A method for preparing a phenylalkylamine compound
By using an alkali as a promoter in an oxygen atmosphere, benzaniline compounds are prepared by reacting diphenyl ethyl ketone compounds with aniline compounds. This method solves the problems of expensive catalysts and heavy metal pollution in existing technologies, and achieves green and efficient synthesis and low-cost production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- NANCHANG UNIV
- Filing Date
- 2023-09-22
- Publication Date
- 2026-06-26
AI Technical Summary
Existing methods for synthesizing benzene-anisamine compounds require expensive transition metal catalysts, involve harsh reaction conditions, and generate heavy metal pollution, making it difficult to achieve green and efficient synthesis.
In an oxygen atmosphere, using a base as a promoter and controlling the temperature at 50-70℃, benzaniline compounds are prepared by reacting the C=O double bond in diphenyl ethyl ketone compounds with aniline compounds, thus avoiding the use of expensive transition metal catalysts and producing environmentally friendly byproducts.
The synthesis of benzene-anisidine compounds has been achieved in a green and environmentally friendly manner. The reaction conditions are mild, the byproducts are easy to handle, the synthesis cost is reduced, and it is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, and more particularly to a method for preparing a benzene-anisidine compound. Background Technology
[0002] Benzanilides are important structural units in many natural products and drugs (Miyamura, H.; Min, H.; Soulé, J.-F.; Kobayashi, S., Angewandte Chemie International Edition 2015, 54 (26), 7564-7567.). In addition, these compounds can be used to prepare ligands, artificial dyes, electronic materials and optical materials (Allen, CL; Williams, JMJ, Chemical Society Reviews 2011, 40 (7).).
[0003] Therefore, many methods for synthesizing phenyl anisidine compounds have been developed. Among these methods, the most classic methods are the modified peroxide oxidation reaction (Zhao, Q.; Li, H.; Wang, L., Organic & Biomolecular Chemistry 2013, 11 (39).) and the palladium-copper catalytic reaction (Wang, Z.; Fan, W.; Deng, G.-J.; Zhou, W., Tetrahedron Lett. 2015, 56 (40), 5449-5452; Yang, G.-P.; Li, K.; Liu, W.; Zeng, K.; Liu, Y.-F., Organic & Biomolecular Chemistry 2020, 18(35), 6958-6964).
[0004] However, the above methods have drawbacks, including the need for expensive transition metals and the residue of precious metals after the reaction, which are detrimental to atom economy. Although transition metal-catalyzed amidation reactions of diphenyl ethyl ketone compounds are widely used, they also have a series of disadvantages, such as: 1) the need for expensive ligands, catalysts, and additives; 2) the need for harsh conditions (high temperature or long reaction time); 3) the generation of heavy metal pollution, especially when synthesizing compounds with high requirements for heavy metal content; and 4) the removal of directing groups from the reaction substrate. Therefore, exploring green and efficient synthetic methods remains urgently needed. Summary of the Invention
[0005] The purpose of this invention is to provide a method for preparing benzene-anisamine compounds that is simple, environmentally friendly, avoids the use of expensive transition metal catalysts, and has mild and controllable reaction conditions, producing environmentally friendly byproducts.
[0006] The present invention provides a method for preparing a benzaniline compound, comprising the following steps:
[0007] In a solvent, with alkali as a promoter, under an atmosphere of 20-100% oxygen concentration and with the temperature of the reaction system controlled at 50-70℃, diphenyl ethyl ketone compound I and aniline compound II undergo the following reaction to obtain benzanisidine compound III.
[0008]
[0009] Among them, R 1 R 2 R 3 R 4 R 5 and R 6 They are independently hydrogen and C1-C 40 aliphatic groups, C4-C 60 The aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxy group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group, where X is C or N.
[0010] This invention provides a method for preparing benzaniline compounds. In an alkaline environment with oxygen, the C=O double bond in diphenyl ethyl ketone compounds is selectively cleaved, and aniline compounds are used as the amine source to initiate a free radical coupling reaction to obtain the benzaniline compounds. The advantages are that the reaction is simple, environmentally friendly, avoids the use of expensive transition metal catalysts, and the reaction conditions are mild and controllable, producing environmentally friendly byproducts.
[0011] Optionally, when reacting diphenyl ethyl ketone compound I with aniline compound II, diphenyl ethyl ketone compound I needs to be in excess. This has the advantage of promoting the forward reaction, thereby increasing the yield of phenylanisidine compound III.
[0012] Optionally, when reacting the diphenyl ethyl ketone compound I with the aniline compound II, the molar ratio of the diphenyl ethyl ketone compound I to the aniline compound II is (1.5-2.5):1, that is, the diphenyl ethyl ketone compound I needs to be in excess.
