A method for synthesizing alpha-thioacetate sulfones based on dichloromethane and thioformate

Abstract

The application discloses a method for synthesizing alpha-thioacetic acid sulfide based on dichloromethane and thioformic acid ester, and belongs to the technical field of organic synthesis chemistry. The method uses inexpensive and easily available dichloromethane and thioformic acid ester as starting materials, and under the action of a transition metal palladium catalyst, the target product can be efficiently prepared in an organic solvent under mild reaction conditions for 12 hours. Compared with traditional synthesis methods, the application has the following significant advantages: a one-step sulfonylation reaction strategy is adopted, the atomic economy is high, and the reaction efficiency is significantly improved; the reaction condition is mild (50 DEG C), the operation is simple, and the synthesis process is easy to scale up production; the use of toxic gas CO and foul-smelling sulfenyl reagent is avoided, and the reaction process is safer and more environmentally friendly. The application provides an economic, green and efficient synthesis path for the large-scale production of alpha-thioacetic acid sulfide compounds.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular, to a method for synthesizing alpha-thioacetic acid thioester based on dichloromethane and thioformic acid ester. BACKGROUND

[0002] Alpha-thioacetic acid thioester is an important branch of thioester compounds, which has attracted widespread attention due to its unique chemical and biological activity. Many active skeletons have this substructure, and it also has more applications in organic synthesis. For example, stirodroning for treating liver disease; penicillin antibiotics effective for infectious diseases and some drug-resistant bacteria; protoporphyrinogen oxidase inhibitors that can cause the accumulation of toxic intermediates by interfering with the synthesis of plant chlorophyll, causing weeds to die; polyketide synthase and polypeptide synthase in organisms use thioformate in the molecular structure of fatty acids and amino acids as an important reaction site to synthesize and assemble biologically active polyketides and polypeptides. Therefore, the effective synthesis of alpha-thioacetic acid thioester is particularly important.

[0003] The traditional synthesis method of thioester is through the direct nucleophilic addition-elimination reaction of mercaptan or thiophenol substances with appropriate acyl chloride or acid anhydride; in addition, such substances can also be obtained by condensation of corresponding carboxylic acid and mercaptan or thiophenol under the condition of different catalysts to obtain corresponding thioformate; on this basis, chemical researchers develop efficient catalysts to expand the universality of the substrates of such reactions, from active acyl chloride, acid anhydride to carboxylic acid, and then to less active ester and amide. Due to the high-efficiency catalysis of the catalyst, thioformate target products can also be obtained in high yield. These methods are some classical synthesis methods, all of which use carboxylic acid derivatives as precursors; in addition, the use of mercaptan substances with a foul odor is required. Although the above-mentioned synthesis of thioformate provides an important way for the synthesis of such substances, it still faces some challenges, such as (1) high temperature and high pressure are usually required in the above-mentioned reaction; (2) in addition, equivalent mercaptan or thiophenol is required, and such substances have an unpleasant foul odor and are not environmentally friendly; (3) the carbonyl source used in the reaction comes from toxic CO gas, which has a low safety factor and requires a high operating environment.

[0004] Therefore, it is an urgent problem to be solved by the present application to provide a more efficient, simple, green and environmentally friendly method for synthesizing alpha-thioacetic acid thioester. SUMMARY

[0005] The purpose of the present application is to provide a method for synthesizing alpha-thioacetic acid thioester based on dichloromethane and thioformic acid ester, which has the advantages of simple operation, easy-to-obtain reagents, mild conditions, and no direct participation of toxic CO and foul-smelling thiophenol.

[0006] In order to achieve the above object, the present application provides a method for synthesizing alpha-thioacetate sulfide based on dichloromethane and thioformate, the method comprising: mixing reaction of thioformate (formula I), dichloromethane, metal catalyst, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and base to obtain alpha-thioacetate sulfide (formula II); wherein the R group is one of aryl, naphthalene or alkyl carbon chain.

[0007]

[0008] Preferably, the concentration of dichloromethane is 0.1-1M.

[0009] Preferably, the temperature of the mixing reaction is 20-50℃, and the reaction time is 11-13h.

