A 2,3-disubstituted indole derivative and its preparation method

Abstract

The invention discloses a 2,3-disubstituted indole derivative and a preparation method thereof, and belongs to the field of organic synthesis technology. The present invention uses benzyl malononitrile compounds and aryl isonitrile compounds as substrates to add them to a solvent for heating reaction to obtain 2,3-disubstituted indole derivatives. The present invention uses 2-(4-methylbenzylidene)malononitrile and 4-methoxyaryl isonitrile to undergo nucleophilic reaction to generate a three-membered ring intermediate, followed by Friedel-Crafts reaction and ring opening to ultimately obtain 2,3-disubstituted indole derivatives. This method synthesizes 2,3-disubstituted indole derivatives in one step under catalyst-free conditions. The method is green and efficient, does not require indole as a reaction substrate, and uses easily available isonitrile and 2-(4-methylbenzylidene)malononitrile to undergo alkylation reaction, providing a simple and efficient new synthesis method for the de novo synthesis of 2,3-disubstituted indole derivatives.

Description

Technical Field

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

[0002] Indole and its derivatives possess a wide range of biological activities, including anti-tumor, antihypertensive, anti-inflammatory, central nervous system stimulatory, and antibacterial effects. They are also often used as important intermediates in the synthesis of pharmaceuticals and agricultural chemicals, and their potential applications have attracted widespread attention among synthetic chemists.

[0003] 2,3-Disubstituted indoles are a class of chemically active compounds. These compounds, with one or more substituents attached to the indole ring, exhibit broad pharmacological activity, including inhibition of tumor cell proliferation, and are used in the preparation of anti-tumor drugs. Therefore, 2,3-disubstituted indole derivatives hold a crucial position in both medicinal chemistry and organic synthesis. These compounds have a wide range of applications in medicinal chemistry, natural product synthesis, and other fields. Among them, 2-substituted indoles are particularly prominent among pharmaceutically 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 the paper "Synthesis and Biological Activity of 2-(Substituted Styryl) Indole Derivatives," which reported that 2-(Substituted Styryl) Indole derivatives not only inhibited DMBA-induced rat breast cancer but also inhibited histamine 1 receptor, dopamine 2 receptor, and adrenaline α-2 receptor (Acta Pharmaceutica Sinica, 2001, 36, 100-104). Furthermore, the paper "Synthesis and Antitumor Activity of a Class of Polysubstituted Indole Compounds" (Guangzhou Chemistry, October 2023, Vol. 48, No. 5) reported that polysubstituted indole compounds had a strong inhibitory effect on the proliferation of both the gastric cancer cell line SGC7901 and the lung cancer cell line A549.

[0004] Despite the development of numerous methods for constructing 2,3-disubstituted indoles, research on synthetic methodologies for 2,3-disubstituted indole derivatives has remained burgeoning. These synthetic methods typically require preformed indole precursors. Numerous synthetic methods exist, including the Fischer indole synthesis, the Gassman synthesis, the Madelung synthesis, the Larock indole synthesis, and the Bischler indole synthesis. The application of microwaves, ultrasound, and metal catalysis in organic synthesis has facilitated the synthesis of polysubstituted indole compounds and the discovery of corresponding active compounds. However, most of these methods suffer from harsh reaction conditions, complex reaction operations, environmental unfriendliness, low yields, and atom uneconomical yields. Among these synthetic methods, those capable of synthesizing indole derivatives in a single step have garnered the most attention. 2-Substituted indole derivatives, 3-Substituted indole derivatives, or 2,3-Substituted indole derivatives are primarily obtained through a single-step reaction of malononitrile, an aldehyde, and indole. For example, reports such as "Green Synthesis of β-Indole Derivatives in Deep Eutectic Solvents" (Tang Liping et al., Fine Chemicals, Vol. 32, No. 6, June 2015) and "Choline Chloride-Catalyzed Three-Component Yonemitsu Condensation of Aldehydes, Indoles, and Malononitrile" (Yang Zhonghua et al., Organic Chemistry, DOI: 10.6023 / cjoc201803007) both required choline chloride as a catalyst. However, choline chloride is a low-toxic compound, presenting safety risks and not meeting the requirements of green chemistry. Therefore, the development of more bioefficient and green methods for the synthesis of 2,3-disubstituted indole derivatives is needed. Summary of the Invention

[0005] In response to the above-mentioned prior art, the present invention aims to provide a 2,3-disubstituted indole derivative and a method for preparing the same. In the present invention, 2-(4-methylbenzylidene)malononitrile undergoes a nucleophilic reaction with 4-methoxyaryl isonitrile to form a three-membered ring intermediate, which is then subjected to a Friedel-Crafts reaction and ring opening to ultimately yield a polysubstituted indole derivative. This method synthesizes 2,3-disubstituted indole derivatives in a single step under catalyst-free conditions. This method is green and efficient, and does not require indole as a reaction substrate. Instead, the alkylation reaction of 2-(4-methylbenzylidene)malononitrile with a readily available isonitrile is carried out, 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:

[0007] In a first aspect of the present invention, a 2,3-disubstituted indole derivative is provided, wherein the structural formula of the 2,3-disubstituted indole derivative is:

[0008] ;

[0009] Among them, R 1is selected from the C1-C20 straight or branched chain alkyl, aryl, halogen atom, and hydrogen atom;

[0010] R 2 is selected from aryl, fused aryl, heteroaryl or alkyl;

[0011] R 3 Selected from alkyl groups.

[0012] Preferably, the R 1 is selected from 4-phenyl, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-carboethoxy, 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-carboethoxy, 3,4-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 4-methylbenzyl, 4-chlorobenzyl or a hydrogen atom;

[0013] 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;

[0014] R 3 Selected from 2-methylmalononitrile, 2-methyl-3-oxosuccinic acid dimethyl ester, 2-nitro-1-phenylpropan-1-onyl, 2-methyl-1-phenylpropan-1-onyl, 2-methyl-3-oxobutyronitrile and 2,4,4-trimethyl-3-oxopentanonitrile.

[0015] Preferably, the 2,3-disubstituted indole derivative is 5-methoxy-3-p-tolyl-2-malononitrile indole, and its structural formula is:

[0016] .

[0017] The second aspect of the present invention provides a method for preparing a 2,3-disubstituted indole derivative, which comprises:

[0018] A benzyl propylene dinitrile compound and an aromatic isonitrile compound are added to a solvent and heated for reaction to obtain a 2,3-disubstituted indole derivative.

[0019] Preferably, the structural formula of the benzyl propylene malononitrile compound is:

[0020] ;

[0021] Among them, R 2is selected from aryl, fused aryl, heteroaryl or alkyl.

[0022] Preferably, the 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.

[0023] Preferably, the R 2 The benzyl propylene malononitrile compound is 2-(4-methylbenzylidene) malononitrile.

[0024] Preferably, the structural formula of the aromatic isonitrile compound is:

[0025] ;

[0026] Among them, R 1 Selected from the C1-C20 straight or branched alkyl group, aryl group, halogen atom, and hydrogen atom.

[0027] Preferably, the R 1 is selected from 4-phenyl, 4-methyl, 4-methoxy, 4-fluoro, 4-chloro, 4-bromo, 4-iodo, 4-carboethoxy, 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-carboethoxy, 3,4-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 4-methylbenzyl, 4-chlorobenzyl or a hydrogen atom.

[0028] Preferably, the molar ratio of the 2-(4-methylbenzylidene)malononitrile compound to the aromatic isonitrile compound is 1:1; and the solvent is selected from at least one of ethylene glycol dimethyl ether, ethanol or water.

[0029] Preferably, the R 1 Selected from 4-methoxy; the aromatic isocyanide compound is 4-methoxy aromatic isocyanide.

[0030] Preferably, the heating reaction temperature is 60-80° C., and the heating reaction time is 1-3 hours.

[0031] Beneficial effects of the present invention:

[0032] (1) The present invention uses 2-(4-methylbenzylidene)malononitrile to react with isonitrile to form a three-membered ring intermediate, which then undergoes a Friedel-Crafts reaction and ring opening to finally obtain an important synthon of polysubstituted indole. This method synthesizes 2,3-disubstituted indole derivatives in one step under catalyst-free conditions. This method is green and efficient. It does not require indole as a reaction substrate. The alkylation reaction of 2-(4-methylbenzylidene)malononitrile with isonitrile, which is easily available, provides a simple and efficient new method for the synthesis of 2,3-disubstituted indole derivatives.

[0033] (2) The present invention uses 2-(4-methylbenzylidene)malononitrile and various isonitriles as substrates, without the need for metal reagents or base catalysis, and without the need to isolate water or oxygen, to react in an organic solvent to obtain 2,3-disubstituted indole derivatives.

[0034] (3) The present invention has short reaction time, mild conditions, simple operation, and readily available raw materials and reagents. It is highly practical and suitable for the synthesis of polysubstituted indole derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 : Hydrogen spectrum of the 2,3-disubstituted indole derivative prepared in Example 1;

[0036] Figure 2 : Carbon spectrum of 2,3-disubstituted indole derivatives prepared in Example 1. DETAILED DESCRIPTION

[0037] It should be noted that the following detailed descriptions are illustrative and 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 skilled in the art to which the present application belongs.

