A pyrazole-based ionic liquid and a method for catalyzing the Betti reaction using the same

Abstract

The present invention relates to the field of the synthesis of Betti base aminoalkylnaphthols, specifically to a pyrazole-based ionic liquid 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate and its synthesis method, and a method for catalyzing the Betti reaction by using the same; at 70 °C, the pyrazole ionic liquid is used as a catalyst and a solvent, and an aromatic aldehyde, pyrrolidine and β-naphthol are subjected to a three-component Betti reaction, and the product and the catalyst are separated by ethanol to obtain Betti base aminoalkylnaphthol; by screening the types of ionic liquids, solvents, material ratios of reactants, amounts of ionic liquids used, and reaction temperatures, a series of betti bases with higher yields are obtained under the optimized conditions, and the yields are in the range of 72% - 94%. Moreover, the catalyst used is green and effective, has good thermal stability, can catalyze the synthesis of betti base in a short time, the product and the catalyst are easily separated, which is beneficial to industrialization, and the catalyst can be recycled multiple times.

Description

Technical Field

[0001] The present invention relates to the field of synthesis of Betti base aminoalkylnaphthols, and specifically relates to a pyrazole-based ionic liquid and a method for catalyzing the Betti reaction using the same. Background Art

[0002] 1-Aminoalkyl-2-naphthols and their n-substituted derivatives can also be converted into 1,3-oxazine compounds. As a special class of bioactive heterocycles, they are present in many important biological natural products and candidate drugs, and they have many biological activities, such as antibiotics, analgesics, antimalarials, antianginals, and antirheumatics. Currently, the main methods for synthesizing aminoalkylnaphthols include using catalysts such as inorganic acids, organic acids, and alcoholamine ionic liquids. Traditional acidic catalysts have strong corrosiveness, are toxic, can also corrode equipment and pollute the environment, are difficult to recycle, and the reaction time using alcoholamine catalysis is relatively long. Summary of the Invention

[0003] The present invention overcomes the deficiencies of the prior art and provides a pyrazole-based ionic liquid and a method for catalyzing the Betti reaction using the same. The ionic liquid can be used both as a catalyst and as a solvent. This method is green and environmentally friendly, and the obtained product is also easily separated from the catalyst. The reaction time is short and it can be recycled. Therefore, this method has become a clean process route for producing betti base. The used pyrazole-based ionic liquid catalyst is green and environmentally friendly, has good catalytic activity, and the reaction conditions are mild, obtaining a product with a relatively high yield.

[0004] To solve the above technical problems, the technical solution adopted by the present invention is: a pyrazole-based ionic liquid, and the pyrazole ionic liquid is 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate, and its structural formula is as follows:

[0005]

[0006] The present invention also provides a synthesis method of the above pyrazole-based ionic liquid. After stirring a mixture of dimethyl sulfoxide and potassium hydroxide, 3,5-dimethyl-1H-pyrazole is added, and it is stirred at room temperature. Then benzyl bromide is added dropwise. After stirring and reacting at room temperature, the mixture is treated to obtain a white solid, 1,2-dibenzyl-3,5-dimethylpyrazolium bromide, with a yield of 97.8%. Subsequently, 1,2-dibenzyl-3,5-dimethylpyrazolium bromide and distilled water are added to a round-bottom flask, potassium hexafluorophosphate is added, and after reacting at room temperature, it is washed with water and tested with silver nitrate solution until no precipitate appears. After drying, 8.2 g of a white solid (i.e., 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate) is obtained with a yield of 97.1%. 1 H NMR (600 MHz, CDCl3) δ=7.27 (d, J= 2.0 Hz, 6H), 6.88–6.82 (m, 4H), 6.59 (s, 1H), 5.46 (s, 4H), 2.49 (s, 6H). 13 13C NMR (151 MHz, CDCl3) δ = 148.22, 131.32, 129.57, 129.03, 125.85, 109.21, 50.63, 12.18 ppm.

