Method for electrochemical synthesis of gramine derivatives

Abstract

The present invention relates to the technical field of organic compound preparation, and more specifically to a method for preparing gramine derivatives in one step by reacting indole-3-acetic acid derivatives with N,N-dimethylformamide under electrochemical conditions. Compared with the prior art, the present invention is the first to achieve a free radical-radical coupling reaction based on the decarboxylation of indole-3-acetic acid derivatives and the decarbonylation of N,N-dimethylformamide under mild electrochemical reaction conditions without transition metals or oxidants. The reaction raw materials are inexpensive and readily available, stable, and safe. The reaction does not require the consumption of organometallic reagents or the use of transition metals. KI is used as an additive, eliminating the need for the use of dangerous peroxides. The method is air-compatible and has the advantages of a one-step reaction, low cost, and simple operation. The method has good application prospects in the field of synthesizing gramine derivatives.

Description

Technical Field

[0001] The present invention relates to the technical field of compound preparation, and in particular to a method for preparing gramine derivatives in one step by reacting indole-3-acetic acid derivatives with N,N-dimethylformamide under electrochemical conditions. Background Art

[0002] Graminine is a natural alkaloid containing an indole skeleton and exhibits extremely high biological activity. Graminine is widely distributed in nature and has growth-inhibiting effects on plants, insects, and microorganisms. Graminine's diverse bioactivities are being exploited to develop biopesticides with diverse bioactivities and applications. Its insect repellent properties have led to the development of related pesticides for use as crop insecticides. Graminine and its derivatives offer promising biopesticide development prospects due to their high efficiency, low toxicity, resistance, and low residue. Graminine compounds are widely found in bioactive molecules such as pharmaceuticals and natural products, and are used in the synthesis of tryptophan and as intermediates in organic synthesis. Graminine compounds also possess anti-mutagenic properties and are used in the treatment of cancer and Alzheimer's disease.

[0003] Currently, the preparation methods of gramine derivatives include: (1) using indole, dimethylamine and formaldehyde as raw materials to prepare gramine and its derivatives through the classic Mannich reaction under the catalysis of glacial acetic acid. This preparation method generally has the disadvantage of requiring a large amount of solvent and has relatively high requirements for substrate substituents; (2) using Lewis acid zinc chloride as a catalyst to efficiently synthesize gramine and its derivatives in anhydrous ethanol solvent. The addition of zinc chloride in this method brings great difficulties to the development of green processes; (3) synthesizing gramine-containing compounds in a one-pot method by adding one equivalent of ethylene glycol without using a catalyst. This method has the disadvantage of requiring the addition of solvent ethylene glycol, resulting in high production costs and environmental pollution.

[0004] Therefore, developing a method for synthesizing gramine derivatives in one pot using safe, stable, inexpensive and readily available chemical reagents as raw materials, without transition metals or other catalysts, without oxidants, and under mild and simple reaction conditions, has important theoretical significance and application value. Summary of the Invention

[0005] In order to overcome the above technical defects, the present invention provides a method for electrochemically synthesizing gramine derivatives, which, under mild conditions, electrocatalyzes the free radical coupling reaction of the decarboxylation of indole-3-acetic acid derivatives and the decarbonylation of DMF to synthesize gramine derivatives in one step, solving the problems that the reaction usually requires the use of pre-prepared raw materials, the reaction steps are cumbersome, or the use of transition metal catalysts, the by-products have a large impact on the environment, and the substrate applicability is poor. In order to achieve the above purpose, the present invention provides a method for electrochemically synthesizing gramine derivatives, under the condition of power supply, the indole-3-acetic acid derivative shown in Formula 1 undergoes a free radical coupling reaction with N,N-dimethylformamide to prepare the gramine derivative shown in Formula 2 in one step;

[0006]

[0007] Among them, R 1 Selected from hydrogen, alkyl, alkoxy, halogen.

