CN114213298B - Method for preparing thiosulfonate compound by directly oxidizing thiophenol - Google Patents

Abstract

The invention relates to a method for preparing thiosulfonate compound by directly oxidizing thiophenol, which comprises the steps of adding thiophenol compound and reaction accelerator into solvent, taking oxygen (air) as oxidant, and carrying out oxidation reaction at room temperature; after the reaction is finished, a crude product is obtained by extraction, drying and distillation, and finally a pure product is obtained by purification. The invention uses oxygen or oxygen in the air as an oxidant, uses NCS as a reaction promoter, has short reaction steps, low temperature, simple operation and higher yield, and is suitable for large-scale industrial production.

Description

A kind of method that prepares thiosulfonate compound by direct oxidation of thiophenol

technical field

The invention belongs to the field of organic synthesis, and in particular relates to an efficient method for preparing thiosulfonate compounds by direct oxidation of thiophenol.

Background technique

Thiosulfonate and its derivatives are sulfonylation reagents that have been widely used in organic synthesis. In the field of pharmaceutical compounds, they can also be used for the synthesis of intermediates of various drugs. At the same time, these compounds also have certain Biological activity, such as antimicrobial and fungicide. Just because of its wide application and importance, people have done a lot of in-depth research on the synthesis of thiosulfonate compounds.

In the prior art, for thiosulfonate compounds, following several methods are arranged: the first, take benzenesulfonic acid and thiophenol as raw material, synthesize under the coexistence of cyanuric chloride and N-methylmorpholine Thiosulfonate; second, using sodium benzenesulfinate and thioether as raw materials, synthesize thiosulfonate under the action of iodine; third, using sodium benzenesulfinate and disulfide as raw materials, N -Bromosuccinimide was used as an accelerator to realize the synthesis of thiosulfonate compounds; fourthly, using the catalysis of metal copper and ligands, sodium benzenesulfinate and thiophenol were used as raw materials to synthesize Corresponding thiosulfonate; Fifth, taking sodium benzenesulfinate and disulfide as raw materials, reacting in the presence of Br to obtain _{thiosulfonate} . The synthesis methods of the above several thiosulfonate compounds use transition metal catalysts, ligands or bromination reagents, which are not environmentally friendly and cannot be industrially produced.

Therefore, developing a method for synthesizing thiosulfonate compounds that is fast, simple, high-yield and applicable to industrial production has become an urgent problem to be solved by those skilled in the art.

Contents of the invention

Aiming at the deficiencies and difficulties in the prior art, the present invention aims to provide an efficient method for preparing thiosulfonate compounds by direct oxidation of thiophenol.

The present invention is achieved through the following technical solutions:

A method for preparing thiosulfonate compounds by direct oxidation of thiophenols, adding thiophenols compounds with structural formula (I) and a reaction accelerator into a solvent, using oxygen (air) as an oxidant, and oxidizing for a certain period of time After the reaction, then purify to obtain the thiosulfonate compound with structural formula (II);

In the formula, R is halogen, nitro or hydrocarbon group.

Preferably, the reaction accelerator is N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS).

Preferably, the reaction time is 15-60 min, and the reaction temperature is 15-60°C.

Preferably, the solvent is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, acetone, acetonitrile, ether, N,N-dimethylformamide, 1,4-di One or more of oxyhexane, benzene, toluene, n-hexane, and petroleum ether.

Preferably, the ratio of the thiophenolic compound to the reaction accelerator is 1:1.5-5 in molar parts.

Preferably, the purification method is one or more of extraction, drying, vacuum distillation, silica gel column chromatography, recrystallization, and filtration.

Compared with prior art, beneficial effect:

(1) It can be obtained through experimental determination that the yield of thiosulfonate compounds prepared by the technical solution provided by the invention can reach 60% to 90%, and the conversion rate is high.

(2) The method for synthesizing thiosulfonate of the present invention is short, the utilization rate of atoms is high, the accelerator used is cheap and easy to obtain, the reaction temperature is low, and the time is short, which is suitable for large-scale industrial promotion.

(3) The synthetic method of a kind of thiosulfonate compound provided by the present invention solves the problem that in the prior art, the synthetic method of thiosulfonate compound has great damage to the environment and cannot be applied to industrial production technical flaws.

