Multiphase preparation method of aniline derivative

Abstract

The invention belongs to the technical field of fine chemicals and related chemistry, and provides a heterogeneous preparation method of an aniline derivative, which comprises the following steps: taking a nitrobenzene derivative as a raw material, and reacting in an organic solvent at 60-100 DEG C for 24 hours in a hydrogen environment under the action of a high-entropy alloy catalyst to obtain the corresponding aniline derivative. According to the method, the high-entropy alloy is used as the catalyst, the reaction selectivity is high, the reaction system is simple, the substrate compatibility is good, the highest yield can reach 97% or above, and the catalyst is good in stability and can be recycled. The aniline derivative prepared by the invention has a wide range of applications, and has an extremely important position in drug design and drug synthesis.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals and related chemical technologies, and provides a multiphase preparation method for aniline derivatives. Background Art

[0002] Aromatic amines are important intermediates in the synthesis of dyes, agricultural compounds, pharmaceuticals, and other substances and fine chemicals. Therefore, developing efficient synthetic methods for aromatic amines is crucial (Science 2006, 313, 332–334; Catal. Commun. 2017, 97, 83–87). The reduction of nitroaromatics to aromatic amines is an ideal synthetic route. However, achieving this reaction often faces many difficulties in actual operation. For example, traditional chemical reduction methods (such as iron powder, zinc powder, etc.) often have harsh conditions, poor selectivity, produce a large amount of chemical waste, and are difficult to be compatible with other sensitive functional groups in complex molecules (such as carbonyl, cyanide, etc.) (Adv. Mater. 2021, 33, 2008599); while the heterogeneous catalytic hydrogenation reduction route can simplify the production process and reduce costs, and has significant advantages. Currently, exploring heterogeneous catalytic hydrogenation systems with mild reaction conditions, high selectivity, simple operation and low cost is a research hotspot (J. Catal., 2025, 447, 116113).

[0003] Although platinum and palladium catalysts possess excellent catalytic properties and demonstrate exceptional catalytic activity in the reaction, their high cost and scarcity preclude their industrial-scale application and production. Iron and nickel catalysts, while relatively economical, suffer from structural instability and metal leaching, leading to rapid deactivation and limiting their application (Chin. J. Catal. 2019, 40, 1557-1565). Ruthenium is cheaper than platinum and palladium and has the ability to activate hydrogen molecules, but heterogeneous ruthenium-catalyzed hydrogenation of nitrobenzene to aniline has been rarely reported. Possible reasons include: 1. insufficient catalytic activity of ruthenium catalysts toward nitro substrates; 2. decreased reduction selectivity due to elevated temperature and hydrogen pressure; 3. insufficient stability of heterogeneous ruthenium catalysts; 4. imperfect catalyst recovery systems; and 5. the cost of ruthenium catalysts. Therefore, the development of novel heterogeneous ruthenium catalysts and novel systems for catalytic hydrogenation to aniline has both theoretical and practical significance.

[0004] In recent years, multimetallic alloys have attracted increasing attention as a unique catalyst with remarkable catalytic capabilities. Their multiple active sites enable them to exhibit enhanced catalytic activity and selectivity compared to traditional monometallic catalysts (Catal. Sci. Technol., 2025, 15, 2369-2378). High-entropy alloys, as special multimetallic alloys composed of five or more elements, possess excellent mechanical properties, corrosion resistance, radiation resistance, and catalytic performance, showing great application potential. Based on the problems existing in heterogeneous ruthenium-catalyzed nitro reduction, and combining the advantages of high-entropy alloys, a six-element high-entropy alloy catalyst containing ruthenium was created and used to synthesize aniline derivatives, thus developing a new method for the synthesis of aniline derivatives. Summary of the Invention

[0005] The present invention provides a multiphase preparation method for aniline derivatives. The method uses a hexavalent high-entropy alloy as a catalyst, has simple reaction conditions, high selectivity, a maximum yield of over 97%, good catalyst stability, and can be recycled using magnetism.

