CN108383770A - A kind of method that microwave copper/Peracetic acid catalysis oxidation indoles prepares indoles -2,3- derovatives - Google Patents

Abstract

The present invention discloses a kind of microwave copper/Peracetic acid catalysis oxidation indoles and prepares indoles 2, the method of 3 derovatives, the catalyst cuprous iodide of catalytic amount is added in the reaction vessel, indoles and its derivative and Peracetic acid are raw material, ethyl alcohol is placed in microwave reaction instrument and is reacted under certain temperature and power, after a certain period of time as solvent, it is concentrated under reduced pressure, product is purified by column chromatography.The present invention is that a kind of raw material is novel, easy to operate, the method for efficiently preparing benzimidizole derivatives.Compared with prior art, obviously accelerate under the more conventional heating of the method reaction speed, reaction condition is mild, easy to operate, yield is high, safety, of low cost, environmental protection.

Description

A Microwave Copper/Peracetic Acid Catalyzed Derivatization of Indole to Indole-2,3-dione way of things

technical field

The present invention relates to a method for preparing indole-2,3-dione derivatives. That is, using substituted indole and peracetic acid as raw materials, introducing microwave as an auxiliary synthesis method, and efficiently catalyzing and rapidly preparing indole-2,3-dione derivatives.

Background technique

Indole-2,3-dione, also known as isatin, is an alkaloid widely present in natural products with a relatively simple structure. It is found in the roots and stems of the acanthaceae plant, Cao Daqing, and it is also an important component of the famous traditional Chinese medicine Qingdai. In addition, it is widely distributed in human organs and body fluids, especially in the hippocampus and other parts of the brain. Indole-2,3-dione and its derivatives have a variety of biological activities, and it is very meaningful to study their activities in anti-tumor, anti-virus, neuroprotection and other aspects.

Indole-2,3-dione is a common raw material for the synthesis of various useful heterocyclic compounds due to its simple structure and an important structural form that widely exists in biologically active natural products, pharmaceutical intermediates, pharmaceuticals, and dye chemistry. Therefore, various methods have been developed for the synthesis of isatin derivatives. At present, aniline can be used as a raw material for large-scale synthesis, and its price is relatively low, and different types of reactions can occur at the 1,2,3-position and benzene ring of indole-2,3-dione. The synthesis provides convenient conditions, so the current research on its synthesis and activity has attracted much attention. However, most methods require the use of difficult-to-prepare starting materials and the direct oxidation of readily available indoles to the corresponding isatin derivatives has been less explored.

The methods for synthesizing benzindole isatin derivatives reported in the literature include: (1) Using substituted anilines as starting materials, reacting with chloral hydrate and hydroxylamine hydrochloride to generate substituted isonitrosoacetanilides, under the action of concentrated sulfuric acid Cyclization, hydrolysis. (2) A method for one-step synthesis of isatin by using 2-indolinone as a substrate through transition metal catalysis. The currently reported methods for synthesizing benzindole isatin derivatives have their own advantages and disadvantages. More or less due to the difficulty in obtaining raw materials, some reagents have potential safety hazards, severe reaction conditions and low yields, etc., so simple, safe, and pollution-free methods are sought. Synthetic pathways are the preferred question.

From the perspective of cost and environmental protection, the synthesis of indole-2,3-dione derivatives using microwave-assisted copper catalysis not only takes advantage of the green and low toxicity of copper catalysts, but also has the advantages of short microwave heating time and high yield. , friendly to the environment and other advantages, has a very attractive prospect.

The present invention discloses a method for synthesizing indole-2,3-dione derivatives. That is, using substituted indole and peracetic acid as raw materials, introducing microwave as an auxiliary synthesis method, and rapidly preparing indole-2,3-dione derivatives through efficient catalysis. Compared with the method described in the prior art, the reaction speed of this system is significantly faster than that under conventional heating, the reaction condition is mild, the operation is simple, the raw material is novel, the yield is high, the product is safe, the cost is low, and it is environmentally friendly.

Contents of the invention

The purpose of the present invention is to provide a method for catalytically synthesizing indole-2,3-dione derivatives under microwave radiation, more specifically, under microwave radiation, a copper salt catalyst catalyzes the substitution of indole and its derivatives and peroxides. A method for synthesizing indole-2,3-dione derivatives from oxyacetic acid.

The technical scheme for realizing the object of the present invention is as follows: the method for catalytically synthesizing indole-2,3-dione derivatives under microwave radiation, such as chemical reaction formula (A), its specific steps are as follows: in the reaction vessel Add a catalytic amount of catalyst cuprous iodide, substituted indole and peracetic acid, and ethanol solvent, place it in a microwave reactor to react at a certain temperature and power, after a certain period of time, concentrate under reduced pressure, and the product is subjected to column chromatography purification;

(A)

Wherein _R1 is methyl, ethyl, n-propyl, phenyl and benzyl; _R2 is H, methyl, ethyl, n-propyl, n-butyl, nitro, F, Cl, Br, hydroxyl, Acetyl, methoxy or nitrile, the R ₂ is located at the 4,5,6 and 7 positions of indole.