Description of drawings

Fig. 1 is the NMR spectrum of the thiosulfonate compound prepared in Example 1 of the present invention;

Fig. 2 is the NMR spectrum of the thiosulfonate compound prepared in Example 2 of the present invention;

Fig. 3 is the NMR spectrum of the thiosulfonate compound prepared in Example 3 of the present invention;

Fig. 4 is the NMR spectrum of the thiosulfonate compound prepared in Example 4 of the present invention;

Fig. 5 is the NMR spectrum of the thiosulfonate compound prepared in Example 5 of the present invention;

Fig. 6 is the NMR spectrum of the thiosulfonate compound prepared in Example 6 of the present invention;

Fig. 7 is the NMR spectrum of the thiosulfonate compound prepared in Example 7 of the present invention;

Fig. 8 is the NMR spectrum of the thiosulfonate compound prepared in Example 8 of the present invention;

detailed description

The invention provides a method for synthesizing thiosulfonate compounds, which solves the technical defects that the method for synthesizing thiosulfonate compounds in the prior art has great damage to the environment and cannot be applied to industrial production.

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

On the premise of not departing from the spirit or essential features of the present invention, the present invention will be further described in conjunction with the examples.

Embodiment 1: synthesis p-toluene thiosulfonic acid S-p-cresyl

In terms of molar ratio, the ratio of the reaction substrate p-cresol and N-chlorosuccinimide is 1:3, with acetonitrile as the solvent, oxygen in the air as the oxidant, and NCS as the accelerator. The specific reaction process of the experiment as follows:

Under air atmosphere at room temperature, put 10mmol (1.24g) of p-cresol (1.24g) and 30mmol (4g) of N-chlorosuccinimide into a round-bottomed flask, add about 20mL of solvent acetonitrile, stir, and react halfway at room temperature. hour, after the reaction was completed, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL × 3), the organic phase of the upper layer was combined, dried, filtered, and distilled to obtain a crude product, which was transferred to a circular In the bottom flask, add ethyl acetate under heating condition until the crude product just dissolves completely, after fully cooling to precipitate the solid, filter to obtain the product p-toluenethiosulfonic acid S-p-cresyl, the yield is 81% (1.13g). The product is a white solid with a melting point of 72-74°C.

As shown in Figure 1, the product p-toluene thiosulfonic acid S-p-cresyl NMR data: ¹ H NMR (400MHz, Chloroform-d) δ7.90-7.84 (m, 4H), 7.41-7.37 (m, 4H ), 2.47 (s, 6H). Molecular weight (as measured by GC-MS): 278.

Embodiment 2: Synthesis of p-fluorobenzenethiosulfonic acid S-p-fluorophenyl ester

In terms of molar ratio, the reaction substrate p-fluorothiophenol, N-chlorosuccinimide feed ratio is 1:3, with acetonitrile as solvent, N-chlorosuccinimide as accelerator, in the air Oxygen is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 10mmol (1.28g) of p-fluorothiophenol and 15mmol (4g) of N-chlorosuccinimide into a round bottom flask, add about 20mL of solvent acetonitrile, stir, and react at room temperature Half an hour, after the reaction was completed, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL×3), the organic phases of the upper layer were combined, dried, filtered, and distilled to obtain a crude product, which was transferred to In the round-bottomed flask, add ethyl acetate under heating conditions until the crude product just dissolves completely, after sufficient cooling to precipitate the solid, filter to obtain the product p-fluorobenzenethiosulfonic acid S-p-fluorophenyl ester, the yield is 70% (1.00g ). The product is a white solid with a melting point of 69-70°C.

As shown in Figure 2, the NMR data of the product p-fluorobenzenethiosulfonic acid S-p-fluorophenyl ester: ¹ H NMR (400 MHz, Chloroform-d) δ7.58-7.55 (m, 2H), 7.36-7.32 ( m, 2H), 7.12-7.08 (m, 2H), 7.06-7.02 (m, 2H). Molecular weight (measured by GC-MS): 286.

Embodiment 3: Synthesis of p-bromobenzenethiosulfonic acid S-p-bromophenyl ester

In terms of molar ratio, the ratio of reaction substrate p-bromothiophenol and N-chlorosuccinimide is 1:3, with acetonitrile as solvent and N-chlorosuccinimide as accelerator, in the air Oxygen is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 10mmol (1.88g) of p-bromothiophenol and 15mmol (4g) of N-chlorosuccinimide into a round bottom flask, add about 20mL of solvent acetonitrile, stir, and react at room temperature Half an hour, after the reaction was completed, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL×3), the organic phases of the upper layer were combined, dried, filtered, and distilled to obtain a crude product, which was transferred to In the round-bottomed flask, add ethyl acetate under heating conditions until the crude product just dissolves completely, after fully cooling and separating out the solid, filter to obtain the product p-bromobenzenethiosulfonic acid S-p-bromophenyl ester, the yield is 68% (1.39g ). The product is a white solid with a melting point of 158-159°C,

As shown in Figure 3, the nuclear magnetic resonance data of S-p-bromophenyl p-bromobenzenethiosulfonate: ¹ H NMR (400MHz, Chloroform-d) δ7.58 (d, J=8.7Hz, 2H), 7.49( d, J=8.6Hz, 2H), 7.41 (d, J=8.7Hz, 2H), 7.22 (d, J=8.6Hz, 2H). Molecular weight (determined by GC-MS): 408.