[0006] The technical solution of the present invention:

[0007] A multiphase preparation method for aniline derivatives, using nitrobenzene derivatives as raw materials, reacts in an organic solvent at 60-100°C for 24 hours under a hydrogen atmosphere and in the presence of a high entropy alloy catalyst to obtain the corresponding aniline derivatives. The synthetic route is as follows:

[0008] Wherein, R is selected from hydrogen atom, alkyl group, alkoxy group, halogen atom, nitro group, formyl group, alkenyl group, heteroaryl group, etc.;

[0009] The hydrogen pressure is 2.5-3.5 MPa;

[0010] The feed ratio of nitrobenzene derivative to high entropy alloy catalyst was 1 mmol: 3 mg;

[0011] The molar concentration of nitrobenzene derivatives in organic solvents was 0.5 mmol / mL;

[0012] The organic solvent is 1,4-dioxane, tert-butanol, acetonitrile, ethanol, isopropanol, dimethyl sulfoxide, tetrahydrofuran, etc., preferably 1,4-dioxane, acetonitrile, isopropanol and tetrahydrofuran;

[0013] The high entropy alloy catalyst is a carbon-based RuMnFeCoNiCu alloy.

[0014] The separation method is column chromatography.

[0015] When using column chromatography to separate products, silica gel can be used as the stationary phase, and the developing solvent is generally a mixed solvent of polar and non-polar solvents, such as ethyl acetate-petroleum ether, ethyl acetate-n-hexane, dichloromethane-petroleum ether, and methanol-petroleum ether.

[0016] H-NMR and C-NMR were used for qualitative analysis, and dibromomethane was used as the internal standard for quantitative analysis.

[0017] Beneficial effects of the present invention: The synthesis method of the present application uses an innovative high-entropy alloy catalyst, the reaction system is simple, the substrate compatibility is good, the product yield is high, it has good application value, the catalyst has good repeatability, and the atom utilization rate is high. The aniline derivatives obtained under this catalytic system have a wide range of uses and play an important role in the synthesis of natural products and drugs. For example, it can be used as a key intermediate for the construction of active alkaloids such as quinolines, and also provides a core synthetic unit for the research and development of sulfonamide antibiotics, tumor-targeted drugs, etc. (Mod. Sample Prep. Chromatogr., 2021, 499-593; Des. Monom. Polym., 2003, 6, 57–65). BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the p-methylaniline in Example 1 1 H NMR spectrum.

[0019] Figure 2 is the p-methylaniline in Example 1 13 C NMR spectrum.

[0020] Figure 3 is the p-anisidine in Example 2 1 H NMR spectrum.

[0021] Figure 4 is the p-anisidine in Example 2 13 C NMR spectrum.

[0022] Figure 5 is the p-bromoaniline in Example 3 1 H NMR spectrum.

[0023] Figure 6 is the p-bromoaniline in Example 3 13 C NMR spectrum.

[0024] Figure 7 It is the intermediate aminobenzene of Example 4 1 H NMR spectrum.

[0025] Figure 8 It is the intermediate aminobenzene of Example 4 13 C NMR spectrum.

[0026] Figure 9 is the 8-aminoquinoline in Example 5 1 H NMR spectrum.

[0027] Figure 10 is the 8-aminoquinoline in Example 5 13 C NMR spectrum.

[0028] Figure 11 is the 5-aminobenzimidazolone in Example 6 1 H NMR spectrum.

[0029] Figure 12 is the 5-aminobenzimidazolone in Example 6 13 C NMR spectrum.

[0030] Figure 13 is the p-aminobenzaldehyde in Example 7 1 H NMR spectrum.

[0031] Figure 14 is the p-aminobenzaldehyde in Example 7 13 C NMR spectrum.

[0032] Figure 15 is the p-aminostyrene in Example 8 1 H NMR spectrum.

[0033] Figure 16 is the p-aminostyrene in Example 8 13 C NMR spectrum.

[0034] Figure 17 It is the catalyst recycling yield result.

[0035] Figure 18 Figure 1 is a diagram of the catalyst recovery process; (a) is the initial catalyst and solution mixture, (b) is the separation by magnet adsorption, (c) is adsorption for 1 minute, (d) is adsorption for 3 minutes, (e) is adsorption for 5 minutes, and (f) is adsorption for 10 minutes.

[0036] Figure 19 are XPS graphs of the catalyst; among them, (a) is the Cu 2p spectrum, (b) is the Ni 2p spectrum, (c) is the Ru 3p spectrum, (d) is the Co 2p spectrum, (e) is the Mn 2p spectrum, and (f) is the Fe 2p spectrum.

[0037] Figure 20 is a scanning electron microscope image of the catalyst; among them, a is an electron image, b is a layered image, c is a Co layered image, d is a Ru layered image, e is a Cu layered image, f is a Mn layered image, g is a Ni layered image, and h is a Fe layered image. DETAILED DESCRIPTION

[0038] The specific implementation of the present invention is further described below in conjunction with the accompanying drawings and technical solutions.

