Preparation method of quinoxaline derivative based on heterogeneous catalysis system

Abstract

The invention discloses a preparation method of a quinoxaline derivative based on a heterogeneous catalysis system, and belongs to the technical field of fine organic synthesis. The preparation method comprises the following steps: mixing alpha-hydroxy acid, 2, 5-dimethoxytetrahydrofuran, nitroaromatic amine, Fe-Ru / gamma-Al2O3 and an alkaline compound according to a molar ratio of (2.0 to 10.0): (1.0 to 2.0): 1: (0.02 to 0.5): (1.0 to 4.0), and dissolving to obtain the quinoxaline derivative. The method has the advantages of simplicity, high efficiency, recyclable catalyst, cheap and easily available raw materials, wide substrate applicability and the like, and the obtained product can be further derived to obtain functional molecules with fluorescent activity.

Description

Technical Field

[0001] The invention belongs to the technical field of fine organic synthesis, and particularly relates to a preparation method of quinoxaline derivatives based on a heterogeneous catalytic system. Background Art

[0002] Quinoxaline and its derivatives are widely used in important organic structures such as anticancer drugs, agrochemicals, anti-leishmania, fluorescent probes and organic light-emitting diodes (OLEDs). Currently, most of quinoxaline and its derivatives are prepared from 2-arylaniline as raw materials, using transition metals, strong acids or oxidants to generate reactive electrophilic C1 substances. Kundu's team proposed an improved Pictet-Spengler cyclization reaction, indoleaniline and aldehyde molecules were oxidized and cyclized under the catalysis of trifluoroacetic acid to generate intermediates, and then the oxidant potassium permanganate was added to oxidize and dehydrogenate at room temperature to obtain quinoxaline derivatives (Agarwal PK, Sawant D, Kundu B, Eur. J. Org. Chem. 2009, 2009, 292-303). Chen's team reported a strategy for synthesizing quinoxaline derivatives from pyrroloaniline and tert-butyl isocyanide under the conditions of metal acetate palladium catalysis and Lewis acid TMSCl (Luo L, Xiong T, Zhou L, Asian J. Org. Chem. 2021, 10, 2927-2931). However, these methods require the addition of additional metals and oxidants, and the reaction conditions are harsh, which can lead to environmental pollution, potential explosiveness or limited functional group tolerance, thus limiting the application of these transformations. Summary of the invention

[0003] In order to overcome the above-mentioned shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing quinoxaline derivatives based on a heterogeneous catalytic system to solve the technical problems of harsh reaction conditions and complex preparation process in the preparation of quinoxaline derivatives.

[0004] In order to achieve the above object, the present invention adopts the following technical solutions: The first aspect of the present invention discloses a method for preparing quinoxaline derivatives based on a heterogeneous catalytic system, wherein an α-hydroxy acid, 2,5-dimethoxytetrahydrofuran, a nitroaromatic amine, Fe-Ru / γ-Al2O3 and an alkaline compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0) are mixed and dissolved to obtain a quinoxaline derivative.

[0005] Preferably, the α-hydroxy acid is glycolic acid, lactic acid or mandelic acid.

[0006] Preferably, the aniline compound is 2-nitroaniline, 2-nitro-3-methylaniline, 2-nitro-6-methoxyaniline, 2-nitro-4-methoxyaniline or 2-nitro-4-chloroaniline.

[0007] Preferably, the basic compound is triethylamine, N-methylpiperidine or 4-methylmorpholine.

[0008] Preferably, the solvent is water.

[0009] More preferably, the molar ratio of nitroaromatic amine to water is 1:(20.0-40.0).

[0010] Preferably, the reaction temperature is 80°C to 140°C.

[0011] Preferably, the reaction time is 4 h to 12 h.

[0012] The second aspect of the present invention discloses a quinoxaline derivative prepared by the above-mentioned method for preparing a quinoxaline derivative based on a heterogeneous catalytic system.

[0013] The third aspect of the present invention discloses the use of the above-mentioned quinoxaline derivatives in the preparation of luminescent materials or in living cell fluorescence imaging.

[0014] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a method for preparing quinoxaline derivatives based on a heterogeneous catalytic system, 1) the raw materials used α 1) Both α-hydroxy acid and 2,5-dimethoxytetrahydrofuran are biomass-based molecules with wide sources and low costs, which conform to the concept of green chemistry; 2) directly use nitroaromatic hydrocarbons, the upper raw material of aromatic amine, which is economical; 3) by adding alkaline compounds to receive the protons of α-hydroxy acid, the source is wide and the effect is good; 4) using Fe-Ru / γ-Al2O3 as a catalyst can significantly improve the reaction efficiency; 5) each raw material is synthesized into quinoxaline derivatives in a one-step method in an aqueous system, the preparation process is simple, and the reaction conditions are mild. Therefore, this method has the advantages of simple and efficient operation, recyclable catalysts, cheap and easy-to-obtain raw materials, and wide applicability of substrates. The obtained products can be further derived to obtain functional molecules with fluorescent activity, which can be used to construct new rotor-based fluorescent groups. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 is the H NMR spectrum of 4-methylpyrrolo[1,2-a]quinoxaline in Example 1 of the present invention; Figure 2 is the NMR carbon spectrum of 4-methylpyrrolo[1,2-a]quinoxaline in Example 1 of the present invention; Figure 3The luminescence performance test results of the quinoxaline compounds in Example 6 of the present invention are shown in Figure 1; wherein (a) is the fluorescence spectra of (E)-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxaline-4-yl)vinyl]aniline in different solvents, and (b) is the fluorescence spectra of (E)-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxaline-4-yl)vinyl]aniline in different solvents. f w Photoluminescence spectra in an acetonitrile / water (MeCN / H2O) mixture, (c) fluorescence imaging in living cells, fluorescence, (d) fluorescence imaging in living cells, bright field, (e) fluorescence imaging in living cells, overlay. DETAILED DESCRIPTION

[0016] In order to enable those skilled in the art to understand the characteristics and effects of the present invention, the following is a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used in the text are the common meanings understood by those skilled in the art for the present invention. In the event of a conflict, the definition in this specification shall prevail.

[0017] The theories or mechanisms described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, that is, the present invention can be implemented without being limited by any specific theory or mechanism.

[0018] In this article, all features such as values, quantities, contents and concentrations defined in the form of numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have included and specifically disclosed all possible secondary ranges and individual values ​​within the range (including integers and fractions).

[0019] In this document, unless otherwise specified, “includes,” “including,” “contains,” “has,” or similar terms cover the meanings of “consisting of” and “mainly consisting of,” for example, “A includes a” covers the meanings of “A includes a and other” and “A only includes a.”

[0020] In this document, in order to make the description concise, not all possible combinations of various technical features in various embodiments or examples are described. Therefore, as long as there is no contradiction in the combination of these technical features, the various technical features in various embodiments or examples can be combined arbitrarily, and all possible combinations should be considered to be within the scope of this specification.

[0021] The present invention provides a preparation method of quinoxaline derivatives based on a heterogeneous catalytic system, comprising mixing an α-hydroxy acid, 2,5-dimethoxytetrahydrofuran, a nitroaromatic amine, Fe-Ru / γ-Al2O3 and an alkaline compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0), dissolving the mixture, reacting the mixture at 80-140°C for 4-12 hours, and separating and purifying the mixture by column chromatography to obtain a quinoxaline derivative; Wherein, the α-hydroxy acid is glycolic acid, lactic acid or mandelic acid; the aniline compound is 2-nitroaniline, 2-nitro-3-methylaniline, 2-nitro-6-methoxyaniline, 2-nitro-4-methoxyaniline or 2-nitro-4-chloroaniline; the alkaline compound is triethylamine, N-methylpiperidine or 4-methylmorpholine; water is used for dissolution, and the molar ratio of nitroaromatic amine to water is 1: (20.0-40.0).

[0022] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0023] The following examples use conventional instruments and equipment in the art. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The various raw materials used in the following examples are conventional commercial products unless otherwise specified, and their specifications are conventional specifications in the art. In the specification of the present invention and the following examples, unless otherwise specified, "%" means weight percentage, and ratio means weight ratio.

[0024] 1. One-step synthesis of quinoxaline derivatives Example 1 Synthesis of 4-methylpyrrolo[1,2-a]quinoxaline

[0025] Weigh (measure) 2-nitroaniline (0.1 mmol), 2,5-dimethoxytetrahydrofuran (1.5 equiv.), lactic acid (10.0 equiv.), Fe-Ru / γ-Al2O3 (2 mol%), triethylamine (4 equiv.) and water (40 equiv.), add them into the reaction tube in sequence, stir and mix evenly, react at 140°C for 6 h, filter and recover the catalyst, and directly use it in the next catalytic system. The filtrate is separated and purified by column chromatography to obtain 4-methylpyrrolo[1,2-a]quinoxaline with a yield of 86%. The H NMR spectrum of 4-methylpyrrolo[1,2-a]quinoxaline is shown in Figure 1 As shown, the NMR carbon spectrum is as follows Figure 2 shown.

[0026] 1 H NMR (400 MHz, CDCl3): δ = 7.96 – 7.88 (m, 2H), 7.83 (d, J = 7.9 Hz,1H), 7.53 – 7.40 (m, 2H), 6.93 – 6.84 (m, 2H), 2.76 (s, 3H) ppm. 13 C NMR (101MHz, CDCl3): δ = 153.5, 135.9, 129.3, 127.3, 126.9, 126.3, 125.1, 114.2, 113.7,113.5, 106.5, 22.0 ppm. Example 2 Synthesis of 4,6-dimethylpyrrolo[1,2-a]quinoxaline

[0027] Weigh 2-nitro-3-methylaniline (0.1 mmol), 2,5-dimethoxytetrahydrofuran (1.5 equiv.), lactic acid (10 equiv.), Fe-Ru / γ-Al2O3 (2 mol%), triethylamine (4 equiv.) and water (40 equiv.), add them into the reaction tube in sequence, stir and mix evenly, react at 140°C for 6 h, filter and recover the catalyst, and use it directly in the next catalytic system. The filtrate is separated and purified by column chromatography to obtain 4,6-dimethylpyrrolo[1,2-a]quinoxaline with a yield of 83%.

[0028] 1 H NMR (400 MHz, CDCl3): δ = 8.33 (dd, J = 2.9 Hz, 1.4 Hz, 1H), 7.83 (dd, J = 7.7 Hz, 1.9 Hz, 1H), 7.37 – 7.28 (m, 2H), 6.96 (dd, J = 4.0 Hz, 1.4 Hz, 1H),6.87 (dd, J = 4.1 Hz, 2.8 Hz, 1H), 2.97 (s, 3H), 2.76 (s, 3H) ppm. 13C NMR (101MHz, CDCl3): δ = 153.3, 137.5, 130.5, 127.7, 125.4, 125.4,124.6, 120.0, 112.9,106.1, 24.0, 21.9 ppm. Example 3 Synthesis of 9-methoxy-4-methylpyrrolo[1,2-a]quinoxaline

[0029] Weigh (measure) 2-nitro-6-methoxyaniline (0.1 mmol), 2,5-dimethoxytetrahydrofuran (1.5 equiv.), lactic acid (10 equiv.), Fe-Ru / γ-Al2O3 (2 mol%), triethylamine (4 equiv.) and water (40 equiv.), add them into the reaction tube in sequence, stir and mix evenly, react at 140°C for 6 h, filter and recover the catalyst, and directly use it in the next catalytic system. The filtrate is separated and purified by column chromatography to obtain 9-methoxy-4-methylpyrrolo[1,2-a]quinoxaline with a yield of 82%.

[0030] 1 H NMR (400 MHz, CDCl3): δ = 8.75 (dd, J = 2.9 Hz, 1.4 Hz, 1H), 7.60 –7.53 (m, 1H), 7.37 (t, J = 8.2 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 4.1Hz, 1.4 Hz, 1H), 6.86 – 6.80 (m, 1H), 4.10 (s, 3H), 2.76 (s, 3H) ppm. 13 C NMR (101 MHz, CDCl3): δ = 153.9, 149.8, 138.2, 126.8, 124.3, 122.1, 121.3, 118.7,112.5, 108.5, 105.9, 56.2, 22.0 ppm. Example 4 Synthesis of 7-methoxypyrrolo[1,2-a]quinoxaline

[0031] Weigh (measure) 2-nitro-4-methoxyaniline (0.1 mmol), 2,5-dimethoxytetrahydrofuran (2 equiv.), glycolic acid (2 equiv.), Fe-Ru / γ-Al2O3 (50 mol%), 4-methylmorpholine (1 equiv.) and water (20 equiv.), add them into the reaction tube in sequence, stir and mix evenly, react at 80°C for 12 h, filter and recover the catalyst, and directly use it in the next catalytic system. The filtrate is separated and purified by column chromatography to obtain 7-methoxypyrrolo[1,2-a]quinoxaline with a yield of 77%.

[0032] Example 5 Synthesis of 7-chloro-4-phenylpyrrolo[1,2-a]quinoxaline

[0033] Weigh (measure) 2-nitro-4-chloroaniline (0.1 mmol), 2,5-dimethoxytetrahydrofuran (1 equiv.), mandelic acid (2 equiv.), Fe-Ru / γ-Al2O3 (20 mol%), N -Methylpiperidine (1 equiv.) and water (40 equiv.) were added to the reaction tube in sequence, stirred and mixed evenly, reacted at 140°C for 4 h, filtered to recover the catalyst, and directly used in the next catalytic system. The filtrate was separated and purified by column chromatography to obtain 7-chloro-4-phenylpyrrolo[1,2-a]quinoxaline with a yield of 82%.

[0034] 2. Application of Quinoxaline Compounds 1. Synthesis ( E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline

[0035] Weigh (measure) 4-methylpyrrolo[1,2-a]quinoxaline (0.1 mmol), 4-dimethylaminobenzaldehyde (1 equiv.) and acetic anhydride (20 equiv.) prepared in Example 1, add them into the reaction tube in sequence, stir and mix evenly, react at 140°C for 1 h, and separate and purify the reaction system by column chromatography to obtain ( E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline in 76% yield.

[0036] 1 H NMR (400 MHz, chloroform- d ): δ = 8.10 (d, J= 15.8 Hz, 1H), 8.02 (dd, J = 6.1, 3.4 Hz, 1H), 7.92 (d, J = 2.9 Hz, 1H), 7.80 (dd, J = 6.2, 3.4 Hz, 1H),7.61 (d, J = 8.3 Hz, 2H), 7.42 (dd, J = 6.3, 3.4 Hz, 2H), 7.31 (d, J = 15.8 Hz,1H), 7.12 (d, J = 4.1 Hz, 1H), 6.89 (t, J = 3.5 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H),3.02 (s, 6H) ppm. 13 C NMR (101 MHz, chloroform- d ): δ = 151.2, 150.4, 137.7,136.0, 129.4, 129.2, 127.1, 126.5, 126.1, 125.4, 124.4, 117.7, 114.6, 113.8,113.7, 112.1, 106.3, 40.3 ppm. 2. Study on the luminescence properties of quinoxaline derivatives 1) Fluorescence spectrum The ( E Fluorescence emission spectrum of )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline.

[0037] Test results such as Figure 3 As shown in (a), it can be seen that ( E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxaline-4-yl)vinyl]aniline showed bright fluorescence in viscous glycerol and PBS, indicating that the molecule is a fluorescent molecule with TICT effect, further indicating that the quinoxaline derivatives prepared by this method can be used to prepare luminescent materials.

[0038] 2) Photoluminescence spectroscopy The water fractions in MeCN / water mixtures were further investigated. f w )( E)-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline.

[0039] Test results such as Figure 3 As shown in (b), it can be seen that with f w From 0 to 40%, the PL intensity gradually increased significantly, and the emission wavelength red-shifted, showing an obvious AIE (Aggregation-induced Emission) phenomenon. With the further increase of water content, the wavelength experienced a further shift, and the emission intensity gradually weakened due to the twisted intramolecular charge transfer (TICT) effect, in which the increase of solvent polarity and the twisted molecular conformation led to enhanced charge separation and narrowing of the band gap, resulting in the observed red shift and emission attenuation, indicating that the molecule has an AIE effect, further indicating that the quinoxaline derivatives prepared by this method can be used to prepare luminescent materials.

[0040] 3) Live cell fluorescence imaging The cells were mixed with ( E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline was co-incubated to make ( E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline fully penetrated the cell membrane and accumulated in the cytoplasm, and the cells were observed using a fluorescence microscope.

[0041] The results are as follows Figure 3 As shown in (c), it can be seen that ( E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline can penetrate cell membranes and selectively accumulate in the cytoplasm, suggesting that it can be used for cell imaging.

[0042] In summary, the luminescent materials prepared by the quinoxaline derivatives synthesized by this method have good TICT and aggregation-induced emission (AIE) effects, indicating the feasibility of constructing new rotor fluorophores based on the cellulose platform through methodological approaches.

[0043] The above contents are only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing quinoxaline derivatives based on a heterogeneous catalytic system, characterized in that: An α-hydroxy acid, 2,5-dimethoxytetrahydrofuran, a nitroaromatic amine, Fe-Ru / γ-Al2O3 and a basic compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0) are mixed and dissolved to obtain a quinoxaline derivative.

2. The method for preparing quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that: The α-hydroxy acid is glycolic acid, lactic acid or mandelic acid.

3. The method for preparing quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that: The aniline compound is 2-nitroaniline, 2-nitro-3-methylaniline, 2-nitro-6-methoxyaniline, 2-nitro-4-methoxyaniline or 2-nitro-4-chloroaniline.

4. The method for preparing quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that: The basic compound is triethylamine, N-methylpiperidine or 4-methylmorpholine.

5. The method for preparing quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that: The solvent is water.

6. The method for preparing quinoxaline derivatives based on a heterogeneous catalytic system according to claim 5, characterized in that: The molar ratio of nitroaromatic amine to water is 1:(20.0-40.0).

7. The method for preparing a quinoxaline derivative based on a heterogeneous catalytic system according to any one of claims 1 to 6, characterized in that: The reaction temperature is 80℃~140℃.

8. The method for preparing a quinoxaline derivative based on a heterogeneous catalytic system according to any one of claims 1 to 6, characterized in that: The reaction time is 4 h~12 h.

9. A quinoxaline derivative obtained by the method for preparing a quinoxaline derivative based on a heterogeneous catalytic system according to any one of claims 1 to 8.

10. Use of the quinoxaline derivative according to claim 9 in preparing luminescent materials or in living cell fluorescence imaging.

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