A method for preparing a gamma-ketosulfone compound

Abstract

This invention discloses a method for preparing γ-ketone sulfone compounds. The method involves first using propargyl ester compound ( ) and sulfinic acid (II) as starting materials, dissolving them thoroughly in an organic solvent at room temperature, then adding p-toluenesulfonic acid monohydrate p-TsOH·H2O as a Brønsted acid, and reacting at 100°C for 1 hour. After the reaction, the reaction product is purified by silica gel column chromatography to obtain the γ-ketone sulfone compound as shown in formula ( ). The raw materials used in this invention are simple and readily available, the operation steps are simple and easy to perform, it is applicable to substrates with various structures, has good substrate scalability, and the yield of the target product is good. The γ-ketone sulfone compounds prepared by this method can serve as important synthetic intermediates in organic synthesis, contribute to the development of novel drug molecules in medicinal chemistry, and be used in the preparation of functional materials in materials science, demonstrating good prospects for widespread application.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing γ-ketosulfone compounds. Background Technology

[0002] γ-Ketosulfones occupy an irreplaceable and important position in organic chemistry, medicinal chemistry, and materials science. In medicinal chemistry, the value of γ-ketosulfones lies in their broad-spectrum and diverse biological activities, providing high-quality lead compounds for the treatment of major diseases such as anti-infection, anti-tumor, and anticoagulation. Their sulfone groups can form various non-covalent interactions with targets such as enzymes and receptors in vivo, including hydrogen bonds and hydrophobic interactions, while the carbonyl groups can participate in target binding and metabolic regulation. The synergistic effect of these two groups gives this class of compounds excellent drug development potential.

[0003] Studies have shown that γ-ketosulfone derivatives have significant inhibitory activity against a variety of fungi and bacteria. They can exert antibacterial effects by disrupting the integrity of microbial cell membranes and interfering with nucleic acid and protein synthesis, and have application prospects in the prevention and control of drug-resistant bacterial infections.

[0004] In the field of organic synthesis, γ-ketosulfone is an indispensable multifunctional synthetic intermediate. The carbonyl and sulfone groups in its structure can be directionally transformed to achieve the efficient construction of carbon-carbon bonds and carbon-heterobonds, and adapt to the modular synthesis of complex molecules.

[0005] As a typical amphiphilic electro / amphiphilic nucleophilic intermediate, γ-ketosulfone can participate in a variety of classic reactions such as addition, condensation, cyclization, and elimination, and is a key precursor for the synthesis of fine chemicals such as olefins, heterocyclic compounds, and polycarbonyl compounds.

[0006] In the field of materials science, the application potential of γ-ketone sulfones is continuously expanding. Relying on their structural stability and the modifiability of their functional groups, they have become important structural units in functional polymers, optoelectronic materials, surfactants, and other materials. The strong electron-withdrawing properties and thermal stability of the sulfone group can improve the heat resistance, mechanical strength, and aging resistance of polymer materials, while the carbonyl group provides active sites for surface modification and functional grafting of materials.

[0007] Furthermore, by introducing γ-ketosulfone units into the polymer backbone through copolymerization, crosslinking, and other methods, novel materials with both high stability and functionality can be prepared for application in high-end fields such as electronic devices and biomedical carriers.

[0008] Traditional methods for synthesizing γ-keto sulfones mainly include: oxidation reactions of sulfur-substituted γ-ketones, and Michael addition reactions of sulfonyl nucleophiles with α,β-unsaturated ketones under acid-base or oxidative conditions. With the development of organocatalysis and transition metal catalysis, N-heterocyclic carbene-catalyzed Stetter reactions of aldehydes with vinyl sulfones and transition metal-catalyzed sulfonation reactions of allyl alcohols with sodium sulfite have been reported.

[0009] In 2022, Professor Wu Anxin's research group achieved the sulfonyl methylation reaction of sulfonium ylide under mild conditions, providing a simple synthetic route for γ-ketosulfones.

