阅读说明：本技术 1-苯硫基-2-芳香酚类化合物的合成方法 (Synthesis method of 1-thiophenyl-2-aromatic phenolic compound ) 是由 徐大振 刘枭鹏 韩东阳 李若璞 于 2021-02-24 设计创作，主要内容包括：本发明公开了一种1-苯硫基-2-芳香酚类化合物的合成方法,所述合成方法包括,在空气环境中,将第一反应物、苯硫酚衍生物于碱性条件下加热反应,从而制备得到1-苯硫基-2-芳香酚类化合物。本发明的合成方法为1-苯硫基-2-芳香酚类化合物提供了全新又简便高效的合成途径,具有良好的工业化前景和潜在应用价值,本发明的有益效果包括：高选择性合成单硫化产物、氧化剂来源为空气、绿色无溶剂反应,并且反应能放大、效果依然非常好。(The invention discloses a synthesis method of a 1-thiophenyl-2-aromatic phenol compound, which comprises the step of heating and reacting a first reactant and a thiophenol derivative under an alkaline condition in an air environment to prepare the 1-thiophenyl-2-aromatic phenol compound. The synthesis method of the invention provides a brand-new, simple and efficient synthesis way for the 1-thiophenyl-2-aromatic phenol compound, has good industrial prospect and potential application value, and has the following beneficial effects: the high-selectivity synthesis of the monosulfide product, the source of the oxidant is air, the green solvent-free reaction is realized, the reaction energy is amplified, and the effect is still very good.)

1. A method for synthesizing 1-thiophenyl-2-aromatic phenolic compounds is characterized by comprising the following steps:

in the air environment, a first reactant, a thiophenol derivative and alkali are stirred and reacted under the heating condition, extraction, filtration and column chromatography separation are carried out, and a 1-thiophenyl-2-aromatic phenol compound is obtained, wherein the ratio of the first reactant, the thiophenol derivative and the alkali is (1-3): (0.5-1.0), wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, lithium tert-butoxide or diazabicyclo.

2. The method of synthesis of claim 1, wherein the first reactant is:wherein R is¹H, Br or CN.

3. The method of synthesis as claimed in claim 2, wherein the thiophenol derivative is Wherein R is²Is Cl, Br, F, Me or NO₂。

4. The synthesis method according to claim 3, wherein the temperature of the stirring reaction is 40-120 ℃.

5. The method of claim 4, wherein the time for stirring the reaction is determined by thin layer chromatography.

6. The synthesis method according to claim 5, characterized in that the stirring reaction time is at least 30min, preferably 30min to 4 h.

7. The synthesis method of claim 6, wherein the eluent used for the column chromatographic separation is a mixture of ethyl acetate and petroleum ether, and the ratio of the ethyl acetate to the petroleum ether is 1 (30-50) in parts by volume.

8. The synthesis method according to claim 7, wherein the extraction is liquid separation extraction by adding ethyl acetate and water.

9. The synthesis process according to claim 8, characterized in that drying with anhydrous sodium sulphate is carried out before filtration.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 1-thiophenyl-2-aromatic phenol compound.

Background

The sulfur element is widely present in commercial drugs, natural products and some basic materials, so that the construction of carbon-sulfur bonds is very important in organic synthesis. The construction of the C-S bond is usually achieved by a cross-coupling reaction of an aryl halide with a thiol or disulfide catalyzed by a transition metal, and these synthetic methods often require expensive transition metal catalysts, organic solvents, and stoichiometric amounts of oxidizing agents.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a synthesis method of a 1-thiophenyl-2-aromatic phenolic compound, which has the advantages of cheap and easily-obtained reaction substrate, simple and convenient operation, short reaction time, low production cost, less pollution, simple post-treatment, single reaction product and higher reaction yield, and particularly has the oxidant source of only air, thereby being an ideal oxidation source which is environment-friendly and extremely popular with people.

The purpose of the invention is realized by the following technical scheme.