Embodiment 4: Synthesis of p-methoxybenzenethiosulfonic acid S-p-methoxyphenyl ester

In terms of molar ratio, the ratio of reaction substrate p-methoxythiophenol to N-chlorosuccinimide is 1:3, with acetonitrile as solvent and N-chlorosuccinimide as accelerator. Oxygen in the air is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 10mmol (1.4g) of p-methoxythiophenol and 30mmol (4g) of N-chlorosuccinimide into a round bottom flask, add about 20mL of solvent acetonitrile, stir, and After the reaction was completed for half an hour, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL×3), the organic phases of the upper layer were combined, dried, filtered, and distilled to obtain the crude product. Transfer to a round-bottomed flask, add ethyl acetate under heating conditions until the crude product just dissolves completely, after fully cooling and separating out the solid, filter to obtain the product p-methoxybenzenethiosulfonic acid S-p-methoxyphenyl ester, the yield is 83 % (1.29 g). The product is a white solid with a melting point of 89-90°C.

As shown in Figure 4, the nuclear magnetic resonance data of the product S-p-methoxyphenyl p-methoxybenzenethiosulfonate: ¹ H NMR (400MHz, Chloroform-d) δ7.48 (d, J=9.0Hz, 2H) , 7.24 (d, J=8.8Hz, 2H), 6.87-6.80 (m, 4H), 3.84 (s, 3H), 3.81 (s, 3H). Molecular weight (measured by GC-MS): 310.

Embodiment 5: Synthesis of p-tert-butylbenzenesulfonic acid S-p-tert-butylphenyl ester

In terms of molar ratio, the reaction substrate p-tert-butylthiophenol, N-chlorosuccinimide feed ratio is 1: 3, with acetonitrile as solvent, N-chlorosuccinimide as accelerator, Oxygen in the air is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 10mmol (1.66g) of p-tert-butylthiophenol and 30mmol (4g) of N-chlorosuccinimide into a round bottom flask, add about 20mL of solvent acetonitrile, stir, and After the reaction was completed for half an hour, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL×3), the organic phases of the upper layer were combined, dried, filtered, and distilled to obtain the crude product. Transfer to a round-bottomed flask, add ethyl acetate under heating conditions until the crude product just dissolves completely, after fully cooling to precipitate solids, filter to obtain the product p-tert-butylbenzenesulfonic acid S-p-tert-butylphenyl ester, yield 90% (1.63 g). The product is a white solid with a melting point of 141-143°C.

As shown in Figure 5, the nuclear magnetic resonance data of the product p-tert-butylbenzenethiosulfonic acid S-p-tert-butylphenyl ester: ¹ H NMR (400MHz, Chloroform-d) δ7.97 (d, J=2.0Hz, 2H ), 7.95 (d, J=2.0Hz, 2H), 7.63 (d, J=2.0Hz, 2H), 7.61 (d, J=1.9Hz, 2H), 1.37 (s, 18H). Molecular weight (GC-MS Determination) is: 362.

Embodiment 6: Synthesis of p-nitrobenzene thiosulfonic acid S-p-nitrophenyl ester

In terms of molar ratio, the reaction substrate p-nitrothiophenol, N-chlorosuccinimide feed ratio is 1:3, with acetonitrile as solvent, N-chlorosuccinimide as accelerator, air Oxygen is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 10mmol (1.55g) of p-nitrothiophenol and 30mmol (4g) of N-chlorosuccinimide into a round bottom flask, add about 20mL of solvent acetonitrile, stir, and React for half an hour, after the reaction is complete, transfer the reaction solution to a 250mL separatory funnel, extract with ethyl acetate (30mL×3), combine the organic phases of the upper layer, dry, filter, and distill to obtain the crude product, transfer the crude product to In a round bottom flask, add ethyl acetate under heating conditions until the crude product just dissolves completely, after fully cooling to precipitate the solid, filter to obtain the product p-nitrobenzenethiosulfonic acid S-p-nitrophenyl ester, the yield is 60% (1.02g). The product is a white solid with a melting point of 181-183°C.

