An electrochemical method for the preparation of alpha-ketoamide compounds

Abstract

An electrochemical method for preparing alpha-ketoamide compounds, comprising the following steps: in an air atmosphere, a sulfoximine compound and an alpha-keto acid are added into a reactor in a molar ratio of 1:3, an acetonitrile solution is added thereto without electrolyte, the mixture is stirred by a magnetic stirring device to dissolve, two electrodes are inserted, a graphite electrode is used as a positive electrode, a stainless steel electrode is used as a negative electrode, 4mA of current is passed, the current passing time is 6h, after the reaction is completed, the solvent is removed by vacuum distillation to obtain a crude product, and the alpha-ketoamide compound is obtained by column chromatography purification. Compared with the traditional synthesis method, the present application has the advantages of mild reaction condition, smooth operation at room temperature, simple operation, all operations can be carried out in an open system, reaction uses current as an oxidation method, avoids pollution of transition metals or chemical oxidants, raw materials are easy to obtain, functional groups have good compatibility, and the scope of substrate application is wide.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to an electrochemical method for preparing an alpha-ketoamide compound. BACKGROUND

[0002] Alpha-ketoamide compounds have core functional motifs in a variety of biologically active natural products and drugs. Traditional alpha-ketoamides are prepared from amines and alpha-keto acids or acyl halides. Under transition metal catalysis, amines or amides react with benzene acetaldehyde, alkyne, aryl acetaldehyde, methyl ketone, alpha-oxycarboxylic acid, 1-aryl ethanol and phenylacetic acid to obtain alpha-ketoamides. Equivalent chemical oxidants are used to promote the reaction. In recent years, electrochemical synthesis has attracted more and more attention because it avoids the use of catalysts and external oxidants, and meets the requirements of green and sustainable chemistry. SUMMARY

[0003] In view of the above problems, the application provides an electrochemical method for preparing alpha-ketoamides, which has the advantages of mild reaction conditions, smooth reaction at room temperature, simple operation, all operations can be carried out in an open system, use of electric current as an oxidation method to avoid the use of chemical oxidants, easy-to-obtain raw materials, high reaction yield, good functional group compatibility, and wide substrate application range.

[0004] To achieve the above object, the application provides the following technical scheme: an electrochemical method for preparing alpha-ketoamides, which comprises the following steps:

[0005] In an air atmosphere, the sulfoximine compound and the alpha-keto acid are added to a reactor in a molar ratio of 1:3, acetonitrile is added to the reactor without electrolyte, the mixture is stirred by a magnetic stirring device to dissolve, two electrodes are inserted, a graphite electrode is used as the anode, a stainless steel (iron sheet) electrode is used as the cathode, 4mA of electricity is passed, the electricity passing time is 6h, after the reaction is completed, the solvent is removed by reduced pressure evaporation to obtain a crude product, and column chromatography is used to purify to obtain the alpha-ketoamide compound.

[0006] In the step, the reactor is a diaphragmless electrolytic cell, and the alpha-ketoamide compound is prepared by an electrochemical reaction, and the preparation method has the following reaction formula:

[0007]

[0008] In the formula, R 1 = phenyl, various substituted phenyl groups and alkyl groups; R 2 = phenyl, various substituted phenyl groups, various substituted aromatic heterocyclic compounds; the solvent is acetonitrile.

[0009] Preferably, the anode electrode sheet is a carbon rod electrode, and the cathode electrode sheet is a stainless steel (iron sheet) electrode.

[0010] Preferably, in the step, the reaction is carried out under open condition and at room temperature, and a direct current stabilized power supply of 30V / 3A is used as the power supply, and the current is 4mA.

[0011] Preferably, the solvent is acetonitrile solvent.

[0012] Preferably, in the step, the eluent used for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 2:1.

[0013] The present application has the following beneficial effects:

[0014] 1. The present application uses cheap and easily available sulfoximine and α-keto acid as raw materials, and the sulfoximine is prepared from the corresponding thioether, and the α-keto acid can be prepared from the corresponding phenylacetone.

[0015] 2. The present application can be operated under air condition, and is not sensitive to water and oxygen, and the reaction condition is relatively mild and the operation is simple.

[0016] 3. The present application uses current as oxidant, which is low in cost and avoids the pollution of traditional transition metal catalyst or equivalent chemical oxidant.

