A novel method for the synthesis of aromatic azo compounds

Abstract

This invention provides a novel method for synthesizing aromatic azo compounds. Using aniline as a raw material, this invention achieves a one-step synthesis of aromatic azo compounds with high yield, strong substrate adaptability, low cost, and is environmentally friendly. It is easily industrialized and has promising application prospects.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a novel method for synthesizing aromatic azo compounds. Background Technology

[0002] Aromatic azo compounds are a class of aromatic compounds with N=N double bonds. They exhibit significant electronic conjugation effects. Furthermore, the double bond structure leads to cis and trans isomerism in azo compounds. Generally, the trans isomer is more stable than the cis isomer. Azo compounds exhibit unique photochromic phenomena, and the cis and trans isomers can interconvert under light or heating conditions. The unique properties of azo compounds make them widely used in bioactive ligands, cosmetics, organic dyes, food additives, and free radical initiators. In particular, organic azo dyes account for one-third of the world's industrial dyes. Therefore, the rapid, simple, and environmentally friendly synthesis of azo compounds is a highly attractive field. There are two traditional methods for synthesizing aromatic azo compounds: one is the coupling reaction of diazonium salts with aromatic amines or phenols under acidic conditions; the other is the Mills reaction of nitrosamines with aromatic amines. Figure 1 As shown.

[0003] When using diazonium salts as reactants, the other substrate needs to have high reactivity for the reaction to proceed. Generally, a hydroxyl (OH) or amino (NH₂) group directly bonded to the benzene ring is required. This limits the reactivity of the reaction.

[0004] To overcome the shortcomings of traditional reactions and in line with sustainable development, the search for greener, more environmentally friendly, and simpler synthetic methods has attracted increasing attention from researchers. Recent reports primarily focus on the use of transition metal compounds such as copper, nickel, palladium, rhodium, iron, and manganese coordination compounds or MOF materials to catalyze the N=N coupling reaction of aromatic amines, or the reduction of N=N coupling by aromatic nitro compounds. Using transition metal compounds as catalysts can not only improve reaction yields but also enhance the selectivity of the reaction. Figure 2 As shown.

[0005] However, existing methods for synthesizing azo compounds still face significant challenges. These methods often suffer from drawbacks such as the use of varying stoichiometric amounts of toxic metal salts, strong oxidizing agents, strong bases, and high-boiling-point solvents (DMSO, DMF, Toluene). In particular, some organic solvents and organic bases can cause environmental damage. Summary of the Invention

[0006] To address the complexity and high cost of traditional azo compound synthesis, this invention provides a novel method for synthesizing aromatic azo compounds.

[0007] The technical solution of the present invention is as follows: A method for preparing an aromatic azo compound, comprising the following steps:

[0008]

[0009] Compounds of Formula 1 and Formula 2 are dissolved in an organic solvent and reacted under the catalysis of a metal salt at a certain temperature to generate compound of Formula 3, wherein the metal salt is selected from CuNO3 or a combination of Cu(OAc)2 and FeCl3, FeCl2, ZnCl2, CoCl2, NiCl2, NiCO3 or NiSO4.

[0010] The compound of formula 1 is substituted by one or more R1, and the compound of formula 2 is substituted by one or more R2; R1 and R2 are independently selected from hydrogen, C1-C4 alkyl, C1-C3 alkoxy, halogen, dimethylamino or phenylamino, and when R1 and R2 are selected from different substituents, R1 and R2 are not substituted in the ortho position of aniline.

[0011] Preferably, the metal salt is selected from a combination of Cu(OAc)2 and NiCl2.

[0012] Preferably, the molar amount of Cu(OAc)2 is 15% of the molar amount of the compound of Formula 1, and the molar amount of NiCl2 is 5% of the molar amount of the compound of Formula 1.

[0013] Preferably, the organic solvent is selected from one or more of THF, DMSO, DMF, 1,4-dioxane or toluene.

[0014] Preferably, the organic solvent is selected from toluene.

[0015] Preferably, the reaction temperature is 60℃~110℃, and more preferably 100℃.

[0016] Preferably, the reaction time is 4 to 8 hours.

[0017] Preferably, the reaction also requires the presence of oxygen.

[0018] This invention also provides a method for preparing an aromatic azo compound, comprising the following steps:

[0019]

[0020] Compounds of Formula 4 and Formula 5 are dissolved in an organic solvent and react under the catalysis of a metal salt at a certain temperature to produce compound of Formula 6.

