Preparation method of 2, 6-bis (4-azidobenzylidene)-4-methyl cyclohexanone

Abstract

The invention relates to the technical field of organic synthesis, and provides a preparation method of 2, 6-bis (4-azidobenzylidene)-4-methyl cyclohexanone, which comprises the following steps: S1, carrying out aromatic nucleophilic substitution reaction on 4-nitrobenzaldehyde and azidotrimethylsilane to obtain 4-azidobenzaldehyde; and S2, carrying out an aldol condensation reaction on the 4-azidobenzaldehyde and 4-methyl cyclohexanone, so as to obtain the 2, 6-bis (4-azidobenzylidene)-4-methyl cyclohexanone. According to the technical scheme, the problems of low product yield, high cost, high energy consumption and inconvenience in large-scale industrial production of a synthetic process of 2, 6-bis (4-azidobenzylidene)-4-methyl cyclohexanone in the related technology are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone. Background Art

[0002] The azide functional group is a versatile chemical tool that can play an important role in many fields, especially in the labeling and connection of biomolecules, photoactivation reactions, etc. Due to their unique photophysical reactivity and synthetic diversity, aromatic azides have been widely used as important chemical building blocks for obtaining various nitrogen-containing compounds in organic synthesis. In addition, aromatic azides are also very important industrial cross-linking agents and play a vital role in the preparation of photoresists. Among them, 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone is particularly commonly used as such a cross-linking agent. The structure of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone is as follows:

[0003] For the chemical synthesis of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, the synthetic route 1 reported in patent US4354976 is as follows: 4-nitrotoluene is used as a starting material, 4-aminobenzaldehyde is first prepared by oxidation-reduction, then an intermediate is obtained by condensation with 4-methylcyclohexanone, and finally 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone is obtained by diazotization and azidation.

[0004]

[0005] literature( Journal of Chemistry. 1987, 27 , 335-336) reported the following synthetic route 2: 4-nitrobenzaldehyde oxime is reduced, azidated, and hydrolyzed to give 4-azidobenzaldehyde, which is then condensed with 4-methylcyclohexanone to give 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0006] However, although the first step of the reaction can be carried out in one pot in synthetic route 1, the overall yield is low. In synthetic route 2, the reaction steps are complicated, the raw materials are expensive, and both routes require a diazotization process, which consumes a lot of energy in industry and is not conducive to large-scale industrial production. Summary of the invention

[0007] The invention provides a preparation method of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, which solves the problems of low product yield, high cost, high energy consumption and unfavorable large-scale industrial production in the synthesis process of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone in the related art.

[0008] The technical solution of the present invention is as follows: A method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone comprises the following steps: S1, 4-nitrobenzaldehyde and azidotrimethylsilane undergo aromatic nucleophilic substitution reaction to obtain 4-azidobenzaldehyde;

[0009] S2, 4-azidobenzaldehyde and 4-methylcyclohexanone undergo an aldol condensation reaction to obtain 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0010]

[0011] As a further technical solution, during the aromatic nucleophilic substitution reaction, the solvent includes one or more of hexamethylphosphoric triamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0012] As a further technical solution, during the aromatic nucleophilic substitution reaction, the temperature is 40-50° C. and the time is 20-24 hours.

[0013] When the aromatic nucleophilic substitution reaction is regulated by the present invention, the temperature is 40-50° C., thereby further improving the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0014] As a further technical solution, the molar ratio of 4-nitrobenzaldehyde to azidotrimethylsilane is 1:1-2.

[0015] The present invention limits the molar ratio of 4-nitrobenzaldehyde to azidotrimethylsilane to 1:1-2, thereby further improving the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0016] As a further technical solution, the aldol condensation reaction is carried out under alkaline conditions.

[0017] As a further technical solution, during the aldol condensation reaction, the solvent includes ethanol and water in a volume ratio of 1:1-2.

[0018] As a further technical solution, the alkaline reagent used in the alkaline condition includes one or more of triethylamine, pyridine, and methylamine.

[0019] As a further technical solution, during the aldol condensation reaction, the temperature is 15-30° C. and the time is 4-5 hours.

[0020] As a further technical solution, the molar ratio of 4-azidobenzaldehyde to 4-methylcyclohexanone is 2:1~1.5.

[0021] As a further technical solution, after the aromatic nucleophilic substitution reaction is completed, the reaction solution is diluted, washed, dried and evaporated.

[0022] As a further technical solution, the diluent used in the dilution is ethyl acetate.

[0023] As a further technical solution, the detergent used in the washing is water.

[0024] As a further technical solution, the drying specifically comprises: drying the organic phase with anhydrous sodium sulfate.

[0025] As a further technical solution, the evaporation is rotary evaporation.

[0026] The working principle and beneficial effects of the present invention are: 1. The present invention provides a method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, which uses 4-nitrobenzaldehyde and azidotrimethylsilane as starting materials to directly carry out azidation, thereby reducing the reaction steps. The steps are simple, the reaction conditions are mild, the raw materials are cheap and easily available, the yield is high, the product purity is high, and the cost is low.

[0027] 2. The route for synthesizing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone in the present invention can directly azidize cheap 4-nitrobenzaldehyde through aromatic nucleophilic substitution, thereby optimizing the reaction process and directly preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone with fewer steps and simple operations. DETAILED DESCRIPTION

[0028] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of 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.

[0029] The parameters of the raw materials in the following examples and comparative examples are as follows: 4-nitrobenzaldehyde is commercially purchased 4-nitrobenzaldehyde with a content of 98 wt %; Azidotrimethylsilane is commercially purchased azidotrimethylsilane with a content of 93 wt %; 4-Methylcyclohexanone is commercially purchased 4-methylcyclohexanone with a content of 98 wt %; Hexamethylphosphoric acid triamide, ethyl acetate, anhydrous sodium sulfate and triethylamine were purchased from commercial sources of analytical grade.