[0010] Preferably, the mixing reaction is carried out under nitrogen protection.

[0011] Preferably, the metal catalyst is selected from one of tris(dibenzylideneacetone)dipalladium, palladium chloride, bis(acetonitrile)palladium chloride, bis(triphenylphosphine)palladium chloride or bis(acetylacetone)palladium.

[0012] Preferably, the base is selected from one of potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate or potassium phosphate.

[0013] The present application also provides an alpha-thioacetate sulfide compound, which is prepared by the above method.

[0014] The present application uses thioformate as raw material, dichloromethane as alkyl source and solvent, and carries out reaction under the action of transition metal catalyst, ligand and base under relatively mild conditions to obtain alpha-thioacetate sulfide compound, which has the advantages of simple operation, easy-to-obtain reagent, mild conditions, no need for direct participation of toxic CO and foul-smelling sulfenyl, etc. A new strategy for efficient catalytic synthesis of sulfenyl is realized, and an excellent method for synthesis of alpha-thioacetate sulfide is provided.

[0015] Other features and advantages of the present application will be described in detail in the following specific embodiments. BRIEF DESCRIPTION OF DRAWINGS

[0016] The accompanying drawings are included to provide a further understanding of the present application, and constitute a part of the specification, and together with the following specific embodiments, serve to explain the present application, but do not constitute a limitation on the present application. In the drawings:

[0017] Figure 1 is the hydrogen spectrum of alpha-thioacetate sulfide prepared in Example 1;

[0018] Figure 2 is the carbon spectrum of alpha-thioacetate sulfide prepared in Example 1. Detailed Implementation

[0019] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0020] Example 1: Preparation of α-thioacetic acid thioester

[0021]

[0022] Tris(dibenzylacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (8.7 mg), and potassium bicarbonate (60.1 mg) were added to a 25 mL Young's tube. The reaction tube was purged three times under nitrogen, and then dichloromethane (3 mL) and S-(4-methylphenyl)thiocarbamate (45.6 mg) were added sequentially. The reaction flask was sealed, and the reaction was carried out in an oil bath at 50 °C for 12 hours. After the reaction, dichloromethane was removed by rotary evaporation under reduced pressure to obtain the crude product. Direct column chromatography yielded 40.5 mg of a colorless oil, with a yield of 94%. NMR characterization data are as follows: 1 H NMR (600MHz, CDCl3) δ7.36(d,J=6.6Hz,2H),7.23(d,J=6.6Hz,2H),7.19(d,J=6.0Hz,2H),7.12(d,J=7.8Hz,2H),3.83(s,2H),2.35(s,3H),2.32(s,3H); 13 CNMR (151MHz, CDCl3) δ195.1,139.9,137.8,134.6,131.2,130.9,130.2,130.1,124.3,45.6,21.4,21.2.

[0023] Example 2: Preparation of α-thioacetic acid thioester

[0024]

[0025] Tris(dibenzylacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (8.7 mg), and potassium bicarbonate (60.1 mg) were added to a 25 mL Young's tube. The reaction tube was purged three times under nitrogen, and then dichloromethane (3 mL) and S-(3-methylphenyl)thiocarbamate (45.6 mg) were added sequentially. The reaction flask was sealed, and the reaction was carried out in an oil bath at 50 °C for 12 hours. After the reaction, dichloromethane was removed by rotary evaporation under reduced pressure to obtain the crude product. Direct column chromatography yielded 37.9 mg of a colorless oil, with a yield of 88%. NMR characterization data are as follows: 1H NMR (600 MHz, CDC13) δ 7.27 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 12 Hz, 2H), 7.06 (d, J = 7.2 Hz, 1H), 3.88 (s, 2H), 2.34 (d, J = 6.6 Hz, 6H); 13 CNMR (101 MHz, CDC13) δ 195.0, 139.2, 139.1, 135.2, 134.3, 131.6, 130.8, 130.5, 129.2, 129.1, 128.2, 127.4, 127.1, 44.9, 21.5, 21.4.

