2, 3-disubstituted indole derivative and preparation method thereof

Abstract

The invention discloses a 2, 3-disubstituted indole derivative and a preparation method thereof, and belongs to the technical field of organic synthesis. The 2, 3-disubstituted indole derivative can be obtained by taking a benzylallenitrile compound and an aryl isonitrile compound as substrates, adding the substrates into a solvent, and carrying out a heating reaction. According to the method, 2-(4-methylbenzylidene) malononitrile and 4-methoxyaryl isonitrile are subjected to a nucleophilic reaction to generate a three-membered ring intermediate, then the three-membered ring intermediate is subjected to a Friedel-Crafts reaction, ring opening is performed, and the 2, 3-disubstituted indole derivative is finally obtained. Indole does not need to be used as a reaction substrate, simple and easy-to-obtain isonitrile and 2-(4-methylbenzylidene) malononitrile are subjected to an alkylation reaction, and a novel simple and efficient synthesis method is provided for de novo synthesis of the 2, 3-disubstituted indole derivative.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a 2,3-disubstituted indole derivative and a preparation method thereof. Background Art

[0002] Indole and its derivatives have a wide range of biological activities, such as anti-tumor, blood pressure lowering, anti-inflammatory, central nervous system excitation, and antibacterial effects. At the same time, it is also often used as an important intermediate for the synthesis of pharmaceuticals and agrochemicals, and its potential application value has attracted extensive attention from synthetic chemists.

[0003] 2,3-Disubstituted indoles are a class of chemically active compounds with one or more substituents attached to the indole ring in their structure, showing broad-spectrum pharmacological activities and having the biological activity of inhibiting the proliferation of tumor cells, and can be used to prepare anti-tumor drugs. Therefore, 2,3-disubstituted indole derivatives play a very important role in both medicinal chemistry and organic synthesis fields. These compounds have extensive applications in medicinal chemistry, natural product synthesis, and other fields. Among them, 2-substituted indoles are particularly prominent in medicinal active compounds, such as ASIC3 (acid-sensing ion channel) inhibitors and PARP (poly(ADP-ribose) polymerase) inhibitors (Genes & Dev, 2020, 34, 360 - 394); another example is that "Synthesis and Biological Activities of 2-(Substituted Styryl)Indole Derivatives" reported that 2-(substituted styryl)indole derivatives not only have an inhibitory effect on DMBA-induced rat breast cancer, but also have inhibitory effects on histamine 1 receptor, dopamine 2 receptor, and adrenergic α-2 receptor (Acta Pharmaceutica Sinica, 2001, 36, 100 - 104). In addition, "Synthesis and Anti-Tumor Activity of a Class of Polysubstituted Indole Compounds" (Guangzhou Chemistry, October 2023, Vol. 48, No. 5) reported that polysubstituted indole compounds have strong inhibitory effects on the proliferation of gastric cancer cell line SGC7901 and lung cancer cell line A549.

[0004] Although many methods for constructing 2,3-disubstituted indoles have been developed, the research on the synthetic methodology of 2,3-disubstituted indole derivatives has been booming. Such synthetic methods usually require pre-formed indole precursors. There are currently many related synthetic methods, such as the Fischer indole synthesis, Gassman synthesis, Madelung synthesis, Larock indole synthesis, and Bischler indole synthesis. With the application of microwave, ultrasonic, metal catalysis, etc. in organic synthesis, it has promoted the synthesis of polysubstituted indole compounds and the discovery of corresponding active compounds. However, most of these methods have relatively harsh reaction conditions, with defects such as complex reaction operations, unfriendly environment, low yield, and atom inefficiency. Among the above synthetic methods, the methods that can synthesize indole derivatives in one step are the most concerned. Among them, 2-substituted indole derivatives, 3-substituted indole derivatives, or 2,3-substituted indole derivatives are mainly obtained by the one-step reaction of malononitrile, aldehyde compounds, and indole. Such as "Green Synthesis of β-Indole Derivatives in Deep Eutectic Solvents" (Tang Liping et al., Fine Chemicals, Vol. 32, No. 6, June 2015), "Choline Chloride-Catalyzed Three-Component Yonemitsu Condensation Reaction of Aldehydes, Indoles, and Malononitrile" (Yang Zhonghua et al., Organic Chemistry, DOI: 10. 6023 / cjoc201803007). The above reports all require choline chloride as a catalyst, and choline chloride is a low-toxic compound, which has potential safety hazards and does not meet the requirements of green chemistry. Therefore, it is necessary to develop a more biocompatible and greener method for synthesizing 2,3-disubstituted indole derivatives. Summary of the Invention

