Method for electrochemical synthesis of donaxine derivative

Abstract

The invention relates to the technical field of preparation of organic compounds, in particular to a method for preparing a donaxine derivative from an indole-3-acetic acid derivative and N, N-dimethylformamide in one step under the electrochemical condition. Compared with the prior art, the free radical-free radical coupling reaction based on indole-3-acetic acid derivative decarboxylation and N, N-dimethylformamide decarbonylation is realized for the first time under mild electric reaction conditions without transition metals and oxidants, the reaction raw materials are cheap, easy to obtain, stable and safe, and the method is suitable for industrial production. According to the method, the reaction does not need to consume an organic metal reagent or use transition metal, KI is used as an additive, dangerous peroxide does not need to be used, and the method is compatible with air, has the advantages of one-step reaction, low cost, simple operation and the like, and has a good application prospect in the field of synthesis of the arunine derivatives.

Description

Technical Field

[0001] The 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] Lucypridine is a natural alkaloid containing an indole skeleton with extremely high biological activity. Lucypridine is widely distributed in nature and has a growth inhibitory effect on environmental plants, insects, microorganisms, etc. People use the different biological activities of lucypridine to develop biological pesticides with different biological activities and different uses. It can be used to develop related pesticides for crop insecticides by making insects repellent. Lucypridine and its derivatives have the characteristics of high efficiency, low toxicity, resistance, and low residue, making it a biological pesticide with broad development prospects. Lucypridine compounds are widely present in biologically active molecules such as drugs and natural products. They are used as tryptophan synthesis and are widely used as organic synthesis intermediates. At the same time, lucypridine compounds have anti-mutagenic properties and can be used to treat cancer and Alzheimer's disease.

[0003] At present, the preparation methods of gramine derivatives include: (1) using indole, dimethylamine and formaldehyde as raw materials, preparing gramine and its derivatives through the classic Mannich reaction under the catalysis of glacial acetic acid. This preparation method generally has the defect 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 process; (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 defect of requiring the addition of solvent ethylene glycol, resulting in high production cost and environmental pollution.

[0004] Therefore, it is of great theoretical significance and application value to develop a method for synthesizing gramine derivatives in one pot using safe, stable, cheap and readily available chemical reagents as raw materials, without transition metals or other catalysts, without oxidants, and under mild and simple reaction conditions. Summary of the invention

[0005] In order to overcome the above technical defects, the present invention provides a method for electrochemically synthesizing gramine derivatives, under mild conditions, electrocatalyzing the free radical coupling reaction of the decarboxylation of indole-3-acetic acid derivatives and the decarbonylation of DMF, synthesizing 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 great 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 on, the indole-3-acetic acid derivative shown in formula 1 undergoes a free radical coupling reaction with N,N-dimethylformamide, and the gramine derivative shown in formula 2 is prepared in one step;

[0006]

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

[0008] Further, 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):2mmol / ml, or (0.2-0.5):2mmol / ml; or (0.3-0.5):2mmol / ml; or 0.4:2mmol / 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; 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 to 5h, or 1.5-4h, or 2-4h, or 2-3.5h, or 2.5-3h.

[0016] Furthermore, the electrochemical electrodes include electrodes including 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 readily 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 reaction 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 spectra;

[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 indicated in the following examples are usually carried out under normal conditions or according to 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 equal to the recorded content can all be applied to the present invention. The preferred implementation methods and materials described in the text are only for demonstration purposes.

[0024] The endpoints and any values ​​of the ranges disclosed in this article 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 endpoint values ​​of each range, the endpoint values ​​of each range and the 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 as specifically disclosed in this article.

[0025] At present, 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 amounts of catalysts, 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 obtains carboxyl anions under the action of a base, and at the same time, the iodine anions lose an electron at the anode to generate iodine free radicals, and then the iodine free radicals and the carboxyl anions undergo a single electron transfer to generate a carboxyl free radical intermediate, which is further deCO2ed to generate a carbon free radical intermediate. At the same time, the iodine anions lose electrons at the anode to generate iodine free radicals, which then react with DMF through hydrogen atom transfer (HAT) to generate a dimethylaminoformyl free radical intermediate, and then the free radical intermediate undergoes decarbonylation to form a dimethylamino free radical; finally, the carbon free radical and the dimethylamino free radical are cross-coupled to generate the target product gramine (see Figure 1 ).