[0010] Despite significant progress made by existing methods, there are still obvious shortcomings, such as: non-commercialization of catalysts, limited substrate range, cumbersome procedures, and the need for strong oxidants / inorganic bases or noble metal catalysis.

[0011] Therefore, in order to solve the problems existing in the prior art, and based on the wide application of γ-ketone sulfone compounds in organic synthesis, medicinal chemistry and materials science, it is an urgent technical problem for those skilled in the art to solve to provide a new method for the synthesis of γ-ketone sulfones that is efficient, metal-free and simple. Summary of the Invention

[0012] In view of this, the present invention provides a method for preparing γ-ketosulfonate compounds, utilizing propargyl ester compounds ( Using p-toluenesulfonic acid (p-TsOH·H2O) as substrates, and Brønsted acid as a catalyst, a method for synthesizing γ-ketone sulfone compounds was developed to achieve the next step of construction. This method provides a readily available, atom-economical, efficient, and promising synthetic approach for γ-ketone sulfone compounds.

[0013] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0014] A method for preparing γ-ketosulfonate compounds, wherein the method first uses a propargyl ester compound ( Using sulfinic acid (II) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) as raw materials, the mixture was fully dissolved in an organic solvent at room temperature. Then, p-TsOH·H2O was added as a Brønsted acid. After the reaction, the product was purified by silica gel column chromatography to obtain the product as shown in formula (…). II) shows the γ-ketosulfone compounds;

[0015] ( ); RSO2H ( ) ; ( I);

[0016] Where, equation ( ), ( ), ( R in II) 1 R 2 R 3 They are: hydrogen, alkyl, and alkoxy, respectively; R 4 R is an alkyl or alkoxy group; R is an alkyl or aryl group with different substituents.

[0017] Preferably, the reaction is carried out at 100°C for 1 hour.

[0018] Preferably, the raw material ( ), ( The molar ratio of the feed material to p-toluenesulfonic acid monohydrate p-TsOH·H2O is 1:1.0~2.5:1.0~2.5.

[0019] Preferably, the raw material ( ), ( The molar ratio of the feed material to p-toluenesulfonic acid monohydrate p-TsOH·H2O is 1:2.5:2.5.

[0020] Preferably, the organic solvent is any one of dichloromethane, 1,2-dichloroethane, acetonitrile, and nitromethane.

[0021] Preferably, the propargyl ester compound ( The molar ratio of raw materials (I), sulfinic acid (II), and NIS is 1:2.5:2.5.

[0022] Preferably, the separation and purification method is as follows: water is added to the reaction solution, then ethyl acetate is added, and the mixture is stirred thoroughly and allowed to stand for separation. The separated aqueous layer is extracted with ethyl acetate, and the ethyl acetate extract and the separated organic layer are combined and washed with saturated brine and dried with anhydrous sodium sulfate, respectively. The ethyl acetate solvent is evaporated, and then the γ-ketosulfone compounds are obtained by silica gel column chromatography.

[0023] The present invention achieves the following technical effects compared to the prior art:

[0024] This invention innovatively proposes a novel synthetic strategy for the efficient construction of γ-ketosulfone compounds. This synthetic method exhibits significant technical advantages:

[0025] First, the reaction system does not require the addition of any metal catalysts or oxidants, fundamentally avoiding the problem of metal residues and the side reactions and environmental pollution that oxidants may cause. The reaction conditions are mild, which greatly reduces the requirements for reaction equipment and the operational risks.

[0026] Secondly, this method has excellent atom economy, making maximum use of the atoms in the reaction raw materials and reducing waste generation, which is in line with the development trend of green chemistry. At the same time, the entire operation process is simple and easy to implement, which facilitates scale-up and promotion in actual production. A series of γ-ketosulfone compounds with different substituents were successfully synthesized by this method, demonstrating its good substrate versatility.

