Compound synthesis method of p-nitrobenzaldehyde

Abstract

The invention provides a synthetic method of p-nitrobenzaldehyde. According to the method, p-nitrobenzyl alcohol is taken as a raw material, Cu (I) salt and imidazole are taken as catalysts, oxygen is taken as an oxidant, and oxidation reaction is carried out under the action of TEMPO to obtain p-nitrobenzaldehyde. The method has the advantages of high reaction activity, mild reaction conditions, cheap and easily available initial raw materials, cleanness, environmental protection and very high industrial application value.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a synthesis method for oxidizing p-nitrobenzyl alcohol with oxygen to generate p-nitrobenzaldehyde. Background Art

[0002] p-Nitrobenzaldehyde, with the molecular formula C 7 H 5 NO 3 , has a molecular weight of 151.12, appears as white or light yellow crystals, has a melting point of 106°C - 107°C, a relative density of 1.496, is insoluble in water, slightly soluble in ether, and easily soluble in ethanol, benzene, and glacial acetic acid. p-Nitrobenzaldehyde is commonly used in the pharmaceutical industry for synthesizing nitrobenzylideneacetone, trimethoprim, acetamide phenylhydrazone, etc., and is also an important intermediate for pharmaceuticals, dyes, and pesticides. Common preparation methods for p-nitrobenzaldehyde include: 1) oxidizing 4-nitrotoluene under alkaline and high-pressure conditions to obtain 4-nitrobenzaldehyde [She Yuanbin, Fan Lili, Zhang Yanhui, etc. A new method for the green synthesis of p-nitrobenzaldehyde by metal porphyrin biomimetic catalysis, Acta Chimica Sinica, 2004]. 2) Using p-nitrobenzoyl chloride as a raw material and obtaining the product through a reduction reaction [Jia, Xueshun; et al Tetrahedron Letters, 2007, 48, 971 - 974]. 3) Using p-nitrobenzoic acid as a raw material and reacting with dimethyl sulfate and borane [CAha, Jin Soon; Park, Jae Hyung; Moon, SukJoung. Bulletin of the Korean Chemical Society, 2001, 22(10), 1089 - 1092]. These methods have defects such as poor atom economy, complex reaction conditions, usually generating a large amount of by-products and three wastes, and expensive and rare reaction reagents, so their applications are greatly limited.

[0003] The present invention provides a method for oxidizing p-nitrobenzyl alcohol to p-nitrobenzaldehyde, which does not require adding a large amount of catalyst, has simple operation, the oxidant is clean and easily available, and has a high reaction conversion rate, etc. Summary of the Invention

[0004] The present invention provides a synthesis method for a p-nitrobenzaldehyde compound. Using p-nitrobenzyl alcohol as a raw material, a complex formed by a Cu(I) salt and imidazole is used as a catalyst, and an oxidation reaction occurs under the action of TEMPO to generate p-nitrobenzaldehyde.

[0005] Using p-nitrobenzyl alcohol as a raw material, a Cu(I) salt (cuprous salt) and an imidazole compound are used as catalysts, oxygen is used as an oxidant, and an oxidation reaction occurs under the action of a catalytic amount of a TEMPO compound to generate p-nitrobenzaldehyde.

[0006] The specific steps are as follows:

[0007] Add p-nitrobenzyl alcohol to the reaction flask and add a solvent to dissolve it. Then add imidazole and cuprous salt, stir at 20 - 50 °C, introduce oxygen, and stir for 0.5 h - 6 h. The solution turns dark green, and the reaction is monitored by TLC until completion. Add dilute hydrochloric acid to quench the reaction, separate the layers, extract with ethyl acetate, dry over anhydrous sodium sulfate, and rotary evaporate to obtain a pale yellow solid.

[0008]

[0009] The reaction medium is one or more of methanol, ethanol, toluene, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, acetonitrile, or dichloromethane. Ethanol is preferred.