[0007] The reaction formula for the synthesis of 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate is as follows:

[0008]

[0009] Furthermore, the molar ratio of potassium hydroxide, 3,5-dimethyl-1H-pyrazole, and benzyl bromide is 10:5:10; the molar ratio of 1,2-dibenzyl-3,5-dimethylpyrazolium bromide and potassium hexafluorophosphate is 20:20; the volume molar ratio of dimethyl sulfoxide to potassium hydroxide is 50 ml:1 mol; the volume ratio of 1,2-dibenzyl-3,5-dimethylpyrazolium bromide and water is 20 mmol:20 mL.

[0010] Furthermore, the stirring time after mixing dimethyl sulfoxide and potassium hydroxide is 20 min, the stirring time after adding 3,5-dimethyl-1H-pyrazole is 10 min, and the stirring time after dropping benzyl bromide is 3 h. The time required for preparing 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate by ion exchange from 1,2-dibenzyl-3,5-dimethylpyrazolium bromide is 20 h.

[0011] A method for catalyzing the Betti reaction with a pyrazole-based ionic liquid uses the above-mentioned pyrazole-based ionic liquid as a catalyst for the reaction. At 70 °C, the pyrazole ionic liquid 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate is used as both a catalyst and a solvent, and a three-component Betti reaction of aromatic aldehyde, pyrrolidine, and β-naphthol is carried out. The product and the catalyst are separated with ethanol to obtain the Betti base aminoalkylnaphthol.

[0012] Furthermore, the molar ratio of the aromatic aldehyde, pyrrolidine, and β-naphthol is 1:1:1.

[0013] Furthermore, the dosage of the pyrazole ionic liquid catalyst is 10% of the total molar amount of the reactants, namely aromatic aldehyde, pyrrolidine, and β-naphthol.

[0014] A method for catalyzing the Betti reaction with a pyrazole-based ionic liquid, and the specific operation steps are as follows:

[0015] (1) Add pyrazolium ionic liquid catalyst, benzaldehyde, pyrrolidine, and β-naphthol into a Schlenk tube respectively, and carry out a one-pot three-component reaction at 70 °C for 2 - 3 h;

[0016] (2) Add ethanol solvent to the reaction in step (1), and separate the product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol and the pyrazolium ionic liquid catalyst by filtration;

[0017] (3) Dry the product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol obtained in step (2) under vacuum to obtain pure 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol.

[0018] Further, the amount of ethanol in step (2) is 20 times the total molar amount of the reactants.

[0019] Further, the vacuum drying temperature in step (3) is 50 - 70 °C.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention provides a pyrazole-based ionic liquid and a method for catalyzing the Betti reaction using the same, synthesizing betaine. By screening the types of ionic liquids, solvents, the molar ratio of reactants, the amount of ionic liquids, and the reaction temperature, a series of betaines with higher yields are obtained under the optimized conditions. The yields are in the range of 72% - 94%. Moreover, the catalyst used is green and effective, has good thermal stability, can catalyze the synthesis of betaine in a short time, the product and the catalyst are easily separated, and the catalyst can be recycled multiple times. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the nuclear magnetic resonance hydrogen spectrum of 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol in Example 2 of the present invention. EMBODIMENTS

[0023] The following further illustrates the present invention with specific embodiments. EXAMPLES

[0024] A pyrazole-based ionic liquid, wherein the pyrazolium ionic liquid is 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate, and its structural formula is as follows:

[0025]

[0026] The synthesis method of the above-mentioned pyrazole-based ionic liquid is as follows: In a 50 ml round-bottom flask, a mixture of 5 ml of dimethyl sulfoxide and 5.6 g (0.10 mol) of potassium hydroxide is added and stirred for 20 min. Then, 4.81 g (0.05 mol) of 3,5-dimethyl-1H-pyrazole is added and stirred at room temperature for 10 min. After that, 17.10 g (0.10 mol) of benzyl bromide is added dropwise and stirred at room temperature for 3 h. After the reaction, the product is treated to obtain a white solid, 1,2-dibenzyl-3,5-dimethylpyrazolium bromide, with a yield of 97.8%. Subsequently, 1,2-dibenzyl-3,5-dimethylpyrazolium bromide and distilled water are added to the round-bottom flask, and then potassium hexafluorophosphate is added. After reacting at room temperature, it is washed with water and tested with silver nitrate solution until no precipitate appears. After drying, 8.2 g of white solid is obtained with a yield of 97.1%. 1 H NMR (600 MHz, CDCl3) δ=7.27 (d, J J = 2.0 Hz, 6H), 6.88–6.82 (m, 4H), 6.59 (s,1H), 5.46 (s, 4H), 2.49 (s, 6H). 13 C NMR (151 MHz, CDCl3) δ=148.22, 131.32,129.57, 129.03, 125.85, 109.21, 50.63, 12.18ppm.

