Method for synthesis of visible light promoted structurally unsymmetrical sulfoxides and applications thereof

Abstract

The application discloses a synthesis method of visible light promoted structural asymmetric sulfoxide, which comprises the following steps: sequentially adding a disulfide compound, a benzoyl peroxide compound, a catalyst, an inorganic base and a solvent, uniformly mixing and stirring, stirring and reacting under the irradiation of a 400-425 nm wavelength light source at room temperature, monitoring the completion of the reaction through thin layer chromatography, removing the solvent under reduced pressure, and separating the residual product through column chromatography to obtain a structural asymmetric sulfoxide compound. The application can obtain various structural asymmetric sulfoxide compounds, has the characteristics of simple operation, good substrate applicability and mild conditions, and overcomes the defects of low reaction efficiency and high catalyst cost in the prior art.

Description

Technical Field

[0001] This invention relates to a visible light-promoted synthesis method for structurally asymmetric sulfoxides and its applications, relating to CO7D, and specifically to the field of heterocyclic compound synthesis. Background Technology

[0002] Asymmetric sulfoxides are important compounds in the pharmaceutical and pesticide fields. Traditional methods typically employ high-temperature oxidation or use peroxides or high-valent iodine oxidants, with transition metal catalysts to promote the reaction. However, these methods suffer from several drawbacks, such as high energy consumption, metal residues in the products, and environmental pollution. Photocatalytic synthesis has become an important technique in synthetic reactions in recent years. Existing literature discloses photocatalytic synthesis using highly reactive substrates, but the raw materials themselves are unstable and unsuitable for industrial production. Therefore, developing a novel method for synthesizing asymmetric sulfoxides with mild reaction conditions, environmental friendliness, and high selectivity is crucial.

[0003] Chinese invention patent CN201210489246.0 discloses a planar chiral ferrocene compound, its synthesis method, and its uses. It uses amine-methyl-substituted ferrocene, substituted arylboronic acid, heteroarylboronic acid, arylvinylboronic acid, or alkylboronic acid as raw materials, and chiral amino acids and palladium as catalysts to synthesize this type of planar chiral ferrocene compound with high efficiency and high correspondence selectivity. However, the catalyst used is a rare metal, resulting in high cost and metal residue. Chinese invention patent CN109810030A discloses a visible light-promoted method for preparing asymmetric sulfoxide compounds, using aryl diazonium salts and aryl thiophenols as raw materials for photocatalytic reaction to obtain asymmetric sulfoxides. However, the aryl diazonium salts and aryl thiophenol substrates have high reactivity, making them inconvenient to use and unsuitable for large-scale industrial production. Summary of the Invention

[0004] To reduce energy consumption during the synthesis of structurally asymmetric sulfoxide compounds and avoid metal residues in the products, a first aspect of the present invention provides a visible light-promoted synthesis method for structurally asymmetric sulfoxides, comprising the following steps:

[0005] S1 is added sequentially with disulfide compounds, benzoyl peroxide compounds, catalysts, inorganic bases, and solvents, and then mixed and stirred until homogeneous.

[0006] S2 was placed at room temperature and stirred under a light source with a wavelength of 400-425 nm for reaction.

[0007] After the reaction was monitored by thin-layer chromatography, the solvent was removed under reduced pressure, and the residue was separated by column chromatography to obtain a structurally asymmetric sulfoxide compound.

[0008] In a preferred embodiment, the wavelength of the light source in step S2 is 405 nm.

[0009] As a preferred embodiment, the structural formula of the disulfide compound is as follows: The structural formula of the benzoyl peroxide compound is as follows: In the formula R 1 Selected from C1-C 12 One of alkyl, aryl, and heteroaryl, R 2 Selected from one of aryl or heteroaryl, R 1 and R 2 They are not the same.

[0010] In a preferred embodiment, the aryl group is a monosubstituted aryl or polysubstituted aryl group, and the aryl group is selected from one of alkyl, alkoxy, alkylamino, halogen, nitro, cyano, and amino groups.

[0011] As a preferred embodiment, the reaction formula for the synthesis reaction is as follows:

[0012]

[0013] In a preferred embodiment, the catalyst is an anthracene compound with the structural formula [structure omitted]. In the formula R 3 It is a C1-C6 alkyl group, and the anthracene compound is selected from one or a combination of several of 9,10-dimethoxyanthracene, 9,10-diethoxyanthracene, 9,10-dipropoxyanthracene, 9,10-diisopropoxyanthracene, and 9,10-dibutoxyanthracene.

[0014] In a preferred embodiment, the catalyst is 9,10-dibutoxyanthracene.

[0015] In a preferred embodiment, the inorganic base is selected from one or a combination of several of sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium carbonate, potassium phosphate, and cesium carbonate.

