An electrochemical method for the preparation of N-alkyl amides

Abstract

An electrochemical method for preparing N-alkyl amide, comprising the following steps: in an air atmosphere, a fatty amine compound and an alpha-keto acid are added into a reactor in a molar ratio of 1:1.2, an electrolyte tetrabutylammonium fluoride is added, and a mixed solution of dichloromethane and tetrahydrofuran in a ratio of 4:1 is added; the mixture is stirred by a magnetic stirring device to be dissolved, two electrodes are inserted, a graphite electrode is used as a positive electrode, a platinum sheet electrode is used as a negative electrode, 8mA of current is passed, the current passing time is 2h, after the reaction is completed, the solvent is removed by vacuum distillation to obtain a crude product, and the N-alkyl amide compound is obtained by column chromatography purification. Compared with the traditional synthesis method, the method has the advantages that the reaction condition is mild, the reaction can be smoothly carried out at room temperature, the operation is simple, all operations can be carried out in an open system, the current is used as an oxidation method, pollution of transition metals or chemical oxidants is avoided, raw materials are easy to obtain, functional group compatibility is good, and the scope of application of substrates is wide.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an electrochemical method for preparing N-alkylamides. Background Technology

[0002] Amide structures are among the most fundamental chemical building blocks found in nature. They form the backbone of biologically essential proteins and are present in a large number of synthetic structures (Science 2020, 367, 281-285). Due to the rapidly increasing interest in polypeptides, important amide-containing biopolymers in biological organisms, efficient methods for constructing amide bonds have been extensively studied and represent one of the most fundamental and important transformations in organic synthesis. Therefore, the synthesis of N-alkylamide compounds has significant application and research value.

[0003] Currently reported methods for synthesizing amide compounds mainly involve dehydration condensation reactions based on carboxylic acids and amines, using saturated amounts of chemical oxidants or condensing agents to promote the reaction. In recent years, electrochemical synthesis has received increasing attention due to its avoidance of catalysts and external oxidants, aligning with the requirements of green and sustainable chemistry. Summary of the Invention

[0004] To address the above problems, this invention provides an electrochemical method for preparing N-alkylamides, which has the advantages of mild reaction conditions that can be carried out smoothly at room temperature; simple operation that can be performed in an open system; the use of electric current as an oxidation method to avoid the use of transition metals and chemical oxidants; readily available raw materials; high reaction yield; good functional group compatibility; and a wide range of applicable substrates.

[0005] To achieve the above objectives, the present invention provides the following technical solution: an electrochemical method for preparing N-alkyl sulfoxide imide, the preparation method comprising the following steps:

[0006] In an air atmosphere, aliphatic amine compounds and α-keto acids were added to a reactor at a molar ratio of 1:1.2. Tetrabutylammonium fluoride electrolyte was added, followed by a 4:1 mixture of dichloromethane and tetrahydrofuran. The mixture was stirred with a magnetic stirrer until dissolved. Two electrodes were inserted, with a graphite electrode as the positive electrode and a platinum electrode as the negative electrode. An 8 mA current was applied for 2 hours. After the reaction was completed, the solvent was removed by vacuum distillation to obtain a crude product, which was then purified by column chromatography to obtain an N-alkylamide compound.

[0007] In the aforementioned steps, the reactor is a diaphragm-free electrolytic cell, and N-alkylamide compounds are prepared through an electrochemical reaction. The preparation method and reaction formula are as follows:

[0008]

[0009] In the formula R 1 =Benzyl, various substituted alkyl groups; R 2 =Phenyl, substituted phenyl, substituted aromatic heterocyclic compounds; the electrolyte is tetrabutylammonium fluoride.

[0010] Preferably, the anode electrode is a carbon rod electrode and the cathode electrode is a platinum sheet electrode.

[0011] Preferably, the electrolyte is tetrabutylammonium fluoride with a concentration of 0.05 mol / L.

[0012] Preferably, in the above steps, the reaction is carried out under open conditions and at room temperature, and the power supply used for the reaction is a 30V / 3A DC regulated power supply with a current of 8mA.

[0013] Preferably, the solvent is a mixture of dichloromethane and tetrahydrofuran, wherein the ratio of dichloromethane to tetrahydrofuran is 4:1.

[0014] Preferably, in the above steps, 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 3:1.

[0015] Beneficial effects of this invention:

[0016] 1. This invention uses inexpensive and readily available α-keto acids and fatty amines as raw materials. α-keto acids can be prepared from the corresponding acetophenones, and fatty amines can be obtained through commercial channels.

[0017] 2. This invention can be operated under air conditions, is not sensitive to water and oxygen, has relatively mild reaction conditions, and is simple to operate.

