A green synthesis method of gamma-carbonyl sulfone compounds
By using a sulfonic acid-based eutectic/water solvent system, aldehydes and aromatic acetylenes as raw materials, and sodium sulfite as a catalyst, a highly efficient and green synthesis of γ-carbonyl sulfone was achieved. This solves the problems of narrow applicability of raw materials, long reaction time, and low yield in existing technologies, and is suitable for drug synthesis.
Patent Information
- Application Number
- CN202311305845.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-10-10
- Publication Date
- 2025-11-11
- Estimated Expiration
- 2043-10-10
AI Technical Summary
Existing methods for synthesizing γ-carbonyl sulfone suffer from problems such as a narrow range of applicable raw materials, long reaction time, unsatisfactory yield, and the need for toxic solvents and expensive catalysts, which limit their application in drug synthesis.
Using aldehydes and aromatic acetylenes as starting materials, and sulfonic acid-type eutectic/water as solvent, a two-step reaction is carried out at room temperature, using sodium sulfite as a catalyst to prepare γ-carbonyl sulfone compounds. This method avoids the use of toxic solvents and expensive catalysts in traditional methods and simplifies the reaction steps.
A high-yield synthesis of γ-carbonyl sulfone compounds was achieved, with convenient raw material sources, mild reaction conditions, and environmental friendliness, making it suitable for large-scale production.
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Figure CN117402092B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of compound synthesis technology, and specifically relates to a green synthesis method for γ-carbonyl sulfone compounds. Background Technology
[0002] Ketone sulfones, containing both carbonyl and sulfonyl groups, have shown wide applications in pharmaceuticals and functional materials. Among them, γ-carbonyl sulfones possess a wide range of biological properties, such as anticancer, antibacterial, and anticoagulant effects. Furthermore, the carbonyl and sulfonyl groups can be converted into other important organic functional groups through conventional reactions; therefore, γ-carbonyl sulfones are of great significance in organic synthesis.
[0003]
[0004] Currently, the traditional synthesis of γ-carbonyl sulfone mainly involves the reaction of aromatic thiophenols with chalcone, followed by the oxidation of the thioether to sulfone. This step requires a large amount of oxidant, resulting in poor atom economy, and the aromatic thiophenols produce a strong odor. Sreedhar et al. synthesized γ-carbonyl sulfone in dichloromethane using sodium p-toluenesulfinate and chalcone as raw materials, ferric chloride as a catalyst, and trimethylsilyl chloride as an additive (Synlett 2018, 1949-1952). However, this reaction system has a narrow substrate applicability and suffers from heavy metal residues, limiting its application in pharmaceutical synthesis.
[0005]
[0006] Lu Guoping et al. achieved the above reaction in an aqueous phase using hydrochloric acid as a promoter (ACS SustainableChem.Eng. 2016,4,1804-1809). This reaction requires the use of an equivalent amount of hydrochloric acid, resulting in significant acid pollution. Similarly, N-p-toluenesulfonylhydrazone (J.Org.Chem. 2014,79,441-445) and p-toluenesulfonylimide (Angew.Chem.Int.Ed. 2013,52,12354-12358) can also react with chalcones under the action of a base or carbene catalyst to generate the corresponding γ-carbonyl sulfone. These methods require the raw materials to be synthesized through multiple steps and necessitate expensive catalysts, resulting in high reaction costs. Sulfonyl chlorides can react with chalcones under photocatalytic conditions; however, this process requires the use of an expensive iridium catalyst (Angew.Chem.Int.Ed. 2020,59,11620-11626).
[0007] As the background literature above indicates, current methods for synthesizing γ-carbonyl sulfones primarily involve reacting various sulfonyl compounds (sodium benzenesulfinate, sulfonylhydrazone, sulfonyl hydrazine, sulfonyl chloride, etc.) with chalcones. It should be noted that both some sulfonyl compounds and chalcones with different substituents require multiple reaction and purification steps, and commercially available starting materials only involve those with simple substituents. Furthermore, these reaction processes suffer from drawbacks such as unsatisfactory yields, narrow substrate scope, long reaction times, and the need for environmentally unfriendly organic solvents. Therefore, given the significant reactivity of γ-carbonyl sulfones, it is essential to develop a universal and environmentally friendly synthetic method that utilizes simple and readily available starting materials, operates under mild reaction conditions, employs a simple reaction system, achieves high yields, and is inexpensive. Summary of the Invention
[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a green synthesis method for γ-carbonyl sulfone compounds, which has mild reaction conditions, convenient raw material sources, high yield, and green reaction system.
