CN118439966A - A kind of synthetic method of p-nitroaniline compound - Google Patents

Abstract

The present invention provides a method for synthesizing a p-nitroaniline compound, and relates to the technical field of organic synthesis. The synthesis method provided by the present invention comprises the following steps: in an oxygen-containing atmosphere at 20-100°C, in a solvent environment, in the presence of a base promoter, an amide compound II or an amino acid compound I replaces a p-nitrobenzene compound III, and then extracts and purifies the corresponding p-nitroaniline compound. The synthesis method provided by the present invention is simple, does not require the use of an expensive transition metal catalyst, and has mild reaction conditions, is green and environmentally friendly, and has low-cost effects, and is conducive to the large-scale synthesis and application of p-nitroaniline compounds.

Description

A kind of synthetic method of p-nitroaniline compound

Technical Field

The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing p-nitroaniline compounds.

Background technique

Amino acid or amide substituted p-nitrobenzene compounds are important structural units of many natural products and drugs. At the same time, these compounds can be used to prepare ligands, artificial dyes, electronic materials and optical materials. Therefore, many methods for synthesizing amino acid or amide substituted p-nitrobenzene compounds have been developed. Among these methods, the most classic method is the production of p-nitrochlorobenzene by ammonolysis under copper catalysis and acetanilide by nitration and hydrolysis.

For example, under the catalytic system of _Pd2 (dba) ₃ and _{Al2O3 ,} indole-2-carboxylic acid reacted with p-bromonitrobenzene under microwave conditions, and the product yield was 53%; and under the catalytic system of _Pd2 (dba) ₃ and cesium carbonate, 1-trifluoromethanesulfonyl-4-nitronaphthalene reacted with L-alanine methyl ester derivatives at 100°C, and the product yield was 43-79%; the reaction mechanism of the above catalytic reactions is that under high temperature conditions, the transition metal catalyst is inserted into the CX bond in the aromatic halogen, and then the amide is added to the transition metal, and the transition metal leaves to undergo an elimination reaction, thereby generating the target product.

The disadvantages of these methods are that they require transition metal catalysis, generate isomeric byproducts at other sites, or use nitric acid and other reaction conditions that are not convenient for subsequent treatment, which are not conducive to atom economy and green environmental protection requirements. Although transition metal-catalyzed N-substituted p-nitroaniline compounds are widely used, they also have a series of disadvantages, such as: 1) The nitration reaction is highly dangerous and easily causes explosions; 2) It requires harsh conditions (high temperature and high pressure or nitric acid oxidation); 3) It produces heavy metal pollution, especially when synthesizing compounds with high heavy metal content requirements; 4) The selectivity of the reaction product site. Reactions without transition metal catalysis are more environmentally friendly and economical. Although transition metal catalysts are effective in some reactions, they are usually expensive and may produce toxic waste during use, causing environmental pollution. Therefore, it is necessary to develop a green and environmentally friendly synthesis method.

Summary of the invention

The purpose of the present invention is to provide a method for synthesizing p-nitroaniline compounds. The method is simple, does not require the use of expensive transition metal catalysts, and has mild reaction conditions. It has the effects of being green, environmentally friendly, and low-cost, and is conducive to the large-scale synthesis and application of p-nitroaniline compounds.

In a first aspect, the present invention provides a method for synthesizing a p-nitroaniline compound, comprising reacting an amide compound II with a nitrobenzene compound III in an oxygen-containing atmosphere and a solvent environment at 20-100° C. in the presence of a base promoter for 1-8 hours, and then purifying and isolating a p-nitroaniline compound V;

;

Wherein, R ⁴ and R ⁵ are independently hydrogen or C ₁ -C ₅ alkyl, and R ⁶ is hydrogen, C ₁ -C ₄₀ aliphatic group, C ₄ -C ₆₀ aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, ester, amino, sulfonyl, amide or halogen.

Optionally, the base promoter includes at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, and lithium tert-butoxide.

Optionally, the solvent includes at least one of toluene, tetrahydrofuran, dimethyl sulfoxide, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, diethyl ether, and carbon tetrachloride.

Optionally, the C ₁ -C ₄₀ aliphatic group includes at least one of methyl, ethyl, propyl, isopropyl, butyl and benzyl.