[0021] Compound of Formula 4 is substituted by one or more R4s, and compound of Formula 5 is substituted by one or more R5s; R4 and R5 are independently selected from hydrogen, C1-C4 alkyl, C1-C3 alkoxy, halogen, dimethylamino or phenylamino, and when R4 and R5 are selected from different substituents, R4 and R5 are not substituted in the ortho position of aniline.

[0022] The organic solvent is selected from toluene, the reaction temperature is 100℃, the reaction time is 4h, and the metal salt is selected from the combination of Cu(OAc)2 and NiCl2, wherein the molar amount of Cu(OAc)2 is 15% of the molar amount of compound 4, and the molar amount of NiCl2 is 5% of the molar amount of compound 4.

[0023] The beneficial effects of this invention are as follows: This invention uses aniline as a raw material to synthesize aromatic azo compounds in one step, with high yield, strong substrate adaptability, low cost, green and environmentally friendly properties, and easy industrialization. Attached Figure Description

[0024] Figure 1 Traditional methods for synthesizing azo compounds

[0025] Figure 2 A new method for synthesizing azo compounds

[0026] Figure 3 Gram-scale coupling reaction Detailed Implementation

[0027] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0028] 1. Synthetic route

[0029]

[0030] A certain amount of copper salt and another metal salt, along with an aromatic amine (1 mmol), were added to a 10 mL reaction flask. Finally, 4 mL of toluene was added, and the reaction was carried out at 100 °C for 4 h. After cooling to room temperature, the mixture was filtered to remove insoluble solid impurities. The filtered reaction solution was then removed by rotary evaporation or vacuum distillation at 50 °C to remove the solvent toluene, precipitating a solid. The precipitated solid was dissolved in 10 mL of dichloromethane, washed three times with 15 mL of pure water, and the dichloromethane was collected and dried over anhydrous sodium sulfate. Purification was performed using ethyl acetate (EA) and petroleum ether (PE) (1:100) as eluents, packed into a column with silica gel powder (100-200 mesh). A yellow solid azo compound was obtained.

[0031] The catalyst determines the course of the reaction. Next, the types of two metal compounds participating in the reaction and the amounts of the two catalysts were screened. Subsequently, the reaction temperature, time, and atmosphere were varied to determine the optimal catalytic conditions. When screening metal catalysts, metals close to copper in the periodic table, such as iron salts in different valence states (numbers 2-3), were selected. The results showed that the azo yield was consistent with that of copper acetate alone, indicating that the iron compounds did not form a good catalytic system with copper acetate. When using a zinc chloride and copper acetate catalytic system for N=N coupling, the azo yield increased to 65% (number 4). This indicates that zinc chloride can enhance the catalytic effect of copper acetate, but it did not achieve the desired effect. In subsequent experiments, catalytic systems composed of cobalt chloride or nickel chloride and copper acetate were used. Notably, the azo compound yields of both catalytic systems reached 84% (numbers 5-6). After further testing with different substrates and cross-reactions, a catalytic system composed of nickel chloride and copper acetate was ultimately selected for the catalytic experiments. Considering the catalytic effects of copper and nickel, different anions in the metal salts will lead to different catalytic effects. When nickel chloride is replaced with nickel sulfate or nickel carbonate, the azo yield decreases to 32%, which does not improve the yield (items 7-8).

[0032] Table 1 Screening of bimetallic catalysts [a]

[0033]

[0034]

[0035]

[0036] [a] Reaction conditions: aniline (1 mmol), toluene 4 mL, 100℃, 8 h. [b] Yield was obtained through gas chromatography.

[0037] After determining the catalytic system consisting of copper acetate and nickel chloride, the amounts of the two catalysts, solvent, temperature, and reaction time were optimized, and the results are shown in Table 2.

[0038] Table 2 Optimization of reaction conditions [a]

[0039]

[0040] [a] Experimental conditions: aniline 0.5 mmol, copper acetate 0.075 mmol, nickel chloride 0.025 mmol, toluene 3 mL, 100℃, 8 h. [b] Yield was measured using genomic analysis.[c] The reaction was carried out under an argon atmosphere.

