Method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone
By using the aromatic nucleophilic substitution and aldol condensation reaction of 4-nitrobenzaldehyde with azidotrimethylsilane, the problems of low yield and high cost in the synthesis of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone were solved, and efficient and low-cost industrial production was achieved.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- HEBEI CHIRAL STAR TECH CO LTD
- Filing Date
- 2025-03-28
- Publication Date
- 2026-05-28
AI Technical Summary
Existing synthetic processes for 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone have low product yields, high costs, and high energy consumption, which are not conducive to large-scale industrial production.
4-Azidebenzaldehyde was prepared by reacting 4-nitrobenzaldehyde with azidotrimethylsilane in an aromatic nucleophilic substitution reaction, and then carried out with 4-methylcyclohexanone in an aldol condensation reaction under alkaline conditions. The reaction conditions were optimized, the temperature and molar ratio were controlled, and the number of steps and raw material costs were reduced.
The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone were improved, the synthesis process was simplified, the production cost was reduced, and it is suitable for industrial production.
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Abstract
Description
A method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone Technical Field
[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone. Background Technology
[0002] Azide functional groups are versatile chemical tools that play important roles in multiple fields, particularly in the labeling and linking of biomolecules and photoactivated reactions. Aryl azides, due to their unique photophysical reactivity and synthetic versatility, have been widely used as crucial chemical building blocks in organic synthesis to obtain various nitrogen-containing compounds. Furthermore, aromatic azides are also very important industrial crosslinking agents, playing a vital role in the preparation of photoresists. Among them, 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone is particularly commonly used as such crosslinking agents. 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: starting with 4-nitrotoluene, 4-aminobenzaldehyde is first prepared by redox reaction, 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] The synthetic route 2 reported in the literature (Zeitschrift für Chemie. 1987, 27, 335-336) is as follows: 4-nitrobenzaldehyde oxime is reduced, azidated and hydrolyzed to obtain 4-azidobenzaldehyde, which is then condensed with 4-methylcyclohexanone to obtain 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.
[0005] However, in synthetic route 1, although the first step of the reaction can be carried out in a one-pot process, the overall yield is low. In synthetic route 2, the reaction steps are cumbersome, the raw materials are expensive, and both routes require a diazotization process, which has high energy consumption in industrial applications and is not conducive to large-scale industrial production. Summary of the Invention
[0006] This invention proposes a method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, which solves the problems of low product yield, high cost, and high energy consumption in the synthesis process of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone in related technologies, which are not conducive to large-scale industrial production.
[0007] The technical solution of the present invention is as follows:
[0008] A method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone includes the following steps:
[0009] S1. 4-Nitrobenzaldehyde is reacted with azidotrimethylsilane in the first solvent to undergo an aromatic nucleophilic substitution reaction to obtain 4-azidobenzaldehyde;
[0010] S2. 4-Azidebenzaldehyde and 4-methylcyclohexanone are subjected to an aldol condensation reaction in a second solvent to obtain 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.
[0011] As a further technical solution, during the aromatic nucleophilic substitution reaction, the first solvent includes one or more of hexamethylphosphoric triamine, N,N-dimethylacetamide, and N-methylpyrrolidone.
[0012] As a further technical solution, the aromatic nucleophilic substitution reaction is carried out at a temperature of 40–50°C for a time of 20–24 hours.
[0013] This invention adjusts the temperature during the aromatic nucleophilic substitution reaction, controlling the temperature to 40–50 °C, which further improves 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 to 2.
[0015] The present invention limits the molar ratio of 4-nitrobenzaldehyde to azidotrimethylsilane to 1:1 to 2, which further improves 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 second solvent comprises ethanol and water in a volume ratio of 1:1 to 2.
[0018] As a further technical solution, the alkaline reagent used in the alkaline conditions includes one or more of triethylamine, pyridine, and methylamine.
[0019] As a further technical solution, the aldol condensation reaction is carried out at a temperature of 15-30°C for 4-5 hours.
[0020] As a further technical solution, the molar ratio of 4-azidobenzaldehyde to 4-methylcyclohexanone is 2:1 to 1.5.
[0021] As a further technical solution, after the aromatic nucleophilic substitution reaction is completed, the resulting reaction solution is diluted, washed, dried, and evaporated to obtain 4-azidobenzaldehyde.
[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 process is water.
[0024] As a further technical solution, the drying process specifically involves 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 this invention are as follows:
[0027] 1. This invention provides a method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, which uses 4-nitrobenzaldehyde and azidotrimethylsilane as starting materials to directly perform azidation, reducing the number of reaction steps. The method is not only simple, but also has mild reaction conditions, inexpensive and readily available raw materials, high yield, high product purity, and low cost.
[0028] 2. The route for synthesizing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone in this invention can directly azidize inexpensive 4-nitrobenzaldehyde via aromatic nucleophilic substitution, optimizing the reaction process and allowing for the direct preparation of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone with fewer steps and simpler operation. Detailed Implementation
[0029] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0030] The parameters of the raw materials in the following examples and comparative examples are as follows:
[0031] 4-Nitrobenzaldehyde is a commercially available 98 wt% 4-nitrobenzaldehyde.
[0032] The azidotrimethylsilane is a commercially available azidotrimethylsilane with a content of 93 wt%.