As shown in Figure 6, the nuclear magnetic resonance data of the product p-nitrobenzenethiosulfonic acid S-p-nitrophenyl ester: ¹ H NMR (400MHz, Chloroform-d) δ8.50 (d, J=2.0Hz, 2H), 8.48 (d, J=2.1Hz, 2H), 8.28 (d, J=2.1Hz, 2H), 8.26 (d, J=2.0Hz, 2H). Molecular weight (measured by GC-MS): 339.

Example 7: Using 6-chloro-2-mercaptobenzothiazole as raw material to synthesize thiosulfonate compounds

In terms of molar ratio, the ratio of reaction substrate 6-chloro-2-mercaptobenzothiazole and N-chlorosuccinimide is 1:3, with acetonitrile as solvent and N-chlorosuccinimide as Accelerator, oxygen in the air is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 0.5mmol (101mg) of p-6-chloro-2-mercaptobenzothiazole and 1.5mmol (200mg) of N-chlorosuccinimide into a round bottom flask, and add about 2mL of solvent acetonitrile , stirred, and reacted at room temperature for half an hour. After the reaction was completed, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL×3), the organic phases of the upper layer were combined, dried, filtered, and distilled to obtain crude The product was finally separated by column chromatography, the column ratio was PE:EA=90:1, and the product yield was 75% (81mg). The product is a colorless oily liquid.

As shown in Figure 7, the NMR data of the product: ¹ H NMR (400MHz, Chloroform-d) δ7.89-7.83 (m, 2H), 7.78-7.75 (m, 2H), 7.45-7.42 (m, 2H). Molecular weight (measured by GC-MS): 431.

Example 8: Using 4-methyl-2-mercaptobenzothiazole as raw material to synthesize thiosulfonate compounds

In terms of molar ratio, the reaction substrate 4-methyl-2-mercaptobenzothiazole, N-chlorosuccinimide feed ratio is 1:3, with acetonitrile as solvent, N-chlorosuccinimide as Accelerator, oxygen in the air is used as an oxidant, and the specific reaction process of the experiment is as follows:

Under air atmosphere at room temperature, put 0.5 mmol (90 mg) of 4-methyl-2-mercaptobenzothiazole and 1.5 mmol (200 mg) of N-chlorosuccinimide into a round-bottomed flask, and add about 2 mL of solvent acetonitrile , stirred, and reacted at room temperature for half an hour. After the reaction was completed, the reaction solution was transferred to a 250mL separatory funnel, extracted with ethyl acetate (30mL×3), the organic phases of the upper layer were combined, dried, filtered, and distilled to obtain crude The product was finally separated by column chromatography, the column ratio was PE:EA=90:1, and the product yield was 79% (77mg). The product is a colorless oily liquid.

As shown in Figure 8, the NMR data of the product: ¹ H NMR (400MHz, Chloroform-d) δ7.60(d, J=7.7Hz, 2H), 7.30-7.26(m, 2H), 7.24(d, J= 7.4Hz, 2H), 2.69(s, 6H). Molecular weight (measured by GC-MS): 391.

The above description only expresses the preferred implementation of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as limiting the patent scope of the present invention. It should be noted that those skilled in the art can make several modifications, improvements and substitutions without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims (5)

1. A method for preparing a thiosulfonate compound by directly oxidizing thiophenol is characterized in that the method comprises the steps of adding the thiophenol compound with a structural formula (I) and a reaction promoter into a solvent, adopting oxygen or air as an oxidant, carrying out oxidation reaction for a certain time, and then purifying to obtain the thiosulfonate compound with a structural formula (II); the reaction promoter is N-chlorosuccinimide or N-bromosuccinimide;

in the formula, R is halogen, nitryl or alkyl.

2. The method for preparing the thiosulfonate compound by the direct oxidation of the thiophenol according to claim 1, wherein: the oxidation reaction time is 15-60 min; the reaction temperature is 15-60 ℃.

3. The method for preparing the thiosulfonate compound by the direct oxidation of the thiophenol according to claim 1, wherein: the molar equivalent ratio of the thiophenol compound to the reaction promoter is 1.5-5.

4. The method for preparing the thiosulfonate compound by the direct oxidation of the thiophenol according to claim 1, wherein: the solvent is one or more of dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, tetrahydrofuran, acetone, acetonitrile, diethyl ether, N-dimethylformamide, 1, 4-dioxane, benzene, toluene, N-hexane and petroleum ether.

5. The method for preparing the thiosulfonate compound by the direct oxidation of the thiophenol according to claim 1, wherein: the purification method comprises one or more of extraction, drying, reduced pressure distillation, silica gel column chromatography, recrystallization and filtration.

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