[0013] Optionally, when an alkali is used as a promoter, the alkali is an inorganic alkali and / or an inorganic alkali.
[0014] Optionally, when an alkali is used as a promoter, the alkali includes one of t-BuOK, t-BuONa, KOH, NaOH, and K2CO3.
[0015] Optionally, when a base is used as a promoter, the molar ratio of the base to the aniline compound II is (2-4):1.
[0016] Optionally, after reacting diphenyl ethyl ketone compound I with aniline compound II, the reaction product is separated by column chromatography to obtain phenyl anisidine compound III.
[0017] Optionally, when separating the reaction products by column chromatography, the stationary phase is silica gel or neutral alumina, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of (10-100):1.
[0018] Optionally, the C1-C 40 The aliphatic groups include methyl, ethyl, propyl, isopropyl, butyl, or benzyl; the C4-C 60 The aromatic groups include pyridyl, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl; the halogens include fluorine, chlorine, bromine or iodine. Detailed Implementation
[0019] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art. The terms "comprising" and similar expressions used herein mean that the element or object preceding the word covers the element or object listed after the word and its equivalents, but does not exclude other elements or objects.
[0020] This invention provides a method for preparing benzanisidine compounds, comprising the following steps:
[0021] In a solvent, with alkali as a promoter, under an oxygen atmosphere, and with the temperature of the reaction system controlled at 50-70℃, diphenyl ethyl ketone compound I and aniline compound II undergo the following reaction to obtain benzanisidine compound III;
[0022]
[0023] Among them, R 1 R 2 R 3 R4 R 5 and R 6 They are independently hydrogen and C1-C 40 aliphatic groups, C4-C 60 The aromatic group, alkoxy group, trifluoromethoxy group, trifluoromethyl group, nitro group, cyano group, alkyl group, hydroxy group, carboxyl group, aldehyde group, carbonyl group, ester group, amino group, sulfonyl group, amide group or halogen group, where X is C or N.
[0024] In fact, during the reaction, due to the reactivity of the C=O double bond in diphenyl ethyl ketone compound I, in an alkaline environment, using aniline compound II as the amine source, the amidation reaction of diphenyl ethyl ketone compound I was achieved, thereby producing benzene-anisidine compound III. This reaction process does not require the use of expensive transition metals, and the byproducts are mainly phenylacetic acid compounds. The post-processing is simple, environmentally friendly, and does not easily cause pollution.
[0025] Specifically, both diphenyl ethyl ketone compound I and aniline compound II are commercially available conventional products, and can be purified using conventional purification methods in the art when necessary. Furthermore, the diphenyl ethyl ketone compound I and aniline compound II used can also be synthesized in the laboratory.
[0026] In some embodiments, C1-C 40 The aliphatic groups include methyl, ethyl, propyl, isopropyl, butyl, or benzyl, C4-C. 60 The aromatic groups include pyridyl, phenyl, substituted phenyl, 1-naphthyl or 2-naphthyl, and the halogens include fluorine, chlorine, bromine or iodine.
[0027] In some embodiments, when diphenyl ethyl ketone compound I reacts with aniline compound II, excess diphenyl ethyl ketone compound I and aniline compound II are mixed and reacted.
[0028] In fact, when excess diphenyl ethyl ketone compound I is mixed with aniline compound II for reaction, the molar ratio of diphenyl ethyl ketone compound I to aniline compound II is (1.5-2.5):1.
[0029] In some embodiments, when diphenyl ethyl ketone compound I reacts with aniline compound II in a solvent, the solvent is one of toluene, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, 1,4-dioxane, diethyl ether, and carbon tetrachloride. In practice, the solvent can be any solvent commonly used in the art for organic reactions, provided it can dissolve the reactants and products without reacting with them.
[0030] In some embodiments, when diphenyl ethyl ketone compound I reacts with aniline compound II in a solvent, the molar ratio of the solvent to aniline compound II is (40-100):1. In practice, the amount of solvent used is sufficient to completely dissolve the reactants.
[0031] In some embodiments, when a base is used as a promoter, the base is an organic base and / or an inorganic base. That is, when diphenyl ethyl ketone compound I reacts with aniline compound II, an organic base or an inorganic base can be used as a promoter, or a mixture of organic and inorganic bases in any proportion can be used as a promoter, as long as it can provide an alkaline environment for the reaction system, all of which can achieve a good promoting effect.
