阅读说明：本技术 一种3,3-二取代-2-吲哚酮的绿色合成方法 (Green synthesis method of 3, 3-disubstituted-2-indolone ) 是由 陈训 徐丹 白丽丽 孔杜林 于 2019-09-26 设计创作，主要内容包括：本发明提供一种3,3-二取代-2-吲哚酮的绿色合成方法,该方法包括以下步骤：在金属盐和碱存在的条件下,以水为溶剂,N-亚硝基芳胺和乙烯酮在室温条件发生反应,反应完成后,经后处理得到所述的3,3-二取代-2-吲哚酮衍生物。该合成方法主要以水为溶剂,比较绿色环保,同时反应产率较高,反应条件温和,对水和空气都不敏感,操作简便。(The invention provides a green synthesis method of 3, 3-disubstituted-2-indolone, which comprises the following steps: under the condition of the existence of metal salt and alkali, water is used as a solvent, N-nitrosoarylamine and ketene react at room temperature, and after the reaction is finished, the 3, 3-disubstituted-2-indolone derivative is obtained through post-treatment. The synthesis method mainly takes water as a solvent, is relatively green and environment-friendly, and has the advantages of high reaction yield, mild reaction conditions, insensitivity to water and air and simple and convenient operation.)

1. A green synthesis method of 3, 3-disubstituted-2-indolone is characterized by comprising the following steps:

In the presence of metal salt and alkali, N-nitrosoarylamine reacts with ketene by taking water as a solvent to prepare a 3, 3-disubstituted-2-indolone derivative;

the structure of the N-nitrosoarylamine is shown as a formula (I), the structure of ketene is shown as a formula (II), and the structure of 3, 3-disubstituted-2-indolone is shown as a formula (III):

2. a green synthesis process of 3, 3-disubstituted-2-indolinone according to claim 1, wherein R is in formula (I) and formula (III)¹Is one of hydrogen, alkyl, alkoxy, halogen atom, aldehyde group or ketocarbonyl, nitro, cyano and ester group; r²Is one of alkyl, benzyl and phenyl.

3. A green synthesis process of 3, 3-disubstituted-2-indolinones according to claim 1, wherein R is in formula (II) and formula (III)³Is one of alkyl, phenyl, 4-methylphenyl, 4-chlorphenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-thienyl, 2-furyl and ester group; r⁴Is one of ester group, aldehyde group or ketone carbonyl, carboxyl and amido.

4. The green synthesis method of 3, 3-disubstituted-2-indolone according to claim 1, wherein R is¹Is C₁～C₄Alkyl or C₁～C₄Alkoxy radical, the said R²、R³Are all C₁～C₄an alkyl group.

5. A green synthesis method of 3, 3-disubstituted-2-indolone according to claim 1, wherein the molar ratio of N-nitrosoarylamine to ketene is 1 (1-3).

6. A green synthesis process of 3, 3-disubstituted-2-indolones as claimed in claim 5 wherein the molar ratio of N-nitrosoarylamine to ketene is 1: 1.5.

7. The method for green synthesis of 3, 3-disubstituted-2-indolone according to claim 1, wherein said metal salt is a transition metal salt, and said transition metal salt is one of palladium dichloride, palladium acetate, palladium trifluoroacetate, dichlorodiacetonitrile palladium, dichloroditriphenylphosphine palladium, cupric acetate, cupric chloride, cupric bromide, cupric trifluoromethanesulfonate, cuprous chloride, cuprous bromide, cuprous iodide or cuprous cyanide.

8. A green synthesis process of a 3, 3-disubstituted-2-indolinone as claimed in claim 1 wherein the base is one of cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium acetate, lithium acetate, sodium acetate, potassium acetate, sodium pivalate, sodium ethoxide, sodium tert-butoxide or lithium tert-butoxide.

9. The green synthesis method of 3, 3-disubstituted-2-indolone according to claim 1, wherein the reaction temperature is 20-30 ℃ and the reaction time is 5-7 hours.

10. The green synthesis method of 3, 3-disubstituted-2-indolone as claimed in any one of claims 1 to 9, characterized in that after the reaction is finished, the product is separated and purified by column chromatography, and the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a green synthesis method of 3, 3-disubstituted-2-indolone.

Background

The 3, 3-disubstituted-2-indolone framework structure is an important organic structural unit and is widely present in natural products and drug molecules. The skeleton derivative is reported to have important biological activities of resisting tumors, cardiovascular diseases and the like, and has potential application value in the fields of biological medicines and the like. Such as Convolutamycin A, which is a compound derived from the body of marine grass carpesium amathisacocolvauta, exhibits excellent inhibitory activity against human leukemia cell lines (HL-60). Therefore, the development of an efficient and green synthetic method for preparing the 3, 3-disubstituted-2-indolone derivative is of great significance.

