Preparation method of 3-nitro-2-indolone compound
阅读说明：本技术 一种3-硝基-2-吲哚酮类化合物的制备方法 (Preparation method of 3-nitro-2-indolone compound ) 是由 吴燕 陈锦杨 刘嘉陵 钟春涛 于 2019-10-14 设计创作，主要内容包括：本发明涉及一种3-硝基-2-吲哚酮类化合物的制备方法。该方法是在溶剂中以2-吲哚酮类化合物和硝酸铜为原料,然后在氧化剂的作用下进行硝化反应,至原料反应完全,再过滤除去固体残余物旋干直接得到3-硝基-2-吲哚酮类化合物。本发明以硝酸铜作为硝化试剂,硝化反应过程中无亚硝基自由基产生,不仅减少了副反应,还提高了反应选择性,大幅度提高了硝化反应收率,且缩短了反应时间,反应完成后,无需柱层析过柱,过滤除去固体残余物旋干直接得到目标产物。该方法具有操作简便、原料廉价易得、反应条件温和、高效稳定的优点,特别适合于工业化生产,具有良好的应用前景,同时也为自由基硝化反应提供了一种新思路。(The invention relates to a preparation method of a 3-nitro-2-indolone compound. The method comprises the steps of taking 2-indolone compounds and copper nitrate as raw materials in a solvent, then carrying out nitration reaction under the action of an oxidant until the raw materials react completely, filtering to remove solid residues, and spin-drying to directly obtain the 3-nitro-2-indolone compounds. The method takes the copper nitrate as the nitration reagent, no nitroso free radical is generated in the nitration reaction process, side reaction is reduced, reaction selectivity is improved, the nitration reaction yield is greatly improved, the reaction time is shortened, column chromatography and column chromatography are not needed after the reaction is finished, solid residues are removed by filtration, and the target product is directly obtained by spin drying. The method has the advantages of simple operation, cheap and easily obtained raw materials, mild reaction conditions, high efficiency and stability, is particularly suitable for industrial production, has good application prospect, and provides a new idea for the free radical nitration reaction.)
1. A preparation method of 3-nitro-2-indolone compounds is characterized by comprising the following steps:
taking a 2-indolone compound and copper nitrate as raw materials in a solvent, then carrying out nitration reaction under the action of an oxidant until the raw materials are completely reacted, and carrying out post-treatment to obtain the 3-nitro-2-indolone compound, wherein the reaction formula is as follows:
in the above formula, 1 represents a 2-indolone compound and I represents a 3-nitro-2-indolone compound, R1Is C1-C6Alkyl, phenyl or C5-C14An aryl group; r2Is hydrogen, C1-C6Alkyl radical, C1-C6Ester group or C5-C14An aryl group; r3Is 1 or more substituents on the phenyl ring to which it is attached, each R3Independently of one another, from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy or halogen.
2. The method for preparing 3-nitro-2-indolone compounds according to claim 1, wherein the oxidant is selected from any one or a mixture of potassium persulfate, iodobenzene acetate, silver carbonate, potassium hydrogen persulfate complex salt and di-tert-butyl peroxide; potassium persulfate is preferred.
3. The method for preparing 3-nitro-2-indolone compounds according to claim 1, wherein the solvent is selected from one or more of ethyl acetate, tetrahydrofuran, 1,4-dioxane, 1, 2-dichloroethane and N, N-dimethylformamide; preferably ethyl acetate.
4. The method for preparing 3-nitro-2-indolone compounds according to claim 1, wherein the molar ratio of the 2-indolone compounds to the copper nitrate to the oxidant is 1: 1-2: 1.2-2.
5. The method for preparing 3-nitro-2-indolone compounds according to claim 1, wherein the temperature of the nitration reaction is 25-40 ℃.
6. The method for preparing 3-nitro-2-indolone compounds according to claim 1, wherein the atmosphere of the nitration reaction is air.
7. The method for preparing 3-nitro-2-indolone compounds according to claim 1, wherein the post-treatment is specifically performed as follows: after the reaction is finished, adding ethyl acetate into the reaction liquid, filtering to remove solid residues, and removing the solvent by decompression and concentration to obtain the 3-nitro-2-indolone compound.
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a 3-nitro-2-indolone compound by simple and efficient nitration reaction of a copper nitrate-involved 2-indolone compound under mild conditions.
Background
The 3-nitro-2-indolone compounds are compounds with wide biological activity and pharmacodynamic activity. Therefore, the synthesis and preparation of the compounds are always highly regarded by organic chemists.