[0017] 4. The present application can obtain the target product in one step, has high yield, good functional group compatibility, simple post-treatment and good application potential. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The hydrogen spectrum of the product obtained in Example 1 of the present application is shown in the figure;

[0019] Figure 2 The carbon spectrum of the product obtained in Example 1 of the present application is shown in the figure;

[0020] Figure 3 The hydrogen spectrum of the product obtained in Example 2 of the present application is shown in the figure;

[0021] Figure 4 The carbon spectrum of the product obtained in Example 2 of the present application is shown in the figure;

[0022] Figure 5 The hydrogen spectrum of the product obtained in Example 3 of the present application is shown in the figure;

[0023] Figure 6 The carbon spectrum of the product obtained in Example 3 of the present application is shown in the figure;

[0024] Figure 7 The hydrogen spectrum of the product obtained in Example 4 of the present application is shown in the figure;

[0025] Figure 8 The carbon spectrum of the product obtained in Example 4 of the present application is shown in the figure;

[0026] Figure 9 H NMR of the product obtained in Example 5;

[0027] Figure 10 C NMR of the product obtained in Example 5; DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings, so that the persons skilled in the art can better understand the advantages and features of the present application, and the protection scope of the present application can be defined more clearly. The embodiments described in the present application are only some of the embodiments of the present application, but not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by the persons skilled in the art without creative labor shall fall within the protection scope of the present application.

[0029] Example 1:

[0030] A carbon rod electrode (electrode size: diameter Φ 6 mm) was assembled as an anode and a stainless steel sheet (size: 10 mm x 10 mm x 0.1 mm) was assembled as a cathode in a 10 mL electrolytic cell without a diaphragm, and then p-methylsulfoximine (33.8 mg, 0.20 mmol), benzoylformic acid (90.0 mg, 0.6 mmol), and acetonitrile 5 mL were added, and the reaction was stirred at room temperature at a constant current of 4 mA for 6 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 57.8 mg of the target product, with a yield of 96%. The structural formula of the obtained product is as follows:

[0031]

[0032] The structural characterization data of the obtained product are as follows:

[0033] 1 H NMR (500 MHz, Chloroform-d) δ 8.10-8.01 (m, 2H), 7.95 (dd, J = 8.4, 2.1 Hz, 2H), 7.60 (td, J = 6.6, 5.7, 3.6 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.45-7.39 (m, 2H), 3.47 (s, 3H), 2.47 (s, 3H); 13 C NMR (125 MHz, Chloroform-d) δ 190.3, 173.3, 145.8, 134.5, 134.2, 132.8, 130.6, 130.2, 128.7, 127.2, 45.0, 21.7.

[0034] Example 2:

[0035] A carbon rod electrode (electrode size: diameter Φ 6 mm) was assembled as an anode, and a stainless steel sheet (size: 10 mm x 10 mm x 0.1 mm) was assembled as a cathode in a 10 mL cell without a separator, and then 2- thiophenesulfoximine (32.2 mg, 0.20 mmol), benzoylformic acid (90.0 mg, 0.6 mmol), and acetonitrile 5 mL were added, and the reaction was stirred at room temperature for 6 hours at a constant current of 4 mA. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a crude product, and 46.3 mg of the target product was obtained by column chromatography purification with a yield of 79%. The structural formula of the obtained product is as follows:

[0036]

[0037] The structural characterization data of the obtained product are as follows:

[0038] 1 H NMR (500 MHz, Chloroform-d) δ 8.09-7.98 (m, 4H), 7.68-7.57 (m, 3H), 7.49 (t, J = 7.7 Hz, 2H), 3.50 (s, 3H); 13 C NMR (125 MHz, Chloroform-d) δ 190.0, 173.2, 141.4, 136.1, 134.4, 133.8, 132.6, 130.3, 130.2, 128.7, 44.9.

[0039] Example 3:

[0040] A carbon rod electrode (electrode size: diameter Φ 6 mm) was assembled as an anode, and a stainless steel sheet (size: 10 mm x 10 mm x 0.1 mm) was assembled as a cathode in a 10 mL cell without a separator, and then 2- thiophenesulfoximine (32.2 mg, 0.20 mmol), benzoylformic acid (90.0 mg, 0.6 mmol), and acetonitrile 5 mL were added, and the reaction was stirred at room temperature for 6 hours at a constant current of 4 mA. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a crude product, and 46.3 mg of the target product was obtained by column chromatography purification with a yield of 79%. The structural formula of the obtained product is as follows:

[0041]

[0042] The structural characterization data of the obtained product are as follows:

[0043] 1H NMR (500 MHz, Chloroform-d) δ 8.31 (dt, J = 3.6, 1.8 Hz, 1H), 8.10 - 7.96 (m, 2H), 7.61 (td, J = 7.3, 3.7 Hz, 1H), 7.57 (dt, J = 5.5, 2.8 Hz, 1H), 7.54 - 7.50 (m, 1H), 7.48 (td, J = 7.8, 2.0 Hz, 2H), 3.55 (d, J = 2.3 Hz, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 190.2, 173.2, 136.8, 134.3, 133.3, 132.7, 130.2, 129.6, 128.7, 125.1, 45.1.