A method for synthesizing 1-thiophenyl-2-aromatic phenolic compounds comprises the following steps:

in the air environment, a first reactant, a thiophenol derivative and alkali are stirred and reacted under the heating condition, extraction, filtration and column chromatography separation are carried out, and a 1-thiophenyl-2-aromatic phenol compound is obtained, wherein the ratio of the first reactant, the thiophenol derivative and the alkali is (1-3): (0.5-1.0), wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, lithium tert-butoxide or Diazabicyclo (DBU).

In the above technical solution, the first reactant is: wherein R is¹H, Br or CN.

In the technical scheme, the thiophenol derivative isWherein R is²Is Cl, Br, F, Me or NO₂。

In the technical scheme, the stirring reaction temperature is 40-120 ℃.

In the technical scheme, the time for stirring the reaction is determined by adopting thin layer chromatography.

In the above technical scheme, the stirring reaction time is at least 30min, preferably 30min to 4 h.

In the technical scheme, the eluent used for column chromatography separation is a mixture of ethyl acetate and petroleum ether, and the ratio of the ethyl acetate to the petroleum ether is (30-50) according to volume parts.

In the technical scheme, the extraction is to add ethyl acetate and water.

In the above technical scheme, drying is carried out by using anhydrous sodium sulfate before filtration.

The synthesis method of the invention provides a brand-new, simple and efficient synthesis way for the 1-thiophenyl-2-aromatic phenol compound, has good industrial prospect and potential application value, and has the following beneficial effects:

1. high selectivity synthesis of monosulfide.

2. Green and solvent-free reaction.

3. The reaction energy is amplified and the effect is still very good.

Detailed Description

The technical scheme of the invention is further explained by combining specific examples.

In the specific implementation mode of the invention, the reagents and medicines involved in the synthesis are purchased from Tianjin reagent six factories in commercial way, the purity of the medicines is analytically pure, and the reagents and the medicines are directly used without any pretreatment.

The synthesis method of the invention continuously stirs in the whole process, and the model of an electromagnetic heating stirrer used for stirring is NUOVAII (Temaran, USA); the rotary evaporator was model RE-2000A (Otsuwa instruments liability Co., Ltd., Otsu). Nuclear magnetic resonance instrument model: bruker AV-400spectrometer, 400MHz, DMSO-d 6.

In the invention, the reaction is carried out under the condition of heating to 40-120 ℃, and the degree of the reaction progress is detected by Thin Layer Chromatography (TLC). In thin layer chromatography, silica gel plate type G254 with size of 15mm × 50mm is used; the developing solvent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1:15

The eluent used for column chromatography separation in the following examples is a mixture of ethyl acetate and petroleum ether, and the ratio of ethyl acetate to petroleum ether is 1:30 by volume.

The detection process uses a ZF-I type three-purpose ultraviolet analyzer (Shanghai Ching Tang), the used medicines are purchased from Tianjin reagent six factories, the purity of the medicines is analytical purity, all medicines are directly used, and no pretreatment is carried out. When TLC detection shows that the first reactant of the raw material disappears and the target product point does not change any more, the synthesis method of the invention is marked to end the reaction, and the next separation operation can be continued.

The temperature of the cooling water in the following examples was 20 ℃.

The following examples were all carried out in air.

The reaction principle of the synthetic method of the invention is as follows: firstly, oxidizing thiophenol derivatives by oxygen in the air under the alkaline condition to generate peroxysulfide, further generating thiophenol free radicals, and simultaneously generating only a byproduct water (a); phenol can generate three free radical tautomers (b) under the action of thiophenol free radical; combining thiophenol free radical with stable phenol free radical, and tautomerizing to obtain final product (c)

Example 1

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (p-chlorophenylthio) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (the reaction time is 1.5h), cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting the solution twice by using 20ml of ethyl acetate, drying the organic phase by anhydrous sodium sulfate, filtering and distilling the solution, separating and purifying the product by column chromatography, and drying the product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₁₆H₁₁ClOS)0.266g, purity greater than 99%, reaction yield 93%.