[0039] Example 1: Synthesis of p-methylaniline

[0040] To a reaction kettle, p-nitrotoluene (137.1 mg, 1.0 mmol) and a carbon-based RuMnFeCoNiCu alloy (3.0 mg) were added sequentially. After dissolving the mixture in 2.0 mL of 1,4-dioxane, the mixture was purged with nitrogen and hydrogen five times, followed by a flow of 3 MPa of hydrogen. The reaction was sealed and allowed to react at 80°C for 24 h. After completion of the reaction, the product was isolated by column chromatography. 103 mg of p-methylaniline was obtained with a yield of 97%.

[0041] p-Toluidine

[0042] Brown powder; 1 H NMR (400 MHz, Chloroform-d) δ 6.86 (s, 2H), 6.50 (d, J =8.3 Hz, 2H), 3.46 (s, 2H), 2.15 (s, 3H); 13 C NMR (101 MHz, Chloroform-d) δ144.00, 129.85, 127.77, 115.36, 20.55.

[0043] Example 2: Synthesis of p-Anisidine

[0044] The operation was the same as in Example 1 to obtain 115 mg of p-anisidine from 4-methoxynitrobenzene with a yield of 94%.

[0045] p-Anisidine

[0046] Brown solid; 1 H NMR (400 MHz, Chloroform-d) δ 6.77 (d, J = 8.8 Hz, 2H), 6.64 (d, J = 8.8 Hz, 2H), 3.75 (s, 3H), 3.43 (s, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 152.74, 140.21, 116.46, 114.87, 55.74.

[0047] Example 3: Synthesis of p-bromoaniline

[0048] The operation was the same as in Example 1 to obtain 145 mg of p-bromoaniline from p-bromonitrobenzene with a yield of 84%.

[0049] p-Bromoaniline

[0050] Light yellow solid; 1 H NMR (400 MHz, Chloroform-d) δ 7.19 (d, J = 8.7 Hz, 2H), 6.49 (d, J = 8.7 Hz, 2H), 3.62 (s, 2H); 13 C NMR (101 MHz, Chloroform-d) δ145.65, 132.03, 116.82, 110.05.

[0051] Example 4: Synthesis of m-aniline

[0052] m-Nitrobenzene (123.3 mg, 1.0 mmol) and a carbon-based RuMnFeCoNiCu alloy (3.0 mg) were added to a reaction kettle in sequence. After dissolution in 2.0 mL of acetonitrile, the mixture was purged with nitrogen and hydrogen five times, followed by a flow of 3.5 MPa of hydrogen. The mixture was sealed and allowed to react at 60°C for 24 hours. After completion of the reaction, the product was isolated by column chromatography. 100 mg of p-methylaniline was obtained with a yield of 93%.

[0053] m-Aniline

[0054] Yellow solid; 1 H NMR (400 MHz, Chloroform-d) δ 6.82 (t, J = 7.9 Hz, 1H), 5.98 (d, J = 2.2 Hz, 1H), 5.96 (d, J = 2.2 Hz, 1H), 5.80 (t, J = 1.9 Hz, 1H), 3.45 (s, 4H); 13 C NMR (101 MHz, Chloroform-d) δ 147.77, 130.19, 105.98,102.25, 102.24.

[0055] Example 5: Synthesis of 8-aminoquinoline

[0056] 8-Nitroquinoline (174.2 mg, 1.0 mmol) and a carbon-based RuMnFeCoNiCu alloy (3.0 mg) were added sequentially to a reaction vessel. After dissolution in 2.0 mL of isopropanol, the mixture was purged with nitrogen and hydrogen five times, followed by a flow of 2.5 MPa of hydrogen. The reaction was sealed and allowed to react at 100°C for 24 hours. After completion of the reaction, the product was isolated by column chromatography. 110 mg of p-methylaniline was obtained with a yield of 97%.

[0057] 8-Nitroquinoline

[0058] Yellow solid; 1 H NMR (400 MHz, Chloroform-d) δ 8.57 (d, J = 6.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.13 (t, J=9.9Hz, 1H), 7.09 (t, J=6.3Hz, 1H), 6.94(d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 4.93 (s, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 147.48, 144.17, 138.48, 136.05, 128.93, 127.50, 121.40,116.00, 110.11.