[0027] The reaction equation for the synthesis of 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate is as follows:

[0028] Example

[0029] A method for catalyzing the Betti reaction with a pyrazole-based ionic liquid, which is carried out using 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate prepared in Example 1, specifically includes the following steps:

[0030] (1) In a Schlenk tube, 0.0674 g of pyrazole ionic liquid catalyst, 0.203 mL of benzaldehyde, 0.167 mL of pyrrolidine, and 0.288 g of β-naphthol are added respectively, and a one-pot three-component reaction is carried out at 70 °C for 2 h.

[0031] (2) Approximately 5 mL of ethanol solvent is added to the reaction in step (1), and the product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol and the pyrazole ionic liquid catalyst are separated by filtration.

[0032] (3) The product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol obtained in step (2) was dried under vacuum at 70 °C to obtain 0.582 g of the product. The filtrate was distilled under reduced pressure at 50 °C for 10 - 20 min. The solid substance obtained was a pyrazolium ionic liquid, namely 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate, which could be recycled, and the recycling rate was maintained above 90%.

[0033] Figure 1 1H NMR spectrum of 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol 1 H NMR (600MHz, CDCl3) δ=13.91 (s, 1H), 7.88 (dd, J J = 8.6, 3.2 Hz, 1H), 7.71 (dt, J J =8.1, 1.8Hz, 1H), 7.67 (dd, J J = 8.9, 2.7 Hz, 1H), 7.63–7.60 (m, 2H), 7.38(ddt, J J = 8.4, 6.8,2.0 Hz, 1H), 7.28–7.27 (m, 1H), 7.26–7.15 (m, 4H), 5.14(d, J J = 1.7 Hz, 1H), 3.30 (s, 1H), 2.67 (s, 1H), 2.25 (s, 2H), 1.92–1.79 (m,4H). Example

[0034] (1) 0.0674 g of pyrazolium ionic liquid catalyst, 0.281 mL of 4-chlorobenzaldehyde, 0.167 mL of pyrrolidine and 0.288 g of β-naphthol were added into a Schlenk tube respectively, and a one-pot three-component reaction was carried out at 70 °C for 2 h.

[0035] (2) Approximately 5 mL of ethanol solvent was added to the reaction in step (1), and the product 1-((4-chlorophenyl)(pyrrolidin-1-yl)methyl)-2-naphthol and the pyrazolium ionic liquid catalyst were separated by filtration.

[0036] (3) The product 1-((4-chlorophenyl)(pyrrolidin-1-yl)methyl)-2-naphthol obtained in step (2) was dried under vacuum at 70 °C to obtain 0.607 g of the product. The filtrate was distilled under reduced pressure at 50 °C for 10 - 20 min. The solid substance obtained was a pyrazolium ionic liquid, namely 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate, which could be recycled, and the recycling rate was maintained above 90%. Example

[0037] (1) Add 0.0674 g of pyrazolium ionic liquid catalyst, 0.32 g of p-bromobenzaldehyde, 0.237 mL of 4-methylpyridine, and 0.288 g of β-naphthol into a Schlenk tube respectively, and carry out a one-pot three-component reaction at 70 °C for 2 h.

[0038] (2) Add about 5 mL of ethanol solvent to the reaction in step (1), and separate the product 1-((4-bromophenyl)(4-methylpiperidin-1-yl)methyl)-2-naphthol and the pyrazolium ionic liquid catalyst by filtration.

[0039] (3) Dry the product 1-((4-bromophenyl)(4-methylpiperidin-1-yl)methyl)-2-naphthol obtained in step (2) under vacuum at 70 °C to obtain 0.706 g of the product. The filtrate is distilled under reduced pressure at 50 °C for 10 - 20 min, and the solid substance obtained is the pyrazolium ionic liquid, namely 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate, which can be recycled, and the recycling rate remains above 80%.