[0038] As mentioned in the background technology section, 2-substituted indole derivatives, 3-substituted indole derivatives, or 2,3-substituted indole derivatives are currently primarily prepared through a one-step reaction of malononitrile, an aldehyde, and indole using choline chloride as a catalyst. These reactions all require indole as a substrate and a catalyst.

[0039] Based on this, the purpose of the present invention is to provide a 2,3-disubstituted indole derivative and a preparation method thereof, which does not require indole as a reaction substrate and does not require the addition of a catalyst. Due to its unique reactivity, isocyanide has been proven to be a universal synthetic building block in many transformations. However, due to the existence of self-dimerization, polymerization and other side reactions of the same isocyanide, the development and application of multi-component reactions and cross-heterocyclization reactions of isocyanide are greatly limited. Therefore, based on the simple and easily available isocyanide, a simple and efficient new synthetic method is provided for the de novo synthesis of 2,3-disubstituted indole derivatives through the alkylation reaction of isocyanide with 2-(4-methylbenzylidene)malononitrile. The present invention uses 2-(4-methylbenzylidene)malononitrile and isocyanide compounds as reaction substrates, adds them to a solvent and heats the reaction to obtain 2,3-disubstituted indole derivatives. Its synthetic route is:

[0040] .

[0041] The reaction principle is: 2-(4-methylbenzylidene) malononitrile reacts with isonitrile to form a three-membered ring intermediate, which then undergoes a Friedel-Crafts reaction and ring opening to finally obtain an important synthon of polysubstituted indoles. The reaction process is as follows:

[0042] .

[0043] Therefore, the present invention does not require metal reagents or base catalysis, does not require isolation of water or oxygen, has the advantages of a wide substrate adaptability and 100% atom economy, and can synthesize polysubstituted indole derivatives from scratch in an organic solvent in a one-pot reaction.

[0044] 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 with reference to specific embodiments.

[0045] Note: 4-methoxyaryl isocyanide in the present invention is also called 4-methoxybenzene isocyanide;

[0046] The systematic name of 5-methoxy-3-p-tolyl-2-malononitrile indole is also called 2-(5-methoxy-3-(p-tolyl)-1H-indol-2-yl)malononitrile.

[0047] The test materials used in the examples of the present invention are all conventional test materials in the art and can be purchased through commercial channels.

[0048] Example 1: Preparation of 2,3-disubstituted indole derivatives

[0049] The synthetic route of 2-(5-methoxy-3-(p-tolyl)-1H-indol-2-yl)malononitrile is: .

[0050] To a 15 mL pressure tube, 40.36 mg of 2-(4-methylbenzylidene)malononitrile (1a, 0.24 mmol, excess), 26.6 mg of 4-methoxyaryl isocyanide (2a, 0.2 mmol), and 2 mL of ethylene glycol dimethyl ether (solvent) were added sequentially. A stirring bar was added, the stopcock of the pressure tube was tightened, and the tube was placed in a metal block preheated to 60°C and heated with stirring for 2 h. After the disappearance of 2a by TLC, the reaction system was isolated and purified to obtain a light green solid 3a (57.25 mg, 95% yield). 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): δ HRMS (ESI) m / z: [M+H] + calcd for C 12 H9N3O + 211.0740; found211.0736. Figure 1 is the H NMR spectrum of the 2,3-disubstituted indole derivative obtained in Example 1, Figure 2 Its NMR carbon spectrum.

[0051] Example 2: Preparation of 2,3-disubstituted indole derivatives

[0052] The difference from Example 1 was that ethylene glycol dimethyl ether was replaced with an equal volume of ethanol, and the mixture was heated and stirred in a metal block preheated to 80°C for 2 h. Finally, a light green solid 3a (55.31 mg, 92% yield) was obtained.

[0053] Example 3: Preparation of 2,3-disubstituted indole derivatives

[0054] The difference from Example 1 was that ethylene glycol dimethyl ether was replaced with 1.5 mL of ethanol and 0.5 mL of water, and the mixture was heated and stirred in a metal block preheated to 60°C for 2 h. Finally, a light green solid 3a (48.82 mg, 81% yield) was obtained.

[0055] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A method for preparing a 2,3-disubstituted indole derivative, characterized in that: The preparation method is: Adding a benzyl propylene dinitrile compound and an aromatic isonitrile compound to a solvent and heating the reaction to obtain a 2,3-disubstituted indole derivative, the structural formula of which is: ； The benzyl allylic malononitrile compound is 2-(4-methylbenzylidene) malononitrile; and the aryl isocyanide compound is 4-methoxyaryl isocyanide.

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

3. The preparation method according to claim 1, characterized in that The temperature of the heating reaction is 60-80° C., and the time of the heating reaction is 1-3 hours.

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