In 1982, Takeshi Ohnuma et al ("THE OXIDATION REACTION OF INDOLES WITH THALLIUM (II1) TRINITRATE", "HETEROCYCLES" Vol.17, p. 377 380) used 3-methylindole as a raw material, and obtained 3-methyl-3-nitro-2-indolone compound in 27% yield in THE presence OF THALLIUM nitrate, but this method produced 3-methyl-3-nitro-2-indolone compound and also produced 3-methyl-3-oxynitro-2-indolone, and THE yield was low, selectivity was poor, and did not have industrially feasible utility value, and THALLIUM nitrate was a highly toxic control; in 2017, Wei et al ("Metal-Free inversion of the C (sp)3) H Bonds of 2-oxides through radial Coupling Reaction at Room Temperature ", adv. Synth. Cat. 359, 3551-3554) reported a method for preparing 3-nitro-2-indolone derivatives by nitration with tert-butyl nitrite in a metal-free catalytic system. Meanwhile, the Chinese patent of invention (ZL2017105897515) of Wei et al also discloses that 2-indolone derivatives are used as raw materials, 1,4-dioxane is used as a reaction solvent, and the 2-indolone derivatives and tert-butyl nitrite react under the conditions of room temperature and air to obtain the 3-nitro-2-indolone derivatives with high yield. However, the method uses unstable tert-butyl nitrite as a nitration reagent, has potential danger in the reaction, generates nitroso free radicals in the reaction process, reduces the utilization efficiency of the nitration reagent, and is easy to generate side reaction. In addition, the target product must be purified and separated by a column chromatography method after the reaction is finished, which not only wastes time and labor, but also brings about consumption of a large amount of organic elution machines and loss of the target product, and is not beneficial to further industrial production and utilization. Therefore, a new method for preparing more concise, more efficient and more green 3-nitro-2-indolone compounds is urgently needed to be developed.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of a 3-nitro-2-indolone compound, which solves the problems of unstable nitration reagent, low reaction selectivity, uncontrollable reaction system, low reaction efficiency, long reaction time and complex post-reaction treatment in the existing nitration reaction.
In order to solve the technical problems, the invention adopts the following technical scheme: a preparation method of 3-nitro-2-indolone compounds comprises the following steps:
taking a 2-indolone compound and copper nitrate as raw materials in a solvent, then carrying out nitration reaction under the action of an oxidant until the raw materials are completely reacted, and carrying out post-treatment to obtain the 3-nitro-2-indolone compound, wherein the reaction formula is as follows:
in the above formula, 1 represents a 2-indolone compound and I represents a 3-nitro-2-indolone compound, R1Is C1-C6Alkyl, phenyl or C5-C14An aryl group; r2Is hydrogen, C1-C6Alkyl radical, C1-C6Ester group or C5-C14An aryl group; r3Is 1 or more substituents on the phenyl ring to which it is attached, each R3Independently of one another, from hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy or halogen.
Further, the oxidant is selected from any one or a mixture of more of potassium persulfate, iodobenzene acetate, silver carbonate, potassium hydrogen persulfate complex salt and di-tert-butyl peroxide; potassium persulfate is preferred.
Further, the solvent is selected from any one or a mixture of more of ethyl acetate, tetrahydrofuran, 1,4-dioxane, 1, 2-dichloroethane and N, N-dimethylformamide; preferably ethyl acetate.
Further, the molar ratio of the 2-indolone compound to the copper nitrate to the oxidant is 1: 1-2: 1.2-2.
Further, the temperature of the nitration reaction is 25-40 ℃.
Further, the atmosphere of the nitration reaction is air.
Further, the post-processing specifically operates as follows: after the reaction is finished, adding ethyl acetate into the reaction liquid, filtering to remove solid residues, and removing the solvent by decompression and concentration to obtain the 3-nitro-2-indolone compound.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a novel preparation method of 3-nitro-2-indolone compounds, which takes commercially available and stable copper nitrate as a nitrating reagent, only generates single nitro free radical under the action of an oxidant, avoids the process that when tert-butyl nitrite is used as the nitrating reagent, nitroso free radical is generated at the same time, and greatly improves the reaction selectivity; moreover, because of less side reaction and full reaction conversion, after the reaction is finished, column chromatography is not needed, and only solid residues are filtered and removed and are dried by spinning to directly obtain the 3-nitro-2-indolone compounds. The reaction yield of the invention can reach 96 percent, the reaction time is 2 hours, and the reaction efficiency is greatly improved, thereby realizing the preparation of the 3-nitro-2-indolone compound with high selectivity and high yield under a mild oxidation system, and solving the problems of unstable nitration reagent, low reaction selectivity, uncontrollable reaction system, low reaction efficiency, long reaction time and complex post-reaction treatment existing in the existing 2-indolone nitration reaction.
2. The preparation method of the invention takes 2-indolone compounds and copper nitrate as reaction raw materials, under the promotion of an oxidant, a series of target products are obtained through high-selectivity nitration reaction in a free radical process, other functional groups are not introduced while nitration reaction is carried out, the reaction selectivity is high, the requirements of chemical synthesis stability and high efficiency can be met, and the application range of the preparation method is expanded. The method has the advantages of simple and convenient operation, cheap and easily obtained raw materials, low cost, wide reaction substrate application range, mild reaction conditions, high efficiency and stability, is particularly suitable for industrial production, has good application prospect, and provides a new idea for nitration reaction.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited thereto.
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and starting materials, if not otherwise specified, are commercially available and/or may be prepared according to known methods.