Preparation process for efficiently synthesizing imine under catalysis of organic base

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process for efficiently synthesizing imine under catalysis of an organic base, the preparation process takes water as a solvent, takes the organic base as a catalyst and takes primary amine and aldehyde as raw materials to react to obtain a reaction product, the reaction product can be separated to obtain the target product imine, and the organic base is DBU. According to the present invention, the water is adopted as the reaction solvent, the DBU is adopted as the catalyst, such that the efficient preparation from the primary amine to the imine can be achieved, the environmental pollution caused by the use of the organic solvent during the imine synthesis can be avoided, the yield can achieve more than 80%, the yield is high, and the operation is simple.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation process for efficiently synthesizing imines catalyzed by an organic base. Background Art

[0002] Imine structures are generally formed through the dehydration condensation of C=O and R-NH2, and their chemical structure is widely present in natural products and pharmaceutical molecules. These small molecules containing imine structures have numerous pharmacological activities, attracting the attention of numerous organic and medicinal chemists. In organic synthesis, imines act as electrophilic reagents that react with other reagents to form nitrogen-containing compounds. Imine synthesis methods require the presence of Lewis acids or metal catalysts. Conventional methods can synthesize imines when highly reactive carbonyl compounds or highly nucleophilic amines are the reaction substrates. However, primary amines with lower nucleophilicity have difficulty dehydrating with carbonyl compounds to form the corresponding imines.

[0003] Existing research has found a pyrrolidine-catalyzed method for the efficient synthesis of N-sulfenyl imines and N-sulfonyl imines. In this method, an aldehyde first reacts with pyrrolidine to form an intermediate state, which then reacts with a primary amine compound to form the target product, the imine, while releasing pyrrolidine and a molecule of water. Because the electrophilicity of the intermediate state is more than ten orders of magnitude higher than that of the aldehyde, even (in)sulfonamides with very poor nucleophilicity can react well with the intermediate state, thereby obtaining the imine product in high yield. However, this reaction system requires the participation of the organic solvent DCM, and the large-scale use of organic solvents in industrial production is prone to environmental pollution. How to efficiently catalyze primary amines to produce the corresponding imines in an aqueous environment has not been reported in the relevant literature. Summary of the Invention

[0004] The purpose of the present invention is to address the above-mentioned problems existing in the prior art and to provide a preparation process for the efficient synthesis of imines catalyzed by an organic base, which can efficiently catalyze primary amines to generate corresponding imines in an aqueous environment.

[0005] To achieve the above objectives, the technical solutions of the present invention are as follows:

[0006] The invention provides a preparation process for the efficient synthesis of imines catalyzed by an organic base. The preparation process comprises: using water as a solvent, an organic base as a catalyst, and primary amines and aldehydes as raw materials to react to obtain a reaction product, and separating the target product, the imine, from the reaction product; the organic base is DBU.

[0007] The addition ratio of the primary amine, aldehyde, organic base and water is 1-3 mol: 1-3 mol: 0.1-0.3 mol: 1-3 L.

[0008] The addition ratio of the primary amine, aldehyde, organic base and water is 1 mol:1 mol:0.1 mol:3 L.

[0009] The reaction temperature is 25-100° C., and the reaction time is 3-16 hours.

[0010] The reaction temperature is 100° C., and the reaction time is 16 h.

[0011] The reaction product was separated using a chromatography column with ethyl acetate:petroleum ether = 2:1 to obtain the target product imine.

[0012] The primary amine is p-methoxyaniline, the aldehyde is benzaldehyde, and the target product is N-benzylidene-4-methoxyaniline.

[0013] The primary amine is aniline, the aldehyde is p-bromobenzaldehyde, and the target product is N-p-bromobenzylidene-aniline.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] The invention discloses a highly efficient preparation process for synthesizing imines using an organic base catalyst. The process uses water as a solvent, an organic base as a catalyst, and primary amines and aldehydes as raw materials to react to obtain a reaction product, from which a target product, imine, can be separated. The organic base is DBU. The method uses water as a reaction solvent and DBU as a catalyst to achieve highly efficient preparation of imines from primary amines, avoids environmental pollution caused by the use of organic solvents in imine synthesis, and achieves a yield of over 80%. The method has high yield, simple operation, and potential industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the NMR spectrum of the target product N-benzylidene-4-methoxyaniline in Example 1.

