CN111187188A - Synthesis method of substituted thiophenol - Google Patents
Synthesis method of substituted thiophenol Download PDFInfo
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- CN111187188A CN111187188A CN202010069880.3A CN202010069880A CN111187188A CN 111187188 A CN111187188 A CN 111187188A CN 202010069880 A CN202010069880 A CN 202010069880A CN 111187188 A CN111187188 A CN 111187188A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/06—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols from sulfides, hydropolysulfides or polysulfides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/04—Sulfinic acids; Esters thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/22—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides
- C07C319/24—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of hydropolysulfides or polysulfides by reactions involving the formation of sulfur-to-sulfur bonds
Abstract
The invention provides a method for synthesizing substituted thiophenol, which comprises the following steps: with a compound of formula V and NaHSO3Or KHSO3Reaction of a Compound of formula IV with SO2Reaction to synthesize the compound of the formula III, and the compound of the formula III is prepared by NaBH in NaOH solution4Reducing and synthesizing a compound of a formula II, and finally acidifying the compound of the formula II to obtain the compound of the formula I. The method for synthesizing the substituted thiophenol provided by the invention has the advantages of greenness, high efficiency, easiness in industrial application and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of substituted thiophenol.
Background
Thiophenols are important chemical raw materials, mainly used in the fields of medicines, pesticides, high molecular materials, organic synthesis auxiliaries and the like, and also used for preparing local anesthetics. The method for synthesizing thiophenol compounds is various, such as chlorobenzene method and phenol method, wherein chlorobenzene and hydrogen sulfide are subjected to high temperature of 450-500 ℃ to obtain thiophenol under the catalysis of ZnS. However, this method has two problems: firstly, the service life of the catalyst is short, the catalyst can only run for 300 hours, and the poisoned catalyst can not be regenerated; secondly, the catalyst needs to be prepared by zinc acetate and active carbon additionally, and the method is complicated. The phenol method is that phenol and hydrogen sulfide are reacted at 550 ℃ with diatomite V2O5Is used as a catalyst and is prepared by reaction. The process has low phenol conversion, only about 48% of phenol is reacted and 75% of it is converted to thiophenol.
At present, there are two main methods for industrially synthesizing thiophenols, which are also commonly used in the industry at present. One such method is the preparation of substituted thiophenols by zinc powder reduction of substituted phenylsulfonyl chlorides under concentrated sulfuric acid as reported in Tetrahedron, 1994, 50(16), 4115-4194, the equation is shown below (2, 4-dimethylthiophenol is taken as an example):
the synthesis method has the yield of 47-82 percent and simple synthesis process, but has higher equipment requirement due to the use of a large amount of concentrated sulfuric acid in the process, and can generate a large amount of waste acid and salt in the post-treatment, so that the treatment cost of the three wastes is high, and the method does not meet the environmental protection requirements of the existing atom economy and green chemical industry.
Another method for the industrial synthesis of thiophenols is reported in the document J.Am.chem.Soc., 2002, 124, 17, 4642-one 4646. The process uses substituted aniline as initial raw material, and the substituted thiophenol is obtained through diazotization, substitution, decarboxylation, salification and acidification. The reaction equation of the method is as follows:
compared with the first method for industrially synthesizing substituted thiophenol, the process has longer steps, but the reagents and reaction conditions used in each step are mild, and no special requirements are imposed on equipment. However, this process uses substituted anilines as the potentially genotoxic material and produces genotoxic diazonium salts, and therefore requires high quality control and detection of the substituted thiophenols, and in addition, requires high impurity removal capacity for processes using the substituted thiophenols as starting materials or reagents to prevent the potential genotoxic impurities therein from exceeding standards.
The process has the defects of use of potential genotoxic impurities, high requirement on equipment, high production cost, environmental pollution and the like, and is not beneficial to industrial production.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provides a method for synthesizing substituted thiophenol compounds, which is green, efficient and easy for industrial application.
According to an object of the present invention, there is provided a method for synthesizing a compound of formula I, comprising the steps of:
step a) reaction of a compound of formula V with NaHSO3Or KHSO3The compound of the formula IV is synthesized by reaction,
step b) Compound of formula IV with SO2The compound of the formula III is synthesized by reaction,
step c) passing the compound of formula III through NaBH in the presence of NaOH4Reducing and synthesizing the compound of the formula II,
step d) acidifying the compound of formula II to obtain a compound of formula I;
the chemical reaction equation is as follows:
wherein R is1～R5Can be independently selected from H or-CH3，R1～R5May be the same or different.
