In the present 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.

[0013] 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.

[0014] In the present invention, the chemical structural formula of o-iodine aryl ether is as follows: ; The chemical structure of thiophenol is as follows: ; The chemical structure of thiol is as follows: ; The structural formula of the product sulfur-containing ether compound is as follows: , ; In the above structural formula, R 1 It can be hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl, halogen, etc.; R 2 It is various straight-chain alkanes, branched-chain alkanes, cycloalkanes, such as methyl, ethyl, propyl, benzyl, cyclopentyl, etc.; R 3 It is hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl and the like.

[0015] In the above structural formula, R 1 When is halogen, the o-iodoaryl ether is a halogen-substituted o-iodoaryl ether.

[0016] In previous studies, the preparation of aryl sulfide from aryl halides and thiophenols or thiols requires the catalysis of transition metals such as palladium, copper, iron, nickel, and cobalt. The reaction is generally carried out at a relatively high temperature. The functional group tolerance of the method is poor, and there is a risk of heavy metal residues. The present invention uses sodium hydride and lithium iodide as activators to act on o-iodine aryl ether, thiophenol or thiol to react, thereby obtaining an aryl sulfide product containing sulfur element ether compound. The method of the present invention has cheap and easily available raw materials, simple operation, mild reaction conditions, and does not require (transition) metal catalysis. DETAILED DESCRIPTION

[0017] The present invention uses o-iodine aryl ether and thiophenol or thiol as raw materials, and reacts in the presence of sodium hydride (60% NaH mineral oil dispersion) and lithium iodide to obtain a sulfur-containing ether compound. The specific method is to weigh NaH in a reaction bottle, add anhydrous THF, and then add thiophenol or thiol and o-iodine aryl ether THF solutions in sequence under stirring, and react at 40°C to obtain an aryl thioether product sulfur-containing ether compound.

[0018] 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 13C 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).

[0019] Embodiment 1 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 o-iodoanisole 1a (70.2 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 40 °C for 6 h (TLC monitoring of the reaction completion was performed using a 254 nm UV detector lamp). Then, saturated NH4Cl solution was added at 0 °C to quench the reaction, and the mixture was extracted 3 times with ethyl acetate and 2 times with aqueous phase. Finally, the organic phases were combined and washed with saturated NaCl solution, and anhydrous Na2SO4 was added to the organic phase for drying, filtered, and silica gel powder was added to the filtrate for sample mixing. 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.

[0020] Table 1 Results under different reaction conditions

[0021]

[0022] Embodiment 2 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 (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) were added dropwise in sequence and reacted at 40 °C for 6 h. After the reaction was completed, saturated NH4Cl solution was added to quench at 0 °C, and the reaction solution was transferred to a separatory funnel, extracted with ethyl acetate 3 times, and back-extracted with water 2 times. 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 to mix the sample. The corresponding products (3b-3l) were separated by flash column chromatography (pure petroleum ether).

[0023] The corresponding reaction substrates (substituted o-iodine aryl ether 1 and p-toluene thiophenol 2a) and the obtained aryl thioether products are shown in Table 2. The substituents of the raw material substituted o-iodine aryl ether 1 are the same as those of the corresponding product 3.

[0024] Table 2 Reaction of substituted o-iodoaryl ethers with p-toluenethiophenol 2a

[0025] The above product data are characterized as follows: (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 H 15 OS (M+H)]+ : 231.0838, found: 231.0846. (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. (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. 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. (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. (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). 19F NMR (377 MHz, CDCl3): δ -61.65 (s). HRMS (ESI):calculated for [C 15 H 14 F3OS (M+H)] + : 299.0712, found: 299.0708. (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. (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. (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. (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. (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. (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). 13C 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.

[0026] Embodiment 3 When a halogen is added to the o-iodoaryl ether and used as a raw material, the reaction product will be more complex. However, adding TEMPO (2,2,6,6-tetramethylpiperidinyl oxide) can better achieve the selective substitution of thiophenol.

[0027] 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) were placed in a sealed tube and 1 mL of anhydrous THF was added. After stirring at room temperature for 5 min, 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) were added dropwise and reacted at 40 °C for 6 h. After the reaction, saturated NH4Cl solution was added at 0°C to quench the reaction. The reaction solution was transferred to a separatory funnel and extracted with ethyl acetate three times and aqueous solution twice. 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 to mix the sample. The corresponding product (3m-3t) was separated by rapid column chromatography (pure petroleum ether).

[0028] The corresponding reaction substrates (substituted aryl halides 1m-1t and p-toluene thiophenol 2a) and the obtained aryl sulfide derivatives 3m-3t are shown in Table 3. The substituent R of the raw material 1 1 Same as the corresponding product.

[0029] Table 3 Reaction of halogen-substituted o-iodoaryl ethers with p-toluenethiophenol 2a

[0030] The above product data are characterized as follows: (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. (2-fluoro-6-methoxyphenyl)(p-tolyl)sulfane (3n) 1 H 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). 13C 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. (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). 13 C 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. (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. (4-bromo-2-methoxyphenyl)(p-tolyl)sulfane (3q) 1 H 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. (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. (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). 1313C 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 19F NMR(377 MHz, CDCl3): δ -122.58 (s). HRMS (ESI): calculated for [C 14 H 14 FOS (M+H)] + : 249.0744, found: 249.0452. 5-bromo-2-methoxy-3-(p-tolylthio)pyridine (3t) 1 1H 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). 13 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.