Optionally, the C ₄ -C ₆₀ aromatic group includes at least one of a pyridine derivative, a phenyl group, a substituted phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

Optionally, the halogen includes at least one of fluorine, chlorine, bromine and iodine.

Optionally, the volume fraction of oxygen in the oxygen-containing atmosphere is 20-100%.

Optionally, the oxygen-containing atmosphere includes at least one of an oxygen atmosphere and an air atmosphere.

Optionally, the molar ratio of the amide compound II to the nitrobenzene compound III is 1:(1-10).

Optionally, the molar ratio of the base promoter to the reactant is 6:10, wherein the reactant includes an amide compound II and a nitrobenzene compound III.

Optionally, the molar concentration of the reactants in the solvent is 0.01-100 mol/L, wherein the reactants include amide compound II and nitrobenzene compound III.

Optionally, the process of purifying and separating the p-nitroaniline compound V includes: using an extractant to extract the reaction system after the reaction is completed, separating and obtaining an organic phase, and then performing column chromatography separation on the organic phase to obtain the p-nitroaniline compound V.

Optionally, the structural formula of the amide compound II includes at least one of the following chemical formulas II-1 to II-3:

.

In a second aspect, the present invention provides a method for synthesizing a p-nitroaniline compound, wherein an amino acid compound I reacts with a nitrobenzene compound III in an oxygen-containing atmosphere and a solvent environment at 20-100° C. in the presence of a base promoter for 1-8 hours, and then a p-nitroaniline compound IV is purified and separated;

;

Wherein, R ¹ , R ² , and R ³ are independently hydrogen or C ₁ -C ₅ alkyl, and R ⁶ is hydrogen, C ₁ -C ₄₀ aliphatic group, C ₄ -C ₆₀ aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, ester, amino, sulfonyl, amide or halogen.

Optionally, the base promoter includes at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, and lithium tert-butoxide.

Optionally, the solvent includes at least one of toluene, tetrahydrofuran, dimethyl sulfoxide, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, diethyl ether, and carbon tetrachloride.

Optionally, the C ₁ -C ₄₀ aliphatic group includes at least one of methyl, ethyl, propyl, isopropyl, butyl and benzyl.

Optionally, the C ₄ -C ₆₀ aromatic group includes at least one of a pyridine derivative, a phenyl group, a substituted phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

Optionally, the halogen includes at least one of fluorine, chlorine, bromine and iodine.

Optionally, the volume fraction of oxygen in the oxygen-containing atmosphere is 20-100%.

Optionally, the oxygen-containing atmosphere includes at least one of an oxygen atmosphere and an air atmosphere.

Optionally, the molar ratio of the amino acid compound I to the nitrobenzene compound III is 1:(1-10).

Optionally, the molar ratio of the base promoter to the reactant is 6:10, wherein the reactant includes amino acid compound I and nitrobenzene compound III.

Optionally, the molar concentration of the reactants in the solvent is 0.01-100 mol/L, wherein the reactants include amino acid compound I and nitrobenzene compound III.

Optionally, the process of purifying and separating the p-nitroaniline compound IV includes: using an extractant to extract the reaction system after the reaction is completed, separating and obtaining an organic phase, and then performing column chromatography on the organic phase to obtain the p-nitroaniline compound IV.

Optionally, the structural formula of the amino acid compound I includes at least one of the following chemical formulas I-1 to I-2:

.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a hydrogen NMR spectrum of the p-nitroaniline compound prepared in Example 1 of the present invention;

FIG2 is a carbon NMR spectrum of the p-nitroaniline compounds prepared in Example 1 of the present invention;

FIG3 is a hydrogen NMR spectrum of the p-nitroaniline compounds prepared in Example 2 of the present invention;

FIG4 is a carbon NMR spectrum of the p-nitroaniline compounds prepared in Example 2 of the present invention;

FIG5 is a hydrogen NMR spectrum of the p-nitroaniline compound prepared in Example 8 of the present invention;

FIG6 is a carbon NMR spectrum of the p-nitroaniline compound prepared in Example 8 of the present invention;

FIG. 7 is a reaction equation of amide compound II and nitrobenzene compound III provided by the present invention.

Detailed ways

In order to make the purpose, 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 part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein should be understood by people with general skills in the field to which the present invention belongs. "Including" and similar words used in this article mean that the elements or objects appearing before the word include the elements or objects listed after the word and their equivalents, without excluding other elements or objects.