The synthesis method of the compound of the formula I is characterized in that the compound V and NaHSO3Or KHSO3During reaction, the pH value is adjusted by NaOH or KOH, the pH value of a reaction system is 5.5-6.5, and the compound V and NaHSO3Or KHSO3The molar ratio of (A) to (B) is 1: 1-1: 1.2, the temperature of the dropwise addition of the compound of formula V is 30-80 ℃, the time of the dropwise addition of the compound of formula V is 2-4 hours after the dropwise addition of the compound of formula V is finished.
The synthesis method of the compound of the formula I is characterized in that the compound of the formula IV can be directly used without separation.
The synthesis method of the compound of the formula I is characterized in that the compound V and SO2The molar ratio is 1: 1.1-1: 1.5, and SO is introduced2The post-reaction temperature is 80-120 ℃, and the reaction time is 5-10 hours.
The method for synthesizing the compound shown in the formula I is characterized in that the solvent used for synthesizing the compound shown in the formula II is methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile and the like.
The method for synthesizing the compound shown in the formula I is characterized in that when the compound shown in the formula II is synthesized, the molar ratio of the compound shown in the formula III to NaOH is 1: 1.2-1: 1.6, and the compound shown in the formula III to NaBH4The molar ratio of (A) to (B) is 1: 0.2-1: 1, and the reaction temperature is 50-100 ℃.
And c) after the reaction in the step b) is finished, reducing the pressure of the reaction system, standing for layering, discarding the water phase, separating out a disulfide organic phase, and washing the organic phase with a proper amount of water to obtain the compound shown in the formula III, wherein the yield is about more than 98%.
And c) after the reaction in the step c), distilling out the organic solvent, cooling to 50-60 ℃, adding ethyl acetate, adding concentrated hydrochloric acid to adjust the pH value to 1-2, separating out an organic phase, and concentrating the organic phase to obtain the compound shown in the formula I, wherein the yield is about 90% or more.
The synthesis of compounds of formula I using the present invention has significant advantages: the use of a large amount of strong acid is avoided, the use of special equipment is avoided, a large amount of three wastes generated in the post-treatment process are avoided, and the environmental protection requirement of green chemical industry is facilitated; avoidThe use of potential genotoxic materials is beneficial to reducing the subsequent detection pressure and the quality control requirement; the compound of formula IV can be used directly without separation, with reduced post-treatment steps, with SO2The liquid enters the reaction, the utilization rate is high, the atom economy is high, and the waste of materials is avoided; the whole process is green and efficient, and meets the current environmental protection requirement.
Detailed Description
Embodiments of the present invention are described in detail below with reference to specific examples, but it should be understood by those skilled in the art that the examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention.
The examples, in which specific conditions are not specified, were conducted under conventional conditions, conditions recommended by the manufacturer or supplier. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound of formula III (1, 2-bis (2, 4-dimethylphenyl) disulfide)
125g (0.54mol) of NaHSO3The aqueous solution (45 mass percent) and 400ml of water were added to a reaction vessel under nitrogen protection, the pH was adjusted to 6 with 45 mass percent NaOH aqueous solution, and the mixed solution was heated to 40 ℃. Dropping 100g (0.49mol) of 2, 4-dimethyl benzene sulfonyl chloride at 40-50 ℃, and simultaneously dropping a NaOH aqueous solution with the mass fraction of 45% to keep the pH value of the reaction system at 6. After the dropwise addition of 2, 4-dimethylbenzenesulfonyl chloride, stirring was continued for 3 hours.
Twice with nitrogen replacement, 37.6g (0.59mol) SO at room temperature2Is pressed into the reaction vessel in liquid form. The reaction was heated to 115 ℃ for about 2 hours, and then stirring was continued at this temperature for 6 hours.
After the reaction, the reaction mixture was cooled to 30 ℃ and the pressure vessel was depressurized, the aqueous phase was discarded, and the organic phase of the disulfide compound was separated and washed with water. 133.2g of 1, 2-bis (2, 4-dimethylphenyl) disulfide, in a yield of 99.0% based on 2, 4-dimethylbenzenesulfonyl chloride.