[0029] In some specific embodiments, a method for synthesizing gramine derivatives by free radical coupling reaction of electrocatalytic decarboxylation of indole-3-acetic acid and decarbonylation of DMF under mild conditions is provided, namely: at room temperature, the indole-3-acetic acid derivative shown in formula 1 reacts with N,N-dimethylformamide under power-on conditions in one pot to obtain the 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, and 4-bromoindole-3-acetic acid.

[0033] In some embodiments of this embodiment, the indole-3-acetic acid described in Formula 1 and N,N-dimethylformamide are reacted by free radical coupling reaction to synthesize the gramine derivative, and the gramine derivative is 1-(1H-indol-3-yl)-N,N-dimethylmethylamine, N,N-dimethyl-1-(5-methyl-1H-indol-3-yl)methylamine, N,N-dimethyl-1-(7-methyl-1H-indol-3-yl)methylamine, 1-(5-methoxy-1H-indol-3-yl)-N,N-dimethylmethylamine, 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, and the obtained 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; preferably, a graphite carbon electrode is used for the anode and a platinum electrode is used for the cathode, or a platinum electrode is used for the anode and a platinum electrode is used for the cathode; most preferably, a platinum electrode is used for the anode and a platinum electrode is used 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 to understand for those skilled in the art that the additive plays a role of catalysis and promotion of the electrolytic reaction in the reaction, and 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 used is 2 ml, the amount of potassium iodide used is 1 mol / L, the amount of potassium carbonate used is 2 mol / L, the current is 10 mA, the time is 3 hours, and the reaction temperature is 30°C.

[0041] The technical solution of the present invention is 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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 83% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 80% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 40% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 82% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature, extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 50% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with 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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 80% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature, extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 50% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature, extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 61% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature, extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with 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] Embodiment 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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the tube was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 40% (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 conditions, and the reaction was carried out at 30 ° C for 3 h with constant current 10 mA magnetic stirring. After the reaction, the mixture was cooled to room temperature and extracted with ethyl acetate (3×10 mL), and the organic phases were combined. The organic phase was washed with saturated brine (3×15 mL), the organic phase was separated and dried with anhydrous Na2SO4, filtered, and the solvent was concentrated under reduced pressure. Finally, the pure product was purified by thin layer chromatography or column chromatography (silica gel, petroleum ether / ethyl acetate / triethylamine = 1:5:0.1, v:v:v) as a white solid with a yield of 40% (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 the tube was sealed under air conditions. The reaction tube was placed in an oil bath pot with a set temperature, stirring was started, and the reaction was carried out 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 Indole-3-acetic acid and N, N-dimethylformamide reaction control group experiment

[0072]

[0073]

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

[0075] As can be seen from the above table, for the reaction of generating gramine derivatives, there is no need to add phase transfer catalyst and oxidant to the reaction system; the base has a great influence on the reaction, and no product will be generated without adding 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 will be generated without adding 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 by both platinum electrodes for the positive and negative electrodes, and no product will be generated by using carbon electrodes.

[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 a variety of similar expressions without violating the purpose and claims of the present invention, and such changes all fall within the protection scope of the present invention.

Claims

1. A method for electrochemically synthesizing gramine derivatives, characterized in that: Under the condition of electricity, the indole-3-acetic acid derivative shown in Formula 1 undergoes a free radical coupling reaction with N,N-dimethylformamide to obtain the gramine derivative shown in Formula 2 in one step; Among them, R 1 Selected from hydrogen, alkyl, alkoxy, halogen.

2. The method according to claim 1, characterized in that 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.

3. The method according to claim 1, characterized in that The free radical coupling reaction conditions are as follows: dissolving the indole-3-acetic acid derivative, additives and alkaline substances shown in Formula 1 in N,,N-dimethylformamide, electrolyzing at a rated current of 4 to 15 mA, and stirring the reaction; the obtained mixture is prepared by post-treatment.

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

5. The method according to claim 3, characterized in that: 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.

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

7. The method according to claim 3, characterized in that 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.

8. The method according to claim 3, characterized in that The additive is at least one selected from 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.

9. The method according to any one of claims 1 to 3, 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; the reaction time is 1-5h, or 1.5-4h, or 2-4h, or 2-3.5h, or 2.5-3h.

10. The method according to any one of claims 1 to 3, characterized in that: The electrochemical electrodes include one or a combination of two of nickel, copper, gold, zinc, platinum, and graphite carbon; preferably, the 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; most preferably, the anode is a platinum electrode and the cathode is a platinum electrode.

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