阅读说明：本技术 一种n-芳基吲哚啉衍生物的制备方法 (A kind ofNProcess for preparing (E) -arylindoline derivatives ) 是由 蔡琥 张真 谢永发 张天奇 岳树升 王德粮 于 2020-07-31 设计创作，主要内容包括：本发明涉及有机化学合成技术领域,具体涉及<I>N</I>-芳基取代吲哚啉衍生物的制备方法,是以碱为促进剂,有机溶剂条件下,吲哚啉化合物和硝基苯化合物,以1:1~1:3的摩尔比,在-50～0<Sup> o</Sup>C温度条件下、充氧气的条件下反应17小时；反应结束后加水淬灭,有机溶剂萃取,柱层析分离,得到<I>N</I>-芳基取代吲哚啉衍生物。本发明利用硝基苯作为Ar-H来源和取代吲哚啉作为仲胺,在<I>t</I>-BuONa/DMSO/O<Sub>2</Sub>体系下,实现吲哚啉的直接芳胺化反应。这种方法有以下优点：方便简单,高的原子经济性,避免使用了昂贵的过渡金属,温和的反应条件,产生的是环境友好的副产物。(The invention relates to the technical field of organic chemical synthesis, in particular to N The preparation method of the aryl-substituted indoline derivative is characterized in that an alkali is used as an accelerator, and an indoline compound and a nitrobenzene compound are in a molar ratio of-50-0 to 1:3 under the condition of an organic solvent o C, reacting for 17 hours under the condition of temperature and oxygen charging; adding water to quench after the reaction is finished, extracting by an organic solvent, and separating by column chromatography to obtain N -aryl-substituted indoline derivatives. The invention uses nitrobenzene as Ar-H source and substituted indoline as secondary amine in t ‑BuONa/DMSO/O 2 Under the system, the direct arylamine reaction of indoline is realized. This method has the following advantages: convenient and simple, high atom economy, avoidance of expensive transition metal, mild reaction conditions, and environment-friendlyGood by-products.)

1. A kind ofNThe preparation method of the-aryl substituted indoline derivative is characterized in that an alkali is used as an accelerator, and under the condition of an organic solvent, the indoline compound and a nitrobenzene compound are in a molar ratio of 1: 1-3 of-50-0^oCReacting for 17 hours under the conditions of temperature and oxygen charging; adding water to quench after the reaction is finished, extracting by an organic solvent, and separating by column chromatography to obtainN-aryl-substituted indoline derivatives.

2. A method as claimed in claim 1NThe preparation method of the aryl-substituted indoline derivative is characterized in that the indoline compound is various substituted indoline derivatives, and the structural formula of the indoline derivative is as follows:

wherein X = C or N;

R¹、R²and R³Is hydrogen, C₁～C₄₀Aliphatic radical of (2), C₄～C₆₀Aromatic groups, alkoxy groups, hydroxyl groups, nitro groups, amine groups or halogens.

3. A method as claimed in claim 2NA process for producing an aryl-substituted indoline derivative, characterized in that C is₁～C₄₀The aliphatic group of (a) is methyl, ethyl, propyl, isopropyl, butyl or benzyl; c₄～C₆₀The aromatic group in the aromatic group is pyridine derivative group, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; halogen is fluorine, chlorine, bromine or iodine.

4. A method as claimed in claim 1NThe preparation method of the aryl-substituted indoline derivative is characterized in that the nitrobenzene compound has the structure as follows:

R³and R⁴Is hydrogen, C₁～C₄₀Aliphatic radical of (2), C₄～C₆₀Aromatic groups, alkoxy groups, hydroxyl groups, nitro groups, amine groups or halogens.

5. A process according to claim 4NA process for producing an aryl-substituted indoline derivative, characterized in that C₁～C₄₀The aliphatic group of (a) is methyl, ethyl, propyl, isopropyl, butyl or benzyl; c₄～C₆₀The aromatic group in the aromatic group is pyridine derivative group, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; halogen is fluorine, chlorine, bromine or iodine.

6. A method as claimed in claim 1NThe preparation method of the aryl-substituted indoline derivative is characterized in that the accelerator base ist-BuONa、t-BuOK, KOH, NaOH or K₂CO₃The dosage of the accelerator is 1 to 3 times of the molar weight of the indoline derivative.

7. A method as claimed in claim 1NThe preparation method of the aryl-substituted indoline derivative is characterized in that the organic solvent adoptsN,N-Dimethyl formamide,N,NDimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, dichloromethane, chlorineChloroform, carbon tetrachloride, 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, diethyl ether, ethylene glycol dimethyl ether or tetrahydrofuran.

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and relates to a synthetic method of a compoundN-arylindoline derivativesA method for preparing the same.

Background

Indoline derivatives are widely found in natural products, and the indoline skeleton is also an important structural unit of biologically active alkaloids and drugs (Boger, d. l.; Boyce, c. w.; garbacco, r. m.; Goldberg, J.A).Chem. Rev.1997, 97, 787-791. Horton, D. A.; Bourne, G. T.; Smythe, M. L.Chem. Rev.2003, 103, 893-930.). For example, the biologically active alkaloid vindoline, pentopril with angiotensin converting enzyme inhibitory activity (Goodman, F. R.; Bromidge, S. M.; Weiss, G. B.; Hurley, M. E).Cardiovasc. Drug. Rev.1985, 3, 57-69.), an N-aryl substituted indoline with cyclooxygenase inhibiting activity (Sano, H.; Noguchi, t.; tananati, a.; Hashimoto, y.; Miyachi, H).Bioorg. Med. Chem.2005, 13, 3079-3091)), these compounds all have indoline fragments. Therefore, it is necessary to develop a simple and efficient method for synthesizing indoline derivatives, which provides more references for the synthesis of alkaloids or active drug molecules.