[0041] When using only one metal as a catalyst, copper acetate yielded 32%, while nickel chloride showed no catalytic effect (items 1-2). The amounts of both copper acetate and nickel chloride catalysts were then varied, with 15 mmol% copper acetate and 5 mmol% nickel chloride ultimately finding the optimal catalytic concentration (items 3-8). Changing the solvent, using THF, DMSO, DMF, and 1,4-dioxane as solvents, the highest yield reached only 72% (items 9-12). Reaction temperature provided the energy for the experiment; neither increasing nor decreasing the temperature further improved the azo yield (items 13-15), and the reaction could not proceed below 60°C. Shortening the reaction time from 8 h to 4 h still achieved an 87% yield; however, reacting for only 3 h reduced the yield to 34% (items 16-18). To verify the role of oxygen in this experiment, the reaction was carried out in an argon atmosphere via gas conversion. The result showed that the azo yield was only 47% (number 19), indicating that oxygen participated in the cycle.

[0042] 2. Substrate Expansion

[0043] Under optimal reaction conditions, substrate expansion was carried out for aromatic amines containing different functional groups to examine changes in the functional group tolerance of the catalytic system, as well as the synthesis of a series of asymmetric azo compounds.

[0044] Under optimal experimental conditions, a series of aromatic primary amines were selected to synthesize symmetrical azo compounds, and a substrate range was further investigated, as shown in Table 3.

[0045] Table 3 Substrate Expansion [a]

[0046]

[0047]

[0048] [a] Experimental conditions: 0.5 mmol of aromatic amine, 0.075 mmol of copper acetate, 0.025 mmol of nickel chloride, 3 mL of toluene, 100 °C, 4 h. The yield was determined by gas chromatography (2a-2u) and separated by column chromatography (2v-2x). DMSO was used as the solvent for p-nitroaniline (2y).

[0049] The asymmetric azo compounds were synthesized under optimal conditions, as shown in Table 4.

[0050] The two aromatic amines used were in a 1:1 ratio. Based on the results shown in the experiments synthesizing symmetrical azo compounds, cross-coupling experiments were conducted using substrates containing functional groups with different properties.

[0051] Experimental results show that this catalytic system can catalyze various cross-coupling experiments. Cross-coupling between aromatic amines containing electron-withdrawing and electron-donating groups (3a-3e), between aromatic amines containing electron-withdrawing groups (3f), and between aromatic amines containing electron-donating groups such as methyl, methoxy, and ethyl groups (3g-3l) yields cross-coupling products in moderate yields. When an aromatic amine with an ortho-receptor group (3m) is involved, no cross-coupling product is obtained; the yield of the cross-coupling product containing the less reactive 3-chloroaniline and 3-bromoaniline is only 10%.

[0052] Table 4 Cross-coupling of aromatic amines [a]

[0053]

[0054]

[0055] [a] Experimental protocol: 0.5 mmol of each aromatic amine, 0.15 mmol of copper acetate, 0.05 mmol of nickel chloride, 5 mL of toluene, incubated at 100 °C for 4 h. The yield was determined by gas chromatography-mass spectrometry (GC-MS). The reaction was carried out in gram quantities.

[0056] Scale-up catalytic experiments is of great significance for both experimental research and industrial production. Therefore, a representative aromatic amine was selected for a gram-scale coupling reaction of the starting materials. For example... Figure 3 As shown.

[0057] The following are the proton and carbon spectral data of some compounds.

[0058]

[0059] 1 H-NMR (400MHz, Chloroform-d): δ7.90–7.81(m,4H),7.50–7.36(m,6H);

[0060] 13 C-NMR(101MHz,Chloroform-d)δ152.80,131.16,129.25,123.02.

[0061]

[0062] 1H-NMR(400MHz,Chloroform-d):δ7.74(d,J=8.3Hz,4H),7.23(d,J=8.1Hz,4H),2.36(s,6H);

[0063] 13 C-NMR(101MHz,Chloroform-d)δ151.01,141.39,129.90,122.92,21.67.

[0064]

[0065] 1 H-NMR(400MHz,Chloroform-d):δ7.81(d,J=9.0Hz,4H),6.93(d,J=9.0Hz,4H),3.82(s,6H);

[0066] 13 C-NMR(101MHz,Chloroform-d):δ161.75,147.26,124.53,114.35,55.74.