[0027] Furthermore, the starting materials used in this invention are all common and readily available chemicals, effectively controlling production costs. The yield of the target product is also good, ensuring the practicality and economy of the method. In summary, this invention combines multiple advantages, including inexpensive and readily available reagents, no need for oxidants, non-metallic participation, mild reaction conditions, simple process operation, and high synthesis efficiency, providing a highly competitive and promising new route for the synthesis of γ-ketosulfone compounds. Attached Figure Description

[0028] Figure 1 This is a diagram of representative bioactive molecules containing the γ-ketosulfone skeleton of this invention. Detailed Implementation

[0029] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] This invention discloses a method for preparing γ-ketosulfonates, firstly using propargyl ester compounds ( Using sulfinic acid (II) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) as raw materials, the mixture was fully dissolved in an organic solvent at room temperature. Then, p-TsOH·H2O was added as a Brønsted acid. After the reaction, the product was purified by silica gel column chromatography to obtain the product as shown in formula (…). II) shows the γ-ketosulfone compounds;

[0031] ( ); RSO2H ( ) ; ( I);

[0032] Where, equation ( ), ( ), ( R in II) 1 R 2 R 3 They are: hydrogen, alkyl, and alkoxy, respectively; R 4 R is an alkyl or alkoxy group; R is an alkyl or aryl group with different substituents.

[0033] The reaction was carried out at 100°C for 1 hour.

[0034] raw material( ), ( The molar ratio of the feed material to p-toluenesulfonic acid monohydrate p-TsOH·H2O is 1:1.0~2.5:1.0~2.5.

[0035] raw material( ), ( The molar ratio of the feed material to p-toluenesulfonic acid monohydrate p-TsOH·H2O is 1:2.5:2.5.

[0036] The organic solvent is any one of dichloromethane, 1,2-dichloroethane, acetonitrile, and nitromethane.

[0037] propargyl ester compounds ( The molar ratio of raw materials (I), sulfinic acid (II), and NIS is 1:2.5:2.5.

[0038] The separation and purification method is as follows: water is added to the reaction solution, followed by ethyl acetate. After thorough stirring, the mixture is allowed to stand and separate into layers. The aqueous layer is extracted with ethyl acetate. The ethyl acetate extract and the separated organic layer are combined and washed with saturated brine and dried with anhydrous sodium sulfate, respectively. The ethyl acetate solvent is evaporated, and then the γ-ketosulfone compounds are obtained by silica gel column chromatography.

[0039] Example 1: Preparation of γ-ketosulfone compound III-1

[0040]

[0041] A typical implementation process: At room temperature, propargyl ester compounds are added sequentially to the reaction flask. I-1 (20.4 mg, 0.1 mmol) and sulfinic acid (II-1) (39 mg, 0.25 mmol) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) (43.4 mg, 0.25 mmol) were reacted in 1 mL of nitromethane, and the reaction was then carried out at 100 °C for 1 hour.

[0042] The reaction progress was monitored by TLC. After the reaction was completed, water was added to the reaction solution, followed by ethyl acetate. After stirring thoroughly, the mixture was allowed to stand and separate into layers. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract and the separated organic layer were combined and washed with saturated brine and dried with anhydrous sodium sulfate. The ethyl acetate solvent was removed by evaporation, and then the mixture was purified by silica gel column chromatography to obtain γ-ketosulfone compound III-1 (30 mg, 94% yield). 1H NMR (400 MHz, CDCl3): δ ppm 7.83 (d,J = 8.8 Hz, 2 H), 7.76 (d, J = 8 Hz, 2 H), 7.30 (d, J = 8 Hz, 2 H), 6.87 (d,J = 8.8 Hz, 2 H), 3.82 (s, 3 H), 3.48 - 3.43 (m, 2 H), 3.38 - 3.37 (m, 2 H), 2.38 (s, 3 H). 13 C NMR (100 MHz, CDCl3): 194.0, 164.0, 144.9, 136.2, 130.4,130.0, 129.0, 128.0, 113.9, 55.5, 55.3, 31.1, 21.6. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 19 O4S: 319.0999; Found: 319.0992.

