Process for the preparation of benzoxazine derivatives
By employing a synergistic approach of electrochemical and thermal promotion, benzoxazine derivatives can be synthesized efficiently under mild conditions without the need for additional oxidants. This solves the environmental and efficiency problems of existing benzoxazine synthesis techniques and realizes a green and concise synthetic route.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-04-08
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for synthesizing benzoxazine derivatives suffer from problems such as the use of excessive chemical oxidants, noble metal catalysts, harsh reaction conditions, and complex processes. They lack green, simple, and scale-up synthetic methods, and are particularly inefficient in the oxidative cyclization reactions of 2-methylquinoline compounds.
By employing the synergistic effect of electrochemical and thermal promotion, the cyclization reaction of 2-methylquinoline and o-aminobenzyl alcohol is achieved under mild conditions in an electrolytic cell. Electrons are used as a clean reaction driving force, eliminating the need for additional chemical oxidants. Combined with auxiliaries such as tetrabutylammonium iodide, ammonium chloride, and succinic acid, benzoxazine derivatives can be efficiently constructed.
It significantly improves the synthesis efficiency and selectivity of benzoxazine derivatives, reduces byproduct generation, simplifies the process, reduces environmental burden, and enhances atom economy and renewable energy compatibility.
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Figure CN122105424A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of benzoxazine derivative preparation technology. Background Technology
[0002] Benzoxazine derivatives are an important class of nitrogen- and oxygen-containing six-membered heterocyclic compounds. Due to their structural features of both aromatic rings and N,O heterocyclic skeletons, they have attracted widespread attention in fields such as medicinal chemistry, organic synthesis, fine chemicals, and functional molecule construction.
[0003] On the one hand, these compounds have good structural modifiability and functional group compatibility, and can be used as synthetic intermediates for a variety of complex nitrogen-containing heterocyclic molecules to further construct molecular skeletons with biological activity or special functions. On the other hand, benzoxazine skeletons themselves also have high application potential in the design of a variety of active molecules. Therefore, developing efficient, green and simple synthetic methods for benzoxazine derivatives has important research significance and application value.
[0004] Currently, the main synthetic methods for benzoxazine derivatives include condensation, cyclization, or oxidative cyclization reactions between o-aminobenzyl alcohol substrates and aldehydes, ketones, nitriles, or other substrates that can participate in cyclization reactions under the action of acids, bases, metal catalysts, or oxidation systems.
[0005] These methods can achieve the construction of the target framework to a certain extent, but they still have some shortcomings. For example, some methods require the use of excessive chemical oxidants, such as peroxides, high-valent iodine reagents, or metal oxidants, which not only increases the reaction cost but also leads to more by-products, complex post-processing, and a heavy environmental burden. Some methods rely on precious metal catalysts or harsh reaction conditions, such as high temperature, high pressure, inert atmosphere, or strictly anhydrous and oxygen-free environment, thus limiting the practicality and industrial scale-up potential of the methods. In addition, some reaction routes have many raw material pretreatment steps and long synthetic routes, which are not conducive to the simplification of processes and the achievement of green synthesis goals.
[0006] With the continuous development of green chemistry and sustainable synthesis concepts, utilizing electrochemical methods to achieve redox transformations of organic molecules has become an important research direction in the field of organic synthesis. Electrochemical synthesis methods use electrons as "clean reagents," enabling substrate activation and transformation under the drive of an applied current. This reduces or even eliminates the use of traditional chemical oxidants or reductants, offering advantages such as mild reaction conditions, good reaction controllability, environmental friendliness, and ease of integration with modern synthetic processes. Particularly in the field of heterocyclic compound construction, electrochemical methods have provided new reaction modes and technical means for CN-CO bonds and various cyclization reactions.
[0007] However, for the construction of benzoxazine derivatives, existing technologies still lack a synthetic method that is based on readily available raw materials, simple to operate, requires no additional chemical oxidants, has a relatively green and clean reaction system, and possesses good process compatibility. In particular, how to efficiently achieve the oxidative cyclization transformation of relevant substrates under relatively simple conditions through the synergistic effect of electrochemical and thermal promotion, and thus construct the benzoxazine skeleton, remains a technical problem that needs further resolution in this field.