The molar ratio of the substituted indole and CuI catalyst to peracetic acid is 1:0.05:5. .

The reaction temperature in the microwave reactor in the above specific steps is 20-200°C, preferably 50-60°C.

The reaction time in the microwave reactor in the above specific steps is 10-60 min, preferably 10-15 min.

The power in the microwave reactor in the above specific steps is 10-200 W, preferably 120-150 W.

The oxygen source can be selected from hydrogen peroxide, tert-butanol peroxide, cyclohexanone peroxide, di-tert-butyl peroxide and peracetic acid, preferably peracetic acid.

The solvent is methanol, ethanol, acetonitrile, 1,2-dichloromethane, 1,4-dioxane, preferably ethanol.

The target catalyst is CuCl, CuI, Cu ₂ O, CuCl ₂ , preferably CuI.

According to the present invention, the substrate (I) is a substituted indole, and indole-2,3-dione derivatives can be synthesized in this reaction system.

The above formula (I) wherein _R1 is methyl, ethyl, n-propyl, phenyl and benzyl; _R2 is H, methyl, ethyl, n-propyl, n-butyl, nitro, F, Cl , Br, hydroxyl, acetyl, methoxy or nitrile, the R ₂ is located at the 4,5,6 and 7 positions of indole.

In a preferred embodiment of the present invention, based on 1 mol of substituted indole (I) as a standard, the catalyst is used in an amount of 0.01 mol to 0.5 mol, preferably 0.1 mol to 0.4 mol, more preferably 0.05 mol.

In a preferred embodiment of the present invention, based on 1 mol of substituted indole (I) as a standard, the amount of the oxygen source used is 1 to 10 mol, preferably 1 to 6 mol, more preferably 5 mol.

In a microwave reactor, the reaction temperature is 20°C-200°C, preferably 50°C-60°C.

The reaction time in the microwave reactor is 10 min-60 min, preferably 10 min-15 min.

The microwave power in the microwave reactor is 10 W-200 W, preferably 120 W-150 W.

The advantages of the present invention are: the present invention is an environment-friendly, simple and convenient operation, novel raw material and high-efficiency method for preparing indole-2,3-dione derivatives. Compared with the prior art, the reaction speed of this method is significantly faster than that under conventional heating, the reaction condition is mild, the operation is simple, the yield is high, the method is safe, low in cost and environment-friendly.

Detailed ways

Example 1: Indole-2,3-dione: 1 mmol of indole was added to a reaction vessel, followed by 0.05 mmol of cuprous iodide, 4 mmol of peracetic acid, and 3 ml of ethanol. Placed in a microwave reactor and heated to 60 °C under 120 W power for continuous reaction for 10 min. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the product was purified by column chromatography to obtain a red solid with a yield of 68%.

Example 2: 1-methylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 1-methylindole to obtain a red solid with a yield of 65%.

Example 3: 1-ethylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 1-ethylindole to obtain a red solid with a yield of 61%.

Example 4: 1-propylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 1-propylindole to obtain a red solid with a yield of 58%.

Example 5: 1-phenylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 1-phenylindole to obtain a brown solid with a yield of 54%.

Example 6: 1-benzylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 1-benzylindole to obtain a brown solid with a yield of 50%.

Example 7: 4-methylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 4-methylindole to obtain a red solid with a yield of 50%.

Example 8: 4-ethylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 4-ethylindole to obtain a red solid with a yield of 47%.

Example 9: 4-propylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 4-propylindole to obtain a red solid with a yield of 45%.

Example 10: 4-butylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 4-butylindole to obtain a red solid with a yield of 43%.

Example 11: 4-nitroindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-nitroindole to obtain a red solid with a yield of 70%.

Example 12: 4-fluoroindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-fluoroindole to obtain a red solid with a yield of 67%.

Example 13: 4-chloroindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-chloroindole to obtain a red solid with a yield of 63%.

Example 13: 4-bromoindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-bromoindole to obtain a red solid with a yield of 60%.

Example 14: 4-oxindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-oxindole to obtain a red solid with a yield of 60%.

Example 15: 4-acetylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-acetylindole to obtain a red solid with a yield of 65%.

Example 16: 4-cyanindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 4-cyanindole to obtain a red solid with a yield of 53%.

Example 17: 4-methoxyindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 4-methoxyindole to obtain a red solid with a yield of 43%.

Example 18: 5-methylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-methylindole to obtain a red solid with a yield of 52%.

Example 19: 5-ethylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-ethylindole to obtain a red solid with a yield of 48%.

Example 20: 5-propylindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 5-propylindole to obtain a red solid with a yield of 47%.

Example 21: 5-butylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-butylindole to obtain a red solid with a yield of 46%.