[0008] Furthermore, the indole-3-acetic acid derivative described in Formula 1 is indole-3-acetic acid, 5-methylindole-3-acetic acid, 7-methylindole-3-acetic acid, 5-methoxyindole-3-acetic acid, 5-fluoroindole-3-acetic acid, 5-chloroindole-3-acetic acid, 5-bromoindole-3-acetic acid, 6-fluoroindole-3-acetic acid, 6-chloroindole-3-acetic acid, 6-bromoindole-3-acetic acid, 4-chloroindole-3-acetic acid, and 4-bromoindole-3-acetic acid.

[0009] Furthermore, the free radical coupling reaction conditions are as follows: dissolving the indole-3-acetic acid derivative shown in Formula 1, a catalyst and an alkaline substance in N,N-dimethylformamide, electrolyzing at a rated current of 4 to 15 mA, and stirring the reaction; the resulting mixture is post-treated to obtain the product.

[0010] Furthermore, the molar volume ratio of the indole-3-acetic acid derivative and the N,N-dimethylformamide is (0.1-0.5):2 mmol / ml, or (0.1-0.4):2 mmol / ml; or (0.1-0.3):2 mmol / ml; or 0.2:2 mmol / ml.

[0011] Furthermore, the molar volume ratio of the catalyst to the N,N-dimethylformamide is (0.1-0.5):2 mmol / ml, or (0.1-0.4):2 mmol / ml; or (0.1-0.3):2 mmol / ml; or 0.2:2 mmol / ml.

[0012] Furthermore, the molar volume ratio of the alkaline substance to the N,N-dimethylformamide is (0.1-0.5):2 mmol / ml, or (0.2-0.5):2 mmol / ml; or (0.3-0.5):2 mmol / ml; or 0.4:2 mmol / ml.

[0013] Furthermore, the alkaline substance is selected from at least one of sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate, lithium carbonate, ammonium carbonate, potassium bicarbonate, and potassium acetate; preferably potassium carbonate or sodium bicarbonate; most preferably potassium carbonate.

[0014] Furthermore, the additive is selected from at least one of potassium iodide, sodium iodide, tetramethylammonium iodide, tetrabutylammonium iodide, ammonium iodide, potassium bromide, and potassium chloride; preferably sodium iodide or potassium iodide; and most preferably potassium iodide.

[0015] Furthermore, the reaction temperature is 10-40°C, or 10-30°C, or 20-40°C, or 25-35°C, or 20-30°C; the reaction time is 1-5h, or 1.5-4h, or 2-4h, or 2-3.5h, or 2.5-3h.

[0016] Furthermore, the electrochemical electrodes include electrodes comprising one or a combination of two of nickel, copper, gold, zinc, platinum, and graphite carbon; preferably, a graphite carbon electrode is used as the anode and a platinum electrode is used as the cathode, or a platinum electrode is used as the anode and a platinum electrode is used as the cathode; most preferably, a platinum electrode is used as the anode and a platinum electrode is used as the cathode.

[0017] Beneficial effects: Compared with the prior art, the present invention realizes for the first time a free radical-free radical coupling reaction based on the decarboxylation of indole-3-acetic acid derivatives and the decarbonylation of N,N-dimethylformamide under mild electroreaction conditions without transition metals and oxidants. The reaction raw materials are cheap and easily available, stable and safe, and the reaction does not require the consumption of organic metal reagents or the use of transition metals. KI is used as an additive, and no dangerous peroxides are required. The invention is compatible with air and has the advantages of one-step reaction, low cost, simple operation, etc., and has good application prospects in the field of synthesis of gramine derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is a reaction scheme of the gramine derivatives of the present invention;

[0019] Figure 2 The product obtained in Example 1 1 H NMR spectra;

[0020] Figure 3 The product obtained in Example 1 13 C NMR spectrum;

[0021] Figure 4 The product obtained in Example 2 1 H NMR spectra;

[0022] Figure 5 The product obtained in Example 2 13 C NMR spectrum. DETAILED DESCRIPTION

[0023] In order to make those skilled in the art better understand the technical scheme of the present invention, the present invention is described in detail below in conjunction with specific embodiments. The experimental methods for which specific conditions are not specified in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. The test materials used in the following examples, unless otherwise specified, are purchased from conventional biochemical reagent stores. Unless otherwise specified, percentages and parts are calculated by weight. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar to or equivalent to the described content can be applied to the present invention. The preferred implementation methods and materials described in the text are only for demonstration purposes.

[0024] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0025] Currently, the reaction pathway of gramine derivatives is as follows:

[0026]

[0027] The above two reaction pathways require the participation of transition metals, the use of dangerous oxidants, unstable reaction reagents, large catalyst dosage, expensive reagents, high method costs, many reaction steps, and harsh reaction conditions.

[0028] Based on a large number of experimental summaries and reference to previous literature reports, the present invention proposes the following reaction mechanism: indole-3-acetic acid generates a carboxyl anion under the action of a base, and the iodine anion loses an electron at the anode to generate an iodine free radical, and then the iodine free radical and the carboxyl anion undergo a single electron transfer to generate a carboxyl free radical intermediate, which is further de-CO2ed to generate a carbon free radical intermediate. At the same time, the iodine anion loses electrons at the anode to generate an iodine free radical, which then reacts with DMF through a hydrogen atom transfer (HAT) to generate a dimethylaminoformyl free radical intermediate. Subsequently, the free radical intermediate undergoes decarbonylation to form a dimethylamino free radical; finally, the carbon free radical and the dimethylamino free radical cross-couple to generate the target product rutin (see Figure 1 ).

[0029] In some specific embodiments, a method for synthesizing gramine derivatives by electrocatalytic free radical coupling reaction of indole-3-acetic acid decarboxylation and DMF decarbonylation under mild conditions is provided, namely, at room temperature, an indole-3-acetic acid derivative shown in Formula 1 is reacted with N,N-dimethylformamide in a one-pot reaction under electric conditions to obtain a gramine derivative shown in Formula 2;

[0030]

[0031] Among them, R 1 Selected from hydrogen, alkyl, alkoxy, halogen.

[0032] In some specific embodiments, the indole-3-acetic acid described in Formula 1 is indole-3-acetic acid, 5-methylindole-3-acetic acid, 7-methylindole-3-acetic acid, 5-methoxyindole-3-acetic acid, 5-fluoroindole-3-acetic acid, 5-chloroindole-3-acetic acid, 5-bromoindole-3-acetic acid, 6-fluoroindole-3-acetic acid, 6-chloroindole-3-acetic acid, 6-bromoindole-3-acetic acid, 4-chloroindole-3-acetic acid, or 4-bromoindole-3-acetic acid.

[0033] In some examples of this embodiment, the indole-3-acetic acid described in Formula 1 and N,N-dimethylformamide are reacted by free radical coupling to synthesize the gramine derivative, and the gramine derivative is 1-(1H-indol-3-yl)-N,N-dimethylmethanamine, N,N-dimethyl-1-(5-methyl-1H-indol-3-yl)methanamine, N,N-dimethyl-1-(7-methyl-1H-indol-3-yl)methanamine, 1-(5-methoxy-1H-indol-3-yl)-N,N-dimethylmethanamine, 1-(5-fluoro-1H-indol-3-yl)-N,N-dimethyl Methylamine, 1-(5-chloro-1H-indol-3-yl)-N,N-dimethylmethylamine, 1-(5-bromo-1H-indol-3-yl)-N,N-dimethylmethylamine, 1-(6-fluoro-1H-indol-3-yl)-N,N-dimethylmethylamine, 1-(6-chloro-1H-indol-3-yl)-N,N-dimethylmethylamine, 1-(6-bromo-1H-indol-3-yl)-N,N-dimethylmethylamine, 1-(4-chloro-1H-indol-3-yl)-N,N-dimethylmethylamine, 1-(4-bromo-1H-indol-3-yl)-N,N-dimethylmethylamine.

[0034] In some specific embodiments, the indole-3-acetic acid derivative shown in Formula 1, additives and alkaline substances are dissolved in N,N-dimethylformamide, electrolyzed at a rated current of 4 to 15 mA, and stirred for reaction. The resulting mixture is post-treated to obtain the product.

[0035] In some examples of this embodiment, the electrode combination (anode / cathode) is at least one of platinum electrode / platinum electrode, platinum electrode / graphite carbon electrode, graphite carbon electrode / platinum electrode, and graphite carbon electrode / graphite carbon electrode; it is more preferred to use a graphite carbon electrode for the anode and a platinum electrode for the cathode, or a platinum electrode for the anode and a platinum electrode for the cathode; it is most preferred to use a platinum electrode for the anode and a platinum electrode for the cathode.

[0036] In some examples of this embodiment, the additive is at least one of potassium iodide, sodium iodide, tetramethylammonium iodide, tetrabutylammonium iodide, ammonium iodide, potassium bromide, and potassium chloride;

[0037] It is easy for those skilled in the art to understand that the additive plays a role in catalysis and promoting the electrolytic reaction. The preferred additive is sodium iodide or potassium iodide; the most preferred additive is potassium iodide.

[0038] In some examples of this embodiment, the alkaline substance is at least one of sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate, lithium carbonate, ammonium carbonate, potassium bicarbonate, and potassium acetate; preferably potassium carbonate or sodium bicarbonate; the most preferred base is potassium carbonate.

[0039] In some examples of this embodiment, the anode is a platinum electrode, the cathode is a platinum electrode, potassium iodide is an additive, and its dosage is 0.5-1 mol / L, potassium carbonate is an alkaline substance, and its dosage is 0.5-2 mol / L, the dosage of N,N-dimethylformamide is 1.5-2 ml, the current is 8-15 mA, the time is 1.5-3 hours, and the reaction temperature is 20-30°C.

[0040] In a further preferred embodiment, the amount of N,N-dimethylformamide is 2 ml, the amount of potassium iodide is 1 mol / L, the amount of potassium carbonate is 2 mol / L, the current is 10 mA, the time is 3 hours, and the reaction temperature is 30°C.

[0041] The technical solutions of the present invention are further described in detail below in conjunction with specific embodiments and drawings. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention.

[0042] Example 1

[0043] Indole-3-acetic acid (35.0 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in an 83% yield (29.0 mg). 1 H NMR (400MHz, CDCl3) δ: 8.86 (s, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.21-7.06 (m, 2H), 7.03 (s, 1H), 3.65 (s, 2H), 2.30 (s, 6H).; 13 C NMR (100MHz, CDCl3) δ: 136.29, 127.94, 124.17, 121.82, 119.44, 119.10, 112.55, 111.27, 54.35, 45.21.

[0044] Example 2

[0045] 5-Methylindole-3-acetic acid (36.7 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na₂SO₄, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in an 80% yield (30.1 mg). 1 H NMR (400MHz, CDCl3) δ: 8.36 (s, 1H), 7.47 (s, 1H), 7.21 (d, J = 8.0Hz, 1H), 7.08-6.95 (m, 2H), 3.60 (s, 2H), 2.44 (s, 3H), 2.29 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 134.60, 128.72, 128.12, 123.99, 123.54, 118.79, 112.55, 110.80, 54.54, 45.30, 45.28, 21.56.