[0059] Example 6: Synthesis of 5-aminobenzimidazolone

[0060] The same operation as in Example 5 was carried out to obtain 137 mg of 5-aminobenzimidazolone from 5-nitrobenzimidazolone with a yield of 92%.

[0061] 5-aminobenzimidazolone

[0062] Amber solid; 1 H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 10.06 (s, 1H), 6.59 (d, J = 8.2 Hz, 1H), 6.26 (s, 1H), 6.19 (d, J = 8.2 Hz, 1H), 4.70 (s, 2H); 13 C NMR (101 MHz, DMSO-d6) δ160.77, 148.28, 135.76, 125.85, 114.02,112.08, 100.81.

[0063] Example 7: Synthesis of p-aminobenzaldehyde

[0064] To a reaction kettle, p-nitrobenzaldehyde (151.3 mg, 1.0 mmol) and a carbon-based RuMnFeCoNiCu alloy (3.0 mg) were added sequentially. After dissolution in 2.0 mL of tetrahydrofuran, the mixture was purged with nitrogen and hydrogen five times, followed by a flow of 3 MPa of hydrogen. The reaction was sealed and allowed to react at 60°C for 24 hours. After completion of the reaction, the product was isolated by column chromatography. 113 mg of p-methylaniline was obtained, with a yield of 94%.

[0065] p-Aminobenzaldehyde

[0066] Yellow solid; 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 6.68 (d, J = 8.6Hz, 2H), 5.76 (d, J = 8.6 Hz, 2H), 5.42 (s, 2H); 13 C NMR (101 MHz, DMSO-d6) δ189.98, 155.50, 132.54, 125.27, 113.39.

[0067] Example 8: Synthesis of p-aminostyrene

[0068] The operation was the same as in Example 7 to obtain 0.060 g of p-aminostyrene from p-nitrostyrene with a yield of 67%.

[0069] p-Aminostyrene

[0070] Yellow solid; 1 H NMR (400 MHz, Chloroform-d) δ 7.22 (d, J = 8.3 Hz, 2H), 6.71 – 6.49 (m, 3H), 5.54 (d, J = 17.5 Hz, 1H), 5.03 (d, J = 10.8 Hz, 1H), 3.68 (s, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 146.21, 136.57, 128.41,127.39, 115.03, 110.04.

[0071] Catalyst cycle test results:

[0072] The stability of the catalyst was investigated through cycle testing. Figure 18It shows that after five cycles, the yield is still as high as 93%, which shows the high stability of the catalyst. In the catalyst recycling process, the magnetic properties of the high entropy alloy catalyst are used for recycling. The recycling effect is shown in the attached figure. Figure 19 shown.

[0073] Comparison of catalyst experimental results:

[0074] To visually demonstrate the performance differences between the catalyst of the present invention and commercial ruthenium-carbon, alloy ruthenium-carbon, and ruthenium-free catalysts, the following table summarizes the reduction product yields of 4-methylnitrobenzene for various catalysts under the same reaction conditions.

[0075] The experimental results clearly show that the catalyst of the present invention has better comprehensive performance and its activity is significantly improved compared with commercial ruthenium carbon and alloy ruthenium carbon.

[0076] Table 1. Substrate yields of different metal catalysts under the reaction conditions

[0077] .

Claims

1. A multiphase preparation method of aniline derivatives, characterized in that: Using nitrobenzene derivatives as raw materials, in a hydrogen atmosphere, under the action of a high entropy alloy catalyst, in an organic solvent, the reaction is carried out at 60-100°C for 24 hours to obtain the corresponding aniline derivatives. The synthetic route is as follows: ； wherein R is selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a nitro group, a formyl group, an alkenyl group, and a heteroaryl group; The hydrogen pressure is selected to be 2.5-3.5MPa; The feed ratio of nitrobenzene derivative to high entropy alloy catalyst was 1 mmol:3 mg; The molar concentration of the nitrobenzene derivative in the organic solvent was 0.5 mmol / mL.

2. The multiphase preparation method of stilbene derivatives according to claim 1, characterized in that: The organic solvent is one or a mixture of two or more of 1,4-dioxane, tert-butanol, acetonitrile, ethanol, isopropanol, dimethyl sulfoxide and tetrahydrofuran.

3. The multiphase preparation method of stilbene derivatives according to claim 1, characterized in that: The high entropy alloy catalyst is a carbon-based RuMnFeCoNiCu alloy.

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