[0030] Example 1 S1. Preparation of 4-azidobenzaldehyde: 4-nitrobenzaldehyde (2 g, 13.23 mmol) and azidotrimethylsilane (1.52 g, 13.23 mmol) were dissolved in 30 mL of hexamethylphosphoric acid triamide in a light-proof reaction bottle, and stirred at 40°C for 24 h. After the reaction was completed, the reaction solution was diluted with 20 mL of ethyl acetate, and the reaction solution was washed with water three times to remove the hexamethylphosphoric acid triamide in the organic phase. The organic phase was dried with anhydrous sodium sulfate, and the yellow-brown liquid obtained by rotary evaporation to remove the solvent was 4-azidobenzaldehyde; S2. Preparation of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone: 4-Methylcyclohexanone (500 mg, 4.46 mmol) was dissolved in 6 mL of ethanol, 4-azidobenzaldehyde (1.31 g, 8.91 mmol) and 6 mL of water were added and stirred for 5 min, 2 mL of triethylamine was added and stirred at 25 °C, and yellow solid was continuously precipitated. The reaction was carried out for 4 h until TLC showed that the reaction was complete. The reaction solution was filtered, the filter residue was washed with water, and dried at 70 °C to obtain 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0031] Example 2 S1. Preparation of 4-azidobenzaldehyde: 4-nitrobenzaldehyde (2 g, 13.23 mmol) and azidotrimethylsilane (3.04 g, 26.46 mmol) were dissolved in 30 mL of N,N-dimethylacetamide in a light-proof reaction bottle, and stirred at 50°C for 20 h. After the reaction, the reaction solution was diluted with 20 mL of ethyl acetate, and the reaction solution was washed with water three times to remove N,N-dimethylacetamide in the organic phase. The organic phase was dried with anhydrous sodium sulfate, and the yellow-brown liquid obtained by rotary evaporation to remove the solvent was 4-azidobenzaldehyde; S2. Preparation of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone: 4-Methylcyclohexanone (749.28 mg, 6.69 mmol) was dissolved in 6 mL of ethanol, 4-azidobenzaldehyde (1.31 g, 8.91 mmol) and 12 mL of water were added, and the mixture was stirred for 5 min. 2 mL of methylamine was added and stirred at 15 °C, and a yellow solid was continuously precipitated. The reaction was carried out for 5 h until TLC showed that the reaction was complete. The reaction solution was filtered, and the residue was washed with water and dried at 80 °C to obtain 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0032] Example 3 The only difference from Example 1 is that the reaction temperature in S1 is 30°C.

[0033] Example 4 The only difference from Example 1 is that the reaction temperature in S1 is 60°C.

[0034] Example 5 The only difference from Example 1 is that the amount of azidotrimethylsilane used in S1 is 1.15 g (10 mmol).

[0035] Example 6 The only difference from Example 1 is that the amount of azidotrimethylsilane used in S1 is 3.80 g (33 mmol).

[0036] Comparative Example 1 The only difference from Example 1 is that azidotrimethylsilane is replaced by an equimolar amount of sodium azide (0.860 g, 13.23 mmol).

[0037] The mass and yield of 4-azidobenzaldehyde and the mass and yield of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Examples 1 to 6 and Comparative Example 1 are shown in Table 1; Yield = actual mass ÷ theoretical mass × 100%.

[0038] Table 1 The mass and yield of 4-azidobenzaldehyde and the mass and yield of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone

[0039] It can be seen from Table 1 that the method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone provided by the present invention can prepare 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone with high yield and high purity.

[0040] Compared with Comparative Example 1, Example 1 uses azidotrimethylsilane and Comparative Example 1 uses sodium azide. The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Example 1 are higher than those in Comparative Example 1, indicating that the use of 4-nitrobenzaldehyde and azidotrimethylsilane as starting materials can improve the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0041] The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Example 1 are higher than those in Examples 3 and 4, indicating that when the temperature of the aromatic nucleophilic substitution reaction is 40 to 50° C., the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone can be further improved.

[0042] The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Example 1 are higher than those in Examples 5 and 6, indicating that the molar ratio of 4-nitrobenzaldehyde to azidotrimethylsilane is 1:1 to 2, which can further improve the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

[0043] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, characterized in that: The following steps are involved: S1, 4-nitrobenzaldehyde and azidotrimethylsilane undergo aromatic nucleophilic substitution reaction to obtain 4-azidobenzaldehyde; S2, 4-azidobenzaldehyde and 4-methylcyclohexanone undergo an aldol condensation reaction to obtain 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.

2. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: During the aromatic nucleophilic substitution reaction, the solvent includes one or more of hexamethylphosphoric triamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

3. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: During the aromatic nucleophilic substitution reaction, the temperature is 40-50° C. and the time is 20-24 hours.

4. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: The molar ratio of the 4-nitrobenzaldehyde to the azidotrimethylsilane is 1:1-2.

5. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: The aldol condensation reaction is carried out under alkaline conditions.

6. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: During the aldol condensation reaction, the solvent includes ethanol and water in a volume ratio of 1:1-2.

7. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 5, characterized in that: The alkaline reagent used in the alkaline condition includes one or more of triethylamine, pyridine and methylamine.

8. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: During the aldol condensation reaction, the temperature is 15-30° C. and the time is 4-5 hours.

9. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: The molar ratio of the 4-azidobenzaldehyde to 4-methylcyclohexanone is 2:1-1.

5.

10. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that: After the aromatic nucleophilic substitution reaction is completed, the reaction solution is diluted, washed, dried and evaporated.

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