[0043] Example 2: Preparation of γ-ketosulfone compound III-2

[0044]

[0045] At room temperature, propargyl ester compounds were added sequentially to the reaction flask. The reaction mixture was prepared in 1 mL of nitromethane and sulfinic acid (II-2) (18.8 mg, 0.1 mmol), p-toluenesulfonic acid monohydrate (p-TsOH·H2O) (43.4 mg, 0.25 mmol), and then the reaction was carried out at 100 °C for 1 hour.

[0046] The reaction progress was monitored by TLC, and the separation and purification steps were the same as in Example III-1, yielding γ-ketosulfone compound III-2 (15.4 mg, 51%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.76 - 7.73 (m, 4 H), 7.29 (d, J= 7.2 Hz, 2 H), 7.19 (t, J = 4 Hz, 2 H), 3.48 - 3.44 (m, 2 H), 3.40 - 3.36(m, 2 H), 2.38 (s, 3 H), 2.34 (s, 3 H). 13C NMR (100 MHz, CDCl3): 195.1,144.9, 144.7, 136.2, 133.4, 130.0, 129.5, 128.2, 128.0, 51.2, 31.3, 21.7,21.6. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 19 O3S: 303.1049; Found: 303.1047.

[0047] Example 3: Preparation of γ-ketosulfone compound III-3

[0048]

[0049] At room temperature, propargyl ester compounds were added sequentially to the reaction flask. -3) (21.8 mg, 0.1 mmol) and sulfinic acid (II-1) (39 mg, 0.25 mmol) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) (43.4 mg, 0.25 mmol) were added to 1 mL of nitromethane, and the reaction was then carried out at 100 °C for 1 hour.

[0050] The reaction progress was monitored by TLC, and the separation and purification steps were the same as in Example III-1, yielding γ-ketosulfone compound III-3 (24.6 mg, 74%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.75 (d, J = 8 Hz, 2 H), 7.47 -7.44 (m, 1 H), 7.30 - 7.28 (m, 3 H), 6.78 (d, J = 8 Hz, 1 H), 5.98 (s, 2 H), 3.46 - 3.40 (m, 2 H), 3.36 - 3.30 (m, 2 H), 2.38 (s, 3 H). 13 C NMR (100 MHz, CDCl3): 193.5, 152.3, 148.4, 144.9, 136.2, 130.7, 130.0, 128.0, 124.5, 108.0,107.8, 102.0, 51.3, 31.2, 21.6. HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 17O5S:333.0791; Found: 333.0788

[0051] Example 4: Preparation of γ-ketosulfone compound III-4

[0052]

[0053] At room temperature, propargyl ester compounds were added sequentially to the reaction flask. -4) (23.4 mg, 0.1 mmol) and sulfinic acid (II-1) (39 mg, 0.25 mmol) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) (43.4 mg, 0.25 mmol) were added to 1 mL of nitromethane, and the reaction was then carried out at 100 °C for 1 hour.

[0054] The reaction progress was monitored by TLC, and the separation and purification steps were the same as in Example III-1, yielding γ-ketosulfone compound III-4 (28 mg, 80%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.75 - 7.69 (m, 3 H), 7.28 (d, J = 8Hz, 2 H), 6.44 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 3.82 (s, 3 H), 3.78 (s, 3H), 3.44 - 3.41 (m, 2 H), 3.37 - 3.33 (m, 2 H), 2.38 (s, 3 H). 13 C NMR (100MHz, CDCl3): 194.9, 165.1, 161.2, 144.7, 136.4, 133.0, 129.9, 128.1, 119.6,105.5, 98.2, 55.6, 55.5, 51.7, 36.6, 21.6. HRMS (ESI) m / z: [M + H] + Calcd forC 18 H 21 O5S: 349.1104; Found: 349.1109.

[0055] Example 5: Preparation of γ-ketosulfone compound III-5

[0056]

[0057] At room temperature, propargyl ester compounds were added sequentially to the reaction flask. I-1) (23.4 mg, 0.1 mmol) and sulfinic acid (II-2) (44.1 mg, 0.25 mmol) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) (43.4 mg, 0.25 mmol) were reacted in 1 mL of nitromethane, and the reaction was then carried out at 100 °C for 1 hour.