The embodiment of the present invention provides a method for synthesizing a p-nitroaniline compound, comprising reacting an amide compound II with a nitrobenzene compound III in an oxygen-containing atmosphere and a solvent environment at 20-100° C. in the presence of an alkali promoter for 1-8 hours, and then purifying and isolating a p-nitroaniline compound V.

In fact, the use of a transition metal-free catalytic method to catalyze the reaction of amide compounds with nitrobenzene compounds to produce p-nitroaniline compounds is more environmentally friendly and has a lower economic cost, which is conducive to the application of p-nitroaniline compounds in organic ligands, artificial dyes, electronic materials and optical materials.

Specifically, referring to FIG7 , when the amide compound II reacts with the nitrobenzene compound III, the reaction equation is as follows:

;

Wherein, ^R4 and ^R5 are independently hydrogen or _C1 - _C5 alkyl, and ^R6 is hydrogen, _C1 - _C40 aliphatic group, _C4 - _C60 aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, ester, amino, sulfonyl, amide or halogen. In fact, ^R4 and ^R5 can also be cyclic substituents or chain substituents.

Specifically, the C ₁ -C ₄₀ aliphatic group includes at least one of methyl, ethyl, propyl, isopropyl, butyl and benzyl; the C ₄ -C ₆₀ aromatic group includes at least one of pyridine derivative, phenyl, substituted phenyl, 1-naphthyl and 2-naphthyl; and the halogen includes at least one of fluorine, chlorine, bromine and iodine.

In some embodiments, when the amide compound II reacts with the nitrobenzene compound III, the nitrobenzene compound III can be set in excess, which is conducive to the forward reaction and improves the conversion rate of the amide compound II and the yield of the p-nitroaniline compound V. Specifically, the molar ratio of the amide compound II to the nitrobenzene compound III during the reaction can be 1: (1-10).

In fact, under the action of the base promoter, the amide compound II loses an H proton and is converted into an N anion, which is then oxidized into an N radical by the oxygen in the oxygen-containing atmosphere. The N radical is highly reactive and attacks the C-H bond at the para position of the nitrobenzene compound III, thereby causing a coupling reaction to form a stable p-nitroaniline compound.

In some embodiments, the base promoter may be at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, and lithium tert-butoxide. In fact, when the amide compound II reacts with the nitrobenzene compound III under the base promoter, the molar ratio of the base promoter to the reactant (amide compound II and nitrobenzene compound III) is 6:10, which is conducive to the base promoter being fully in contact with the amide compound II and the nitrobenzene compound III in the reaction system, thereby improving the reaction efficiency.

In some embodiments, the oxygen-containing atmosphere may be a mixed atmosphere with an oxygen volume fraction of 20-100%. In fact, as the oxygen content in the oxygen-containing atmosphere increases, it helps to oxidize the N anion after the amide compound II loses an H proton, thereby helping to improve the reaction efficiency. Specifically, the oxygen-containing atmosphere may be an air atmosphere or an oxygen atmosphere.

In some embodiments, the solvent environment can be at least one of toluene, tetrahydrofuran, dimethyl sulfoxide, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, ether, and carbon tetrachloride. In fact, the solvent environment can be selected from organic solvents commonly used in the art, which must be able to completely dissolve the reactants and the target product without chemical reaction.

Specifically, when the amide compound II reacts with the nitrobenzene compound III in a solvent environment, the molar concentration of the amide compound II and the nitrobenzene compound III after mixing in the solvent is 0.01-100 mol/L.

In some embodiments, the amide compound II may specifically include at least one of the following chemical formulas II-1 to II-3:

.

In fact, the process of purifying and separating the p-nitroaniline compound V includes: using an extractant to extract the reaction system after the reaction is completed, separating and obtaining an organic phase, and then performing column chromatography separation on the organic phase to obtain the p-nitroaniline compound V. In fact, when the extractant is used for extraction, the target product p-nitroaniline compound V can be transferred to the extractant, so that the organic phase is separated and purified by column chromatography, which is conducive to improving the product purity of the p-nitroaniline compound V. Specifically, the extractant can be ethyl acetate.