[0032] Specifically, the organic base includes t-BuOK and / or t-BuONa. That is, when using an organic base as a promoter in the reaction system, t-BuOK or t-BuONa can be specifically selected as the promoter, or a mixture of t-BuOK and t-BuONa in any proportion can be selected as the promoter.
[0033] Specifically, inorganic bases include KOH, NaOH, Cs2CO3, or K2CO3. That is, when using an inorganic base as a reaction promoter, one of KOH, NaOH, Cs2CO3, and K2CO3 can be selected as the promoter, or any two, three, or four of KOH, Cs2CO3, NaOH, and K2CO3 in any proportion can be used as the promoter.
[0034] In fact, using a combination of t-BuOK, t-BuONa, KOH, Cs2CO3, NaOH and K2CO3 as a promoter is inexpensive and readily available, which helps to reduce the cost of the synthesis reaction of benzene-anisidine compounds III. In addition, the raw materials diphenyl ethyl ketone compounds I and aniline compounds II are also relatively inexpensive, thus making the overall reaction cost lower and the synthesis process simple.
[0035] In some embodiments, when a base is used as a promoter, the molar ratio of the base to aniline compound II is (2-4):1. Specifically, when potassium hydroxide is used as a promoter in the reaction system, the molar ratio of potassium hydroxide to aniline compound II is 3:1.
[0036] In some embodiments, when diphenyl ethyl ketone compound I reacts with aniline compound II in a solvent, using a base as a promoter, under an oxygen atmosphere, and controlling the temperature of the reaction system at 50-70°C, the reaction process to prepare benzaniline compound III includes the following steps:
[0037] S1. Add diphenyl ethyl ketone compound I, aniline compound II and base used as a promoter into a reaction vessel. Add solvent to the reaction vessel in an oxygen atmosphere and stir to dissolve. Control the reaction temperature at 50-70℃.
[0038] S2. The reaction product in S1 is separated and purified to obtain benzanisidine compound III.
[0039] In practice, during step S1, after adding diphenyl ethyl ketone compound I, aniline compound II, and the base used as a promoter to the reaction vessel, oxygen is circulated to replace the gas inside the reaction vessel, thus creating an oxygen atmosphere. Specifically, the oxygen is circulated three times.
[0040] In some embodiments, the reaction vessel used in performing step S1 may be a Schlenk tube.
[0041] In some embodiments, during step S1, when the reaction is stirred at 50-70°C, the reaction time is controlled to be 2-6 hours.
[0042] In some embodiments, during step S2, after adding deionized water to the reaction product in S1 for quenching, the reaction product is extracted using an organic solvent, and the extracted product is separated and purified to obtain benzene-anisidine compound III.
[0043] Specifically, the organic solvent used can be dichloromethane, ethyl acetate, or diethyl ether, and the amount of organic solvent used is 30-80 equivalents of aniline compound II.
[0044] Specifically, when separating and purifying the extract, conventional purification methods in the art can be used, such as rotary evaporation of solvents and column chromatography. When using column chromatography to separate and purify benzanilide compounds III, silica gel or neutral alumina is used as the stationary phase, and a mixture of petroleum ether and ethyl acetate in a volume ratio of 10-100 is used as the eluent.
[0045] In some embodiments, when performing step S1, the reaction product in S1 is directly packed into a column, with silica gel or neutral alumina as the stationary phase and a mixture of petroleum ether and ethyl acetate in a volume ratio of 10-100 as the eluent, and column chromatography is performed to obtain benzene-anisidine compounds III.
[0046] Examples 1-7:
[0047] Examples 1-7 provide a method for preparing benzanisidine compounds, comprising the following steps:
[0048] S1. 78.4 mg (0.4 mmol) of diphenyl ethyl ketone compound I, 21.8 mg (0.2 mmol) of aniline compound II and 33.6 mg (0.6 mmol) of potassium hydroxide were added to a Schlenk tube. The gas in the Schlenk tube was replaced by oxygen circulation. 50 mL of dimethyl sulfoxide (DMSO) was added to the Schlenk tube in an oxygen atmosphere and stirred to dissolve. The mixture was then stirred and reacted at 60 °C for 5 h.
[0049] S2. Mix the reaction solution from S1 with silica gel powder and pack it into a column. Use a column chromatography separation with an eluent prepared by petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain pure benzene-anisidine compound III and calculate its yield.
[0050] The structural formulas of diphenyl ethyl ketone compound I and aniline compound II in Examples 1-7, the structural formula of the product phenyl anisidine compound III, and the yield are shown in Table 1.