[0031] Example 4 When a halogen is added to the o-iodine aryl ether, if TEMPO (2,2,6,6-tetramethylpiperidinyl oxide) is not added, double substitution, deiodination, and low yield will occur when reacting with thiophenol.

[0032] 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, 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) were added dropwise and reacted at 40 °C for 6 h. After the reaction is completed, saturated NH4Cl solution is added at 0°C to quench the reaction. The reaction solution is transferred to a separatory funnel and extracted with ethyl acetate for 3 times and aqueous phase for 2 times. Finally, the organic phases are combined, washed with saturated NaCl solution, dried by adding anhydrous Na2SO4, filtered, and silica gel powder is added to the filtrate to mix the sample. The corresponding products (3p, 3p1 or 3q1, 3q2) are separated by rapid column chromatography (pure petroleum ether).

[0033]

[0034] The data of 3p1, 3q1, and 3q2 are characterized as follows: (4-methoxy-1,3-phenylene)bis(p-tolylsulfane) (3p1) 1 H 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. (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. (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.

[0035] Example 5 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, thiophenol or thiol 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) were added dropwise in sequence and reacted at 40 °C for 6 h. After the reaction was completed, saturated NH4Cl solution was added at 0 °C to quench, and the reaction solution was transferred to a separatory funnel, extracted with ethyl acetate three times, and aqueous phase was extracted twice. 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 (3u-3y) were separated by rapid column chromatography (pure petroleum ether). The corresponding products of o-iodoanisole 1a and different substituted thiophenols or thiols 2b-2f and the obtained aryl thioether derivatives 3u-3y are shown in Table 4. The substituent R of the raw material 2 3 Same as the corresponding product.

[0036] Table 4 Reaction of o-iodoanisole 1a with substituted thiophenols

[0037] The above product data are characterized as follows: (4-(tert-butyl)phenyl)(2-methoxyphenyl)sulfane (3u) 1 H 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). 13C 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. (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 [C 15 H 17 OS (M+H)] + : 245.0995, found: 245.0987. bis(2-methoxyphenyl)sulfane (3w) 1H 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. 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 [C 13 H 14 O2S (M+H)] + : 235.0787, found: 235.0780. tert-butyl(2-methoxyphenyl)sulfane (3y) 1H 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. The invention discloses a method for preparing a sulfur-containing ether compound by coupling an o-iodine aryl ether with thiophenol or thiol, comprising the following steps: in the presence of sodium hydride and lithium iodide, using the o-iodine aryl ether and thiophenol or thiol as raw materials, reacting to prepare an aryl sulfide. Specifically, in the presence of sodium hydride and lithium iodide, the o-iodine aryl ether and thiophenol or thiol are reacted in a solvent to obtain an aryl sulfide product.

[0038] 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.

[0039]

[0040] Weigh K2CO3 (1.1 g, 8.0 mmol, 2.0 equiv.) and o-iodophenol (880.8 mg, 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 °C 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 o-iodoanisole derivatives with a yield of 70%-90%.

[0041] 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. The invention discloses a method for preparing an aryl sulfide by reacting NaH and LiI together with an o-iodine aryl ether to produce an m-benzyne, which is then reacted with thiophenol or thiol. 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 aryl sulfide and having 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 is subjected to a coupling reaction with thiophenol or mercaptan to prepare the sulfur-containing ether compound.

2. The method for preparing the sulfur-containing ether compound according to claim 1, characterized in that: The molar ratio of o-iodine aryl 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-tetramethylpiperidinyl oxide, a halogen-substituted o-iodoaryl ether is coupled with thiophenol or thiol to prepare a sulfur-containing ether compound.

4. The method for preparing the sulfur-containing ether compound according to claim 3, characterized in that: The molar ratio of halogen-substituted o-iodine aryl ether, thiophenol or thiol, sodium hydride, lithium iodide and 2,2,6,6-tetramethylpiperidinyl 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 to 60°C and the reaction time is 5 to 20 hours.

6. The method for preparing the sulfur-containing ether compound according to claim 1 or 3, characterized in that: The reaction is carried out in a solvent.

7. The method for preparing the sulfur-containing ether compound according to claim 1 or 3, characterized in that: The chemical structure of o-iodoaryl ether is as follows: ； The chemical structures of thiophenol and mercaptan are as follows: ， ； The structural formula of the product sulfur-containing ether compound is as follows: 、 ； In the above structural formula, R 1 is hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl or halogen, R 1 When it is halogen, the o-iodoaryl ether is a halogen-substituted o-iodoaryl ether; R 2 It is a straight-chain alkane, a branched-chain alkane, or a cycloalkane; R 3 It is hydrogen, methoxy, methyl, tert-butyl, phenyl, trifluoromethyl.

8. The method for preparing the sulfur-containing ether compound according to claim 7, characterized in that: R 2 It is methyl, ethyl, propyl, benzyl or cyclopentyl.

9. The sulfur-containing ether compound prepared according to the method for preparing the sulfur-containing ether compound according to claim 1 or 3.

10. Application of sodium hydride and lithium iodide in the coupling reaction of o-iodoaryl ether with thiophenol or thiol to prepare sulfur-containing ether compounds.

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