[0008] Therefore, developing a method for preparing benzoxazine derivatives that has a wide range of raw material sources, simple reaction conditions, is environmentally friendly, and suitable for scale-up is of great significance for enriching the synthetic strategies of this type of heterocyclic compound, improving the practicality of the process, and promoting its application in medicinal chemistry and fine organic synthesis.
[0009] When using 2-methylquinoline compounds as substrates, existing chemical synthesis methods generally suffer from limitations such as large amounts of oxidant, harsh reaction conditions, poor substrate compatibility, and low product yields.
[0010] For example, Ahmed Kamal's group established an iodine-catalyzed one-pot method to efficiently synthesize heteroarylbenzimidazoles and heteroarylbenzothiazoles from 2-methyl heteroaryl hydrocarbons and o-phenylenediamine / o-aminothiophenol via Csp³–H oxidative functionalization, and evaluated their cytotoxic activities.
[0011] An-Xin Wu's research group proposed an oxidative cyclization method under the I2-DMSO system, which directly oxidatively functionalizes the sp³ C–H bonds of methyl azaarenes, efficiently preparing triazolopyridine compounds without metal catalysis. It can also synthesize triazolopyridine-quinoline bicyclic rings. This method has a wide substrate range and good functional group tolerance.
[0012] Summary of the Invention
[0013] This invention utilizes the synergistic effect of electrochemical and thermal promotion to efficiently achieve the oxidative cyclization transformation of relevant substrates. It proposes a strategy that uses electrons as the clean reaction driving force, eliminating the need for additional chemical oxidants, and efficiently achieving the cyclization reaction of 2-methylquinoline and o-aminobenzyl alcohol under mild conditions. This significantly improves the synthesis efficiency and selectivity of target benzoxazine derivatives, demonstrating more prominent technical advantages and application potential compared to traditional methods.
[0014] This invention provides a method for preparing benzoxazine derivatives, which involves adding 2-methylquinoline, o-aminobenzyl alcohol, and dimethyl sulfoxide into an electrolytic cell for reaction.
[0015] Furthermore, the structural formula of the o-aminobenzyl alcohol compound is as follows: Wherein, R is hydrogen, phenyl, 4-fluorophenyl or 4-chlorophenyl.
[0016] Furthermore, the molar ratio of the 2-methylquinoline and the o-aminobenzyl alcohol compound is 1:2.
[0017] Furthermore, both the cathode and anode of the electrolytic cell are platinum sheets.
[0018] Furthermore, the current in the electrolytic cell is 10 mA.
[0019] Furthermore, the reaction temperature is 100 °C.
[0020] Furthermore, the reaction time is 4 hours.
[0021] Furthermore, tetrabutylammonium iodide is added to the reaction; the molar ratio of 2-methylquinoline, o-aminobenzyl alcohol, and tetrabutylammonium iodide is 1:2:1.
[0022] Furthermore, ammonium chloride and succinic acid are also added to the reaction; the molar ratio of 2-methylquinoline, o-aminobenzyl alcohol, ammonium chloride and succinic acid is 1:2:1:1.
[0023] Furthermore, the molar to volume ratio of the o-aminobenzyl alcohol compound and methyl sulfoxide is 4:5. Attached Figure Description
[0024] Figure 1 These are the proton NMR spectra of the product from Example 1.
[0025] Figure 2 These are the carbon spectrum data of the product from Example 1.
[0026] Figure 3 These are the proton NMR spectra of the product from Example 2.
[0027] Figure 4 These are the carbon spectrum data of the product from Example 2.
[0028] Figure 5 These are the proton NMR spectra of the product from Example 3.
[0029] Figure 6 These are the carbon spectrum data of the product from Example 3.
[0030] Figure 7 These are the proton NMR spectra of the product from Example 4.
[0031] Figure 8 These are the carbon spectrum data of the product from Example 4. Detailed Implementation
[0032] This invention discloses a method for preparing benzoxazine derivatives. This method uses electrons as the clean, residue-free reaction driving force, replacing traditional chemical oxidants and eliminating the use of toxic oxidizing agents and the generation of byproducts from the source. This makes the reaction system more atom-economical and environmentally friendly. Furthermore, the raw materials 2-methylquinoline and o-aminobenzyl alcohol are widely available and inexpensive. This method can efficiently construct structurally diverse benzoxazine functional heterocycles. The reaction requires precise electrochemical driving to achieve efficient conversion, offering advantages such as significant carbon reduction potential, strong adaptability to renewable energy, high atom economy, simple operation, and ease of continuous production. Utilizing the catalytic effect of electrochemistry, the reaction conversion efficiency can be significantly improved, the synthetic route shortened, and the process complexity reduced.