[0067]

[0068] 1 H-NMR(400MHz,Chloroform-d):δ7.86(d,J=8.8Hz,4H),7.49(d,J=8.7Hz,4H);

[0069] 13 C-NMR(101MHz,Chloroform-d):δ151.02,137.45,129.62,124.41.

[0070]

[0071] 1 H-NMR(400MHz,Chloroform-d):δ7.90(d,J=8.6Hz,4H),7.38(d,J=8.0Hz,4H),2.77(q,J=7.6Hz,4H),1.33(t,J=7.5Hz,7H);

[0072] 13 C-NMR(101MHz,Chloroform-d):δ151.24,147.64,128.70,123.01,29.02,15.63.

[0073]

[0074] 1 H-NMR(400MHz,Chloroform-d):δ7.75(d,J=7.2Hz,4H),7.49–7.38(m,2H),7.30(d,J=7.6Hz,2H),2.47(s,6H);

[0075] 13 C-NMR(101MHz,Chloroform-d):δ152.97,139.15,131.88,129.08,123.05,120.66,21.56.

[0076]

[0077] 1 H-NMR(400MHz,Chloroform-d):δ7.88(d,J=8.8Hz,4H),7.56(d,J=8.2Hz,4H),1.40(s,18H);

[0078] 13 C-NMR(101MHz,Chloroform-d):δ154.41,150.98,126.16,122.67,35.17,31.50.

[0079]

[0080] 1 H-NMR(400MHz,Chloroform-d):δ7.69(d,J=7.8Hz,1H),7.53(d,J=9.7Hz,1H),7.49–7.38(m,1H),7.13(t,J=8.2Hz,1H);

[0081] 13 C-NMR(101MHz,Chloroform-d):δ164.71,162.24,154.01,153.94,130.58,130.50,121.03,121.00,118.53,118.31,108.44,108.21.

[0082]

[0083] 1 H-NMR(400MHz,Chloroform-d):δ7.90(s,1H),7.84(td,J=4.2,1.8Hz,1H),7.47(d,J=5.5Hz,2H);

[0084] 13 C-NMR(101MHz,Chloroform-d):δ153.29,135.43,131.41,130.40,122.84,122.08.

[0085]

[0086] 1 H-NMR(400MHz,Chloroform-d):δ7.97(s,2H),7.80(d,J=7.9Hz,2H),7.54(d,J=8.1Hz,2H),7.33(t,J=7.9Hz,2H);

[0087] 13 C-NMR(101MHz,Chloroform-d):δ153.35,134.32,130.71,124.92,123.42,123.38.

[0088]

[0089] 1 H-NMR(400MHz,Chloroform-d):δ7.83(dd,J=9.0,5.2Hz,4H),7.10(t,J=8.6Hz,4H);

[0090] 13 C-NMR(101MHz,Chloroform-d):δ165.83,163.33,149.19,149.17,125.06,124.97,116.38,116.15.

[0091]

[0092] 1 H-NMR(400MHz,Chloroform-d):δ7.83(dd,J=9.1,5.8Hz,2H),7.31(dd,J=8.3,2.7Hz,2H),7.08(ddd,J=9.0,7.6,2.7Hz,2H).

[0093]

[0094] 1 H-NMR(400MHz,Chloroform-d):δ7.95(d,J=8.2Hz,4H),7.72(d,J=8.4Hz,4H).

Claims

1. A method for preparing an aromatic azo compound, comprising the following steps: Compounds of Formula 1 and Formula 2 are dissolved in an organic solvent and reacted at 100℃~110℃ for 4~8h in the presence of oxygen under the catalysis of a metal salt to generate compound of Formula 3, wherein the metal salt is selected from a combination of Cu(OAc)2 and NiCl2. The organic solvent is selected from 1,4-dioxane or toluene; The molar amount of Cu(OAc)2 is 15% of the molar amount of compound 1, and the molar amount of NiCl2 is 5% of the molar amount of compound 1. The compound of formula 1 is substituted by one or more R1, and the compound of formula 2 is substituted by one or more R2; R1 and R2 are independently selected from hydrogen, methyl, ethyl, methoxy, butyl, F, and Cl; when R1 and R2 are selected from different substituents, R1 and R2 are not substituted in the ortho position of aniline.

2. The preparation method according to claim 1, characterized in that, Compounds of Formula 1 and Formula 2 are selected from the following compounds,

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