[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:
[0010] A green synthesis method for γ-carbonyl sulfone compounds includes the following steps:
[0011] Using aldehydes and aromatic acetylenes as starting materials, and sulfonic acid-type eutectic / water as solvent, the reaction was carried out in a flask with stirring for 1 to 3 hours at 25°C to 40°C. After the reaction was completed, sodium sulfite was added, and the reaction was continued with stirring for 1 to 2 hours to prepare γ-carbonyl sulfone compounds.
[0012] The reaction route is as follows:
[0013]
[0014] In the γ-carbonyl sulfone compounds of the present invention, R 1 R 2 and R 3 The type and position of substituents are not limited. R 1 It can be an alkyl group, or a benzene ring containing different substituents. R 2 The substituents can be hydrogen, methyl, methoxy, halogen, etc., and their positions are not limited; they can be ortho, meta, or para. R 3 It can be a substituent such as phenyl, p-methylphenyl, or methyl.
[0015] In the sulfonic acid type deep eutectic solvents (DES), the hydrogen bond acceptor includes one of choline chloride and betaine; the hydrogen bond donor includes one of p-toluenesulfonic acid and trifluoromethanesulfonic acid; the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:1 to 3.
[0016] As a preferred embodiment, the eutectic compound is selected from choline chloride / p-toluenesulfonic acid, choline chloride / trifluoromethanesulfonic acid, betaine / p-toluenesulfonic acid, and betaine / trifluoromethanesulfonic acid. A preferred choline chloride / p-toluenesulfonic acid eutectic compound consists of choline chloride and p-toluenesulfonic acid in a molar ratio of 1:1 to 3. A preferred choline chloride / trifluoromethanesulfonic acid eutectic compound consists of choline chloride and trifluoromethanesulfonic acid in a molar ratio of 1:1 to 2. A preferred betaine / p-toluenesulfonic acid eutectic compound consists of betaine and p-toluenesulfonic acid in a molar ratio of 1:1 to 3. A preferred betaine / trifluoromethanesulfonic acid eutectic compound consists of betaine and trifluoromethanesulfonic acid in a molar ratio of 1:1 to 2. Among these eutectic compounds, γ-carbonyl sulfone compounds can be successfully generated, with yields of the target product all above 75%. Choline chloride / trifluoromethanesulfonic acid is the best eutectic compound for this reaction. In particular, when choline chloride / trifluoromethanesulfonic acid are composed in a molar ratio of 1:1.5, the yield of the target product reaches the best, with a yield as high as 92%.
[0017] The solvent is a mixture of sulfonic acid-type eutectic material and water, with a volume ratio of 1:0.2 to 1. The amount of mixed solvent used is the same as that of conventional solvents. For example, if aldehyde is used as a standard substrate, its concentration in the mixed solvent is 0.05 to 0.2 mol / L, preferably 0.05 to 0.1 mol / L.
[0018] The molar ratio of the aldehyde, arylyn, and sodium sulfite is 1:1.2-1.5:1.5-2.
[0019] The reaction time is 1-3 hours for the first step of the reaction between the aldehyde and the aromatic yne, followed by the addition of sodium sulfite and a further reaction time of 1-2 hours.
[0020] After the above two-step reaction is completed, extraction is performed using an organic solvent. The residue is then separated by column chromatography to obtain a γ-carbonyl sulfone compound. The organic solvent is ethyl acetate, and the column chromatography eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1. The raffinate consists of a eutectic compound, water, and a small amount of residual sodium sulfinate. It requires no additional treatment and can be reused directly.
[0021] The advantages and beneficial effects of this invention are as follows:
[0022] 1. This invention provides a general synthetic method for γ-carbonyl sulfone compounds, laying the foundation for the convenient synthesis of such compounds.
[0023] 2. The present invention provides a method for synthesizing γ-carbonyl sulfone compounds that does not require a catalyst, produces few byproducts that are essentially non-toxic, and the reaction is carried out in two steps at room temperature without the need for intermediate purification steps. The process is simple, green, and highly atom-economical.
[0024] 3. This invention provides a method for synthesizing γ-carbonyl sulfone compounds, using eutectic solvents and water as solvents. The eutectic solvent is a novel solvent with excellent physicochemical properties, formed from quaternary ammonium salts and acids. These eutectic solvents are essentially non-toxic, have low vapor pressure, are biodegradable, and reusable. Their preparation process requires only stirring, achieving 100% atom utilization, making them the best alternative to traditional, highly toxic, and volatile organic solvents.