[0016] In a preferred embodiment, the inorganic base is sodium carbonate.

[0017] In a preferred embodiment, the solvent is an organic solvent selected from one or a combination of several of dichloromethane, 1,2-dichloroethane, acetonitrile, and N,N-dimethylformamide.

[0018] In a preferred embodiment, the solvent is acetonitrile.

[0019] In a preferred embodiment, the reaction temperature in step S2 is 20-30℃ and the reaction time is 6-24h.

[0020] In a preferred embodiment, the reaction temperature in step S2 is 23-28°C and the reaction time is 6-15 hours.

[0021] In a preferred embodiment, the reaction temperature in step S2 is 25°C and the reaction time is 6-8 hours.

[0022] In a preferred embodiment, the concentration of the disulfide compound in the system is 0.05-0.2 mol / L, and the concentration of the benzoyl peroxide compound in the system is 0.05-0.2 mol / L.

[0023] In a preferred embodiment, the concentration of the disulfide compound in the system is 0.1-0.2 mol / L, and the concentration of the benzoyl peroxide compound in the system is 0.1-0.2 mol / L.

[0024] In a preferred embodiment, the concentration of the disulfide compound in the system is 0.1 mol / L, and the concentration of the benzoyl peroxide compound in the system is 0.1 mol / L.

[0025] In a preferred embodiment, the mass ratio of the disulfide compound, the benzoyl peroxide compound, the catalyst, and the inorganic base is 1:(1-3):(0.01-0.1):(1-3).

[0026] In a preferred embodiment, the mass ratio of the disulfide compound, the benzoyl peroxide compound, the catalyst, and the inorganic base is 1:(2-3):(0.03-0.08):(1-2).

[0027] In a preferred embodiment, the mass ratio of the disulfide compound, the benzoyl peroxide compound, the catalyst, and the inorganic base is 1:2:0.05:1.

[0028] Currently, there are many methods for preparing structurally asymmetric sulfoxides, but these methods suffer from drawbacks such as the presence of impurities in the resulting asymmetric sulfoxides, unstable substrates, difficulty in obtaining the product, and high production costs. This application uses highly stable disulfide compounds and benzoyl peroxide compounds as substrates for photocatalytic reactions. Existing synthetic reactions use transition metals such as copper, silver, and cobalt as catalysts or oxidize sulfides at high temperatures, resulting in metal residues in the obtained structurally asymmetric sulfoxides, posing safety risks when used in the pharmaceutical field. High-temperature reactions also require high energy consumption. This application innovatively discovers that using anthracene catalysts, especially 9,10-dibutoxyanthracene, can reduce the activation energy required during the reaction, lower energy consumption, and simultaneously avoid the introduction of metal catalysts, preventing metal residues and improving the safety of the product.

[0029] The applicant further discovered that when anthracene catalysts are used in conjunction with the addition of inorganic bases, the amount of catalyst used can be reduced and the reaction efficiency improved. The possible reason is that the introduction of inorganic bases makes the reaction environment of the system alkaline. Under alkaline conditions, anthracene catalysts catalyze the decarbonylation of benzoyl peroxide compounds, and disulfide compounds react with benzoyl peroxide to obtain intermediate-valence sulfides with high reactivity, thereby improving the reaction efficiency and reducing production costs.

[0030] A second aspect of the present invention provides an application of a visible light-promoted synthesis method for structurally asymmetric sulfoxides, which is used in the preparation of structurally asymmetric sulfoxides.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) The visible light-promoted synthesis method of asymmetric sulfoxides described in this invention uses 9,10-dibutoxyanthracene as a catalyst, which can reduce the activation energy required in the reaction process, reduce energy consumption, and avoid the introduction of metal catalysts, avoid metal residues, and improve the safety of the product.

[0033] (2) The visible light-promoted synthesis method of asymmetric sulfoxides described in this invention, by adding an inorganic base while using an anthracene catalyst, can reduce the amount of catalyst used and improve the reaction efficiency under visible light.

[0034] (3) The visible light-promoted synthesis method of asymmetric sulfoxides described in this invention can obtain a variety of asymmetric sulfoxide compounds. It has the advantages of simple operation, good substrate applicability, and mild conditions. It also overcomes the disadvantages of low reaction efficiency and high catalyst cost of existing technologies. Attached Figure Description

[0035] Figure 1 The structurally asymmetric sulfoxide compound prepared in Example 1 1 H NMR spectrum;

[0036] Figure 2 The structurally asymmetric sulfoxide compound prepared in Example 1 13 C NMR spectrum;

[0037] Figure 3 The structurally asymmetric sulfoxide compound prepared in Example 2 1 H NMR spectrum;

[0038] Figure 4 The structurally asymmetric sulfoxide compound prepared in Example 2 13 C NMR spectrum;