[0026] Example 3: Preparation of α-thioacetic acid thioester

[0027]

[0028] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL vial. The reaction vial was flushed with nitrogen three times, then dichloromethane (3 mL), S-(2-methylphenyl)thioformate (45.6 mg) were added sequentially. The reaction vial was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was completed, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product, which was directly purified by column chromatography to give colorless oil 36.4 mg in 84% yield. The NMR characterization data are 1 H NMR (600 MHz, CDC13) δ 7.27 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.20 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 12 Hz, 2H), 7.06 (d, J = 7.2 Hz, 1H), 3.88 (s, 2H), 2.34 (d, J = 6.6 Hz, 6H); 13 CNMR (101 MHz, CDC13) δ 194.2, 142.3, 138.5, 136.0, 133.7, 130.9, 130.5, 130.4, 129.6, 127.2, 127.1, 126.8, 126.7, 44.0, 20.7, 20.6.

[0029] Example 4: Preparation of α-thioacetic acid thioester

[0030]

[0031] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL vial. The reaction vial was flushed with nitrogen three times and then dichloromethane (3 mL), S-(4- isopropylphenyl)thioformate (54.0 mg) were added sequentially. The reaction vial was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was complete, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product which was directly column chromatographed to give colorless oil 40.5 mg in 78% yield. NMR characterization data are 1 H NMR (600 MHz, CDC13) δ 7.39 (d, J = 8.4 Hz, 2H), 7.26 (m, 4H), 7.18 (d, J = 7.8 Hz, 2H), 3.86 (s, 2H), 2.90 (m, 2H), 1.24 (t, J = 6.0 Hz, 12H); 13 C NMR (101 MHz, CDC13) δ 195.3, 150.6, 148.6, 134.6, 131.2, 131.0, 127.6, 127.4, 124.6, 45.4, 34.1, 33.9, 24.0, 23.9.

[0032] Example 5: Preparation of a-thioacetic acid thioester

[0033]

[0034] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL vial. The reaction vial was flushed with nitrogen three times and then dichloromethane (3 mL), S-(4- isopropylphenyl)thioformate (54.0 mg) were added sequentially. The reaction vial was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was complete, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product which was directly column chromatographed to give colorless oil 40.5 mg in 78% yield. NMR characterization data are 1 H NMR (600 MHz, CDC13) δ 7.39 (d, J = 8.4 Hz, 2H), 7.26 (m, 4H), 7.18 (d, J = 7.8 Hz, 2H), 3.86 (s, 2H), 2.90 (m, 2H), 1.24 (t, J = 6.0 Hz, 12H); 13C NMR (101 MHz, CDCI3) δ 194.5, 164.9 (dd, J = 100.0, 98.0 Hz), 136.7, 133.8, 129.2 (d, J = 4.0 Hz), 122.8 (d, J = 3.0 Hz), 116.8, 116.6, 116.4, 45.8; 19 F NMR (376 MHz, CDCI3) δ -110.7, -113.2.

[0035] Example 6: Preparation of a-thioacetic acid thioester

[0036]

[0037] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL vial. The reaction vial was flushed with nitrogen three times and then dichloromethane (3 mL), S-(4-chlorophenyl)thioformate (51.8 mg) were added sequentially. The reaction vial was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was completed, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product which was directly column chromatographed to give colorless oil 24.8 mg in 50% yield. The NMR characterization data are 1 H NMR (600 MHz, CDCI3) δ 7.37 (d, J = 8.3 Hz, 4H), 7.28 (m, 4H), 3.87 (s, 2H); 13 C NMR (101 MHz, CDCI3) δ 194.1, 136.2, 135.8, 133.8, 132.7, 131.8, 129.7, 129.5, 125.9, 45.0.

[0038] Example 7: Preparation of a-thioacetic acid thioester

[0039]

[0040] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL vial. The reaction vial was flushed with nitrogen three times and then dichloromethane (3 mL), S-(4-chlorophenyl)thioformate (51.8 mg) were added sequentially. The reaction vial was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was completed, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product which was directly column chromatographed to give colorless oil 24.8 mg in 50% yield. The NMR characterization data are 1H NMR (600 MHz, CDC13) δ 7.53 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 3.87 (s, 2H); 13 C NMR (101 MHz, CDC13) δ 194.1, 136.2, 135.8, 133.8, 132.7, 132.5, 131.8, 129.5, 125.9, 45.0.