[0051] Table 1
[0052]
[0053] The spectroscopic characterization of the product (N-(2-hydroxyphenyl)benzamide) prepared in Example 1 is as follows:
[0054] 1 H NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 8.34 (s, 1H), 8.00 (d, J = 7.5Hz, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 2H), 7.38 (s, J =7.1Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.02 (t, J = 7.4Hz, 1H). 13 C NMR (CDCl3, 100 MHz) δ 168.48, 150.14, 134.56, 133.89, 120.33, 128.68, 128.64, 126.99, 123.69, 122.03, 121.19.
[0055] The spectroscopic characterization of the product (N-(3-hydroxypyridin-2-yl)benzamide) prepared in Example 2 is as follows:
[0056] 1H NMR (CDCl3, 400 MHz) δ 10.60 (brs, 1H), 9.44 (brs, 1H), 8.18-8.00(m, 2H), 7.92 (d, J = 3.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.64-7.54 (m, 2H), 7.50 (dd, J = 1.4, 8.1 Hz, 1H), 7.22 (dd, J = 4.6, 8.6 Hz, 1H). 13 C NMR (CDCl3, 100MHz) δ 169.18, 146.24, 141.22, 140.23, 134.39, 133.59, 130.32, 129.60,129.07, 124.21.
[0057] The spectroscopic characterization of the product (N-(pyridin-4-yl)benzamide) prepared in Example 3 is as follows:
[0058] 1 H NMR (CDCl3, 400 MHz) δ 8.65 (d, J = 6.2 Hz, 2H), 8.25 (brs, 1H), 7.99-7.87 (m, 2H), 7.73-7.67 (m, 3H), 7.60-7.56 (t, J = 7.24 Hz, m, 2H). 13 CNMR (CDCl3, 100 MHz) δ 167.49, 152.17, 146.38, 135.43, 133.87, 130.32,128.49, 115.15.
[0059] The spectroscopic characterization of the product (N-phenylnicotinamide) prepared in Example 4 is as follows:
[0060] 1 H NMR (DMSO-d6, 400 MHz) δ 10.61 (brs, 1H), 8.90 (dd, J = 1.6, 4.4Hz, 2H), 7.96 (dd, J = 1.6, 4.4 Hz, 2H), 7.87 (d, J = 7.6 Hz, 2H), 7.50-7.45(m, 2H), 7.26-7.23 (m, 1H). 13C NMR (DMSO-d6, 100 MHz) δ 164.94, 151.16, 143.03, 139.57, 129.70, 125.19, 122.60, 121.47.
[0061] The spectroscopic characterization of the product (N-phenylthiazole-4-carboxamide) prepared in Example 5 is as follows:
[0062] 1 H NMR (DMSO-d6, 400 MHz) δ 10.41 (brs, 1H), 9.36 (d, J = 2.0 Hz, 1H), 8.60 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 8.3 Hz, 2H),7.20 (t, J = 7.4 Hz, 1H). 13 C NMR (DMSO-d6, 100 MHz) δ 160.09, 156.04, 151.69,139.47, 129.58, 126.50, 124.83, 121.38.
[0063] The spectroscopic characterization of the product (N-(pyridin-2-yl)isonicotinamide) prepared in Example 6 is as follows:
[0064] 1 H NMR (DMSO-d6, 400 MHz) δ 11.21 (brs, 1H), 8.86 (dd, J = 1.6, 4.4Hz, 2H), 8.53-8.50 (m, 1H), 8.30-8.27 (m, 1H), 8.01 (dd, J = 1.6, 4.4 Hz,2H), 7.99-7.85 (m, 1H), 7.32-7.29 (m, 1H). 13 C NMR (DMSO-d6, 100 MHz) δ165.63, 152.71, 151.19, 149.05, 142.20, 139.28, 122.77, 121.28, 115.85.
[0065] The spectroscopic characterization of the product (N-phenylcyclohexanecarboxamide) prepared in Example 7 is as follows:
[0066] 1H NMR (CDCl3, 400 MHz) δ 7.64 (d, J =7.9 Hz, 2H), 7.45 (brs, 1H),7.40 (t, J = 7.6 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 2.37-2.34 (m, 1H), 2.07-2.04 (brd, 2H), 1.93 (brd, 2H), 1.81 (brs, 1H), 1.69-1.59 (m, 2H), 1.45-1.35(m, 3H). 13 C NMR (CDCl3, 100 MHz) δ 175.79, 139.44, 130.25, 125.37, 121.11, 47.85, 30.98, 26.98.