[0033] Example 1
[0034] Compound 1a (0.2 mmol), compound 2a (0.4 mmol), tetrabutylpotassium iodide (0.2 mmol), ammonium chloride (0.2 mmol), succinic acid (0.2 mmol), and dimethyl sulfoxide (5 mL) were added sequentially to an electrolytic cell. Platinum sheets were used for both the cathode and anode. A constant DC current of 10 mA was passed between the anode and cathode, and the reaction was carried out at 100 °C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the compound 3a was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) in 75% yield. The reaction equation is as follows:
[0035] .
[0036] The product spectral data are as follows:
[0037] 1 H NMR (600 MHz, CDCl3) δ 8.41-8.37 (m, 2 H), 8.28-8.26 (m, 1 H), 8.20-8.18 (m, 1 H), 7.93-7.91 (m, 1 H), 7.79-7.81 (m, 1 H), 7.67-7.64 (m, 1H), 7.44-7.42 (m, 1H), 7.37-7.35 (m, 1H), 7.20-7.17 (m, 1H), 4.86 (s, 2H).
[0038] 13C NMR (151 MHz, CDCl3) δ 163.3, 149.9, 146.6, 137.9, 137.1, 131.2,130.4, 130.2, 129.6, 129.5, 129.4, 128.3, 127.9, 125.0, 122.8, 119.1, 64.1.
[0039] Example 2
[0040] In an electrolytic cell, 1b (0.2 mmol), 2b (0.4 mmol), tetrabutylammonium iodide (0.2 mmol), ammonium chloride (0.2 mmol), succinic acid (0.2 mmol), and dimethyl sulfoxide (5 mL) were added sequentially. Platinum sheets were used for both the cathode and anode. A constant DC current of 10 mA was passed between the anode and cathode, and the reaction was carried out at 100 °C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the compound 3b was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) in 50% yield. The reaction equation is as follows:
[0041] .
[0042] The product spectral data are as follows:
[0043] 1 H NMR (600 MHz, CDCl3) δ 8.33-8.29 (m, 2 H), 8.40 (d, J = 8.23 Hz, 1H), 9.60 (d, J = 7.84 Hz, 1 H), 7.76-7.73 (m, 1 H), 7.60-7.59 (m, 1 H), 9.60 (d, J = 7.52 Hz, 1 H), 7.39-7.37 (m, 3 H), 13.80 (d, J = 7.31 Hz, 2 H), 7.25-7.23 (m, 1 H), 7.80 (d, J = 6.94 Hz, 1 H), 6.61 (s, 1 H).
[0044] 13C NMR (151 MHz, CDCl3) δ 155.5, 150.4, 147.9, 138.8, 138.4, 136.7,134.9, 130.8, 129.9, 129.5, 129.1, 129.0, 128.9, 128.0, 127.7, 127.5, 126.1,125.4, 124.8, 120.5, 77.9.
[0045] Example 3
[0046] In an electrolytic cell, 1a (0.2 mmol), 2c (0.4 mmol), tetrabutylammonium iodide (0.2 mmol), ammonium chloride (0.2 mmol), succinic acid (0.2 mmol), and dimethyl sulfoxide (5 mL) were added sequentially. Platinum sheets were used for both the cathode and anode. A constant DC current of 10 mA was passed between the anode and cathode, and the reaction was carried out at 100 °C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the compound 3c was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) in 62% yield. The reaction equation is as follows:
[0047] .
[0048] The product spectral data are as follows:
[0049] 1 H NMR (600 MHz, CDCl3) δ 8.33-8.29 (m, 2 H), 9.00 (d, J = 8.23 Hz, 1H), 9.60 (d, J = 7.84 Hz, 1 H), 7.76-7.73 (m, 1 H), 7.60-7.58 (m, 1 H), 9.60(d, J = 7.53 Hz, 1 H), 7.43-7.40 (m, 3 H), 7.24-7.23 (m, 1 H), 7.02-7.01(m, 2H), 8.40 (d, J = 6.94 Hz, 1 H), 6.62 (s, 1 H).