[0005] In view of the above-mentioned prior art, the object of the present invention is to provide a 2,3-disubstituted indole derivative and a preparation method thereof. The present invention uses 2-(4-methylbenzylidene)malononitrile to undergo a nucleophilic reaction with 4-methoxyaryl isocyanide to generate a three-membered ring intermediate, and then undergoes a Friedel-Crafts reaction and ring opening to finally obtain a polysubstituted indole derivative. This method synthesizes 2,3-disubstituted indole derivatives in one step without a catalyst. This method is green and efficient, does not require indole as a reaction substrate, and undergoes an alkylation reaction with simple and readily available isocyanide and 2-(4-methylbenzylidene)malononitrile, providing a simple and efficient new method for the synthesis of 2,3-disubstituted indole derivatives.

[0006] To achieve the above object, the present invention adopts the following technical solutions: In the first aspect of the present invention, there is provided a 2,3-disubstituted indole derivative, and the structural formula of the 2,3-disubstituted indole derivative is: ; Wherein, R 1 is selected from the C1-C20 straight-chain or branched-chain alkyl group, aryl group, halogen atom, hydrogen atom; R2 Selected from aryl, fused aryl, heteroaryl or alkyl; R 3 Selected from alkyl.

[0007] Preferably, said R 1 Selected from 4-phenyl, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-ethoxycarbonyl, 4-benzoyl, 4-cyano, 4-nitro, 4-trifluoromethyl, 3-methyl, 3-methoxy, 3-bromo, 3-benzoyl, 2-phenyl, 2-cyano, 2-methyl, 2-chloro, 2-bromo, 2-ethoxycarbonyl, 3,4-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 4-methylbenzyl, 4-chlorobenzyl or hydrogen atom; R 2 Selected from 4-methyl, 4-methoxy, 4-phenyl, 4-fluoro, 4-chloro, 4-bromo, 4-nitro, 4-hydroxy, 2-methyl, 2-methoxy, 2-chloro, 2-nitro, 3-methyl, 3-methoxy, 3-chloro, 3-nitro, 2-furyl, 2-pyrrolyl, 2-thienyl, cyclohexyl, n-butyl or hydrogen atom; R 3 Selected from 2-methylmalononitrile group, dimethyl 2-methyl-3-oxosuccinate group, 2-nitro-1-phenylpropan-1-one group, 2-methyl-1-phenylpropan-1-one group, 2-methyl-3-oxobutyronitrile group and 2,4,4-trimethyl-3-oxovaleronitrile group.

[0008] Preferably, said 2,3-disubstituted indole derivative is 5-methoxy-3-p-tolyl-2-propanedinitrile indole, and its structural formula is: .

[0009] In the second aspect of the present invention, a preparation method of a 2,3-disubstituted indole derivative is provided, and said preparation method is: Adding a benzylidene malononitrile compound and an aryl isocyanide compound into a solvent, and heating and reacting to obtain a 2,3-disubstituted indole derivative.

[0010] Preferably, the structural formula of said benzylidene malononitrile compound is: ; wherein, R 2 Selected from aryl, fused aryl, heteroaryl or alkyl.

