Synthesis method and application of visible-light-promoted asymmetric-structure sulfoxide

Abstract

The method 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, placing at room temperature, stirring and reacting under the irradiation of a light source with the wavelength of 400-425nm, and after the completion of the reaction is monitored by thin-layer chromatography, separating and purifying to obtain the sulfoxide with the asymmetric structure. Removing the solvent under reduced pressure, and performing column chromatography separation on residues to obtain the sulfoxide compound with the asymmetric structure. According to the method, various sulfoxide compounds with asymmetric structures can be obtained, the method has the characteristics of simplicity in operation, good substrate applicability, mild conditions and the like, and the defects of low reaction efficiency and high catalyst cost in the prior art are overcome.

Description

Technical Field

[0001] The invention relates to a visible light-promoted synthesis method of asymmetric sulfoxide and application thereof, and relates to C07D, and in particular to the field of heterocyclic compound synthesis. Background Art

[0002] Asymmetric sulfoxides are important compounds in the fields of medicine and pesticides. Traditional methods generally use high temperature conditions for oxidation, or use peroxides or high-valent iodine oxidants, and transition metal catalysts to promote the reaction, but there are many problems, such as high production energy consumption, metal residues in the product, and environmental unfriendliness. Photocatalytic synthesis is an important means in the field of synthetic reactions in recent years. Existing literature discloses the use of highly reactive substrates for photocatalytic synthesis, but the raw materials themselves are unstable and not suitable for industrial production. Therefore, it is crucial to develop a new method for synthesizing asymmetric sulfoxides, so that the reaction conditions are mild, environmentally friendly, and highly selective.

[0003] Chinese invention patent CN201210489246.0 discloses a planar chiral ferrocene compound, a synthesis method and uses, using aminomethyl-substituted ferrocene, substituted aryl boronic acid or heteroaryl boronic acid or aryl vinyl boronic acid or alkyl boronic acid as raw materials, chiral amino acid and palladium as catalysts to synthesize this type of planar chiral ferrocene compound with high efficiency and high corresponding selectivity. However, the catalyst used is a rare metal, the cost is high, and there is metal residue. Chinese invention patent CN109810030A discloses a visible light-promoted preparation method of asymmetric sulfoxide compounds, using aryl diazonium salt and aryl thiophenol as raw materials for photocatalytic reaction to obtain asymmetric sulfoxide, but the reaction activity of aryl diazonium salt and aryl thiophenol substrates is high, inconvenient to use, and not suitable for industrial large-scale production. Summary of the invention

[0004] In order to reduce the energy consumption in the process of synthesizing structural asymmetric sulfoxide compounds and avoid metal residues in the product, the first aspect of the present invention provides a visible light-promoted method for synthesizing structural asymmetric sulfoxides, comprising the following steps:

[0005] S1 adds disulfide compound, benzoyl peroxide compound, catalyst, inorganic base and solvent in sequence, and mixes and stirs evenly;

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

[0007] After the reaction of S3 was completed by monitoring with 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] As a preferred implementation, 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 The structural formula of the benzoyl peroxide compound is Where R 1 Selected from C1-C 12 One of alkyl, aryl and heteroaryl, R 2 is selected from one of an aryl group and a heteroaryl group, R 1 and R 2 Not the same.

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

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

[0012]

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

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

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

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

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

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

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

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

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

[0022] As 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] As 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] As 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] As 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] As 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] As 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] There are many methods for preparing structural asymmetric sulfoxides at present, but there are problems that the generated product structural asymmetric sulfoxides contain impurities or the preparation substrate is unstable, difficult to obtain, and the production cost is high. In the present application, disulfide compounds and benzoyl peroxide compounds with high stability are used as substrates to carry out photocatalytic reactions. The existing synthesis reactions are prepared by using transition metals such as copper, silver, and cobalt as catalysts or by oxidizing sulfides under high temperature conditions. There will be metal residues in the obtained product structural asymmetric sulfoxides, which have potential safety hazards in the application in the medical field. The energy consumption required for reaction production under high temperature conditions is high. In the present application, it is creatively discovered that the use of anthracene catalysts, especially 9,10-dibutoxyanthracene as a catalyst, 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.

[0029] The applicant further discovered that when an anthracene catalyst is used and an inorganic base is added at the same time, the amount of catalyst used can be reduced and the reaction efficiency can be improved. The possible reason is speculated to be: the introduction of the inorganic base makes the reaction environment of the system alkaline. In an alkaline environment, the anthracene catalyst catalyzes the removal of carbon dioxide from the benzoyl peroxide compound, and the disulfide compound reacts with the benzoyl peroxide to obtain an intermediate valence sulfide with high reaction activity, thereby improving the reaction efficiency and reducing the production cost.