[0039] Figure 5The structurally asymmetric sulfoxide compound prepared in Example 3 1 H NMR spectrum;

[0040] Figure 6 The structurally asymmetric sulfoxide compound prepared in Example 3 13 C NMR spectrum;

[0041] Figure 7 The structurally asymmetric sulfoxide compound prepared in Example 4 1 H NMR spectrum;

[0042] Figure 8 The structurally asymmetric sulfoxide compound prepared in Example 4 13 C NMR spectrum;

[0043] Figure 9 The structurally asymmetric sulfoxide compound prepared in Example 5 1 H NMR spectrum;

[0044] Figure 10 The structurally asymmetric sulfoxide compound prepared in Example 5 13 C10 NMR spectrum. Detailed Implementation

[0045] The raw materials used in the following specific examples were all purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0046] Example 1

[0047] A method for synthesizing visible light-promoted structurally asymmetric sulfoxides includes the following steps:

[0048] S1 is added sequentially with disulfide compounds, benzoyl peroxide compounds, catalysts, inorganic bases, and solvents, and then mixed and stirred until homogeneous.

[0049] S2 was placed at room temperature and stirred under LED light source irradiation at a wavelength of 405nm.

[0050] After the reaction of S3 was monitored by thin-layer chromatography, the solvent was removed under reduced pressure. The residue was then separated by column chromatography (petroleum ether / ethyl acetate as eluent, volume ratio (3-7):1; silica gel column) to obtain a yellow solid asymmetric sulfoxide compound. The structural formula is as follows:

[0051] The disulfide compound is toluene disulfide (73.9 mg, 0.3 mmol, 1.0 equiv.);

[0052] The benzoyl peroxide compound is benzoyl peroxide (145.3 mg, 0.6 mmol, 2.0 equiv.);

[0053] The catalyst is 9,10-dibutoxyanthracene (4.8 mg, 5 mmol);

[0054] The inorganic base is sodium carbonate (31.8 mg, 0.3 mmol, 1.0 equiv.).

[0055] The solvent is acetonitrile (3 mL).

[0056] In step S2, the reaction temperature is 25°C and the reaction time is 6 hours.

[0057] Spectral data of the obtained products: 1 H NMR (400MHz, CDCl3) δ = 7.63 (d, J = 7.6Hz, 2H), 7.53 (d, J = 7.7Hz, 2H), 7.48–7.41 (m, 3H), 7.25 (d, J = 7.8Hz, 2H), 2.36 (s, 3H). 13 C NMR (100MHz, CDCl3) δ = 145.81, 142.48, 141.66, 130.88, 130.04, 129.26, 125.01, 124.71, 21.39 (-CH3) (ppm).

[0058] Example 2

[0059] A method for synthesizing asymmetric sulfoxides using visible light-promoted synthesis, with the specific steps identical to those in Example 1, except that the disulfide compound is 1,2-bis(4-bromophenyl)disulfide (112.8 mg, 0.3 mmol, 1.0 equiv.). The product structure is as follows. Spectral data of the obtained products: 1 H NMR (400MHz, CDCl3) δ = 7.63 (d, J = 5.4Hz, 2H), 7.60 (d, J = 7.8Hz, 2H), 7.52 (d, J = 7.6Hz, 2H), 7.47 (m, J = 2.2Hz, 3H). 13 C NMR (100MHz, CDCl3) δ = 144.17, 143.80, 131.52, 130.37, 128.48, 125.23, 124.55, 123.72 (ppm).

[0060] Example 3

[0061] A visible light-promoted synthesis method for asymmetric sulfoxides is provided, with the specific steps identical to those in Example 1, except that the disulfide compound used is 1,2-di(naphthyl)disulfide (95.5 mg, 0.3 mmol, 1.0 equiv.). The reaction time is 8 h. The product structure is as follows. Spectral data of the obtained products: 1 H NMR (400MHz, CDCl3) δ = 8.31 (s, 1H), 7.94 (d, J = 4.6Hz, 1H), 7.85 (t, J = 8.5Hz, 2H), 7. 69(d,J=6.9Hz,2H),7.58–7.55(m,2H),7.50(d,J=8.5Hz,1H),7.44(d,J=6.0Hz,3H). 13 C NMR (100MHz, CDCl3) δ = 145.41, 142.55, 134.40, 132.81, 131.14, 129.73, 129.37, 128.66, 128.04, 127.92, 127.31, 125.35, 125.02, 120.70 (ppm).