[0025] 4. The present invention provides a method for synthesizing γ-carbonyl sulfone compounds, using commercially available aldehydes, alkynes and sodium sulfite salts as raw materials. The raw materials are readily available and inexpensive, the reaction conditions are simple, the reaction time is short, and the yield is high. The reaction can be carried out in air, and the post-processing is simple, which is conducive to product purification and large-scale production. Attached Figure Description
[0026] Figure 1 This is the synthetic reaction formula for the γ-carbonyl sulfone compounds of this invention;
[0027] Figure 2 This is the 1H NMR spectrum of γ-carbonyl sulfone compound 4a in Example 1 of this invention;
[0028] Figure 3 This is the carbon NMR spectrum of γ-carbonyl sulfone compound 4a in Example 1 of this invention. Detailed Implementation
[0029] This invention is not limited to the specific embodiments listed below. Those skilled in the art can implement this invention using various other specific embodiments based on the content disclosed herein. Any modifications or alterations made to the design structure and concept of this invention fall within the protection scope of this invention. It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other.
[0030] Comparative Example:
[0031] The following reaction is a three-component reaction (as a standard reaction) of benzaldehyde, phenylacetylene, and sodium p-toluenesulfinate under optimal conditions in a eutectic / water mixed solvent:
[0032]
[0033] In a clean, dry 10 mL Schlenk reaction tube, substrate 1a (0.5 mmol), phenylacetylene 2a (0.6 mmol), choline chloride / trifluoromethanesulfonic acid (ChCl / TfOH, 1:1.5, 4 mL), and water (1 mL) were added sequentially. The reaction was stirred at 25 °C for 3 hours. Then, sodium p-toluenesulfinate 3a (0.75 mmol) was added to the reaction tube, and stirring was continued for 2 hours. After the reaction was complete, 5 mL of ethyl acetate was added for extraction, and the organic phase was separated. The solvent was evaporated to dryness using a rotary evaporator. The resulting residue was then purified by column chromatography using petroleum ether and ethyl acetate (v / v ratio 5:1) as eluents, with a silica gel (200-300 mesh sieve).
[0034] The following control experimental groups 1-16 are compared and explained using standard reaction conditions as a reference:
[0035] experimental group Differences in conditions from the standard reaction Yield 1 Indifference 92％ 2 Choline chloride / p-toluenesulfonic acid can replace choline chloride / trifluoromethanesulfonic acid 80％ 3 Betaine / p-toluenesulfonic acid as a substitute for choline chloride / trifluoromethanesulfonic acid 83％ 4 Betaine / trifluoromethanesulfonic acid as a substitute for choline chloride / trifluoromethanesulfonic acid 85％ 5 Choline chloride:trifluoromethanesulfonic acid = 1:1 80％ 6 Choline chloride:trifluoromethanesulfonic acid = 1:2 75％ 7 n(aldehyde): n(yne): n(sodium sulfite) = 1:1.5:1.5 91％ 8 n(aldehyde): n(yne): n(sodium sulfite) = 1:1.2:2 88％ 9 V(ChCl / TfOH): V(water)=8ml:2ml 86％ 10 V(ChCl / TfOH):V(water) = 2ml:0.5ml 81％ 11 V(ChCl / TfOH): V(water)=2.5ml:2.5ml 70％ 12 V(ChCl / TfOH): V(water)=3.33ml:1.67ml 83％ 13 V(ChCl / TfOH): V(water)=3.75ml:1.25ml 85％ 14 V(ChCl / TfOH): V(water)=4.17ml:0.83ml 90％ 15 No water added 54％ 16 Non-step reaction 62％
[0036] The table above shows that experimental groups 1-4 investigated the effects of different acidic eutectic compounds on the reaction. The experimental data show that all four acidic eutectic compounds have good catalytic activity for the reaction, with yields all above 80%. The reaction effect is best in ChCl / TfOH, with a yield as high as 92%.
[0037] Experimental groups 5 and 6 investigated the effect of the molar ratio of choline chloride to trifluoromethanesulfonic acid in ChCl / TfOH on the reaction. In experimental group 1, the molar ratio of choline chloride to trifluoromethanesulfonic acid was 1:1.5, yielding 92%. When the molar ratio was 1:1 or 1:2, the yield of the target product decreased significantly. This is because trifluoromethanesulfonic acid is the active catalytic center in the eutectic, and insufficient amounts hinder the reaction; while excessive acid easily leads to the formation of byproducts, resulting in a significant decrease in the yield of the target product.