[0017] Figure 2 This is the NMR spectrum of the target product N-p-bromobenzylidene-aniline in Example 2. DETAILED DESCRIPTION

[0018] The present invention will be further described in detail below with reference to specific embodiments and the accompanying drawings.

[0019] The invention discloses a highly efficient preparation process for synthesizing imines using organic base catalysis. The preparation process comprises: using water as a solvent, an organic base as a catalyst, and primary amine and aldehyde as raw materials to react to obtain a reaction product, and separating the target product, the imine, from the reaction product; the organic base is DBU.

[0020] The addition ratio of the primary amine, aldehyde, organic base and water is 1-3 mol: 1-3 mol: 0.1-0.3 mol: 1-3 L.

[0021] The addition ratio of the primary amine, aldehyde, organic base and water is 1 mol:1 mol:0.1 mol:3 L.

[0022] The reaction temperature is 25-100° C., and the reaction time is 3-16 hours.

[0023] The reaction temperature is 100° C., and the reaction time is 16 h.

[0024] The reaction product was separated using a chromatography column with ethyl acetate:petroleum ether = 2:1 to obtain the target product imine.

[0025] The primary amine is p-methoxyaniline, the aldehyde is benzaldehyde, and the target product is N-benzylidene-4-methoxyaniline.

[0026] The primary amine is aniline, the aldehyde is p-bromobenzaldehyde, and the target product is N-p-bromobenzylidene-aniline.

[0027] Example 1:

[0028] Preparation of target product N-benzylidene-4-methoxyaniline

[0029] 1.0 mmol of benzaldehyde and 1.0 mmol of p-anisidine were placed in a 25 mL round-bottom flask. 3 mL of water was added to the flask, followed by 0.1 mmol of catalyst DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The mixture was refluxed at 100° C. for 16 h. The reaction process is shown below:

[0030]

[0031] After the reaction was completed, the target product was separated by column chromatography using ethyl acetate: petroleum ether = 2:1 with a yield of 86%. The NMR spectrum of the target product is shown in FIG. Figure 1 As shown, it can be verified that the target product is N-benzylidene-4-methoxyaniline; 1 H NMR (400MHz, Chloroform-d) δ8.48 (s, 1H, CH=N), 7.97–7.77 (m, 2H, Ph), 7.46 (tt, J= 3.2, 2.0Hz, 3H, Ph), 7.28–7.15 (m, 2H, Ph), 6.99–6.82 (m, 2H, Ph), 3.83 (s, 3H, OCH3).

[0032] The following study examines the effects of different catalyst types, different catalyst amounts, different reaction temperatures, and different solvents on the yield of the target product, N-benzylidene-4-methoxyaniline. The other experimental steps are the same as in Example 1. The results are shown in Table 1.

[0033] Table 1 Yield of target product

[0034]

[0035] Experiments 5 and 6 were blank experiments without the addition of a catalyst. Comparison of Experiment 7 with Experiments 5 and 6 shows that the use of DBU significantly improved the yield. Comparison of Experiment 7 with Experiments 1-4 shows that DBU resulted in higher yields than K2CO3 (inorganic base catalyst), TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene, organic base catalyst), DABCO (1,4-diazabicyclo[2.2.2]octane, organic base catalyst), and p-TsOH (p-toluenesulfonic acid, acid catalyst). Comparison of Experiments 7 and 8 shows that efficient catalysis can be achieved with only 10 mol% of the raw material. The possible catalytic mechanism of DBU is that an aldehyde and a primary amine undergo a nucleophilic addition reaction (the nitrogen atom with a lone pair of charges attacks the carbonyl carbon atom) to produce an α-hydroxyamine intermediate, which then removes a molecule of water to produce an imine. The addition of DBU facilitates the removal of water molecules during this process.