[0058] The reaction progress was monitored by TLC, and the separation and purification steps were the same as in Example III-1, yielding γ-ketosulfone compound III-5 (28.4 mg, 84%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.83 - 7.80 (m, 4 H), 7.47 (d, J= 8.4 Hz, 2 H), 6.87 (d, J =8.8 Hz, 2 H), 3.80 (s, 3 H), 3.50 - 3.46 (m, 2H), 3.38 - 3.35 (m, 2H). 13 C NMR (100 MHz, CDCl3): 193.6, 164.1, 140.7,137.6, 130.4, 129.7, 129.5, 128.8, 114.0, 55.6, 51.3, 30.8. HRMS (ESI) m / z:[M + H] + Calcd for C 16 H 16 ClO4S: 339.0452; Found: 339.0446.

[0059] In summary, this invention efficiently synthesizes a series of γ-ketosulfone compounds in nitromethane solvent under simple reaction conditions, using propargyl ester compounds and sulfinic acid as raw materials, catalyzed by p-toluenesulfonic acid monohydrate. The reaction process in each example was monitored by TLC, and the products were separated and purified using ethyl acetate extraction, saturated brine washing, drying with anhydrous sodium sulfate, and silica gel column chromatography, yielding target products with high yields and purity. The product structures were determined by... 1 HNMR, 13 C10 NMR and HRMS characterization confirmed the feasibility and effectiveness of the preparation method. This method offers advantages such as simple operation, mild reaction conditions, and good substrate applicability, providing a practical route for the synthesis of γ-ketosulfone compounds.

[0060] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the technical scope of the present invention. Therefore, any minor modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a γ-ketosulfone compound, characterized in that, The method is to first use propargyl ester compound ( Using sulfinic acid (II) and p-toluenesulfonic acid monohydrate (p-TsOH·H2O) as raw materials, the mixture was fully dissolved in an organic solvent at room temperature. Then, p-TsOH·H2O was added as a Brønsted acid. After the reaction, the product was purified by silica gel column chromatography to obtain the product as shown in formula (…). II) shows the γ-ketosulfone compounds; ( ); RSO2H ( ) ; ( I); Where, equation ( ), ( ), ( R in II) 1 R 2 R 3 They are: hydrogen, alkyl, and alkoxy, respectively; R 4 R is an alkyl or alkoxy group; R is an alkyl or aryl group with different substituents.

2. The method for preparing a γ-ketone sulfone compound according to claim 1, characterized in that, The reaction was carried out at 100°C for 1 hour.

3. The method for preparing a γ-ketone sulfone compound according to claim 1, characterized in that, The raw materials ( ), ( The molar ratio of the feed material to p-toluenesulfonic acid monohydrate p-TsOH·H2O is 1:1.0~2.5:1.0~2.

5.

4. The method for preparing a γ-ketone sulfone compound according to claim 1, characterized in that, The raw materials ( ), ( The molar ratio of the feed material to p-toluenesulfonic acid monohydrate p-TsOH·H2O is 1:2.5:2.

5.

5. The method for preparing a γ-ketone sulfone compound according to claim 1, characterized in that, The organic solvent is any one of dichloromethane, 1,2-dichloroethane, acetonitrile, and nitromethane.

6. The method for preparing a γ-ketone sulfone compound according to claim 1, characterized in that, The propargyl ester compound ( The molar ratio of raw materials for the following compounds is 1:2.5:2.5:sulfinic acid (II) and p-toluenesulfonic acid monohydrate p-TsOH·H2O.

7. The method for preparing a γ-ketone sulfone compound according to claim 1, characterized in that, The separation and purification method is as follows: water is added to the reaction solution, followed by ethyl acetate. After thorough stirring, the mixture is allowed to stand and separate into layers. The separated aqueous layer is extracted with ethyl acetate. The ethyl acetate extract and the separated organic layer are combined and washed with saturated brine and dried with anhydrous sodium sulfate, respectively. The ethyl acetate solvent is evaporated, and then the mixture is separated and purified by silica gel column chromatography to obtain γ-ketosulfone compounds.

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