[0038] Experiments 7 and 8 investigated the effect of the molar ratio of aldehyde, alkyne, and sodium sulfite on the reaction. When n(aldehyde):n(alkyne):n(sodium sulfite) = 1:1.5:1.5, the reaction yield was 91%; when n(aldehyde):n(alkyne):n(sodium sulfite) = 1:1.2:2, the reaction yield was 88%. This indicates that the reaction conditions are optimal when n(aldehyde):n(alkyne):n(sodium sulfite) = 1:1.2:1.5. Decreasing the amount of each component leads to incomplete reaction, while excessively high amounts generate other byproducts, both of which reduce the yield of the target product.
[0039] Experimental groups 9 and 10 investigated the effect of the amount of mixed solvent on the reaction. Among them, the effect was best when the amount of ChCl / TfOH / water was 5 mL. Increasing the amount to 10 mL or decreasing it to 2.5 mL both reduced the yield. It is best to keep the concentration of reactants in the range of 0.05 to 0.1 mol / L.
[0040] Experimental groups 11–15 investigated the effect of the volume ratio of ChCl / TfOH and water on the reaction. Increasing the water ratio tended to decrease the yield of the target product. This is because the increase in water makes the organic matter less soluble in the solvent; without water, the yield dropped sharply to 54%. This is because the addition of water reduces the viscosity of the reaction system, thus accelerating the contact of the substrate.
[0041] Experiment 16 investigated the effect of a non-stepwise experiment on the reaction. When all three raw materials were added to the reaction system simultaneously, the yield was only 62% after 3 hours of reaction. This is because sodium sulfite in the reaction system can react with alkyne, leading to an increase in byproducts.
[0042] Examples 1-5 below were performed according to the standard reaction described above:
[0043]
[0044] In a clean, dry 10 mL Schlenk reaction tube, aldehyde 1 (0.5 mmol), alkyne 2 (0.6 mmol), choline chloride / trifluoromethanesulfonic acid (ChCl / TfOH, 1:1.5, 4 mL), and water (1 mL) were added sequentially. The reaction was stirred at 25 °C for 3 hours. Then, sodium sulfite 3 (0.75 mmol) was added to the reaction tube, and stirring was continued for 2 hours. After the reaction was completed, 5 mL of ethyl acetate was added for extraction, and the organic phase was separated. The solvent was evaporated to dryness using a rotary evaporator. The resulting residue was then purified by column chromatography using petroleum ether and ethyl acetate (volume ratio 5:1) as eluents, with a silica gel (200-300 mesh sieve).
[0045] Example 1
[0046] 1,3-Diphenyl-3-p-methylbenzenesulfonyl-1-propanone, yield 92%.
[0047] White solid, melting point: 175-177℃. 1H NMR (500MHz, CDCl3) δ2.32(s,3H),3.89(dd,J=18.0,9.5Hz,1H),4.07(dd,J=17.5,3.5Hz,1H),4.87(d d,J=9.5,3.5Hz,1H),7.09-7.20(m,7H),7.35-7.41(m,4H),7.49-7.52(m,1H),7.86(d,J=8.0Hz,2H). 13 C NMR (125MHz, CDCl3) δ21.7,37.2,66.6,128.2,128.6,128.9(2C),129.2,129.5,129.9,132.8,133.7,134.2,136.3,144.8,195.1.
[0048] Example 2
[0049] 1-(4-chlorophenyl)-3-phenyl-3-p-methylbenzenesulfonyl-1-propanone, yield 90%.
[0050] White solid, melting point: 187-189℃. 1 H NMR (500MHz, CDCl3) δ2.41(s,3H),3.93(dd,J=18.0,9.5Hz,1H),4.15(dd,J=17.5,3.5Hz,1H ),4.94(dd,J=9.5,3.5Hz,1H),7.18-7.29(m,7H),7.42-7.47(m,4H),7.90(d,J=8.5Hz,2H). 13 C NMR (125MHz, CDCl3) δ21.7,37.1,66.6,128.5,128.8,129.0,129.1,129.4,129.6,129.8,132.6,134.0,134.6,140.2,144.8,193.9.
[0051] Example 3
[0052] 1,3-Diphenyl-3-p-methoxybenzenesulfonyl-1-propanone, yield 95%.