EXAMPLE 2 Synthesis of Compound of formula I (2, 4-Dimethylthiophenol)
133.2g (0.49mol) of preparation according to example 1Dissolving 1, 2-bis (2, 4-dimethylphenyl) disulfide (NaBH) in 500mL of ethanol and 50mL of water, heating to reflux (78-80 ℃) under the protection of nitrogen, and dropwise adding 9.4g (0.24mol) of NaBH dissolved in an aqueous NaOH solution (52g with a mass fraction of 45%) at the temperature4The dropping time was about 1 hour, and the reaction was continued for 2 hours. After the reaction was complete, ethanol was distilled off, and 200ml of water were added. Cooling to 60 deg.C, adding 400ml ethyl acetate, adding concentrated hydrochloric acid to adjust pH to 1, separating organic phase, and concentrating to remove ethyl acetate to obtain 61.2g 2, 4-dimethylthiophenol oily substance with yield of 90.4% and purity of 99.5%.
1HNMR(CDCl3，500MHz)：δ7.45(d，J＝10Hz，1H)，7.26(s，1H)，7.18(d，J＝10Hz，1H)，3.52(s，1H)，2.62(s，3H)，2.60(s，3H)。
EXAMPLE 3 Synthesis of Compound of formula III (1, 2-bis (2, 3-dimethylphenyl) disulfide)
125g (0.54mol) of NaHSO3The aqueous solution (45 mass percent) and 400ml of water were added to a reaction vessel under nitrogen protection, the pH was adjusted to 6.5 with 45 mass percent NaOH aqueous solution, and the mixed solution was heated to 45 ℃. Dropping 100g (0.49mol) of 2, 3-dimethyl benzene sulfonyl chloride at 40-50 ℃, and simultaneously dropping a NaOH aqueous solution with the mass fraction of 45% to keep the pH value of the reaction system at 6.5. After the dropwise addition of 2, 3-dimethylbenzenesulfonyl chloride, stirring was continued for 2 hours.
Twice with nitrogen replacement, 37.6g (0.59mol) SO at room temperature2Is pressed into the reaction vessel in liquid form. The reaction was heated to 100 ℃ for about 1.5 hours and then stirred at this temperature for an additional 8 hours.
After the reaction, the reaction mixture was cooled to 30 ℃ and the pressure vessel was depressurized, the aqueous phase was discarded, and the organic phase of the disulfide compound was separated and washed with water. 134.2g of 1, 2-bis (2, 3-dimethylphenyl) disulfide, in a yield of 99.8% based on 2, 3-dimethylbenzenesulfonyl chloride.
EXAMPLE 4 Synthesis of Compound of formula I (2, 3-Dimethylthiophenol)
134.2g (0.49mol) of 1, 2-bis (2, 3-dimethylphenyl) disulfide prepared in example 3 are dissolved in 500mL of acetonitrile and 50mL of water, heated to reflux (80-82 ℃ C.) under nitrogen protection and warmed at this temperature7.1g (0.19mol) of NaBH dissolved in aqueous NaOH solution (52g, 45% by mass) are added dropwise to the reaction mixture4The dropping time was about 1 hour, and the reaction was continued for 2 hours. After the reaction was completed, acetonitrile was distilled off while adding 200ml of water. Cooling to 60 deg.C, adding 400ml ethyl acetate, adding concentrated hydrochloric acid to adjust pH to 1.5, separating organic phase, and concentrating to remove ethyl acetate to obtain 2, 3-dimethylthiophenol oily substance 62.3g, yield 92.0%, and purity 99.1%.
1HNMR(CDCl3，600MHz)：δ7.17(d，J＝6Hz，1H)，7.00(d，J＝6Hz，1H)，6.98(d，J＝6Hz，1H)，3.34(s，1H)，2.32(s，3H)，2.30(s，3H)。
EXAMPLE 5 Synthesis of Compound of formula III (1, 2-bis (4-methylphenyl) disulfide)
125g (0.54mol) of NaHSO3The aqueous solution (45 mass percent) and 400ml of water were added to a reaction vessel under nitrogen protection, the pH was adjusted to 5.6 with a 45 mass percent NaOH aqueous solution, and the mixed solution was heated to 60 ℃. Dropping 100g (0.52mol) of 4-methylbenzenesulfonyl chloride at the temperature of 70-75 ℃, and simultaneously dropping a NaOH aqueous solution with the mass fraction of 45% to keep the pH value of the reaction system at 5.6. After the dropwise addition of 4-methylbenzenesulfonyl chloride, stirring was continued for 2 hours.