The embodiment of the present invention also provides a method for synthesizing a p-nitroaniline compound, wherein the amide compound II used in any of the above embodiments is replaced by an amino acid compound I, which is reacted with a nitrobenzene compound III for 1-8 hours, and then purified and separated to obtain a p-nitroaniline compound IV.

Specifically, when the amino acid compound I reacts with the nitrobenzene compound III, the reaction equation is as follows:

;

Wherein, R ¹ , R ² , and R ³ are independently hydrogen or C ₁ -C ₅ alkyl, and R ⁶ is hydrogen, C ₁ -C ₄₀ aliphatic group, C ₄ -C ₆₀ aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, ester, amino, sulfonyl, amide or halogen.

In some embodiments, the amino acid compound I may specifically include at least one of the following chemical formulas I-1 to I-2:

.

In fact, the process of purifying and separating the p-nitroaniline compound IV includes: using an extractant to extract the reaction system after the reaction is completed, separating and obtaining an organic phase, and then performing column chromatography on the organic phase to obtain the p-nitroaniline compound IV. In fact, when the extractant is used for extraction, the target product p-nitroaniline compound IV can be transferred to the extractant, so that the organic phase is separated and purified by column chromatography, which is conducive to improving the product purity of the p-nitroaniline compound IV. Specifically, the extractant can be ethyl acetate.

Example 1

This embodiment 1 provides a method for synthesizing a p-nitroaniline compound substituted with an amino acid compound I, comprising the following steps:

S1. Add 0.2 mmol of glycine I-1 and 0.8 mmol of nitrobenzene III-1 into a reaction vessel and mix them evenly. Then add 0.6 mmol of potassium tert-butoxide as a base promoter. After stirring and mixing, replace the oxygen in the reaction vessel three times. Add dimethyl sulfoxide as a solvent environment under an oxygen atmosphere. Stir and react at 50°C for 3 hours.

S2. After the reaction is completed, water is added to the reaction system to quench it, and ethyl acetate is used as an extraction solvent to extract the reaction system. The organic phase obtained by extraction is separated by column chromatography (V _{petroleum ether} : V _{ethyl acetate} = 2:1) to obtain 33.33 g of 4-nitrohippuric acid IV-1, and the calculated yield is 85%.

Specifically, during the synthesis process of Example 1, the following reaction occurs:

.

The 4-nitrohippuric acid synthesized in Example 1 was characterized by hydrogen and carbon nuclear magnetic spectra, as shown in Figures 1 and 2, respectively, and the characterization data were: ¹ H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 8.00 (d, J = 9.20Hz, 2H), 7.45 (t, J = 6.20 Hz, 1H), 6.66 (d, J = 9.20 Hz, 2H), 3.98 (d J = 6.2 Hz, 2H). ¹³ C NMR (101 MHz, DMSO) δ 171.4, 154.3, 136.3, 126.0, 111.2.

Example 2 to Example 4

Embodiments 2 to 4 of the present invention respectively provide a method for synthesizing a p-nitroaniline compound substituted by an amino acid compound I, which is different from Embodiment 1 in that the type of amino acid compound I, the reaction temperature and the reaction time are different.

Specifically, the structural formula of the amino acid compound I, the structural formula of the nitrobenzene compound III, the structural formula of the target product, the reaction temperature, the reaction time and the yield of the target product used in the synthesis methods of Examples 1 to 4 are shown in Table 1 below.

Table 1

,

Example 5

This embodiment 5 provides a method for synthesizing a p-nitroaniline compound substituted with an amide compound II, comprising the following steps:

S1. Add 0.2 mmol of N-methylformamide II-1 and 0.8 mmol of nitrobenzene III-1 into a reaction vessel and mix them evenly. Then add 0.6 mmol of potassium tert-butoxide as a base promoter. After stirring and mixing, replace the oxygen in the reaction vessel three times. Add dimethyl sulfoxide as a solvent environment under an oxygen atmosphere. Stir and react at 50°C for 3 hours.

S2. After the reaction is completed, water is added to the reaction system to quench it, and ethyl acetate is used as the extraction solvent to extract the reaction system. The organic phase obtained by extraction is separated by column chromatography (V _{petroleum ether} : V _{ethyl acetate} = 2:1) to obtain 29.53g N-(4-nitrophenyl)formamide V-1, and the calculated yield is 82%.

Specifically, during the synthesis process of Example 5, the following reaction occurs:

.