Example 22: 5-nitroindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-nitroindole to obtain a red solid with a yield of 71%.

Example 23: 5-fluoroindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-fluoroindole to obtain a red solid with a yield of 66%.

Example 24: 5-chloroindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-chloroindole to obtain a red solid with a yield of 65%.

Example 25: 5-bromoindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-bromoindole to obtain a red solid with a yield of 63%.

Example 26: 5-oxindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-oxindole to obtain a red solid with a yield of 61%.

Example 27: 5-acetylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-acetylindole to obtain a red solid with a yield of 63%.

Example 28: 5-cyanindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 5-cyanindole to obtain a red solid with a yield of 56%.

Example 29: 5-methoxyindole-2,3-dione: the preparation method is the same as in Example 1, adding 1 mmol of 5-methoxyindole to obtain a red solid with a yield of 45%.

Example 30: 6-methylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 6-methylindole to obtain a red solid with a yield of 51%.

Example 31: 6-ethylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 6-ethylindole to obtain a red solid with a yield of 46%.

Example 32: 7-methylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 7-methylindole to obtain a red solid with a yield of 48%.

Example 33: 7-ethylindole-2,3-dione: The preparation method is the same as in Example 1, adding 1 mmol of 7-ethylindole to obtain a red solid with a yield of 48%.

Example 34: Indole-2,3-dione: 1 mmol of indole was added to a reaction vessel, followed by 0.05 mmol of cuprous chloride, 4 mmol of peracetic acid, and 3 ml of ethanol. Placed in a microwave reactor and heated to 60 °C under 120 W power for continuous reaction for 10 min. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the product was purified by column chromatography to obtain a red solid with a yield of 10%.

Example 35: Indole-2,3-dione: 1 mmol of indole was added to a reaction vessel, followed by 0.05 mmol of cuprous iodide, 4 mmol of peracetic acid, and 3 ml of ethanol. Placed in a microwave reactor and heated to 50 °C under 120 W power for continuous reaction for 10 min. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the product was purified by column chromatography to obtain a red solid with a yield of 32%.

Example 36: Indole-2,3-dione: 1 mmol of indole was added to a reaction vessel, followed by 0.05 mmol of cuprous iodide, 4 mmol of peracetic acid, and 3 ml of ethanol. Placed in a microwave reactor and heated to 60 °C under 120 W power for continuous reaction for 15 min. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the product was purified by column chromatography to obtain a red solid with a yield of 64%.

Example 37: Indole-2,3-dione: 1 mmol of indole was added to a reaction vessel, followed by 0.05 mmol of cuprous iodide, 4 mmol of peracetic acid, and 3 ml of ethanol. Placed in a microwave reactor and heated to 60 °C under 150 W power for continuous reaction for 10 min. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the product was purified by column chromatography to obtain a red solid with a yield of 60%.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications made within the spirit and principles of the present invention, equivalent replacements and improvements, etc., should be included in the protection of the present invention. within range.

Claims (8)

1. A method for preparing indole-2,3-dione derivatives from indole catalyzed by microwave copper/peracetic acid, such as chemical reaction formula (A), the specific steps are as follows: add a catalytic amount of Catalyst cuprous iodide, replacing indole and peracetic acid as raw materials, ethanol as solvent, placed in a microwave reactor at a certain temperature and power to react, after a certain period of time, concentrated under reduced pressure, and the product was purified by column chromatography; (A) Wherein _R1 is methyl, ethyl, n-propyl, phenyl or benzyl; _R2 is H, methyl, ethyl, n-propyl, n-butyl, nitro, F, Cl, Br, hydroxyl, Acetyl, methoxy or nitrile, the R ₂ is at the 4, 5, 6 or 7 position of indole. 2. The method according to claim 1, characterized in that the molar ratio of the substituted indole and CuI catalyst to peracetic acid is 1:0.05:5. 3. The method according to claim 1, characterized in that the catalyst in the specific step is CuCl, CuI, _Cu2O , _CuCl2 , preferably CuI. 4. method according to claim 1, it is characterized in that described oxygen source in the concrete step can select hydrogen peroxide, tert-butanol peroxide, cyclohexanone peroxide, di-tert-butyl peroxide and peracetic acid, preferably peracetic acid. 5. The method according to claim 1, characterized in that the solvent in the specific steps is methanol, ethanol, acetonitrile, 1,2-dichloromethane, 1,4-dioxane, preferably ethanol. 6. The method according to claim 1, characterized in that in the specific steps, the reaction temperature in the microwave reactor is 20-200°C, preferably 50-60°C, and optimally 60°C. 7. The method according to claim 1, characterized in that in the specific steps, the reaction time in the microwave reactor is 10-60 min, preferably 10-15 min, and optimally 10 min. 8. The method according to any one of claims 1-6, characterized in that in the specific steps, the power in the microwave reactor is 10-200 W, 120-150 W, and optimally 120 W.