1H NMR(400MHz,DMSO-d6):δ6.94(d,2H,ArH,J＝8.4Hz),7.25(d,2H,ArH,J＝8.4Hz),7.33-7.38(m,2H,ArH),7.50(t,1H,ArH,J＝7.8Hz),7.89(d,1H,ArH,J＝8Hz),7.98(d,1H,ArH,J＝8.8Hz),8.17(d,1H,ArH,J＝8.8Hz),10.39(s,1H,OH).13C NMR(100MHz,DMSO-d6):δ158.9,137.3,136.1,132.8,129.8,129.3,129.0,128.2,127.7,124.2,123.8,118.9,107.4

Example 2

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (p-bromophenylthio) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.334g) of p-bromothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, placing the flask in the air, heating at 80 ℃, stirring and reacting, monitoring the reaction by TLC (the reaction time is 1h), cooling to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, adding 15ml of cold water for cooling, extracting twice by using 20ml of ethyl acetate, and carrying out anhydrous extraction on an organic phaseDrying with sodium sulfate, filtering, evaporating to remove solvent, separating and purifying the crude product by column chromatography, and drying with petroleum ether and ethyl acetate as eluent to obtain pure compound (formula C)₁₆H₁₁BrOS)0.314g, purity more than 99% and reaction yield 95%.

¹H NMR(400MHz,DMSO-d₆):δ6.90(d,2H,ArH,J＝8.6Hz),7.34-7.39(m,4H,ArH),7.48-7.52(m,1H,ArH),7.89(d,1H,ArH,J＝8.0Hz),7.98(d,1H,ArH,J＝9.0Hz),8.18(d,1H,ArH,J＝8.4Hz),10.41(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ158.9,138.0,136.1,132.9,132.2,129.1,129.0,128.3,128.1,124.3,123.8,119.0,118.0,107.4.

Example 3

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (p-fluorophenylthio) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.230g) of p-fluorobenzothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, placing the flask in the air, heating and stirring at 80 ℃, monitoring the reaction by TLC (the reaction time is 1h), cooling to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting twice by using 20ml of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering, distilling off the solvent, separating and purifying a crude product by column chromatography, and drying by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (a molecular formula C)₁₆H₁₁FOS)0.259g, purity more than 99% and reaction yield 96%.

¹H NMR(400MHz,DMSO-d₆):δ7.00-7.08(m,4H,ArH),7.34-7.37(m,2H,ArH),7.49-7.52(m,1H,ArH),7.88(d,1H,ArH,J＝8.0Hz),7.97(d,1H,ArH,J＝8.0Hz),8.24(d,1H,ArH,J＝8.0Hz),10.33(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ161.8,159.4,158.8,136.2,133.6,132.7,129.1,129.0,128.5,128.4,123.7,119.0,116.6,108.6.

Example 4

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (p-toluenesulfonyl) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.223g) of p-toluenesulfophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, placing the flask in the air, heating and stirring at 80 ℃, monitoring the reaction by TLC (1 h for reaction), cooling to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolution, then adding 15ml of cold water for cooling, extracting twice by using 20ml of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering, distilling off the solvent, separating and purifying a crude product by column chromatography, and drying by using petroleum ether and ethyl acetate as eluent to obtain a pure compound (molecular formula C)₁₇H₁₄OS)0.221g, purity more than 99% and reaction yield 83%.

¹H NMR(400MHz,DMSO-d₆):δ2.17(s,3H,CH),6.88(d,2H,ArH,J＝8.0Hz),6.98(d,2H,ArH,J＝8.0Hz),7.31-7.37(m,2H,ArH),7.47(t,1H,ArH,J＝8.0Hz),7.85(d,1H,ArH,J＝8.0Hz),7.93(d,1H,ArH,J＝8.0Hz),8.23(d,1H,ArH,J＝8.0Hz),10.24(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ158.8,136.3,134.7,134.6,132.4,130.5,130.3,129.1,129.0,128.6,128.0,126.6,124.6,123.7,119.0,108.7,20.9.