[0046] Example 3

[0047] 7-Methylindole-3-acetic acid (36.7 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a 40% yield (15.1 mg). 1H NMR (400MHz, CDCl3) δ: 8.17 (s, 1H), 7.55 (d, J = 8.0Hz, 1H), 7.12 (s, 1H), 7.09-6.94 (m, 2H), 3.63 (s, 2H), 2.54-2.43 (m, 3H), 2.28 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 135.78, 127.47, 123.37, 122.51, 120.21, 119.78, 117.01, 113.75, 54.64, 45.38, 16.65.

[0048] Example 4

[0049] 5-Methoxyindole-3-acetic acid (41.1 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in an 82% yield (33.5 mg). 1 H NMR(400MHz, CDCl3)δ:8.40(s,1H),7.21(d,J=8.8Hz,1H),7.12(d,J=2.4Hz,1H), 7.07(d,J=2.4Hz,1H),6.85-6.82(m,1H),3.84(s,3H),3.60(s,2H),2.29(s,6H). 13 C NMR (100MHz, CDCl3) δ: 154.05, 131.40, 128.31, 124.59, 112.86, 112.14, 111.80, 101.07, 55.93, 54.53, 45.31.

[0050] Example 5

[0051] 5-Fluoroindole-3-acetic acid (38.7 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a 50% yield (20.8 mg). 1 H NMR (400MHz, CDCl3) δ: 8.42 (s, 1H), 7.34 (d, J = 9.6Hz, 1H), 7.29–7.18 (m, 1H), 7.14 (s, 1H), 6.92 (m, 1H), 3.58 (s, 2H), 2.28 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 159.02, 156.69, 132.73, 128.35 (d, J = 9.6Hz), 125.42, 1 11.70(d,J=9.5Hz), 110.49(d,J=26.2Hz), 104.34(d,J=23.3Hz), 54.48, 45.27. 19 F NMR (377MHz, CDCl3) δ: -124.61.

[0052] Example 6

[0053] 5-Chloroindole-3-acetic acid (42.0 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a yield of 76% (31.7 mg). 1H NMR (400MHz, CDCl3) δ: 8.75 (s, 1H), 7.65 (s, 1H), 7.20 (d, J = 8.8Hz, 1H), 7.14–7.03 (m, 2H), 3.58 (s, 2H), 2.28 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 134.60, 128.97, 125.26, 125.20, 122.23, 118.73, 112.89, 112.16, 54.32, 45.27.

[0054] Example 7

[0055] 5-Bromoindole-3-acetic acid (50.9 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in an 80% yield (40.4 mg). 1 H NMR (400MHz, CDCl3) δ: 8.67 (s, 1H), 7.81 (s, 1H), 7.23 (s, 1H), 7.17 (d, J = 8.8Hz, 1H), 7.07 (s, 1H), 3.58 (s, 2H), 2.28 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 134.89, 129.63, 124.97, 124.80, 121.84, 112.88, 112.59, 54.33, 45.27.

[0056] Example 8

[0057] 6-Fluoroindole-3-acetic acid (34.4 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a 50% yield (19.3 mg). 1 H NMR (400MHz, CDCl3) δ: 8.54 (s, 1H), 7.59 (dd, J = 8.46, 5.4Hz, 1H), 7.05 (d, J = 1.4Hz, 1H ),6.99(dd,J=9.6,2.4Hz,1H),6.87(td,J=9.2,2.4Hz,1H),3.60(s,2H),2.28(s,6H). 13 C NMR (100MHz, CDCl3) δ: 159.96 (d, Hz = 235.7Hz), 136.12 (d, J = 12.4Hz), 124.42, 124.03 (d, J = 3. 5Hz), 119.91 (d, J = 10.2Hz), 113.05, 108.26 (d, J = 24.5Hz), 97.33 (d, J = 26.0Hz), 54.49, 45.27. 19 F NMR (377MHz, CDCl3) δ: –121.56.