[0011] Preferably, said R 2Selected from 4-methyl, 4-methoxy, 4-phenyl, 4-fluoro, 4-chloro, 4-bromo, 4-nitro, 4-hydroxy, 2-methyl, 2-methoxy, 2-chloro, 2-nitro, 3-methyl, 3-methoxy, 3-chloro, 3-nitro, 2-furyl, 2-pyrrolyl, 2-thienyl, cyclohexyl, n-butyl or a hydrogen atom.

[0012] Preferably, the R 2 is 4-methyl; the benzylidenemalononitrile compound is 2-(4-methylbenzylidene)malononitrile.

[0013] Preferably, the structural formula of the aryl isocyanide compound is: ; wherein, R 1 is selected from the C1-C20 straight-chain or branched-chain alkyl group, aryl group, halogen atom, hydrogen atom.

[0014] Preferably, the R 1 is selected from 4-phenyl, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-ethoxycarbonyl, 4-benzoyl, 4-cyano, 4-nitro, 4-trifluoromethyl, 3-methyl, 3-methoxy, 3-bromo, 3-benzoyl, 2-phenyl, 2-cyano, 2-methyl, 2-chloro, 2-bromo, 2-ethoxycarbonyl, 3,4-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 4-methylbenzyl, 4-chlorobenzyl or a hydrogen atom.

[0015] Preferably, the molar ratio of the 2-(4-methylbenzylidene)malononitrile compound to the aryl isocyanide compound is 1:1; the solvent is selected from at least one of ethylene glycol dimethyl ether, ethanol or water.

[0016] Preferably, the R 1 is selected from 4-methoxy; the aryl isocyanide compound is 4-methoxyaryl isocyanide.

[0017] Preferably, the temperature of the heating reaction is 60-80 °C, and the time of the heating reaction is 1-3 h.

[0018] Advantages of the present invention: (1) In the present invention, 2-(4-methylbenzylidene)malononitrile undergoes a nucleophilic reaction with isocyanide to generate a three-membered ring intermediate, and then undergoes a Friedel-Crafts reaction and ring opening to finally obtain an important synthon of polysubstituted indoles. This method synthesizes 2,3-disubstituted indole derivatives in one step without a catalyst. This method is green and efficient, and does not require indole as a reaction substrate. Alkylation reaction of simple and readily available isocyanide with 2-(4-methylbenzylidene)malononitrile provides a simple and efficient new method for the synthesis of 2,3-disubstituted indole derivatives.

[0019] (2) In the present invention, 2-(4-methylbenzylidene)malononitrile and various isocyanides are used as substrates. Without the need for metal reagents or base catalysis, and without isolating water or oxygen, the reaction is carried out in an organic solvent to obtain 2,3-disubstituted indole derivatives.

[0020] (3) The reaction of the present invention has a short reaction time, mild conditions, simple operation, easily available raw materials and reagents, and strong practicability, and is applicable to the synthesis of polysubstituted indole derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : 1H NMR spectrum of the 2,3-disubstituted indole derivative prepared in Example 1; Figure 2 : 13C NMR spectrum of the 2,3-disubstituted indole derivative prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0022] It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs.

[0023] As introduced in the background art section, currently, 2-substituted indole derivatives, 3-substituted indole derivatives or 2,3-substituted indole derivatives are mainly obtained by a one-step reaction of malononitrile, aldehyde compounds and indole using choline chloride as a catalyst. Such reactions all require indole as a reaction substrate and need to be catalyzed by a catalyst.

[0024] Based on this, the object of the present invention is to provide a 2,3-disubstituted indole derivative and its preparation method, which do not require indole as a reaction substrate and do not require the addition of a catalyst. Due to its unique reactivity, isocyanide has been proven to be a versatile synthetic building block in many transformations. However, due to the self-dimerization, polymerization and other side reactions of the same isocyanide, the development and application of the multicomponent reaction and cross-heterocyclization reaction of isocyanide are greatly restricted. Therefore, based on easily available isocyanide, through the alkylation reaction of isocyanide with 2-(4-methylbenzylidene)malononitrile, a simple and efficient new synthetic method for the de novo synthesis of 2,3-disubstituted indole derivatives is provided. In the present invention, 2-(4-methylbenzylidene)malononitrile and isocyanide compounds are used as reaction substrates and added to a solvent and heated to react to obtain 2,3-disubstituted indole derivatives. The synthetic route is as follows: .