Example 5

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (p-nitrophenylthio) -2-naphthol) comprises the following steps:

0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.465g) of p-nitrobenzothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide are added into a 10ml dry round-bottom flask in turn, the mixture is put into air and heated at 80 ℃ for stirring reaction,TLC monitoring reaction (reaction time is 1h), cooling to 50 deg.C after reaction, adding 5ml ethyl acetate to dissolve, then adding 15ml cold water to cool, extracting twice with ethyl acetate 20ml, drying organic phase with anhydrous sodium sulfate, filtering and distilling off solvent, purifying crude product by column chromatography, and drying with petroleum ether and ethyl acetate as eluent to obtain pure compound (molecular formula C)₁₆H₁₁NO₃S)0.279g, purity more than 99% and reaction yield 83%.

1H NMR(400MHz,DMSO-d₆):δ7.12(d,2H,ArH,J＝8.8Hz),7.34-7.45(m,2H,ArH),7.52(t,1H,ArH,J＝7.5Hz),7.93(d,1H,ArH,J＝8.0Hz),8.06(d,3H,ArH,J＝8.8Hz),8.12(d,1H,ArH,J＝8.4Hz),10.67(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ159.2,148.7,144.8,135.9,133.5,129.2,129.1,128.5,125.8,124.5,124.0,123.9,119.0,105.6.

Example 6

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (m-chlorophenylthio) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.259g) of m-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (1 h for reaction), cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolution, adding 15ml of cold water for cooling, extracting the mixture twice by using 20ml of ethyl acetate, drying the organic phase by using anhydrous sodium sulfate, filtering and distilling the solvent, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₁₆H₁₁ClOS)0.269g, purity greater than 99%, reaction yield 94%.

¹H NMR(400MHz,DMSO-d₆):δ6.94(d,2H,ArH,J＝12.0Hz),7.11(d,1H,ArH,J＝8.0Hz),7.20(t,1H,ArH,J＝8.0Hz),7.34-7.40(m,2H,ArH),7.50(t,1H,ArH,J＝8.0Hz),7.89(d,1H,ArH,J＝8.0Hz),8.00(d,1H,ArH,J＝12.0Hz),8.20(d,1H,ArH,J＝8.0Hz),10.47(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ159.1,140.9,136.2,134.1,133.1,131.0,129.1,128.3,125.2,125.1,124.7,124.2,123.9,119.0,107.0.

Example 7

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (m-fluorophenylthio) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.230g) of m-fluorobenzothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, placing the flask in the air, heating and stirring at 80 ℃, monitoring the reaction by TLC (the reaction time is 1h), cooling to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting twice by using 20ml of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering, distilling off the solvent, separating and purifying a crude product by column chromatography, and drying by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (a molecular formula C)₁₆H₁₁FOS)0.259g, purity more than 99% and reaction yield 96%.

¹H NMR(400MHz,DMSO-d₆):δ6.71-6.74(m,1H,ArH),6.82-6.84(m,1H,ArH),6.89-6.93(m,1H,ArH),7.22-7.28(m,1H,ArH),7.36-7.43(m,2H,ArH),7.50-7.55(m,1H,ArH),7.92(d,1H,ArH,J＝8.0Hz),8.03(d,1H,ArH,J＝9.2Hz),8.22(d,1H,ArH,J＝8.4Hz),10.52(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ164.1,161.7,159.1,141.2,141.1,136.2,133.1,131.2,131.1,129.1,128.3,124.3,123.8,122.0,121.9,119.0,112.6,112.3,112.2,111.9,107.0.

Example 8

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (o-chlorophenylthio) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.259g) of o-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (1 h for reaction), cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolution, adding 15ml of cold water for cooling, extracting the mixture twice by using 20ml of ethyl acetate, drying the organic phase by using anhydrous sodium sulfate, filtering and distilling the solvent, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₁₆H₁₁ClOS)0.266g, purity greater than 99%, reaction yield 93%.