[0033] 4-Methylcyclohexanone is commercially available 98 wt% 4-methylcyclohexanone.
[0034] Hexamethylphosphoryltriamine, ethyl acetate, anhydrous sodium sulfate, and triethylamine were commercially available analytical grade.
[0035] Example 1
[0036] Preparation of S1,4-azidobenzaldehyde:
[0037] 4-Nitrobenzaldehyde (2 g, 13.23 mmol) and azidotrimethylsilane (1.52 g, 13.23 mmol) were dissolved in 30 mL of hexamethylphosphoric triamine in a light-protected reaction flask 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 washed three times with water to remove hexamethylphosphoric triamine from the organic phase. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The resulting yellow-brown liquid was 4-azidobenzaldehyde.
[0038] Preparation of S2, 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone:
[0039] 4-Methylcyclohexanone (500 mg, 4.46 mmol) was dissolved in 6 mL of ethanol, and 4-azidobenzaldehyde (1.31 g, 8.91 mmol) and 6 mL of water were added and stirred for 5 min. Then, 2 mL of triethylamine was added and stirred at 25 °C. A yellow solid was continuously precipitated. The reaction was continued for 4 h until TLC showed that the reaction was complete. The reaction solution was filtered, and the residue was washed with water and dried at 70 °C to give 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.
[0040] Example 2
[0041] Preparation of S1,4-azidobenzaldehyde:
[0042] 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-protected reaction flask and stirred at 50 °C for 20 h. After the reaction was completed, the reaction solution was diluted with 20 mL of ethyl acetate and washed three times with water to remove N,N-dimethylacetamide from the organic phase. The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The resulting yellow-brown liquid was 4-azidobenzaldehyde.
[0043] Preparation of S2, 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone:
[0044] 4-Methylcyclohexanone (749.28 mg, 6.69 mmol) was dissolved in 6 mL of ethanol, and 4-azidobenzaldehyde (1.31 g, 8.91 mmol) and 12 mL of water were added and stirred for 5 min. Then, 2 mL of methylamine was added and stirred at 15 °C. A yellow solid was continuously precipitated. The reaction was continued 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 give 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.
[0045] Example 3
[0046] The only difference from Example 1 is that the reaction temperature in S1 is 30°C.
[0047] Example 4
[0048] The only difference from Example 1 is that the reaction temperature in S1 is 60°C.
[0049] Example 5
[0050] The only difference from Example 1 is that the amount of azidotrimethylsilane used in S1 is 1.15 g (10 mmol).
[0051] Example 6
[0052] The only difference from Example 1 is that the amount of azidotrimethylsilane used in S1 is 3.80 g (33 mmol).
[0053] Comparative Example 1
[0054] The only difference from Example 1 is that the azidotrimethylsilane is replaced with an equimolar amount of sodium azide (0.860 g, 13.23 mmol).
[0055] The mass and yield of 4-azidobenzaldehyde and 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Examples 1-6 and Comparative Example 1 are shown in Table 1.
[0056] Yield = Actual mass ÷ Theoretical mass × 100%.
[0057] Table 1. Mass and yield of 4-azidobenzaldehyde and 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone
[0058] As can be seen from Table 1, the method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone provided by the present invention yields 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone with high yield and high purity.
[0059] Compared with Comparative Example 1, Example 1 used trimethyl azidosilane, while Comparative Example 1 used sodium azide. The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Example 1 were higher than those in Comparative Example 1, indicating that using 4-nitrobenzaldehyde and trimethyl azidosilane as starting materials can improve the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.
[0060] The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Example 1 were higher than those in Examples 3 and 4, indicating that the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone can be further improved when the temperature of the aromatic nucleophilic substitution reaction is 40-50°C.
[0061] The yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone obtained in Example 1 were higher than those in Examples 5 and 6, indicating that a molar ratio of 4-nitrobenzaldehyde to azidotrimethylsilane of 1:1 to 2 can further improve the yield and purity of 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone.
[0062] The above are merely 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 within the protection scope of the present invention.
Claims
1. A method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone, characterized in that, Includes the following steps: S1. 4-Nitrobenzaldehyde is reacted with azidotrimethylsilane in the first solvent to undergo an aromatic nucleophilic substitution reaction to obtain 4-azidobenzaldehyde; S2. 4-Azidebenzaldehyde and 4-methylcyclohexanone are subjected to an aldol condensation reaction in a second solvent 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 first solvent includes one or more of hexamethylphosphoric triamine, 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, The aromatic nucleophilic substitution reaction is carried out at a temperature of 40–50 °C for 20–24 h.
4. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 1, characterized in that, The molar ratio of 4-nitrobenzaldehyde to azidotrimethylsilane is 1:1 to 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 second solvent comprises ethanol and water in a volume ratio of 1:1 to 2.
7. The method for preparing 2,6-bis(4-azidobenzylidene)-4-methylcyclohexanone according to claim 5, characterized in that, The alkaline reagents used in the alkaline conditions include 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, The aldol condensation reaction is carried out at a temperature of 15–30°C for 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 4-azidobenzaldehyde to 4-methylcyclohexanone is 2:1 to 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 was completed, the resulting reaction solution was diluted, washed, dried, and evaporated to obtain 4-azidobenzaldehyde.