[0058] Example 9

[0059] 6-Chloroindole-3-acetic acid (42.0 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a 61% yield (25.4 mg). 1 H NMR (400MHz, CDCl3)δ: δ8.80(d,J=31.7Hz,1H),7.58(d,J=8.4Hz,1H),7.28–7.24(m,1H),7.09–6.99(m,2H),3.61(s,2H),2.28(s,6H). 13 C NMR (100MHz, CDCl3) δ: 136.59, 127.87, 126.47, 124.31, 120.25, 120.18, 113.39, 111.03, 54.40, 45.28.

[0060] Example 10

[0061] 6-Bromoindole-3-acetic acid (34.4 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a yield of 51% (25.7 mg). 1 H NMR (400MHz, CDCl3) δ: 8.52 (s, 1H), 7.69 (d, J = 7.8Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.21–7.06 (m, 3H), 3.64 (s, 2H), 2.29 (s, 6H). 13C NMR (100MHz, CDCl3) δ: 136.22, 127.91, 123.81, 121.91, 119.51, 119.21, 113.05, 111.13, 54.44, 45.30.

[0062] Example 11

[0063] 4-Chloroindole-3-acetic acid (42.0 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a 40% yield (16.7 mg). 1 H NMR (400MHz, CDCl3) δ: 8.99 (s, 1H), 7.18 (d, J = 7.2Hz, 1H), 7.03 (t, J = 6.2Hz, 3H), 3.86 (s, 2H), 2.34 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 137.84, 126.26, 125.35, 124.27, 122.34, 120.76, 113.40, 110.02, 54.73, 45.10.

[0064] Example 12

[0065] 4-Bromoindole-3-acetic acid (34.4 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol), and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added, two platinum electrodes were inserted, and the tube was sealed under air. The reaction was carried out at 30°C with magnetic stirring at a constant current of 10 mA for 3 h. After completion of the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined and washed with saturated brine (3 × 15 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the product was purified by thin-layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) to obtain the pure product as a white solid in a 40% yield (20.2 mg). 1H NMR (400MHz, CDCl3) δ: 8.96 (s, 1H), 7.30–7.18 (m, 2H), 7.05 (s, 1H), 6.94 (t, J = 7.9Hz, 1H), 3.88 (s, 2H), 2.35 (s, 6H). 13 C NMR (100MHz, CDCl3) δ: 137.73, 125.71, 125.54, 124.26, 122.66, 114.16, 113.81, 110.59, 54.47, 45.08.

[0066] Control test groups 1 to 26:

[0067] Indole-3-acetic acid (35.0 mg, 0.2 mmol), potassium iodide (33.2 mg, 0.2 mmol), potassium carbonate (55.3 mg, 0.4 mmol) and a stirring bar were placed in a 10 mL reaction tube. 2 mL of N,N-dimethylformamide was added. Two platinum electrodes were inserted and sealed under air. The tube was placed in an oil bath at a set temperature, stirred, and reacted at a constant temperature. The product was quantified using nitromethane as an internal standard. 1 H NMR quantitative analysis.

[0068] The synthetic route is as follows:

[0069]

[0070] The specific reaction conditions of each control test group are shown in Table 1.

[0071] Table 1 Control group experiment of the reaction between indole-3-acetic acid and N,N-dimethylformamide

[0072]

[0073]

[0074] Note: a. The amount of N,N-dimethylformamide used was 1.5 ml; b. The reaction was carried out under an argon atmosphere; c. The reaction was carried out under an oxygen atmosphere.

[0075] As can be seen from the above table, for the reaction of generating gramine derivatives, no phase transfer catalyst and oxidant are needed in the reaction system; the base has a great influence on the reaction, and no product is generated without the addition of base, and the best reaction effect is achieved by adding 2 equivalents of potassium carbonate; the electrolyte has a great influence on the reaction, and no product is generated without the addition of electrolyte, and the best reaction effect is achieved by adding 1 equivalent of potassium iodide; different electrodes have a great influence on the reaction, and the best reaction effect is achieved when both the anode and cathode are platinum electrodes, and no product is generated when both carbon electrodes are used.