¹H NMR(400MHz,DMSO-d₆):δ6.31-6.33(m,1H,ArH),6.97-7.01(m,1H,ArH),7.03-7.07(m,1H,ArH),7.35(t,1H,ArH,J＝8.0Hz),7.41-7.50(m,3H,ArH),7.89(d,1H,ArH,J＝8.0Hz),8.01(d,1H,ArH,J＝8.0Hz),8.12(d,1H,ArH,J＝8.0Hz),10.55(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ159.4,137.3,136.2,133.2,130.1,129.9,129.2,129.1,128.3,127.9,126.2,126.1 124.1,123.9,119.1,106.1.

Example 9

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (2, 4-difluorothiophenyl) -2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0864g) of 2-naphthol, 1.8mmol (0.263g) of 2, 4-difluorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, placing the flask in the air, heating at 80 ℃, stirring and reacting, monitoring the reaction by TLC (the reaction time is 2h), cooling to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting twice by using 20ml of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering and distilling off the solvent, separating and purifying a crude product by using column chromatography, and adopting the method of separation and purification by using anhydrous sodium sulfateDrying with petroleum ether and ethyl acetate as eluent to obtain pure compound (formula C)₁₆H₁₀F₂OS)0.268g, purity greater than 99%, reaction yield 93%.

¹H NMR(400MHz,DMSO-d₆):δ6.56-6.62(m,1H,ArH),6.86-6.91(m,1H,ArH),7.30-7.41(m,3H,ArH),7.51-7.56(m,1H,ArH),7.90(d,1H,ArH,J＝8.0Hz),8.01(d,1H,ArH,J＝9.2Hz),8.25(d,1H,ArH,J＝8.4Hz),10.56(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ159.3,136.2,133.0,129.2,129.1,129.0,128.3,124.1,123.8,119.0,112.7,112.7,112.5,112.5,105.9,105.0,104.7,104.5.

Example 10

A synthetic method of a 1-thiophenyl-2-aromatic phenol compound (2- (4-chlorophenylthio) -1-hydroxypyrene) comprises the following steps:

sequentially adding 0.6mmol (0.132g) of 1-hydroxypyrene, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (the reaction time is 4h, cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting the solution twice by using 20ml of ethyl acetate, drying the organic phase by anhydrous sodium sulfate, filtering and distilling off the solvent, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluent to obtain a pure compound (molecular formula C)₂₂H₁₃ClOS)0.240g, purity greater than 98%, reaction yield 67%.

¹H NMR(400MHz,DMSO-d₆):δ7.21(d,2H,ArH,J＝8.8Hz),7.39(d,2H,ArH,J＝8.8Hz),7.95-8.06(m,3H,ArH),8.15-8.22(m,3H,ArH),8.26(s,1H,ArH),8.43(d,1H,ArH,J＝9.2Hz),10.41(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ152.0,135.9,131.8,131.6,131.4,131.1,130.4,130.0,129.7,127.4,127.3,127.2,126.1,125.5,125.3,125.2,124.8,122.1,120.0,117.9.

Example 11

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (4-chlorophenylthio) -6-bromo-2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.133g) of 6-bromo-2-naphthol, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 120 ℃, monitoring the reaction by TLC (the reaction time is 2h), cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate to dissolve the ethyl acetate, adding 15ml of cold water to cool the mixture, extracting the mixture twice with 20ml of ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering and distilling off the solvent, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₁₆H₁₀BrClOS)0.353g, purity more than 99% and reaction yield 97%.

¹H NMR(400MHz,DMSO-d₆):δ6.94(d,2H,ArH,J＝8.4Hz),7.26(d,2H,ArH,J＝8.4Hz),7.39(d,1H,ArH,J＝8.8Hz),7.62(dd,1H,ArH,J₁＝2.0Hz,J₂＝9.0Hz),7.98(d,1H,ArH,J＝8.8Hz),8.10(d,1H,ArH,J＝8.8Hz),8.17(d,1H,ArH,J＝2.0Hz),10.63(s,1H,OH).¹³C NMR(100MHz,DMSO-d6):δ164.1,141.7,139.7,136.8,135.8,135.5,135.1,134.7,134.6,134.3,134.1,132.6,131.5,125.0,121.5,112.7.