[0036] Comparison of Experiment 7 with Experiments 9-10 reveals that temperature significantly affects yield when water is used as the solvent. Experiments conducted at room temperature, 60°C, and 100°C demonstrate that the highest yield is achieved at the boiling point of water. Comparison of Experiment 7 with Experiments 11-14 reveals that the yields of the corresponding catalytic systems using other organic solvents (toluene, dichloromethane, and DMF) are lower than those obtained using water as the solvent, and the yields also decrease when the reaction temperature is raised to the boiling point of the organic solvent.

[0037] Example 2:

[0038] It is basically the same as Example 1, except that:

[0039] The added amounts of benzaldehyde, p-anisidine, DBU, and water are 1 mmol:1 mmol:0.1 mmol:1 mL, respectively.

[0040] Example 3:

[0041] It is basically the same as Example 1, except that:

[0042] The added amounts of benzaldehyde, p-anisidine, DBU, and water are 3 mmol:3 mmol:0.3 mmol:1 mL, respectively.

[0043] Example 4:

[0044] Preparation of target product N-p-bromobenzylidene-aniline

[0045] 1.0 mmol of p-bromobenzaldehyde and 1.0 mmol of aniline were placed in a 25 mL round-bottom flask. 3 mL of water was added to the flask, followed by 0.1 mmol of DBU catalyst. The mixture was refluxed at 100°C for 16 hours. After the reaction, the target product was separated by column chromatography using ethyl acetate:petroleum ether = 1:1 in a yield of 80%. The NMR spectrum of the target product is shown below. Figure 2 As shown, it can be verified that the target product is N-p-bromobenzylidene-aniline. 1 H NMR (400MHz, Chloroform-d) δ 8.40 (s, 1H, CH=N), 7.76 (m, 2H, Ph), 7.60 (m, 2H, Ph), 7.39 (m, 2H, Ph), 7.25 (m, 1H, Ph), 7.22-7.13 (m, 2H, Ph).

[0046] Example 5:

[0047] It is basically the same as Example 1, except that:

[0048] The added amounts of p-bromobenzaldehyde, aniline, DBU, and water are 1 mmol:1 mmol:0.1 mmol:1 mL, respectively.

[0049] Example 6:

[0050] It is basically the same as Example 1, except that:

[0051] The added amounts of p-bromobenzaldehyde, aniline, DBU, and water are 1 mmol:1 mmol:0.1 mmol:1 mL, respectively.

Claims

1. A process for the efficient synthesis of imines catalyzed by organic bases, characterized in that: The preparation process comprises: using water as solvent, an organic base as catalyst, and primary amine and aldehyde as raw materials to react to obtain a reaction product, and separating the target product, imine, from the reaction product; the organic base is DBU.

2. The process for preparing an organic base-catalyzed high-efficiency imine synthesis according to claim 1, characterized in that: The addition ratio of the primary amine, aldehyde, organic base and water is 1-3 mol: 1-3 mol: 0.1-0.3 mol: 1-3 L.

3. The process for preparing an organic base-catalyzed efficient imine synthesis according to claim 2, characterized in that: The addition ratio of the primary amine, aldehyde, organic base and water is 1 mol:1 mol:0.1 mol:3 L.

4. The process for preparing an organic base-catalyzed high-efficiency imine synthesis according to claim 1, characterized in that: The reaction temperature is 25-100° C., and the reaction time is 3-16 hours.

5. The process for preparing an organic base-catalyzed efficient imine synthesis according to claim 4, characterized in that: The reaction temperature is 100° C., and the reaction time is 16 h.

6. The process for preparing an organic base-catalyzed high-efficiency imine synthesis according to claim 1, characterized in that: The reaction product was separated using a chromatography column with ethyl acetate:petroleum ether = 2:1 to obtain the target product imine.

7. The process for preparing an organic base-catalyzed high-efficiency imine synthesis according to claim 1, characterized in that: The primary amine is p-methoxyaniline, the aldehyde is benzaldehyde, and the target product is N-benzylidene-4-methoxyaniline.

8. The process for preparing an organic base-catalyzed high-efficiency imine synthesis according to claim 1, characterized in that: The primary amine is aniline, the aldehyde is p-bromobenzaldehyde, and the target product is N-p-bromobenzylidene-aniline.

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