[0076] Finally, it should be noted that the above description is only a preferred embodiment of the present invention. Under the guidance of the present invention, those skilled in the art can make various similar expressions without violating the purpose and claims of the present invention. Such changes fall within the scope of protection of the present invention.

Claims

1. A method for electrochemically synthesizing gramine derivatives, characterized in that: Under a rated current of 4 to 15 mA, the indole-3-acetic acid derivative, additives and alkaline substances shown in Formula 1 are dissolved in N,N -dimethylformamide, a free radical coupling reaction occurs to prepare the gramine derivative shown in formula 2 in one step; Formula 1 Formula 2 Among them, R 1 is selected from hydrogen, alkyl, alkoxy, halogen; The alkaline substance is selected from at least one of sodium methoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium carbonate, lithium carbonate, ammonium carbonate, potassium bicarbonate, and potassium acetate; The additive is selected from at least one of potassium iodide, sodium iodide, tetramethylammonium iodide, tetrabutylammonium iodide, ammonium iodide, potassium bromide, and potassium chloride.

2. The method according to claim 1, characterized in that The indole-3-acetic acid derivatives described in Formula 1 are indole-3-acetic acid, 5-methylindole-3-acetic acid, 7-methylindole-3-acetic acid, 5-methoxyindole-3-acetic acid, 5-fluoroindole-3-acetic acid, 5-chloroindole-3-acetic acid, 5-bromoindole-3-acetic acid, 6-fluoroindole-3-acetic acid, 6-chloroindole-3-acetic acid, 6-bromoindole-3-acetic acid, 4-chloroindole-3-acetic acid, and 4-bromoindole-3-acetic acid.

3. The method according to claim 1 or 2, characterized in that The molar volume ratio of the indole-3-acetic acid derivative to the N,N-dimethylformamide is (0.1-0.5):2 mmol / ml, or (0.1-0.4):2 mmol / ml; or (0.1-0.3):2 mmol / ml; or 0.2:2 mmol / ml.

4. The method according to claim 1 or 2, characterized in that The molar volume ratio of the additive to the N,N-dimethylformamide is (0.1-0.5):2 mmol / ml, or (0.1-0.4):2 mmol / ml; or (0.1-0.3):2 mmol / ml; or 0.2:2 mmol / ml.

5. The method according to claim 1 or 2, characterized in that The molar volume ratio of the alkaline substance to the N,N-dimethylformamide is (0.1-0.5):2 mmol / ml, or (0.2-0.5):2 mmol / ml; or (0.3-0.5):2 mmol / ml; or 0.4:2 mmol / ml.

6. The method according to claim 1 or 2, characterized in that The alkaline substance is selected from potassium carbonate or sodium bicarbonate.

7. The method according to claim 1 or 2, characterized in that The alkaline substance is selected from potassium carbonate.

8. The method according to claim 1 or 2, characterized in that The additive is selected from sodium iodide or potassium iodide.

9. The method according to claim 1 or 2, characterized in that The additive is selected from potassium iodide.

10. The method according to claim 1 or 2, characterized in that The reaction temperature is 10-40°C, or 10-30°C, or 20-40°C, or 25-35°C, or 20-30°C.

11. The method according to claim 1 or 2, characterized in that The reaction time is 1-5h, or 1.5-4h, or 2-4h, or 2-3.5h, or 2.5-3h.

12. The method according to claim 1 or 2, characterized in that The electrochemical electrode includes one or a combination of two of nickel, copper, gold, zinc, platinum, and graphite carbon.

13. The method according to claim 1 or 2, characterized in that The electrochemical anode is a graphite carbon electrode and the cathode is a platinum electrode, or the anode is a platinum electrode and the cathode is a platinum electrode.

14. The method according to claim 1 or 2, characterized in that The electrochemical anode is a platinum electrode, and the cathode is a platinum electrode.

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