Example 12

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (4-chlorophenylthio) -6-cyano-2-naphthol) comprises the following steps:

0.6mmol (0.101g) of 6-cyano-2-naphthol, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide are successively introduced into a 10ml dry round-bottomed flask,heating and stirring at 120 deg.C in air, TLC monitoring reaction (reaction time is 1h), cooling to 50 deg.C after reaction is completed, adding 5ml ethyl acetate to dissolve, adding 15ml cold water to cool, extracting twice with 20ml ethyl acetate, drying organic phase with anhydrous sodium sulfate, filtering, evaporating to remove solvent, purifying by column chromatography, and drying with petroleum ether and ethyl acetate as eluent to obtain pure compound (molecular formula C)₁₇H₁₀ClNOS)0.274g, purity more than 99%, reaction yield 88%.

¹H NMR(400MHz,DMSO-d₆):δ6.96(d,2H,ArH,J＝8.8Hz),7.27(d,2H,ArH,J＝8.4Hz),7.50(d,1H,ArH,J＝9.2Hz),7.78(dd,1H,ArH,J₁＝1.6Hz,J₂＝8.8Hz),8.13(d,1H,ArH,J＝9.2Hz),8.30(d,1H,ArH,J＝8.8Hz),8.54(d,1H,ArH,J＝1.4Hz),11.13(s,1H,OH).¹³C NMR(100MHz,DMSO-d6):δ161.2,137.7,136.1,134.8,133.1,129.7,129.0,128.3,127.6,127.4,125.2,120.3,119.2,107.9,105.5.

Example 13

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (1- (4-chlorophenylthio) -6-methyl-2-naphthol) comprises the following steps:

sequentially adding 0.6mmol (0.0648g) of p-cresol, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (the reaction time is 2.5h), cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting the solution twice by using 20ml of ethyl acetate, drying the organic phase by anhydrous sodium sulfate, filtering and distilling the solution, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₁₃H₁₁ClOS)0.213g, purity greater than 99%, reaction yield 85%.

¹H NMR(400MHz,DMSO-d₆):δ2.17(s,3H,CH),6.86(d,1H,ArH,J＝7.6Hz),7.06(d,2H,ArH,J＝7.6Hz),7.11(d,2H,ArH,J＝8.8Hz),7.35(d,2H,ArH,J＝8.4Hz),9.77(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ155.1,135.7,134.7,131.0,130.3,129.4,128.9,128.6,117.0,115.9,19.8.

Example 14

A method for synthesizing 1-thiophenyl-2-aromatic phenol compound (2- (4-chlorophenylthio) -3, 5-dimethylphenol) comprises the following steps:

sequentially adding 0.6mmol (0.0648g) of 3, 5-dimethylphenol, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (the reaction time is 2h), cooling the flask to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate for dissolving, then adding 15ml of cold water for cooling, extracting the solution twice by using 20ml of ethyl acetate, drying the organic phase by anhydrous sodium sulfate, filtering and distilling the solvent off, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₂₂H₁₃ClOS)0.208g, purity greater than 99%, reaction yield 93%.

¹H NMR(400MHz,DMSO-d₆):δ2.23(s,3H,CH),2.26(s,3H,CH),6.68(d,2H,ArH,J＝7.2Hz),6.91(d,2H,ArH,J＝8.4Hz),7.27(d,2H,ArH,J＝8.8Hz),9.70(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ159.5,144.0,141.3,137.7,129.5,129.2,127.3,122.9,114.9,112.5,21.4,21.3.

