阅读说明：本技术 一种电化学氧化邻氨基苯酚类似物制备吩恶嗪酮类化合物的合成方法 (Synthesis method for preparing phenoxazinone compound by electrochemically oxidizing o-aminophenol analog ) 是由 蔡云瑞 龚心仪 于 2021-09-05 设计创作，主要内容包括：本发明公开了一种吩恶嗪酮类化合物的电化学合成方法,包括如下步骤：1)配制电解液：向DMF中加入邻氨基苯酚类似物、催化剂TEMPO和四丁基四氟硼酸铵,混合均匀得到电解液；2)将碳棒作为阳极,铂电极作为阴极,在搅拌条件下向电解液中通入直流电进行电化学反应,反应结束后分离得到吩恶嗪酮类化合物。本发明涉及的反应在中性环境、室温下进行,反应条件温和,无需氧化剂。本发明成功实现了在一体池中,高效率地制备吩恶嗪酮类化合物,在生物医药和荧光试剂的合成方面有很大的应用潜力。(The invention discloses an electrochemical synthesis method of a phenoxazinone compound, which comprises the following steps: 1) preparing an electrolyte: adding an o-aminophenol analogue, a catalyst TEMPO and tetrabutylammonium tetrafluoroborate into DMF, and uniformly mixing to obtain an electrolyte; 2) and (3) taking the carbon rod as an anode and the platinum electrode as a cathode, introducing direct current into the electrolyte under the stirring condition to perform electrochemical reaction, and separating after the reaction is finished to obtain the phenoxazinone compounds. The reaction of the invention is carried out in neutral environment and room temperature, the reaction condition is mild, and no oxidant is needed. The invention successfully realizes the high-efficiency preparation of the phenoxazinone compounds in the integrated pool, and has great application potential in the synthesis of biological medicines and fluorescent reagents.)

1. A synthetic method for preparing phenoxazinone compounds by electrochemically oxidizing o-aminophenol analogs is characterized in that: the method comprises the following steps:

1) preparing a three-mouth bottle and electrodes required by reaction;

2) adding magnetons, electrolyte and a substrate o-aminophenol analogue into a three-necked flask;

3) fixing the electrode on the three-mouth bottle;

4) adding a reaction solvent into the three-mouth bottle;

5) stirring the reaction at room temperature, and introducing current to carry out reaction;

6) after the reaction time is over, the reaction solution is extracted by ethyl acetate and water, an organic phase is collected, dried by anhydrous sodium sulfate, and a pure target product is obtained by silica gel column chromatography.

2. The method for synthesizing phenoxazinone compounds by electrochemical oxidation of an o-aminophenol analog according to claim 1 wherein:

in the step 1): the capacity of the three-mouth bottle is 20mL, the anode is a graphite electrode, the cathode is a platinum electrode, and the area size is 10mm multiplied by 10 mm;

in the step 2): 0.5mmol of substrate added, the o-aminophenol analogue comprising o-aminophenol, 2-amino-3-methylphenol, 2-amino-6-fluorophenol, 2-amino-6-chlorophenol, 2-amino-6-bromophenol, 2-amino-3-methoxyphenol, methyl 3-amino-2-hydroxybenzoate;

in the step 2): the catalyst is 10% mol of 2, 2, 6, 6-Tetramethylpiperidine-1-oxyl (TEMPO);

in the step 5): the reaction was carried out for 3 hours with a constant current of 10 mA.

Technical Field

The invention belongs to the field of organic electrochemistry, and relates to a synthetic method for preparing phenoxazinone compounds by electrochemically oxidizing o-aminophenol analogs.

Background

Electrochemical synthesis is a synthesis strategy emerging in recent years, and uses electrons as a clean oxidant or reducing agent, so that toxic and dangerous chemical reagents can be avoided, and the electrochemical synthesis is an important component for developing green chemical synthesis industry in the future.