[0010] The Cu(I) salt is selected from anhydrous CuOTf, CuOAc, CuCl, CuBr, CuI, Cu(MeCN) 4 BF 4 and Cu(MeCN) 4 PF 6 One or more of them. CuOAc is preferred.

[0011] The imidazole has the following general structural formula:

[0012]

[0013] where R 1 、R 2 、R 3 、R 4 are selected from H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 40 alkoxy, halogen, nitro, ester group, cyano, phenyl, substituted phenyl, benzyl, and substituted benzyl. Preferably, R 1 、R 2 、R 3 、R 4 are all H, that is, imidazole.

[0014] The TEMPO (2,2,6,6-tetramethylpiperidine 1-oxide) has the following general structural formula:

[0015]

[0016] where R is selected from H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, C 1 -C40 Alkoxy group, halogen, nitro group, hydroxyl group, ester group, cyano group, phenyl group, substituted phenyl group, benzyl group and substituted benzyl group. Preferably, R is a hydroxyl group, that is, 4-hydroxy TEMPO

[0017] The molar ratio of the p-nitrobenzyl alcohol:imidazole:cuprous:TEMPO is 400 - 20:2 - 4:1:1, preferably 300 - 20:2:1:1

[0018] The oxidation reaction conditions are as follows:

[0019] Temperature: 20 - 120 °C, preferably 20 - 45 °C;

[0020] Time: 0.5 - 24 hours, preferably 4 - 6 hours. The present invention has the following advantages:

[0021] 1. The raw materials and catalysts are cheap and easily available, and the amount of catalyst used is small;

[0022] 2. The reaction has good activity, mild conditions, and uses oxygen for oxidation, which is green and environmentally friendly, suitable for industrialization, and has high industrial application value. Description of the Drawings

[0023] Figure 1 1H NMR spectrum of p-nitrobenzaldehyde prepared in Example 1; Detailed Description of the Invention

[0024] 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 not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer.

[0025] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. The reagents or raw materials used in the present invention can be obtained through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in the conventional manner in the art or according to the product instructions. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are only for demonstration purposes. The nuclear magnetic resonance of the embodiments of the present invention was measured by a Bruker 400 nuclear magnetic resonance spectrometer.

[0026] Example 1

[0027] Take a 250 ml two-necked flask, insert a thermometer, add 15.314 g (0.1 mol) of p-nitrobenzyl alcohol and 80 ml of ethanol, and stir to dissolve at room temperature. Add 0.001 mol of 4-hydroxy TEMPO, 0.002 mol of imidazole and copper acetate (CuOAc), and connect an oxygen balloon. React for 2 h, and perform TLC detection on the solution. The raw materials have completely reacted. Then carry out post-treatment, add 10% (mass concentration) dilute hydrochloric acid dropwise to remove cuprous ions, add ethyl acetate for extraction, separate the layers, extract the aqueous phase with 80 ml × 2 of ethyl acetate (80 ml each time, a total of 2 times), combine the organic phases, dry over anhydrous sodium sulfate, and rotary evaporate. Obtain 14.99 g (0.099 mol) of the product (p-nitrobenzaldehyde), a pale yellow solid, yield: 99%

[0028] 1 H NMR(400MHz,CDCl 3 ):10.17(s,1H),8.40(m,2H),8.08(m,2H);

[0029] Example 2

[0030] The process and conditions are the same as those in Example 1, the difference is that copper acetate (CuOAc) in Example 1 is replaced with an equimolar amount of CuI, and the rest is the same as in Example 1, yield: 73%.

[0031] Example 3

[0032] The process and conditions are the same as those in Example 1, the difference is that copper acetate (CuOAc) in Example 1 is replaced with an equimolar amount of CuCl, and the rest is the same as in Example 1, yield: 82%.

[0033] Example 4

[0034] The process and conditions are the same as those in Example 1, the difference is that copper acetate (CuOAc) in Example 1 is replaced with an equimolar amount of CuBr, and the rest is the same as in Example 1, yield: 85%.