Example 15

A method for synthesizing 1-thiophenyl-2-aromatic phenolic compound (2- (4-chlorophenylthio) -3, 4-methyleneoxyphenol) comprises the following steps:

sequentially adding 0.6mmol (0.0816g) of 3, 4-methyleneoxyphenol, 1.8mmol (0.259g) of p-chlorothiophenol and 0.6mmol (0.0672g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 80 ℃, monitoring the reaction by TLC (the reaction time is 0.5h), cooling the mixture to 50 ℃ after the reaction is completed, adding 5ml of ethyl acetate to dissolve the ethyl acetate, adding 15ml of cold water to cool the mixture, extracting the mixture twice by using 20ml of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering and distilling the solvent, separating and purifying a crude product by using column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (a molecular formula C)₁₄H₁₁ClO₂S)0.245g, purity more than 99% and reaction yield 88%.

¹H NMR(400MHz,DMSO-d₆):δ6.00(s,2H,CH),6.61(s,1H,ArH),6.90(s,1H,ArH),7.03(d,2H,ArH,J＝8.4Hz),7.31(d,2H,ArH,J＝8.8Hz),9.75(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ154.7,150.2,140.9,137.8,130.1,129.3,128.2,114.8,106.3,102.0,98.6.

Gram-order reactions are exemplified by the following example 1a

Sequentially adding 5mmol (0.72g) of 2-naphthol, 7.5mmol (1.08g) of p-chlorothiophenol and 2.5mmol (0.28g) of potassium tert-butoxide into a 25ml dry round-bottom flask, heating and stirring the flask in the air at 120 ℃, monitoring the reaction by TLC (thin layer chromatography) (the reaction time is 2h), cooling the flask to 50 ℃ after the reaction is completed, adding 10ml of ethyl acetate for dissolving, then adding 30ml of cold water for cooling, extracting the solution twice by using 25ml of ethyl acetate, drying the organic phase by anhydrous sodium sulfate, filtering and distilling the solution, separating and purifying the crude product by column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (molecular formula C)₁₆H₁₁ClOS)1.40g, purity greater than 99%, reaction yield 97%.

1H NMR(400MHz,DMSO-d6):δ6.94(d,2H,ArH,J＝8.4Hz),7.25(d,2H,ArH,J＝8.4Hz),7.33-7.38(m,2H,ArH),7.50(t,1H,ArH,J＝7.8Hz),7.89(d,1H,ArH,J＝8Hz),7.98(d,1H,ArH,J＝8.8Hz),8.17(d,1H,ArH,J＝8.8Hz),10.39(s,1H,OH).13C NMR(100MHz,DMSO-d6):δ158.9,137.3,136.1,132.8,129.8,129.3,129.0,128.2,127.7,124.2,123.8,118.9,107.4

Gram-order reactions are exemplified by the following example 15a

Sequentially adding 5mmol (0.69g) of 3, 4-methyleneoxyphenol, 7.5mmol (1.08g) of p-chlorothiophenol and 2.5mmol (0.28g) of potassium tert-butoxide into a 10ml dry round-bottom flask, heating and stirring the flask in the air at 120 ℃, monitoring the reaction by TLC (the reaction time is 1h), cooling the flask to 50 ℃ after the reaction is completed, adding 10ml of ethyl acetate to dissolve the ethyl acetate, adding 30ml of cold water to cool the cooled flask, extracting the solution twice by using 25ml of ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, filtering and distilling off the solvent, separating and purifying a crude product by using column chromatography, and drying the crude product by using petroleum ether and ethyl acetate as eluents to obtain a pure compound (a molecular formula C)₁₄H₁₁ClO₂S)1.31g, purity more than 99% and reaction yield 93%.

¹H NMR(400MHz,DMSO-d₆):δ6.00(s,2H,CH),6.61(s,1H,ArH),6.90(s,1H,ArH),7.03(d,2H,ArH,J＝8.4Hz),7.31(d,2H,ArH,J＝8.8Hz),9.75(s,1H,OH).¹³C NMR(100MHz,DMSO-d₆):δ154.7,150.2,140.9,137.8,130.1,129.3,128.2,114.8,106.3,102.0,98.6.

Comparative ExampleScale and microreaction

The above examples show that the scale-up reactions of the present invention still give high yields, a significant advantage for this reaction.

The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.