[0030] The second aspect of the present invention provides an application of a method for synthesizing a structurally asymmetric sulfoxide promoted by visible light, which is applied to the preparation of a structurally asymmetric sulfoxide.

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

[0032] (1) The visible light-promoted synthesis method of the asymmetric sulfoxide of the present invention uses 9,10-dibutoxyanthracene as a catalyst, which can reduce the activation energy required in the reaction process and reduce energy consumption. At the same time, it avoids the introduction of metal catalysts and metal residues, thereby improving the safety of the product.

[0033] (2) The visible light-promoted method for synthesizing asymmetric sulfoxides of the present invention uses an anthracene catalyst and simultaneously adds an inorganic base. Under the action of visible light, the amount of catalyst used can be reduced and the reaction efficiency can be improved.

[0034] (3) The visible light-promoted synthesis method of asymmetric sulfoxides of the present invention can obtain a variety of asymmetric sulfoxide compounds, and has the characteristics of simple operation, good substrate applicability, mild conditions, etc., and also overcomes the shortcomings of low reaction efficiency and high catalyst cost in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0044] Fig.10 The structurally asymmetric sulfoxide compound prepared in Example 5 13 C NMR spectrum. DETAILED DESCRIPTION

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

[0046] Example 1

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

[0048] S1 adds disulfide compound, benzoyl peroxide compound, catalyst, inorganic base and solvent in sequence, and mixes and stirs evenly;

[0049] S2 was placed at room temperature and stirred for reaction under irradiation with a 405 nm wavelength LED light source;

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

[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 was acetonitrile (3 mL).

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

[0057] The obtained product spectrum data: 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 a structurally asymmetric sulfoxide promoted by visible light, wherein the specific steps are the same as 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 structural formula is The obtained product spectrum data: 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 method for synthesizing asymmetric sulfoxides, the specific steps are the same as those in Example 1, except that the disulfide compound 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 The obtained product spectrum data: 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 method for synthesizing asymmetric sulfoxides, the specific steps are the same as 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 The obtained product spectrum data: 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 method for synthesizing a structurally asymmetric sulfoxide promoted by visible light, wherein the specific steps are the same as 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 The obtained product spectrum data: 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: Weigh the product directly;

[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 was measured using a Bruker-AM-400 instrument. The test temperature was room temperature, the solvent was deuterated chloroform, and the reference was selected: 1 H NMR: CHCl3 7.26 ppm; 13 C NMR: CHCl3 is 77.0ppm. The NMR spectra of Examples 1-5 are shown in Figure 1-10 .

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

[0071] Table 1

[0072]

[0073]

Claims

1. A method for synthesizing a structurally asymmetric sulfoxide promoted by visible light, characterized in that: The following steps are involved: S1 adds disulfide compound, benzoyl peroxide compound, catalyst, inorganic base and solvent in sequence, and mixes and stirs evenly; S2 was placed at room temperature and stirred for reaction under irradiation with a light source having a wavelength of 400-425 nm; After the reaction of S3 was completed by monitoring with 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.

2. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 1, characterized in that: The structural formula of the disulfide compound is The structural formula of the benzoyl peroxide compound is Where R 1 Selected from C1-C 12 One of alkyl, aryl and heteroaryl, R 2 is selected from one of an aryl group and a heteroaryl group, R 1 and R 2 Not the same.

3. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 2, characterized in that: The aryl group is a monosubstituted aryl group or a polysubstituted aryl group, and the aryl group is selected from one of an alkyl group, an alkoxy group, an alkylamino group, a halogen group, a nitro group, a cyano group, and an amine group.

4. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 2, characterized in that: The catalyst is an anthracene compound with the structural formula Where R 3 It is a C1-C6 alkyl group, and the anthracene compound is selected from one or a combination of 9,10-dimethoxyanthracene, 9,10-diethoxyanthracene, 9,10-dipropoxyanthracene, 9,10-diisopropoxyanthracene and 9,10-dibutoxyanthracene.

5. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 2, characterized in that: The inorganic base is selected from one or a combination of sodium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium carbonate, potassium phosphate, and cesium carbonate.

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

7. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 2, characterized in that: In step S2, the reaction temperature is 20-30° C. and the reaction time is 6-24 h.

8. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 2, characterized in that: 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.

9. The method for synthesizing asymmetric sulfoxides promoted by visible light according to claim 2, 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).

10. An application of the method for synthesizing asymmetric sulfoxides promoted by visible light according to any one of claims 1 to 9, characterized in that: Used in the preparation of structurally asymmetric sulfoxides.

Images