[0053] White solid, melting point: 157-159℃. 1H NMR (500MHz, CDCl3) δ3.83(s,3H),3.96(dd,J=17.5,9.5Hz,1H),4.15(dd,J=18.0,3.5Hz,1H),4.92(dd,J=9.5,3.5H z,1H),6.84(d,J=9.0Hz,2H),7.21-7.28(m,5H),7.45-7.48(m,4H),7.57-7.60(m,1H),7.94(dd,J=8.4,1.2Hz,2H). 13 C NMR (125MHz, CDCl3) δ37.1,55.6,66.7,114.0,128.2,128.5,128.8,129.9,131.3,132.9,133.7,136.3,163.8,195.1.
[0054] Example 4
[0055] 1-Phenyl-3-p-methylbenzenesulfonyl-1-hexanone, yield 88%.
[0056] Colorless liquid. 1 H NMR (500MHz, CDCl3) δ7.93-7.91(m,2H),7.81(d,J=8.4Hz,2H),7.60(tt,J=1 .2,7.2Hz,1H),7.48(t,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),4.00-3.94(m,1H ),3.67(dd,J=4.4,18.0Hz,1H),3.17(dd,J=7.2,18.0Hz,1H),2.45(s,3H),1. 97-1.88(m,1H),1.65-1.56(m,1H),1.46-1.23(m,2H),0.86(t,J=7.2Hz,3H). 13 C NMR (125MHz, CDCl3) δ195.7,144.8,136.1,134.8,133.6,129.9,128.8,128.7,128.1,59.6,37.0,31.1,21.6,20.0,13.9.
[0057] Example 5
[0058] 1-Phenylacetyl-1-pentanone, yield 85%.
[0059] Colorless liquid. 1H NMR (500MHz, DMSO-d6) δ8.03-8.01(m,2H),7.64(tt,J=1.2,7.2Hz,1H),7.53(t,J=8.0Hz,1H),3.93-3.87(m,1H),3.76(dd,J=5.2,18. 4Hz,1H),3.26(dd,J=6.0,18.4Hz,1H),2.93(s,3H),2.12-2.03(m,1H),1.78-1.67(m,1H),1.56-1.39(m,2H),0.99(t,J=7.6Hz,3H);. 13 C NMR (125MHz, DMSO-d6) δ195.9,136.0,133.9,128.9,128.2,58.5,39.7,37.2,30.9,20.1,13.9.
[0060] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the technical principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for synthesizing γ-carbonyl sulfone compounds, characterized in that, The reaction includes the following steps: using aldehydes and aromatic acetylenes as starting materials, using sulfonic acid type eutectic / water as solvent, stirring the reaction at 25℃~40℃ for 1~3 hours, after the reaction is completed, adding sodium sulfite salt, and continuing to stir the reaction for 1~2 hours to prepare γ-carbonyl sulfone compound. The structural formula of the γ-carbonyl sulfone compound is as follows: Among them, R 1 It is an alkyl group or a phenyl group containing different substituents; R 2 The substituents are hydrogen, methyl, methoxy, or halogen, and the substituent positions are ortho, meta, or para; R 3 It can be phenyl, p-methylphenyl, or methyl.
2. The method for synthesizing γ-carbonyl sulfone compounds according to claim 1, characterized in that, In the sulfonic acid-type eutectic compound, the hydrogen bond acceptor includes one of choline chloride and betaine; the hydrogen bond donor includes one of p-toluenesulfonic acid and trifluoromethanesulfonic acid; and the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:1 to 3.
3. The method for synthesizing γ-carbonyl sulfone compounds according to claim 1, characterized in that, The solvent is a mixed solvent composed of sulfonic acid-type eutectic material and water at a volume ratio of 1:0.2 to 1; the amount added is calculated based on the amount of aldehyde used, and the concentration of the aldehyde in the mixed solvent is 0.05 to 0.2 mol / L.
4. The method for synthesizing γ-carbonyl sulfone compounds according to claim 1, characterized in that, The molar ratio of the aldehyde, arylyn, and sodium sulfite is 1:1.2-1.5:1.5-2.
5. The method for synthesizing γ-carbonyl sulfone compounds according to claim 1, characterized in that, The steps also include: extracting with an organic solvent, and separating the residue after rotary evaporation by column chromatography to obtain a γ-carbonyl sulfone compound.
6. The method for synthesizing γ-carbonyl sulfone compounds according to claim 5, characterized in that, The organic solvent includes ethyl acetate; the column chromatography eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1.