[0035] Example 5

[0036] The process and conditions are the same as those in Example 1, the difference is that copper acetate (CuOAc) in Example 1 is replaced with an equimolar amount of CuOTf, and the rest is the same as in Example 1, yield: 92%.

[0037] Example 6

[0038] The process and conditions are the same as those in Example 1, the difference is that copper acetate (CuOAc) in Example 1 is replaced with an equimolar amount of [Cu(MeCN) 4 BF 4 instead, and the rest is the same as in Example 1, yield: 68%

[0039] Example 7

[0040] The process and conditions are the same as those in Example 1, except that the cuprous acetate (CuOAc) in Example 1 is replaced with an equimolar amount of [Cu(MeCN) 4 PF 6 The rest is the same as in Example 1, yield: 73%.

[0041] Example 8

[0042] The process and conditions are the same as those in Example 1, except that the imidazole in Example 1 is replaced with an equimolar amount of 1-methylimidazole. The rest is the same as in Example 1, yield: 92%.

[0043] The structure of 1-methylimidazole is as follows (V):

[0044]

[0045] Example 9

[0046] The process and conditions are the same as those in Example 1, except that the imidazole in Example 1 is replaced with an equimolar amount of 1-cyclopropylimidazole. The rest is the same as in Example 1, yield: 92%.

[0047] The structure of 1-cyclopropylimidazole is as follows (VI):

[0048]

[0049] Example 10

[0050] The process and conditions are the same as those in Example 1, except that the imidazole in Example 1 is replaced with an equimolar amount of 5-bromo-1-methylimidazole. The rest is the same as in Example 1, yield: 90%.

[0051] The structure of 5-bromo-1-methylimidazole is as follows (VII):

[0052]

[0053] Example 11

[0054] The process and conditions are the same as those in Example 1, except that the imidazole in Example 1 is replaced with an equimolar amount of 4-methylimidazole. The rest is the same as in Example 1, yield: 85%.

[0055] The structure of 4-methylimidazole is as follows (Ⅷ):

[0056]

[0057] Example 12

[0058] The process and conditions were the same as in Example 1, except that imidazole in Example 1 was replaced with an equimolar amount of 4-nitroimidazole, and the rest was the same as in Example 1. Yield: 85%.

[0059] The structure of 4-nitroimidazole is as follows (IX):

[0060]

[0061] Example 13

[0062] The process and conditions were the same as in Example 1, except that 4-hydroxy TEMPO in Example 1 was replaced with an equimolar amount of TEMPO, and the rest was the same as in Example 1. Yield: 95%.

[0063] The structure of TEMPO is as follows (XXI):

[0064]

[0065] Example 14

[0066] The process and conditions were the same as in Example 1, except that 4-hydroxy TEMPO in Example 1 was replaced with an equimolar amount of 4-methoxy TEMPO, and the rest was the same as in Example 1. Yield: 94%.

[0067] The structure of 4-methoxy TEMPO is as follows (XI):

[0068]

[0069] Example 15

[0070] The process and conditions were the same as in Example 1, except that ethanol in Example 1 was replaced with an equal volume of dichloromethane, and the rest was the same as in Example 1. Yield: 65%.

[0071] Example 16

[0072] The process and conditions were the same as in Example 1, except that ethanol in Example 1 was replaced with an equal volume of ethyl acetate, and the rest was the same as in Example 1. Yield: 54%.

[0073] Example 17

[0074] The process and conditions were the same as in Example 1, except that ethanol in Example 1 was replaced with an equal volume of acetonitrile, and the rest was the same as in Example 1. Yield: 74%.

[0075] Example 18

[0076] The process and conditions were the same as in Example 1, except that ethanol in Example 1 was replaced with an equal volume of toluene, and the rest was the same as in Example 1. Yield: 83%.

[0077] Example 19

[0078] The process and conditions are the same as those in Example 1, except that the ethanol in Example 1 is replaced with an equal volume of 1,4-dioxane, and the rest is the same as in Example 1. Yield: 79%.