[0025] The reaction principle is as follows: A nucleophilic reaction occurs between 2-(4-methylbenzylidene)malononitrile and isocyanide to form a three-membered ring intermediate, and then a Friedel-Crafts reaction occurs and the ring is opened to finally obtain an important synthon for polysubstituted indoles. The reaction process is as follows: .

[0026] Therefore, the present invention does not require metal reagents or base catalysis, does not require isolation of water or oxygen, has advantages such as a wide substrate adaptation range and 100% atom economy, and can directly synthesize polysubstituted indole derivatives in one-pot reaction in an organic solvent.

[0027] In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments.

[0028] Note: 4-methoxyaryl isocyanide in the present invention is also known as 4-methoxybenzene isocyanide; The systematic naming of 5-methoxy-3-p-tolyl-2-propanedinitrile indole is also known as 2-(5-methoxy-3-(p-tolyl)-1H-indol-2-yl)propanedinitrile.

[0029] The test materials used in the embodiments of the present invention are all conventional test materials in the art and can be obtained through commercial channels.

[0030] Example 1: Preparation of 2,3-disubstituted indole derivatives The synthetic route of 2-(5-methoxy-3-(p-tolyl)-1H-indol-2-yl)propanedinitrile is as follows: .

[0031] 40.36 mg of 2-(4-methylbenzylidene)propanedinitrile (1a, 0.24 mmol, in excess), 26.6 mg of 4-methoxyaryl isocyanide (2a, 0.2 mmol) and 2 mL of ethylene glycol dimethyl ether (solvent) were successively added to a 15 mL pressure-resistant tube. A magnetic stir bar was added, and after tightening the pressure-resistant tube stopper, it was placed in a metal block preheated to 60 °C for heating and stirring for 2 h. After detecting the disappearance of reaction 2a by TLC, the reaction system was separated and purified to obtain a light green solid 3a (57.25 mg, yield 95%). 1 H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.71 (s, 3H), 5.16 (s, 1H), 6.65 (s, 1H), 6.80 (dd, J1 = 2.4 Hz, J2 = 8.0 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 9.75 (s, 1H). 13 C NMR(100 MHz, CDCl3): δ21.1, 49.6, 55.2, 55.7, 111.3, 111.4, 113.8, 115.2, 128.4, 129.9, 132.4, 134.7, 135.1, 138.3, 157.2, 176.2. HRMS (ESI) m / z: [M+H] + calcd for C 12 H9N3O + 211.0740; found 211.0736。 Figure 1 1H NMR spectrum of the 2,3-disubstituted indole derivative obtained in Example 1 Figure 2 is its 13C NMR spectrum.

[0032] Example 2: Preparation of 2,3-disubstituted indole derivative The difference from Example 1 is that ethylene glycol dimethyl ether was replaced with an equal volume of ethanol, and heating and stirring were carried out in a preheated metal module at 80 °C for 2 h. Finally, a light green solid 3a (55.31 mg, yield 92%) was obtained.

[0033] Example 3: Preparation of 2,3-disubstituted indole derivative The difference from Example 1 is that ethylene glycol dimethyl ether was replaced with 1.5 mL of ethanol and 0.5 mL of water, and heating and stirring were carried out in a preheated metal module at 60 °C for 2 h. Finally, a light green solid 3a (48.82 mg, yield 81%) was obtained.

[0034] The above are only the preferred embodiments of the present application and are not used to limit the present application. For those skilled in the art, various changes and modifications can be made to the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A 2,3-disubstituted indole derivative, characterized in that, The structural formula of the 2,3-disubstituted indole derivative is as follows: ； wherein, R 1 is selected from said C1-C20 straight-chain or branched-chain alkyl, aryl, halogen atom, hydrogen atom; R 2 selected from aryl, fused aryl, heteroaryl or alkyl; R 3 selected from alkyl groups.