Example 6 to Example 8

Embodiments 6 to 8 of the present invention respectively provide a method for synthesizing a para-nitroaniline compound substituted by an amide compound II, which is different from Embodiment 5 in that the type of amide compound II, reaction temperature and reaction time are different.

Specifically, the structural formula of the amide compound II, the structural formula of the nitrobenzene compound III, the structural formula of the target product, the reaction temperature, the reaction time and the yield of the target product used in the synthesis methods of Examples 5 to 8 are shown in Table 2 below.

Table 2

,

Although the embodiments of the present invention are described in detail above, it is obvious 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 are within the scope and spirit of the present invention as described in the claims. Moreover, the present invention described herein may have other embodiments and may be implemented or realized in a variety of ways.

Claims (8)

1. A method for synthesizing a p-nitroaniline compound, characterized in that, in an oxygen-containing atmosphere and a solvent environment at 20-100° C., in the presence of a base promoter, an amide compound II and a nitrobenzene compound III are reacted for 1-8 hours, and then a p-nitroaniline compound V is purified and separated; ; Wherein, R ⁴ and R ⁵ are independently hydrogen or C ₁ -C ₅ alkyl, and R ⁶ is hydrogen, C ₁ -C ₄₀ aliphatic group, C ₄ -C ₆₀ aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, ester, amino, sulfonyl, amide or halogen. 2. The synthesis method according to claim 1, characterized in that the base promoter comprises at least one of potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, and lithium tert-butoxide; And/or, the solvent includes at least one of toluene, tetrahydrofuran, dimethyl sulfoxide, N,N -dimethylformamide, N,N -dimethylacetamide, 1,4-dioxane, diethyl ether, and carbon tetrachloride; and/or, the C ₁ -C ₄₀ aliphatic group includes at least one of methyl, ethyl, propyl, isopropyl, butyl and benzyl; And/or, the C ₄ -C ₆₀ aromatic group includes at least one of a pyridine derivative, a phenyl group, a substituted phenyl group, a 1-naphthyl group, and a 2-naphthyl group; And/or, the halogen includes at least one of fluorine, chlorine, bromine and iodine; And/or, the oxygen volume fraction in the oxygen-containing atmosphere is 20-100%; And/or, the oxygen-containing atmosphere includes at least one of an oxygen atmosphere and an air atmosphere. 3. The synthesis method according to claim 1, characterized in that the molar ratio of the amide compound II to the nitrobenzene compound III is 1:(1-10); and/or, the molar ratio of the base promoter to the reactant is 6:10, wherein the reactant comprises an amide compound II and a nitrobenzene compound III; And/or, the molar concentration of the reactants in the solvent is 0.01-100 mol/L, wherein the reactants include amide compound II and nitrobenzene compound III. 4. The synthesis method according to claim 1 is characterized in that the process of purifying and separating the p-nitroaniline compound V comprises: using an extractant to extract the reaction system after the reaction is completed, separating and obtaining an organic phase, and then subjecting the organic phase to column chromatography separation to obtain the p-nitroaniline compound V. 5. The synthesis method according to claim 1, characterized in that the structural formula of the amide compound II comprises at least one of the following chemical formulas II-1 to II-3: . 6. A method for synthesizing a p-nitroaniline compound, characterized in that the amide compound II in the synthesis method according to any one of claims 1 to 3 is replaced by an amino acid compound I and reacted with a nitrobenzene compound III for 1-8 hours, and then purified and separated to obtain a p-nitroaniline compound IV; ; Wherein, R ¹ , R ² , and R ³ are independently hydrogen or C ₁ -C ₅ alkyl, and R ⁶ is hydrogen, C ₁ -C ₄₀ aliphatic group, C ₄ -C ₆₀ aromatic group, alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, alkyl, hydroxyl, carboxyl, aldehyde, carbonyl, ester, amino, sulfonyl, amide or halogen. 7. The synthesis method according to claim 6, characterized in that the structural formula of the amino acid compound I comprises at least one of the following chemical formulas I-1 to I-2: . 8. The synthesis method according to claim 6 is characterized in that the process of purifying and separating the p-nitroaniline compound IV comprises: using an extractant to extract the reaction system after the reaction is completed, separating and obtaining an organic phase, and then subjecting the organic phase to column chromatography to obtain the p-nitroaniline compound IV.