[0018] 3. This invention uses electric current as an oxidant, which is inexpensive and avoids the pollution caused by traditional transition metal catalysts or equivalent chemical oxidants.

[0019] 4. This invention can obtain the target product in just one step, with a high yield, good functional group compatibility, simple post-processing, and good application potential. Attached Figure Description

[0020] Figure 1 The hydrogen spectrum of the product obtained in Example 1 of this invention;

[0021] Figure 2 The carbon spectrum of the product obtained in Example 1 of this invention;

[0022] Figure 3 The hydrogen spectrum of the product obtained in Example 2 of this invention;

[0023] Figure 4 The carbon spectrum of the product obtained in Example 2 of this invention;

[0024] Figure 5 The hydrogen spectrum of the product obtained in Example 3 of this invention;

[0025] Figure 6 The carbon spectrum of the product obtained in Example 3 of this invention;

[0026] Figure 7 The hydrogen spectrum of the product obtained in Example 4 of this invention;

[0027] Figure 8 The carbon spectrum of the product obtained in Example 4 of this invention;

[0028] Figure 9 The hydrogen spectrum of the product obtained in Example 5 of this invention;

[0029] Figure 10 The carbon spectrum of the product obtained in Example 5 of this invention; Detailed Implementation

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings, so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the scope of protection of the present invention. The embodiments described in this invention are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0031] Example 1:

[0032] A carbon rod electrode (6 mm in diameter) was assembled as the anode in a 10 mL diaphragm-free electrolyzer, and a platinum sheet (10 mm × 10 mm × 0.1 mm) was used as the cathode. Benzylamine (21.4 mg, 0.20 mmol), benzoylformic acid (36.0 mg, 0.24 mmol), tetrabutylammonium fluoride electrolyte (0.25 mmol), 4 mL of dichloromethane, and 1 mL of tetrahydrofuran were then added. The reaction was carried out at a constant current of 8 mA with stirring at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 35.9 mg of the target product, with a yield of 85%. The structural formula of the obtained product is as follows:

[0033]

[0034] The structural characterization data of the obtained product are shown below:

[0035] 1H NMR(500MHz,Chloroform-d)δ7.82(d,J=7.8Hz,2H),7.51(t,J=7.4 Hz,1H),7.43(t,J=7.6Hz,2H),7.39-7.29(m,5H),6.66(s,1H),4.65(d,J=5.7Hz, 2H). 13 C NMR (125MHz, Chloroform-d) δ167.5,138.2,134.4,131.6,128.8,128.6, 127.9,127.6,127.0,44.1.

[0036] Example 2:

[0037] A carbon rod electrode (6 mm in diameter) was assembled as the anode in a 10 mL diaphragm-free electrolyzer, and a platinum sheet (10 mm × 10 mm × 0.1 mm) was used as the cathode. Then, n-butylamine (14.6 mg, 0.20 mmol), benzoylformic acid (36.0 mg, 0.24 mmol), tetrabutylammonium fluoride electrolyte (0.25 mmol), 4 mL of dichloromethane, and 1 mL of tetrahydrofuran were added. The reaction was carried out at a constant current of 8 mA with stirring at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 26.2 mg of the target product, with a yield of 74%. The structural formula of the obtained product is as follows:

[0038]

[0039] The structural characterization data of the obtained product are shown below:

[0040] 1 H NMR(500MHz,Chloroform-d)δ7.78(d,J=7.6Hz,2H),7.46(t,J=7.3 Hz,1H),7.39(t,J=7.6Hz,2H),6.60(s,1H),3.42(q,J=6.7Hz,2H),1.58(p,J=7.3Hz,2H),1.38(tt,J=11.0,5.5Hz,2H),0.94(t,J=7.4Hz,3H). 13 C NMR (125 MHz, Chloroform-d) δ167.7,134.9,131.2,128.5,126.9,39.8,31.7,20.2,13.8.

[0041] Example 3:

[0042] A carbon rod electrode (6 mm in diameter) was assembled as the anode in a 10 mL diaphragm-free electrolyzer, and a platinum sheet (10 mm × 10 mm × 0.1 mm) was used as the cathode. Then, 2-thiophene methylamine (22.6 mg, 0.20 mmol), benzoylformic acid (36.0 mg, 0.24 mmol), tetrabutylammonium fluoride electrolyte (0.25 mmol), 4 mL of dichloromethane, and 1 mL of tetrahydrofuran were added. The reaction was carried out at a constant current of 8 mA with stirring at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 28.2 mg of the target product, with a yield of 65%. The structural formula of the obtained product is as follows:

[0043]

[0044] The structural characterization data of the obtained product are shown below:

[0045] 1 H NMR(500MHz,Chloroform-d)δ7.80(d,J=7.6Hz,2H),7.51(t,J=7.5 Hz,1H),7.42(t,J=7.6Hz,2H),7.25(d,J=5.1Hz,1H),7.08-6.90(m,2H),6.80(s,1H),4.80(d,J=5.6Hz,2H). 13 C NMR (125MHz, Chloroform-d) δ167.3,140.9, 134.2,131.6,128.6,127.1,127.0,126.2,125.3,38.8.