[0062] Example 4

[0063] A visible light-promoted synthesis method for asymmetric sulfoxides is provided, with the specific steps identical to those in Example 1, except that the benzoyl peroxide compound is thiophene-2-carboxylic acid peroxyanhydride (152.6 mg, 0.6 mmol, 2.0 equiv.), and the reaction time is 8 h. The product structure is as follows. Spectral data of the obtained products: 1 HNMR (400MHz, CDCl3) δ = 7.58 (t, J = 5.8Hz, 3H), 7.54 (d, J = 3.5Hz, 1H), 7.32 (d, J = 7.8Hz, 2H), 7.06 (t, J = 3.9Hz, 1H), 2.41 (s, 3H). 13 C NMR (100MHz, CDCl3) δ = 147.45, 141.00, 131.06, 130.04, 128.92, 126.22, 123.42, 20.43 (-CH3) (ppm).

[0064] Example 5

[0065] A visible light-promoted synthesis method for asymmetric sulfoxides is provided, with the specific steps identical to those in Example 1, except that the disulfide compound is 1,2-dipentyl disulfide (61.9 mg, 0.3 mmol, 1.0 equiv.), and the benzoyl peroxide compound is thiophene-2-carboxylic acid peroxyanhydride (152.6 mg, 0.6 mmol, 2.0 equiv.). The reaction time is 8 h. The product structure is as follows. Spectral data of the obtained products: 1H NMR (400MHz, CDCl3) δ = 7.62 (d, J = 7.6Hz, 2H), 7.56–7.48 (m, 3H), 2.78 (t, J = 7.6Hz, 2H), 1.80–1.72 (m, 1H), 1.41–1.31 (m, 5H), 0.88 (t, J = 6.9Hz, 3H). 13 C NMR (100MHz, CDCl3) δ = 144.13, 130.89, 129.18, 124.04, 57.38, 30.80, 22.25, 21.88, 13.78 (ppm).

[0066] Performance testing

[0067] 1. Yield: Obtained by directly weighing the product;

[0068] 2. Yield: Yield = [(actual product output) ÷ (m)] 二硫醚类化合物 +m 过氧化苯甲酰类化合物 )]×100%.

[0069] 3. The NMR spectrum of the product is shown in the attached figure. 1 H NMR and 13 CNMR measurements were performed using a Bruker AM-400 instrument. The test temperature was room temperature, and the solvent was deuterated chloroform. (Reference selection follows.) 1 ¹H NMR: CHCl₃ was 7.26 ppm; 13 C10 NMR: CHCl3 was 77.0 ppm. The NMR spectra of Examples 1-5 are shown below. Figure 1-10 .

[0070] The test results for yield and productivity are shown in Table 1.

[0071] Table 1

[0072]

[0073]

Claims

1. A method for synthesizing visible light-promoted structurally asymmetric sulfoxides, characterized in that, Includes the following steps: S1 is added sequentially with disulfide compounds, benzoyl peroxide compounds, catalysts, inorganic bases, and solvents, and then mixed and stirred until homogeneous. S2 was placed at room temperature and stirred under a light source with a wavelength of 400-425 nm for reaction. After the reaction of S3 was monitored by thin-layer chromatography, the solvent was removed under reduced pressure, and the residue was separated by column chromatography to obtain a structurally asymmetric sulfoxide compound. The structural formula of the disulfide compound is as follows: The structural formula of the benzoyl peroxide compound is as follows: In the formula R 1 Selected from C1-C 12 One of alkyl, aryl, and heteroaryl, R 2 Selected from one of aryl or heteroaryl, R 1 and R 2 Different; The catalyst is an anthracene compound, which is selected from 9,10-dimethoxyanthracene; The inorganic base is selected from sodium carbonate.

2. The method for synthesizing visible light-promoted structural asymmetric sulfoxides according to claim 1, characterized in that, The aryl group is a monosubstituted aryl or a polysubstituted aryl group, and the substituent is selected from one of alkyl, alkoxy, alkylamino, halogen, nitro, cyano, and amino groups.

3. The method for synthesizing visible light-promoted structural asymmetric sulfoxides according to claim 1, characterized in that, The solvent is an organic solvent selected from one or a combination of several of dichloromethane, 1,2-dichloroethane, acetonitrile, and N,N-dimethylformamide.

4. The method for synthesizing visible light-promoted structural asymmetric sulfoxides according to claim 1, characterized in that, In step S2, the reaction temperature is 20-30℃ and the reaction time is 6-24h.

5. The method for synthesizing visible light-promoted structural asymmetric sulfoxides according to claim 1, characterized in that, The concentration of the disulfide compounds in the system is 0.05-0.2 mol / L, and the concentration of the benzoyl peroxide compounds in the system is 0.05-0.2 mol / L.

6. The method for synthesizing visible light-promoted structural asymmetric sulfoxides according to claim 1, characterized in that, The mass ratio of the disulfide compound, the benzoyl peroxide compound, the catalyst, and the inorganic base is 1:(1-3):(0.01-0.1):(1-3).

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