Vindoline (1), pentopril (2) and N-aryl substituted indoline (3).

Among the methods for synthesizing N-aryl substituted derivatives, the general method can be realized by a method of partial hydrogenation reduction of an N-aryl indole skeleton (Grible, G.W.; Hoffman, J.H).Synthesis.1977, 859. Health-Brown, B.Chem. Ind. (London)1969, 1595.); n-aryl substituted derivatives can also be synthesized by ring closure reactions of 3-chlorostyrene and primary amine compounds (Beller, M.; Breind, C.; Riermeier, Thomas H.; Eichberger, M.; Trauthwein, H.).Angew. Chem. Int. Ed.1998, 37, 3389-3391.); a more classical approach to the synthesis of N-aryl substituted derivatives is the Buchwald-Hartwig coupling (Guram A S, Buchwald S L.J. Am. Chem. Soc. 1994, 116(17): 7901-7902; Paul F, Patt J, Hartwig J.F.J. Am. Chem. Soc. 1994, 116(13): 5969-5970; Shekhar S, Ryberg P, Hartwig JF, et al.J. Am. Chem. Soc. 2006, 128(11): 3584-3591). These methods have the disadvantage of requiring the preparation of aryl halides or complex precursor compounds, with the production of hydrogen halides or the synthesis of complex precursors requiring numerous steps, which are detrimental to atom economy; in addition, the C-N coupling reaction catalyzed by Pd or other transition metals needs expensive ligands, and the problems of heavy metal pollution and the like are also caused. While the problem can be well solved by oxidative dehydrogenation coupling (CDC) amination reaction, the CDC coupling amination reaction is direct coupling of Ar-H bond and N-H bond, and pre-functionalization is not needed. Through literature research, we find that the CDC reaction of Ar-H and N-H direct coupling without metal catalysis is less researched, and still has great challenge and research value.

Disclosure of Invention

The invention aims to provide a series of direct oxidative dehydrogenation coupling (CDC) preparation under nonmetal conditionsNA process for the preparation of-aryl-substituted indoline derivatives using nitrobenzene as the Ar-H source and substituted indolines as the secondary amines, int-BuONa/DMSO/O₂Under the system, the direct arylamine reaction of indoline is realized. This method has the following advantages: the method is convenient and simple, has high atom economy, avoids using expensive transition metal, has mild reaction conditions, and produces environment-friendly byproducts.

According to the inventionNThe preparation method of the-aryl substituted indoline derivative is characterized in that an alkali is used as an accelerator, and an indoline compound and a nitrobenzene compound are in a molar ratio of-50-0 to 1-3 under the condition of an organic solvent^oCReacting for 17 hours under the conditions of temperature and oxygen charging; adding water to quench after the reaction is finished, extracting by an organic solvent, and separating by column chromatography to obtainN-aryl-substituted indoline derivatives.

Further, the indoline compound is various substituted indoline derivatives, and the indoline derivative has a structural formula as follows:

wherein X = C (carbon) or N (nitrogen);

R¹、R²and R³Is hydrogen, C₁～C₄₀Aliphatic radical of (e.g. methyl, ethyl, propyl, isopropyl, butyl, benzyl), C₄～C₆₀Aromatic groups (pyridine derivatives, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl), alkoxy, hydroxyl, nitro, amino or halogen (fluorine, chlorine, bromine, iodine).

Further, the nitrobenzene compound has the structure:

R³and R⁴Is hydrogen, C₁～C₄₀Aliphatic radical of (e.g. methyl, ethyl, propyl, isopropyl, butyl, benzyl), C₄～C₆₀Aromatic groups (pyridine derivatives, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl), alkoxy, hydroxyl, nitro, amino or halogen (fluorine, chlorine, bromine, iodine).

Further, the accelerator base ist-BuONa、t-BuOK, KOH, NaOH or K₂CO₃The dosage of the accelerator is 1 to 3 times of the molar weight of the indoline derivative.

Further, the organic solvent may be usedN,N-Dimethylformamide (DMF),N,NDimethylacetamide (DMA), Dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), dichloromethane (CH)₂Cl₂) Chloroform (CHCl)₃) Carbon tetrachloride (CCl)₄) 1, 2-dichloroethane, 1, 4-dioxane, acetonitrile, diethyl ether, ethylene glycol dimethyl ether (DME), Tetrahydrofuran (THF) and the like.

The inventionNThe synthetic general formula of the aryl substituted indoline derivative is as follows:

compared with the prior art, the invention has the following advantages:

1. the invention takes alkali as the accelerating agent to promote, the indoline derivative reacts with nitrobenzene or nitronaphthalene derivative, and the direct oxidative dehydrogenation coupling (CDC) method is adopted, so that the high-efficiency preparation can be realized in one stepNThe reaction raw materials and the accelerant are cheap and easy to obtain, and the synthesis process is simple.

2. The reaction condition is mild, the reaction can be carried out in the air under the low-temperature condition, and the yield is excellent (can reach 97 percent);

3. the reaction can realize gram-grade reaction synthesis with high yield.

Detailed Description

The invention is further illustrated by the following specific examples.