Twice with nitrogen replacement, 37.6g (0.59mol) SO at room temperature2Is pressed into the reaction vessel in liquid form. The reaction was heated to 110 ℃ for about 1.5 hours and then stirred at this temperature for an additional 8 hours.
After the reaction, the reaction mixture was cooled to 30 ℃ and the pressure vessel was depressurized, the aqueous phase was discarded, and the organic phase of the disulfide compound was separated and washed with water. 128.8g of 1, 2-bis (4-methylphenyl) disulfide was obtained in a yield of 99.7% based on 4-methylbenzenesulfonyl chloride.
EXAMPLE 6 Synthesis of Compound of formula I (4-Methylthiophenol)
128.8g (0.52mol) of 1, 2-bis (4-methylphenyl) disulfide prepared in example 5 are dissolved in 500mL of tetrahydrofuran and 50mL of water, heated to reflux (65 to 67 ℃) under nitrogen protection and 7.6g (0.20mol) of NaBH dissolved in aqueous NaOH solution (52g mass fraction 45%) are added dropwise at this temperature4The dropping time was about 1 hour, and the reaction was continued for 2 hours. After the reaction, the tetrahydrofuran was distilled offPyran while adding 200ml of water. After cooling to 50 ℃, 400ml of ethyl acetate was added, concentrated hydrochloric acid was added to adjust the pH to 1, the organic phase was separated and the ethyl acetate was concentrated off to give 59.3g of a white waxy solid of 4-methylthiophenol in a yield of 91.0% and a purity of 99.0%.
1HNMR(CDCl3，400MHz)：δ7.20(d，J＝8Hz，2H)，7.07(d，J＝8Hz，2H)，3.40(s，1H)，2.32(s，3H)。
Claims (6)
1. A method for synthesizing a compound of formula I, comprising the steps of:
step a) reaction of a compound of formula V with NaHSO3Or KHSO3The compound of the formula IV is synthesized by reaction,
step b) Compound of formula IV with SO2The compound of the formula III is synthesized by reaction,
step c) passing the compound of formula III through NaBH in the presence of NaOH4Reducing and synthesizing the compound of the formula II,
step d) acidifying the compound of formula II to obtain a compound of formula I;
the chemical reaction equation is as follows:
wherein R is1～R5Can be independently selected from H or-CH3，R1～R5May be the same or different.
2. The method of claim 1, wherein compound V is reacted with NaHSO3Or KHSO3During reaction, the pH value is adjusted by NaOH or KOH, the pH value of a reaction system is 5.5-6.5, and the compound V and NaHSO3Or KHSO3The molar ratio of (A) to (B) is 1: 1-1: 1.2, the temperature of the dropwise addition of the compound of formula V is 30-80 ℃, the time of the dropwise addition of the compound of formula V is 2-4 hours after the dropwise addition of the compound of formula V is finished.
3. The method of claim 1, wherein the compound of formula IV is used without isolation.
4. The method of claim 1, wherein compound V is reacted with SO2The molar ratio is 1: 1.1-1: 1.5, and SO is introduced2The post-reaction temperature is 80-120 ℃, and the reaction time is 5-10 hours.
5. The method of claim 1, wherein the solvent used to synthesize the compound of formula II is methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, or the like.
6. The method of claim 1, wherein the compound of formula II is synthesized by mixing the compound of formula III with NaBH in a molar ratio of 1: 1.2 to 1: 1.64The molar ratio of (A) to (B) is 1: 0.2-1: 1, and the reaction temperature is 50-100 ℃.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5659088A (en) * | 1994-06-15 | 1997-08-19 | Bayer Aktiengesellschaft | Process for the preparation of 4-fluorothiophenol |
| CN1554644A (en) * | 2003-12-25 | 2004-12-15 | 天津大学 | Process for preparing p-fluoro thiophenol |
| CN105722830A (en) * | 2013-06-20 | 2016-06-29 | 拜耳作物科学股份公司 | Aryl sulfide derivatives and aryl sulfoxide derivatives as acaricides and insecticides |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5659088A (en) * | 1994-06-15 | 1997-08-19 | Bayer Aktiengesellschaft | Process for the preparation of 4-fluorothiophenol |
| CN1554644A (en) * | 2003-12-25 | 2004-12-15 | 天津大学 | Process for preparing p-fluoro thiophenol |
| CN105722830A (en) * | 2013-06-20 | 2016-06-29 | 拜耳作物科学股份公司 | Aryl sulfide derivatives and aryl sulfoxide derivatives as acaricides and insecticides |
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Application publication date: 20200522 |