Claims

1. A pyrazole-based ionic liquid, characterized in that, The pyrazole-based ionic liquid is 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate, and its structural formula is as follows: 。 2. A method for synthesizing a pyrazole-based ionic liquid, characterized in that, After stirring a mixture of dimethyl sulfoxide and potassium hydroxide, 3,5-dimethyl-1H-pyrazole was added, and the mixture was stirred at room temperature. Then benzyl bromide was added dropwise. After the reaction was stirred at room temperature, the product was worked up to obtain a white solid, 1,2-dibenzyl-3,5-dimethylpyrazolium bromide. Subsequently, 1,2-dibenzyl-3,5-dimethylpyrazolium bromide and distilled water were added to a round-bottom flask, potassium hexafluorophosphate was added, and the reaction was carried out at room temperature. After washing with water and testing with silver nitrate solution until no precipitate appeared, the white solid obtained after drying was 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate.

3. The method for synthesizing a pyrazole-based ionic liquid according to claim 2, characterized in that, The molar ratio of potassium hydroxide, 3,5-dimethyl-1H-pyrazole and benzyl bromide is 10:5:10; the molar ratio of 1,2-dibenzyl-3,5-dimethylpyrazolium bromide and potassium hexafluorophosphate is 20:20; the volume molar ratio of dimethyl sulfoxide to potassium hydroxide is 50 ml:1 mol; the volume ratio of 2-dibenzyl-3,5-dimethyl-1H-pyrazolium bromide and water is 20 mmol:20 mL.

4. The method for synthesizing a pyrazole-based ionic liquid according to claim 2, characterized in that, The stirring time after mixing dimethyl sulfoxide and potassium hydroxide is 20 min, the stirring time after adding 3,5-dimethyl-1H-pyrazole is 10 min, the stirring time after adding benzyl bromide dropwise is 3 h, and the time required for preparing 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate by ion exchange from 1,2-dibenzyl-3,5-dimethylpyrazolium bromide is 20 h.

5. A method for catalyzing the Betti reaction with a pyrazole-based ionic liquid, using the pyrazole-based ionic liquid as claimed in claim 1 as a catalyst for the reaction, characterized in that, At 70 °C, the pyrazole-based ionic liquid 1,2-dibenzyl-3,5-dimethylpyrazolium hexafluorophosphate was used as a catalyst and solvent, and the three-component Betti reaction of aromatic aldehyde, pyrrolidine and β-naphthol was carried out. The product and the catalyst were separated with ethanol to obtain the Betti base aminoalkylnaphthol.

6. The method for catalyzing the Betti reaction with a pyrazole-based ionic liquid according to claim 5, characterized in that, The molar ratio of the aromatic aldehyde, pyrrolidine and β-naphthol is 1:1:

1.

7. The method for catalyzing the Betti reaction with a pyrazole-based ionic liquid according to claim 5, characterized in that, The amount of the pyrazole-based ionic liquid catalyst used is 10% of the total molar amount of the reactants, namely the aromatic aldehyde, pyrrolidine and β-naphthol.

8. The method for catalyzing the Betti reaction with a pyrazole-based ionic liquid according to claim 5, characterized in that, The specific operation steps are as follows: (1) Add the pyrazole-based ionic liquid catalyst, benzaldehyde, pyrrolidine and β-naphthol into a Schlenk tube respectively, and carry out a one-pot three-component reaction at 70 °C for 2 - 3 h; (2) Add an ethanol solvent to the reaction in step (1), and separate the product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol and the pyrazole-based ionic liquid catalyst by filtration; (3) Dry the product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol obtained in step (2) under vacuum to obtain the pure product 1-phenyl((pyrrolidin-1-yl)methyl)-2-naphthol.

9. The method for catalyzing the Betti reaction with a pyrazole-based ionic liquid according to claim 8, characterized in that, The amount of ethanol in step (2) is 20 times the total molar amount of the reactants.

10. The method for catalyzing the Betti reaction with a pyrazole-based ionic liquid according to claim 8, characterized in that, The vacuum drying temperature in step (3) is 50 - 70 °C.

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