[0067] The spectroscopic characterization of the product (N-phenylpropionamide) prepared in Example 8 is as follows:
[0068] 1 H NMR (CDCl3, 400 MHz) δ 7.54 (d, J =7.8 Hz, 2H), 7.34 (t, J = 7.3Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 2.41 (q, J = 7.5 Hz, 2H), 1.27 (t, J = 7.5Hz, 3H). 13 C NMR (CDCl3, 100 MHz) δ 173.49, 139.33, 130.26, 125.45, 121.16, 32.03, 11.00.
[0069] The spectroscopic characterization of the product ((R)-tert-butyl-2-(phenylcarbamoyl)pyrrolidine-1-carboxylate) prepared in Example 9 is as follows: ¹H NMR (CDCl₃, 400 MHz) δ 9.59 (brs, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.09 (s, 1H), 4.58 (s, 1H), 3.54 (s, 2H), 2.67 (s, 1H), 2.11–1.99 (m, 3H), 1.60 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz) δ 170.74, 157.69, 139.41, 129.92, 124.81, 120.64, 81.93, 61.46, 48.21, 29.37, 27.91, 25.63.
[0070] Example 10:
[0071] This embodiment 10 provides a method for preparing benzanisidine compounds, including the following steps:
[0072] S1. Add 4.0 g (20 mmol) of diphenyl ethyl ketone, 1.0 g (10 mmol) of o-aminophenol and 1.7 g (30 mmol) of potassium hydroxide to a Schlenk tube, replace the gas in the Schlenk tube with oxygen circulation, and add 50 mL of dimethyl sulfoxide (DMSO) to the Schlenk tube in an oxygen atmosphere and stir to dissolve. Stir and react at 60 °C for 5 h.
[0073] S2. Mix the reaction solution from S1 with silica gel powder and pack it into a column. Use a column chromatography separation with an eluent prepared by petroleum ether and ethyl acetate in a volume ratio of 10:1. Weigh out 2.1 g of pure benzaniline and calculate the yield as 95%.
[0074] The preparation reaction formula for the benzanisidine compounds in Example 10 is shown below:
[0075] .
[0076] As can be seen from Example 10, the preparation method provided by the present invention can prepare gram-scale benzanisidine compounds. The preparation reaction conditions are mild and environmentally friendly, without the need for expensive transition metal elements. Furthermore, the raw materials and base promoters used in the reaction are relatively inexpensive, resulting in low overall reaction costs. This method is beneficial for the large-scale industrial preparation of benzanisidine compounds and for their application in drug synthesis, artificial dyes, electronic materials, and optical materials.
[0077] While embodiments of the present invention have been described in detail above, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. However, it should be understood that such modifications and variations fall within the scope and spirit of the invention as set forth in the claims. Furthermore, the invention described herein may have other embodiments and can be implemented or carried out in various ways.
Claims
1. A method for preparing a benzanisidine compound, characterized in that, In a solvent, with alkali as a promoter, under an atmosphere of 20-100% oxygen concentration and with the temperature of the reaction system controlled at 50-70℃, diphenyl ethyl ketone compound I and aniline compound II undergo the following reaction to obtain benzanisidine compound III. ， Among them, R 1 R 2 R 3 R 4 R 5 and R 6 They are independently hydrogen and C1-C 40 The aliphatic group, pyridyl, phenyl, 1-naphthyl, 2-naphthyl, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, carboxyl, aldehyde, amino, or halogen, where X is C or N; the base is selected from t-BuOK, t-BuONa, KOH, NaOH, and K2CO3; the C1-C 40 The aliphatic groups are methyl, ethyl, propyl, isopropyl, butyl, or benzyl.
2. The method for preparing benzanisidine compounds according to claim 1, characterized in that, When performing the reaction between diphenyl ethyl ketone compound I and aniline compound II, diphenyl ethyl ketone compound I must be in excess for the reaction.
3. The method for preparing benzanisidine compounds according to claim 2, characterized in that, When the diphenyl ethyl ketone compound I reacts with the aniline compound II, the molar ratio of the diphenyl ethyl ketone compound I to the aniline compound II is (1.5-2.5):
1.
4. The method for preparing benzanisidine compounds according to claim 1, characterized in that, When an alkali is used as a promoter, the molar ratio of the alkali to the aniline compound II is (2-4):
1.
5. The method for preparing benzanisidine compounds according to claim 1, characterized in that, After reacting diphenyl ethyl ketone compound I with aniline compound II, the reaction products were separated by column chromatography to obtain phenyl anisidine compound III.
6. The method for preparing the benzanisidine compound according to claim 5, characterized in that, When separating the reaction products by column chromatography, the stationary phase is silica gel or neutral alumina, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of (100-10):
1.
7. The method for preparing the benzanisidine compound according to claim 1, characterized in that, The halogen is fluorine, chlorine, bromine or iodine.