[0050] 13C NMR (151 MHz, CDCl3) δ 163.1 (d, J = 248.1 Hz, 1 C), 155.6, 150.6,147.9, 139.0, 136.8, 135.9 (d, J = 3.3 Hz, 1 C), 130.8, 130.0, 129.8 (d, J =8.2 Hz, 1 C), 129.5, 128.9, 127.9, 127.7, 127.5, 126.1, 125.4, 125.1, 120.5,115.8 (d, J = 21.7 Hz, 1 C), 78.1.
[0051] Example 4
[0052] In an electrolytic cell, 1a (0.2 mmol), 2d (0.4 mmol), tetrabutylammonium iodide (0.2 mmol), ammonium chloride (0.2 mmol), succinic acid (0.2 mmol), and dimethyl sulfoxide (5 mL) were added sequentially. Platinum sheets were used for both the cathode and anode. A constant DC current of 10 mA was passed between the anode and cathode, and the reaction was carried out at 100 °C for 4 h. The reaction progress was monitored by thin-layer chromatography until the reaction was complete. Finally, the product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain compound 3d in 70% yield. The reaction equation is as follows:
[0053] 。
[0054] The product spectral data are as follows:
[0055] 1 H NMR (600 MHz, CDCl3) δ 8.32-8.30 (m, 2 H), 9.00 (d, J = 8.21 Hz, 1H), 9.60 (d, J = 7.83 Hz, 1 H), 7.75-7.72 (m, 1 H), 7.59-7.56 (m, 1 H), 9.00(d, J = 7.53 Hz, 1 H), 9.60 (d, J = 7.45 Hz, 2 H), 7.36-7.30 (m, 4 H), 7.24-7.21 (m, 1 H), 7.20 (d, J = 6.94 Hz, 1 H), 6.64 (s, 1 H).
[0056] 13C NMR (151 MHz, CDCl3) δ 155.7, 150.6, 147.9, 140.0, 138.9, 136.7,130.8, 129.8, 129.3, 128.9, 128.8, 128.7, 127.8, 127.7, 127.5, 127.4, 126.0,125.5, 125.3, 120.5, 78.8.
[0057] Comparative example
[0058] The existing method for preparing heteroaryl benzimidazole compounds using iodine catalysis involves adding 2-methylquinoline (0.2 mmol), o-phenylenediamine (0.2 mmol), molecular iodine (0.04 mmol, 20 mol%), and dimethyl sulfoxide (5 mL), and stirring the mixture under open air at 110 °C for 8 h. After the reaction is complete, the mixture is cooled to room temperature, quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate, and the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated. The solid is then purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain the target heteroaryl benzimidazole product.
[0059]
[0060] Compared to this method, this invention replaces traditional chemical oxidation with electrochemical oxidation, fundamentally solving the core problems of existing iodine-catalyzed methods such as significant environmental hazards, single product structure, and poor reaction controllability while retaining the high efficiency of the "one-pot method". This provides a new technical path for the green synthesis and structural innovation of heteroaryl benzimidazole compounds.
Claims
1. A method for preparing benzoxazine derivatives, characterized in that, 2-Methylquinoline, o-aminobenzyl alcohol, and dimethyl sulfoxide were added to an electrolytic cell for reaction.
2. The method according to claim 1, characterized in that, The structural formula of the o-aminobenzyl alcohol compounds is: Wherein, R is hydrogen, phenyl, 4-fluorophenyl or 4-chlorophenyl.
3. The method according to claim 1, characterized in that, The molar ratio of the 2-methylquinoline and the o-aminobenzyl alcohol compound is 1:
2.
4. The method according to claim 1, characterized in that, Both the cathode and anode of the electrolytic cell are platinum sheets.
5. The method according to claim 1, characterized in that, The current in the electrolytic cell is 10 mA.
6. The method according to claim 1, characterized in that, The reaction temperature is 100 °C.
7. The method according to claim 1, characterized in that, The reaction time was 4 hours.
8. The method according to claim 1, characterized in that, Tetrabutylammonium iodide is also added to the reaction; the molar ratio of 2-methylquinoline, o-aminobenzyl alcohol and tetrabutylammonium iodide is 1:2:
1.
9. The method according to claim 1, characterized in that, Ammonium chloride and succinic acid are also added to the reaction; the molar ratio of 2-methylquinoline, o-aminobenzyl alcohol, ammonium chloride and succinic acid is 1:2:1:1.