The main synthesis method of 3, 3-disubstituted-2-indolone reported at present is constructed by taking N-aryl acrylamide as a raw material and performing a free radical serial cyclization reaction catalyzed by transition metal. However, the substrate applicability of the method is poor, and the introduction of 3, 3-bifunctional substituent groups can only be directed to some strong electron-withdrawing groups. In addition, the reaction conditions are too harsh, if some expensive ligands need to be added, and the used reaction solvents are all organic solvents and are not environment-friendly.

Disclosure of Invention

Therefore, the invention provides a green synthesis method of 3, 3-disubstituted-2-indolone, which mainly comprises the following steps: 1) the environment-friendly and easily-obtained water is used as a reaction solvent, so that the green chemical concept is met; 2) the reaction condition is mild, and the reaction can be carried out at room temperature; 3) the reaction raw materials are cheap and easy to obtain, and the reaction yield is high; 4) the substrate applicability of the reaction is relatively wide, and the 2-indolone derivatives substituted by various functional groups can be efficiently synthesized; 5) the reaction is not sensitive to oxygen, and the operation process is simple and easy.

The technical scheme of the invention is realized as follows:

A green synthesis method of 3, 3-disubstituted-2-indolone comprises the following steps:

In the presence of metal salt and alkali, N-nitrosoarylamine reacts with ketene by taking water as a solvent to prepare a 3, 3-disubstituted-2-indolone derivative;

The structure of the N-nitrosoarylamine is shown as a formula (I), the structure of ketene is shown as a formula (II), and the structure of 3, 3-disubstituted-2-indolone is shown as a formula (III);

The chemical reaction that takes place in the above process is shown by the following formula:

Further, in the formulae (I) and (III), R¹Is one of hydrogen, alkyl, alkoxy, halogen atom, aldehyde group or ketocarbonyl, nitro, cyano, ester group, etc.; r²Is one of alkyl, benzyl, phenyl, etc.

further, R in the formula (II) and the formula (III)³Is one of alkyl, phenyl, 4-methylphenyl, 4-chlorphenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-thienyl, 2-furyl, ester group and the like; r⁴Is one of ester group, aldehyde group or ketone carbonyl, carboxyl, amide group, etc.

Further, said R¹Is C₁～C₄alkyl or C₁～C₄Alkoxy radical, the said R²、R³are all C₁～C₄an alkyl group.

furthermore, the molar ratio of the N-nitrosoarylamine to the ketene is 1 (1-3). Preferably, the molar ratio of the N-nitrosoarylamine to ketene is 1: 1.5.

Further, the metal salt is a transition metal salt, and the transition metal salt is one of palladium dichloride, palladium acetate, palladium trifluoroacetate, dichlorodiacetonitrile palladium, dichlorodiphenylphosphine palladium, copper acetate, copper chloride, copper bromide, copper trifluoromethanesulfonate, cuprous chloride, cuprous bromide, cuprous iodide or cuprous cyanide; palladium acetate is preferred, with higher yields.

Further, the alkali is one of cesium carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium acetate, lithium acetate, sodium acetate, potassium acetate, sodium pivalate, sodium ethoxide, sodium tert-butoxide or lithium tert-butoxide; cesium acetate is preferred, with higher yields.

Further, the reaction temperature is 0-80 ℃, and the reaction time is 1-36 hours. The preferable reaction temperature is 20-30 ℃, the reaction time is 5-7 hours, the reaction is complete, and the yield is higher.

Further, after the reaction is finished, separating and purifying the product by adopting column chromatography, wherein the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

Compared with the prior art, the invention has the beneficial effects that:

(1) The invention takes water as a reaction solvent, and is relatively green and environment-friendly;

(2) The reaction conditions are mild, the reaction can be carried out at room temperature and under the air condition, the whole operation process is simple and convenient, and the steps are simple;

(3) The method has high reaction yield and wide substrate applicability, and can synthesize various types of functional group-substituted 2-indolone derivatives;

Drawings

FIG. 1 is a hydrogen spectrum of Compound 1 of example 1 of the present invention.

FIG. 2 is a carbon spectrum of Compound 1 of example 1 of the present invention.

FIG. 3 is a hydrogen spectrum of Compound 2 of example 2 of the present invention.

FIG. 4 is a carbon spectrum of Compound 2 of example 2 of the present invention.

FIG. 5 is a hydrogen spectrum of Compound 3 of example 3 of the present invention.

FIG. 6 is a carbon spectrum of Compound 3 of example 3 of the present invention.

FIG. 7 is a hydrogen spectrum of Compound 4 of example 4 of the present invention.

FIG. 8 is a carbon spectrum of Compound 4 of example 4 of the present invention.

Detailed Description

in order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.

The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.

The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.

The N-nitrosoarylamine (I) and ketene (II) compounds as raw materials in the embodiment of the invention are prepared by referring to the existing method, and can be specifically referred to J.Am.chem.Soc.2013,135,16625-16631 and ACS Catal.2016, 6, 7744-7748.

the reaction formula in the embodiment of the invention is as follows: