A process for the preparation of quinoxaline derivatives based on a heterogeneous catalytic system

Abstract

The application discloses a preparation method of quinoxaline derivatives based on a multi-phase catalytic system and belongs to the technical field of fine organic synthesis. The quinoxaline derivatives are obtained by mixing and dissolving alpha-hydroxy acid, 2,5-dimethoxytetrahydrofuran, nitro aromatic amine, Fe-Ru / gamma-Al2O3 and alkaline compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0). The method has the advantages of simplicity and high efficiency, recyclable catalyst, cheap and easily available raw materials and wide applicability of substrates, and the obtained product can be further derived to obtain functional molecules with fluorescent activity.

Description

TECHNICAL FIELD

[0001] The present application 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

[0002] Quinoxaline and its derivatives have a wide range of applications in anticancer drugs, agrochemicals, anti-leishmania, fluorescent probes, and organic light-emitting diodes (OLEDs) and other important organic structures. At present, most quinoxaline and its derivatives are prepared from 2-aryl aniline as raw material, using transition metals, strong acids or oxidants to generate reactive electrophilic C1 substances. Kundu team proposed an improved Pictet-Spengler cyclization reaction, which oxidized the cyclization of indole aniline and aldehyde molecules under the catalysis of trifluoroacetic acid to generate an intermediate product, and then added an oxidant potassium permanganate to oxidize and dehydrogenate at room temperature to obtain quinoxaline derivatives (Agarwal P K, Sawant D, Kundu B, Eur. J. Org. Chem. 2009, 2009, 292-303). Chen team reported a strategy for synthesizing quinoxaline derivatives from pyrrole aniline and tert-butyl isocyanate under the catalysis of metal palladium acetate and Lewis acid TMSCl (Luo L, Xiong T, Zhou L, Asian J. Org. Chem. 2021, 10, 2927-2931). However, these methods require additional addition of metal and no oxidant, and the harsh reaction conditions will cause environmental pollution, potential explosion or limited functional group tolerance, thereby limiting the application of these transformations. SUMMARY

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

[0004] In order to achieve the above-mentioned purpose, the following technical solutions are adopted in the present application:

[0005] In a first aspect of the present application, a preparation method of quinoxaline derivatives based on a heterogeneous catalytic system is disclosed, which comprises mixing and dissolving α-hydroxy acid, 2,5-dimethoxy tetrahydrofuran, nitro aromatic amine, Fe-Ru / γ-Al2O3 and basic compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0) to obtain quinoxaline derivatives.

[0006] Preferably, the α-hydroxy acid is glycolic acid, lactic acid or mandelic acid.

[0007] Preferably, the aniline compound is 2-nitroaniline, 2-nitro-3-methylaniline, 2-nitro-6-methoxyaniline, 2-nitro-4-methoxyaniline or 2-nitro-4-chloroaniline.

[0008] Preferably, the basic compound is triethylamine, N-methylpiperidine or 4-methylmorpholine.

[0009] Preferably, the solvent is water.

[0010] Further preferably, the molar ratio of the nitroaromatic amine to water is 1: (20.0-40.0).

[0011] Preferably, the reaction temperature is 80-140℃.

[0012] Preferably, the reaction time is 4-12 h.

[0013] In a second aspect, the application discloses a quinoxaline derivative prepared by the method for preparing a quinoxaline derivative based on a heterogeneous catalytic system.

[0014] In a third aspect, the application discloses an application of the quinoxaline derivative in preparing a luminescent material or in fluorescence imaging of living cells.

[0015] Compared with the prior art, the application has the following beneficial effects:

[0016] The application provides a method for preparing a quinoxaline derivative based on a heterogeneous catalytic system. α -Both the hydroxy acid and the 2,5-dimethoxytetrahydrofuran are biomass-based molecules, are widely available and have low cost, and meet the concept of green chemistry; 2) The nitroaromatic hydrocarbon, which is an upper raw material of the arylamine, is directly used, and is economical; 3) The basic compound is used to receive the proton of the alpha-hydroxy acid, is widely available and has good effect; 4) The Fe-Ru / gamma-Al2O3 is used as the catalyst, and can significantly improve the reaction efficiency; 5) The quinoxaline derivative is synthesized by one-step method in the aqueous phase system, and the preparation process is simple and the reaction condition is mild. Therefore, the method has the advantages of simple operation, high efficiency, recyclable catalyst, cheap and easily available raw materials, and wide applicability of substrates, and the obtained product can be further derived to obtain functional molecules with fluorescence activity, and can be used to construct a new rotor-based fluorescent group. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 FIG. 4 is a nuclear magnetic hydrogen spectrum of 4-methylpyrrolo[1,2-a]quinoxaline in Example 1 of the application;

[0018] Figure 2 FIG. 4 is a nuclear magnetic hydrogen spectrum of 4-methylpyrrolo[1,2-a]quinoxaline in Example 1 of the application;

[0019] Figure 3 Figure 5 is a graph of the detection results of the luminescence performance of quinoxaline compounds in Example 6 of the present application; wherein (a) is the fluorescence spectrum of (E)-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline in different solvents, (b) is the photoluminescence spectrum in acetonitrile / water (MeCN / H2O) mixture, (c) is the fluorescence imaging in live cells, fluorescence, (d) is the fluorescence imaging in live cells, bright field, (e) is the fluorescence imaging in live cells, overlay. f w DETAILED DESCRIPTION

[0020] To enable persons skilled in the art to understand the features and effects of the present application, the following only generally describes and defines the terms and phrases mentioned in the specification and claims. Unless otherwise specified, all technical and scientific words used herein have their usual meanings to those skilled in the art of the present application, and in case of conflict, the definitions in the present specification shall prevail.

[0021] Theories or mechanisms described and disclosed herein, whether correct or not, should not be considered limiting on the scope of the present application, i.e., the present application can be practiced without regard to any particular theory or mechanism.

[0022] Herein, all features defined in the form of numerical ranges or percentage ranges such as numerical values, amounts, contents and concentrations are only for the sake of brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be considered to have encompassed and specifically disclosed all possible sub-ranges and individual numerical values within the range (including integers and fractions).

[0023] Herein, unless otherwise specified, "comprise", "include", "contain", "have" or similar words encompass the meaning of "consist of" and "consist essentially of", for example, "A comprises a" encompasses the meaning of "A comprises a and other" and "A comprises only a".

[0024] Herein, for the sake of brevity of the description, all possible combinations of the technical features in each embodiment or example are not described. Therefore, as long as the combinations of the technical features do not contradict each other, the technical features in each embodiment or example can be combined arbitrarily, and all possible combinations should be considered as the scope of the present specification.

[0025] ​The application provides a preparation method of quinoxaline derivatives based on a multi-phase catalytic system, which comprises the following steps: mixing and dissolving alpha-hydroxy acid, 2,5-dimethoxytetrahydrofuran, nitro aromatic amine, Fe-Ru / gamma-Al2O3 and alkaline compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0), and then reacting at 80-140 DEG C for 4-12 hours, and then separating and purifying by column chromatography to obtain quinoxaline derivatives.

[0026] The alpha-hydroxy acid is glycolic acid, lactic acid or mandelic acid; the aniline compound is 2-nitroaniline, 2-nitro-3-methylaniline, 2-nitro-6-methylaniline, 2-nitro-4-methylaniline or 2-nitro-4-chloroaniline; and the alkaline compound is triethylamine, N-methylpiperidine or 4-methylmorpholine; and the dissolving is performed with water, and the molar ratio of the nitro aromatic amine to water is 1:(20.0-40.0).

[0027] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application but not used to limit the scope of the application. Furthermore, it should be understood that those skilled in the art can make various modifications or changes to the application after reading the content of the application, and these equivalent forms also fall within the scope of the appended claims of the application.

[0028] The following examples use the conventional instruments and equipment in the art. The experimental methods in the following examples, if not otherwise specified, are usually performed according to the conventional conditions or the conditions suggested by the manufacturers. The following examples use various raw materials, unless otherwise specified, and the conventional commercially available products are used, and the specifications are the conventional specifications in the art. In the specification of the application and the following examples, unless otherwise specified, "%" represents the weight percentage, and the ratio represents the weight ratio.

[0029] I. One-step synthesis of quinoxaline derivatives

[0030] Example 1 Synthesis of 4-methylpyrrolo[1,2-a]quinoxaline

[0031]

[0032] Take (weigh) 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.) in turn into the reaction tube, stir and mix uniformly, react at 140°C for 6 h, filter and recover the catalyst, directly used 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 nuclear magnetic hydrogen spectrum of 4-methylpyrrolo[1,2-a]quinoxaline is shown in Figure 1 , and the nuclear magnetic carbon spectrum is shown in Figure 2 .

[0033] 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.

[0034] Example 2 Synthesis of 4,6-dimethylpyrrolo[1,2-a]quinoxaline

[0035]

[0036] Take (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.) in turn into the reaction tube, stir and mix uniformly, react at 140°C for 6 h, filter and recover the catalyst, directly used 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%.

[0037] 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. 13 C NMR (101 MHz, 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.

[0038] Synthesis of 9-methoxy-4-methylpyrrolo[1,2-a]quinoxaline

[0039]

[0040] Take (weigh) 2-nitro-6-methoxy aniline (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.), in turn into the reaction tube, stirring mixed uniform, under the condition of 140 ℃ reaction 6 h, filter recovery catalyst, direct use in the next catalytic system, the filtrate was separated and purified by column chromatography, to get 9-methoxy-4-methylpyrrolo[1,2-a]quinoxaline, yield of 82%.

[0041] 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.

[0042] Example 4 Synthesis of 7-methoxypyrrolo[1,2-a]quinoxaline

[0043]

[0044] Weigh out 0.1 mmol of 2-nitro-4-methoxyaniline, 2,5-dimethoxytetrahydrofuran (2 equiv.), glycolic acid (2 equiv.), Fe-Ru / γ-Al2O3 (50 mol%), 4-methylmorpholine (1 equiv.), and water (20 equiv.), and add them sequentially to a reaction tube. Stir and mix thoroughly, and react at 80 °C for 12 h. Filter to recover the catalyst, which can be directly used in the next catalytic system. The filtrate is purified by column chromatography to obtain 7-methoxypyrrolo[1,2-a]quinoxaline in a yield of 77%.

[0045] Example 5 Synthesis of 7-chloro-4-phenylpyrrolo[1,2-a]quinoxaline

[0046]

[0047] Weigh out 0.1 mmol of 2-nitro-4-chloroaniline, 1 equiv. of 2,5-dimethoxytetrahydrofuran, 2 equiv. of mandelic acid, and 20 mol% of Fe-Ru / γ-Al2O3. N 1-Methylpiperidine (1 equiv.) and water (40 equiv.) were added sequentially to the reaction tube and stirred until homogeneous. The mixture was reacted at 140 °C for 4 h. The catalyst was recovered by filtration and used directly in the next catalytic system. The filtrate was purified by column chromatography to obtain 7-chloro-4-phenylpyrrolo[1,2-a]quinoxaline in 82% yield.

[0048] II. Applications of Quinoxaline Compounds

[0049] 1. Synthesis ( E)-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline

[0050]

[0051] The 4-methylpyrrolo[1,2-a]quinoxaline (0.1 mmol) prepared in Example 1, 4- dimethylaminobenzaldehyde (1 equiv.) and acetic anhydride (20 equiv.) were weighed (measured) in turn into a reaction tube, stirred to mix well, and reacted at 140°C for 1 h. The reaction system was separated and purified by column chromatography to obtain E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline, with a yield of 76%.

[0052] 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.

[0053] 2. Investigation into the luminescent properties of quinoxaline derivatives

[0054] 1) Fluorescence spectrum

[0055] The synthesis of step 1 was measured in different solvents. E Fluorescence emission spectrum of )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline.

[0056] Test results as follows 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 exhibited bright fluorescence in viscous glycerol and PBS, indicating that the molecule is a fluorescent molecule with TICT effect, further demonstrating that the quinoxaline derivative prepared by this method can be used to prepare luminescent materials.

[0057] 2) Photoluminescence spectrum

[0058] Further investigation was conducted on different water fractions in the MeCN / water mixture. f w )( E Photoluminescence (PL) of )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline.

[0059] Test results as follows Figure 3 As shown in (b), it can be seen that, with f w As the water content increases from 0 to 40%, the PL intensity gradually and significantly increases, while the emission wavelength exhibits a redshift, demonstrating a clear AIE (Aggregation-induced Emission) phenomenon. With further increases in water content, the wavelength undergoes a re-shift, and the emission intensity gradually weakens due to the distorted intramolecular charge transfer (TICT) effect. The increased solvent polarity and the distorted molecular conformation lead to enhanced charge separation and a narrowing of the band gap, resulting in the observed redshift and emission attenuation. This indicates that the molecule possesses an AIE effect, further demonstrating that the quinoxaline derivative prepared by this method can be used to prepare luminescent materials.

[0060] 3) Live-cell fluorescence imaging

[0061] cell with ( E Co-incubation with )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline, so that ( E)-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline can penetrate the cell membrane and accumulate in the cytoplasm, and the cells are observed using a fluorescence microscope.

[0062] The results are shown in Table 1. Figure 3 As shown in (c) in Table 1, it can be seen that, E )-N,N-dimethyl-4-[2-(pyrrolo[1,2-a]quinoxalin-4-yl)vinyl]aniline can penetrate the cell membrane and selectively accumulate in the cytoplasm, indicating that it can be used for cell imaging.

[0063] In summary, the luminescent material prepared from the quinoxaline derivative synthesized by the method has good TICT and aggregation-induced emission (AIE) effect, indicating the feasibility of constructing a new rotor fluorophore based on a cellulose platform by a methodological approach.

[0064] The above is only to illustrate the technical idea of the present application, and cannot limit the protection scope of the present application. Any modification made according to the technical idea of the present application on the basis of the technical scheme falls within the protection scope of the claims of the present application.

Claims

1. A process for the preparation of quinoxaline derivatives based on a heterogeneous catalytic system, characterized by, A quinoxaline derivative is obtained by dissolving a mixture of alpha-hydroxy acid, 2,5-dimethoxytetrahydrofuran, nitro aromatic amine, Fe-Ru / gamma-Al2O3 and basic compound in a molar ratio of (2.0-10.0):(1.0-2.0):1:(0.02-0.5):(1.0-4.0) and reacting at 80-140 DEG C for 4-12 hours. The nitro aromatic amine is 2-nitroaniline, 2-nitro-3-methylaniline, 2-nitro-6-methoxyaniline, 2-nitro-4-methoxyaniline or 2-nitro-4-chloroaniline; and the basic compound is triethylamine, N-methylpiperidine or 4-methylmorpholine.

2. A process for the preparation of quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that, The alpha-hydroxy acid is glycolic acid, lactic acid or mandelic acid.

3. The process for the preparation of quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that, The solvent is water.

4. The process for the preparation of quinoxaline derivatives based on a heterogeneous catalytic system according to claim 1, characterized in that, The molar ratio of nitro aromatic amine to water is 1:(20.0-40.0).

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