[0079] Example 20

[0080] The process and conditions are the same as those in Example 1, except that the reaction temperature in Example 1 is changed from 25°C to 50°C, and the rest is the same as in Example 1. Yield: 82%.

[0081] Example 21

[0082] The process and conditions are the same as those in Example 1, except that the reaction temperature in Example 1 is changed from 25°C to 100°C, and the rest is the same as in Example 1. Yield: 69%.

[0083] The above-described embodiments only represent the implementation manners of the present invention, but should not be construed as limiting the scope of the present invention patent. It should be noted that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing p-nitrobenzaldehyde, characterized in that: With p-nitrobenzyl alcohol as a raw material, Cu(I) salt (cuprous salt) and imidazole compounds as catalysts, and oxygen as an oxidant, an oxidation reaction occurs under the action of TEMPO compounds to generate p-nitrobenzaldehyde.

2. The synthesis method according to claim 1, characterized in that: The p-nitrobenzaldehyde has the following structure: The p-nitrobenzyl alcohol has the following structure:

3. The synthesis method according to claim 1, characterized in that: The Cu(I) salt is selected from one or more of anhydrous CuOTf, CuOAc, CuCl, CuBr, CuI, Cu(MeCN)4BF4 and Cu(MeCN)4PF6.

4. The synthesis method according to claim 1, characterized in that: Imidazole compounds have the following general structural formula: Wherein R1, R2, R3, R4 are selected from H, C1-C 10 Alkyl, C3-C8 cycloalkyl, C1-C 40 One or more of alkoxy, halogen, nitro, ester, cyano, phenyl, substituted phenyl, benzyl and substituted benzyl, the substituents on the substituted phenyl and substituted benzyl are selected from C1-C40 alkoxy (preferably C1-C10 alkoxy, such as one or more of methoxy, ethoxy, etc.), C1-C40 alkyl (preferably C1-C10 alkyl, such as CH3, CH3CH2, (CH3)2CH 、 (CH3)3C, etc.), one or more of nitro, cyano, halogen (F, Cl, Br, I), and the number of substituents is 1-5.

5. The synthesis method according to claim 1, characterized in that: TEMPO, its general structural formula is as follows: Wherein R is selected from H, C1-C 10 Alkyl, C3-C8 cycloalkyl, C1-C 40 One or more of alkoxy, halogen, nitro, hydroxyl, ester, cyano, phenyl, substituted phenyl, benzyl and substituted benzyl, the substituents on the substituted phenyl and substituted benzyl are selected from C1-C40 alkoxy, (preferably C1-C10 alkoxy, such as one or more of methoxy, ethoxy, etc.), C1-C40 alkyl (preferably C1-C10 alkyl, such as CH3, CH3CH2, (CH3)2CH 、 (CH3)3C, etc.) one or more of C1-C40 alkyl, nitro, cyano, halogen (F, Cl, Br, I), the number of substituents is 1-5.

6. The synthesis method according to claim 1, characterized in that: The reaction medium (solvent) is one or more of methanol, ethanol, toluene, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, acetonitrile or dichloromethane.

7. The synthesis method according to claim 1, characterized in that: The molar ratio of nitrobenzyl alcohol: imidazole compound: cuprous salt: TEMPO is 400-20:2-4:1:1, preferably 300-18:2:1:1, and more preferably 260-18:2:1:

1.

8. The synthesis method according to any one of claims 1 to 7, characterized in that: The method is as follows: Add p-nitrobenzyl alcohol to a reaction container, add a solvent to dissolve it; then add imidazole and Cu(I) salt, stir at 20-120°C, introduce oxygen and / or air, stir for 0.5h-24h; add dilute hydrochloric acid to quench, add ethyl acetate to extract, dry, and rotary evaporate to obtain a light yellow solid.

9. The synthesis method according to claim 8, characterized in that: 20-100 ml of solvent for 0.1 mol of p-nitrobenzyl alcohol; The mass concentration of dilute hydrochloric acid is 5-15%.

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