2. The 2,3-disubstituted indole derivative according to claim 1, wherein Said R 1 is selected from 4-phenyl, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-ethyl ester group, 4-benzoyl group, 4-cyano group, 4-nitro group, 4-trifluoromethyl group, 3-methyl, 3-methoxy, 3-bromo, 3-benzoyl group, 2-phenyl, 2-cyano group, 2-methyl, 2-chloro, 2-bromo, 2-ethyl ester group, 3,4-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 4-methylbenzyl, 4-chlorobenzyl or a hydrogen atom; R 2 selected from 4-methyl, 4-methoxy, 4-phenyl, 4-fluoro, 4-chloro, 4-bromo, 4-nitro, 4-hydroxy, 2-methyl, 2-methoxy, 2-chloro, 2-nitro, 3-methyl, 3-methoxy, 3-chloro, 3-nitro, 2-furyl, 2-pyrrolyl, 2-thienyl, cyclohexyl, n-butyl or a hydrogen atom; R 3 Selected from 2-methylmalononitrile group, dimethyl 2-methyl-3-oxosuccinate group, 2-nitro-1-phenylpropan-1-one group, 2-methyl-1-phenylpropan-1-one group, 2-methyl-3-oxobutyronitrile group and 2,4,4-trimethyl-3-oxovaleronitrile group.

3. The 2,3-disubstituted indole derivative according to claim 1, wherein The 2,3-disubstituted indole derivative is 5-methoxy-3-p-tolyl-2-propanedinitrile indole, and its structural formula is as follows: 。 4. A method for preparing a 2,3-disubstituted indole derivative according to any one of claims 1 to 3, characterized in that, The preparation method is as follows: Add the benzylidene malononitrile compound and the aryl isocyanide compound into a solvent, and heat and react to obtain the 2,3-disubstituted indole derivative.

5. The preparation method according to claim 4, characterized in that, The structural formula of the benzylidene malononitrile compound is as follows: ； wherein, R 2 is selected from 4-methyl, 4-methoxy, 4-phenyl, 4-fluoro, 4-chloro, 4-bromo, 4-nitro, 4-hydroxy, 2-methyl, 2-methoxy, 2-chloro, 2-nitro, 3-methyl, 3-methoxy, 3-chloro, 3-nitro, 2-furyl, 2-pyrrolyl, 2-thienyl, cyclohexyl, n-butyl or a hydrogen atom.

6. The preparation method according to claim 5, characterized in that, The R 2 is 4-methyl; the benzylidenemalononitrile compound is 2-(4-methylbenzylidene)malononitrile.

7. The preparation method according to claim 4, characterized in that, The structural formula of the aryl isocyanide compound is as follows: ； Among them, R 1 is selected from 4-phenyl, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-ethyl ester group, 4-benzoyl group, 4-cyano group, 4-nitro group, 4-trifluoromethyl group, 3-methyl, 3-methoxy, 3-bromo, 3-benzoyl group, 2-phenyl, 2-cyano group, 2-methyl, 2-chloro, 2-bromo, 2-ethyl ester group, 3,4-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 4-methylbenzyl, 4-chlorobenzyl or a hydrogen atom.

8. The preparation method according to claim 7, characterized in that, The R 1 is selected from 4-methoxy; the aryl isocyanide compound is 4-methoxy aryl isocyanide.

9. The preparation method according to claim 4, wherein The molar ratio of the 2-(4-methylbenzylidene) malononitrile compound to the aryl isocyanide compound is 1:1; the solvent is selected from at least one of ethylene glycol dimethyl ether, ethanol or water.

10. The preparation method according to claim 4, wherein The temperature of the heating reaction is 60-80 °C, and the time of the heating reaction is 1-3 h.

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