[0041] Example 8: Preparation of a-thioacetic acid thioester

[0042]

[0043] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL vial. The reaction vial was flushed with nitrogen three times and then dichloromethane (3 mL), S-2-naphthalene thioformic acid ester (56.5 mg) were added sequentially. The reaction vial was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was completed, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product, which was directly column chromatographed to give green solid 48.6 mg in 90% yield. NMR characterization data 1 H NMR (600 MHz, CDC13) δ 7.92 (s, 1H), 7.85 (s, 1H), 7.82-7.74 (m, 6H), 7.54-7.45 (m, 5H), 7.35 (d, J = 8.5 Hz, 1H), 4.03 (s, 2H). 13 C NMR (101 MHz, CDC13) δ 195.0, 134.6, 133.8, 133.6, 133.5, 132.4, 131.9, 130.9, 129.0, 128.7, 128.1, 127.9, 127.9, 127.7, 127.5, 127.3, 126.9, 126.7, 126.4, 124.9, 44.8.

[0044] Example 9: Preparation of a-thioacetic acid thioester

[0045]

[0046] Tris(dibenzylideneacetone)dipalladium (6.9 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.7 mg), potassium bicarbonate (60.1 mg) were added to a 25 mL pear shaped flask. The reaction flask was purged with nitrogen three times and then dichloromethane (3 mL), S-benzyl thiocarbonate (45.6 mg) were added sequentially. The reaction flask was sealed and placed in a 50 °C oil bath for 12 h. After the reaction was completed, the dichloromethane was removed by rotary evaporation under reduced pressure to give the crude product which was directly column chromatographed to give 8.4 mg of white solid with a yield of 19%. NMR characterization data 1 H NMR (600 MHz, CDCl3) δ 7.32-7.27 (m, 8H), 7.26-7.23 (m, 2H), 4.15 (s, 2H), 3.79 (s, 2H), 3.27 (s, 2H); 13 C NMR (101 MHz, CDCl3) δ 196.1, 137.3, 136.9, 129.3, 129.0, 128.8, 128.7, 127.5, 40.6, 36.7, 34.0.

[0047] From the above examples, the preparation method provided by the present application has high yield, and common solvent dichloromethane is used as alkyl chloride source, and the reaction reagent is relatively inexpensive, which greatly reduces the cost.

[0048] The above describes preferred embodiments of the present application, but the present application is not limited to the specific details in the above embodiments, and various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, and these simple modifications all belong to the protection scope of the present application.

[0049] In addition, it should be noted that various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, the present application will not further describe various possible combination manners.

[0050] In addition, various different embodiments of the present application can also be combined in any manner, as long as it does not deviate from the technical concept of the present application, and it should be considered as disclosed by the present application.

Claims

1. A method for the synthesis of α-thioacetate thioesters based on dichloromethane and thioformic acid ester, characterized in that, The method comprises: mixing a thiocarbamate (formula I), dichloromethane, a metal catalyst, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and a base to obtain an α-thioacetic acid sulfide (formula II); wherein the R group is one of an aryl group or an alkyl carbon chain; ； The metal catalyst is selected from one of tris(dibenzylideneacetone)dipalladium, palladium chloride, bis(acetonitrile)palladium chloride, bis(triphenylphosphine)palladium chloride or bis(acetylacetone)palladium; and the base is selected from one of potassium bicarbonate, sodium bicarbonate, sodium acetate, potassium acetate or potassium phosphate.

2. The method for synthesizing an α-thioacetate thioester based on dichloromethane and thioformic acid ester according to claim 1, characterized by, The concentration of dichloromethane is 0.1-1M.

3. The method for synthesizing an α-thioacetate thioester based on dichloromethane and thioformic acid ester according to claim 1, characterized by, The temperature of the mixing reaction is 20-50°C, and the reaction time is 11-13h.

4. The method of synthesizing a-thioacetate thioesters based on dichloromethane and thioformic acid ester according to claim 1, characterized in that, The mixing reaction is carried out under nitrogen protection.

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