[0044] Example 4:

[0045] A 10 mL cell with no diaphragm was assembled with a carbon rod electrode (electrode size: diameter Φ 6 mm) as an anode, a stainless steel sheet (size: 10 mm x 10 mm x 0.1 mm) as a cathode, and then 2,2,6,6-tetramethylpiperidine (31.0 mg, 0.20 mmol), p-tolylglyoxylic acid (98.4 mg, 0.6 mmol), and acetonitrile 5 mL were added, and the reaction was stirred at room temperature for 6 hours at a constant current of 4 mA. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 43.9 mg of the target product at a yield of 73%. The structural formula of the obtained product is as follows:

[0046]

[0047] The structural characterization data of the obtained product are as follows:

[0048] 1 H NMR (500 MHz, Chloroform-d) δ 8.09 (dd, J = 7.3, 2.2 Hz, 2H), 7.99 - 7.93 (m, 2H), 7.77 - 7.69 (m, 1H), 7.68 - 7.61 (m, 2H), 7.28 (dd, J = 8.3, 2.8 Hz, 2H), 3.49 (s, 3H), 2.43 (s, 3H); 13 C NMR (125 MHz, Chloroform-d) δ 189.9, 173.5, 145.4, 137.7, 134.5, 130.4, 130.2, 129.9, 129.4, 127.2, 44.8, 21.9.

[0049] Example 5:

[0050] A carbon rod electrode (electrode size: diameter Φ 6 mm) was installed as an anode and a stainless steel sheet (size: 10 mm x 10 mm x 0.1 mm) was installed as a cathode in a 10 mL electrolysis cell without a separator, and then sulfoximine (31.0 mg, 0.20 mmol), m-methoxybenzoylformic acid (108 mg, 0.6 mmol), and acetonitrile 5 mL were added, and the reaction was stirred at room temperature for 6 hours at a constant current of 4 mA. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude product, and column chromatography was performed to purify the crude product to obtain 39.3 mg of the target product at a yield of 62%. The structural formula of the obtained product is as follows:

[0051]

[0052] The structural characterization data of the obtained product are as follows:

[0053] 1 H NMR (500 MHz, Chloroform-d) δ 8.12-8.02 (m, 2H), 7.78-7.71 (m, 1H), 7.69-7.60 (m, 3H), 7.59-7.54 (m, 1H), 7.39 (td, J = 8.0, 2.3 Hz, 1H), 7.22-7.13 (m, 1H), 3.85 (s, 3H), 3.50 (s, 3H); 13 C NMR (125 MHz, Chloroform-d) δ 190.0, 173.3, 159.8, 137.6, 134.5, 134.0, 130.0, 129.7, 127.2, 123.4, 121.4, 113.2, 55.5, 44.8.

Claims

1. An electrochemical method for preparing α-ketoamide compounds, characterized in that: The preparation method includes the following steps: In an air atmosphere, sulfoxide imine compounds and α-keto acids are added to a reactor at a molar ratio of 1:

3. Acetonitrile solution is then added without the need for electrolytes. The mixture is stirred with a magnetic stirrer to dissolve it. Two electrodes are inserted, with a carbon rod electrode as the anode and an iron sheet electrode as the cathode. The reaction is carried out under open conditions and at room temperature. The power supply used for the reaction is a 30V / 3A DC regulated power supply with a current of 4 mA and an energizing time of 6 h. After the reaction is completed, the solvent is removed by vacuum distillation to obtain the crude product, which is then purified by column chromatography to obtain the α-ketoamide compound. In the aforementioned steps, the reactor is a diaphragm-free electrolytic cell, and the α-ketoamide compound is prepared through an electrochemical reaction. The reaction equation is as follows: , In the formula R 1 =Phenyl, substituted phenyl and alkyl groups; R 2 =Phenyl, substituted phenyl, substituted aromatic heterocyclic compounds; the solvent is acetonitrile.

2. The electrochemical method for preparing α-ketoamide compounds according to claim 1, characterized in that: In the steps described above, the eluent used for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 2:1.

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