[0046] Example 4:

[0047] A carbon rod electrode (6 mm in diameter) was assembled as the anode in a 10 mL diaphragm-free electrolyzer, and a platinum sheet (10 mm × 10 mm × 0.1 mm) was used as the cathode. Benzylamine (21.4 mg, 0.20 mmol), p-bromobenzoylformic acid (55.0 mg, 0.24 mmol), tetrabutylammonium fluoride electrolyte (0.25 mmol), 4 mL of dichloromethane, and 1 mL of tetrahydrofuran were then added. The reaction was carried out at a constant current of 8 mA with stirring at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography to give 31.2 mg of the target product, with a yield of 74%. The structural formula of the obtained product is as follows:

[0048]

[0049] The structural characterization data of the obtained product are shown below:

[0050] 1H NMR(500MHz,Chloroform-d)δ7.72-7.63(m,2H),7.55(dd,J=8.6,2.1 Hz,2H),7.41-7.29(m,5H),6.63(s,1H),4.62(d,J=5.7Hz,2H). 13 C NMR (125 MHz, Chloroform-d) δ166.5,138.0,133.2,131.8,128.8,128.6,127.9,127.7,126.3,44.2.

[0051] Example 5:

[0052] A carbon rod electrode (6 mm in diameter) was assembled as the anode in a 10 mL diaphragm-free electrolyzer, and a platinum sheet (10 mm × 10 mm × 0.1 mm) was used as the cathode. Benzylamine (21.4 mg, 0.20 mmol), p-cyanobenzoylformic acid (42.0 mg, 0.24 mmol), tetrabutylammonium fluoride electrolyte (0.25 mmol), 4 mL of dichloromethane, and 1 mL of tetrahydrofuran were then added. The reaction was carried out at a constant current of 8 mA with stirring at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain 25.5 mg of the target product, with a yield of 54%. The structural formula of the obtained product is as follows:

[0053]

[0054] The structural characterization data of the obtained product are shown below:

[0055] 1 H NMR (500MHz, Chloroform-d) δ7.91 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 7.9 Hz, 2H), 7.37 (hept, J = 7.3 Hz, 5H), 6.51 (s, 1H), 4.67 (d, J = 5.6 Hz, 2H). 13 C NMR (125MHz, Chloroform-d) δ165.6,138.3,137.5,132.5,129.0,128.0,128.0,127.7,118.0,115.2,44.5.

Claims

1. An electrochemical method for preparing N-alkylamides, characterized in that: The preparation method includes the following steps: In an air atmosphere, aliphatic amine compounds and α-keto acids are added to a reactor at a molar ratio of 1:1.2, and the electrolyte tetrabutylammonium fluoride is added. Then, a mixed solution of dichloromethane and tetrahydrofuran at a ratio of 4:1 is added. The mixture is stirred with a magnetic stirrer to dissolve it. Two electrodes are inserted, with a graphite electrode as the positive electrode and a platinum sheet electrode as the negative electrode. An energizer of 8 mA is applied for 2 hours. 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 N-alkylamide compound. In the aforementioned steps, the reactor is a diaphragm-free electrolytic cell, and N-alkylamide compounds are prepared through an electrochemical reaction. The reaction equation is as follows: In the formula R 1 =Benzyl, various substituted alkyl groups; R 2 =Phenyl, substituted phenyl, substituted aromatic heterocyclic compounds; the electrolyte is tetrabutylammonium fluoride.

2. The electrochemical method for preparing N-alkylamides according to claim 1, characterized in that: The anode electrode is a carbon rod electrode, and the cathode electrode is a platinum sheet electrode.

3. The electrochemical method for preparing N-alkylamides according to claim 1, characterized in that: The electrolyte is tetrabutylammonium fluoride with a concentration of 0.05 mol / L.

4. The electrochemical method for preparing N-alkylamides according to claim 1, characterized in that: In the aforementioned steps, 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 8mA.

5. The electrochemical method for preparing N-alkylamides according to claim 1, characterized in that: The solvent is a mixture of dichloromethane and tetrahydrofuran, with a dichloromethane to tetrahydrofuran ratio of 4:

1.

6. The electrochemical method for preparing N-alkylamides according to claim 1, characterized in that: In the aforementioned steps, 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 3:1.

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