Phenoxazinone alkaloids are natural products with various structures, have wide biological activity, and are widely applied to various disease models such as anti-tumor, anti-virus, anti-inflammatory, antibacterial and anti-Alzheimer's disease models. The phenoxazinone compounds can also be used as dyes, and are gradually developed into biological probe dyes for living cell imaging. Thus, chemists have developed various synthetic methods for phenoxazinones, of which dimerization of 2-aminophenol derivatives is one of the most efficient synthetic strategies. In this chemical conversion process, a catalyst and an oxidant are two types of factors that are essential. At present, catalysts including laccase (enzyme), metal complex, organic phosphorus reagent, heterogeneous nano material, etc. have been reported, and peroxides, high-valence metal salts, high-pressure oxygen, etc. are often used as the oxidizing agent. However, these synthetic strategies suffer from one or more of the following problems: (1) the used catalyst and oxidant are not easy to obtain and are expensive; (2) reagents are dangerous; (3) a large amount of chemical waste is generated; (4) the reaction conditions are severe, etc. These disadvantages limit the application of this synthetic strategy and the development of new phenoxazinone compounds.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a synthetic method for preparing phenoxazinone compounds by electrochemically oxidizing o-aminophenol analogues.

In order to achieve the above object, the present invention provides a method for synthesizing phenoxazinone compounds by electrochemically oxidizing ortho-aminophenol analogues, which is characterized in that: the method comprises the following steps:

1) preparing a three-mouth bottle and electrodes required by reaction;

2) adding magnetons, electrolyte, catalyst and a substrate o-aminophenol analogue into a three-necked flask;

3) fixing the electrode on the three-mouth bottle;

4) adding a reaction solvent into the three-mouth bottle;

5) stirring the reaction at room temperature, and introducing current to carry out reaction;

6) after the reaction time is over, the reaction solution is extracted by ethyl acetate and water, an organic phase is collected, dried by anhydrous sodium sulfate, and a pure target product is obtained by silica gel column chromatography.

Preferably, in the step 1): the capacity of the three-mouth bottle is 20mL, the anode is a graphite electrode, the cathode is a platinum electrode, and the area size is 10mm multiplied by 10mm

In the step 2): 0.5mmol of substrate added, the o-aminophenol analogue comprising o-aminophenol, 2-amino-3-methylphenol, 2-amino-6-fluorophenol, 2-amino-6-chlorophenol, 2-amino-6-bromophenol, 2-amino-3-methoxyphenol, methyl 3-amino-2-hydroxybenzoate;

in the step 2): the catalyst is 10% mol of 2, 2, 6, 6-Tetramethylpiperidine-1-oxyl (TEMPO);

in the step 5): introducing constant current of 10mA for reaction for 3 hours;

under electrochemical conditions, TEMPO is first oxidized at the anode to TEMPO⁺And TEMPO⁺Is a strong oxidant, and can oxidize an o-aminophenol analog to generate a 2-aminophenoxy radical. The free radical intermediate loses an electron and a proton to form a key intermediate o-benzoquinone monoimine, and the intermediate o-benzoquinone monoimine is covalently added with another molecule of o-aminophenol analogue to generate phenoxazinone compounds through cyclization and aromatization.

The method has the following advantages and beneficial effects:

the method successfully realizes the oxidative condensation of the o-aminophenol analogue to prepare the phenoxazinone compound in the integrated pool with high efficiency; the reaction is carried out in a neutral environment at room temperature, the reaction condition is mild, the process is simple and easy to operate, cheap and easy-to-process TEMPO is used as a catalyst, electrons are used as an oxidant, and compared with the reported synthesis method of the phenoxazinone compounds, the method disclosed by the invention does not need to use a metal catalyst and an oxidant with reaction equivalent, so that the generation of chemical waste reagents is reduced, and the method is more environment-friendly.

Drawings

FIG. 1 is a structural diagram of the chemical formula of the phenoxazinone compounds according to the present invention.

FIG. 2 is a schematic diagram of the reaction mechanism process involved in the present invention.

Detailed Description

The invention is further described in detail with reference to the following figures and specific examples.

Example 1: preparation of 2-amino-3H-phenoxazin-3-ones

A20 mL three-necked flask was charged with magneton, o-aminophenol (0.5mmol), TEMPO (0.05mmol) and nBu₄NBF₄(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted on a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time was over, the reaction solution was extracted with ethyl acetate (50mL × 3) and water, the organic phase was collected and purified by silica gel column chromatography to give the pure desired product in 84% yield.¹H NMR(500MHz，DMSO)：δ7.68-7.37(4H，m)，6.81(2H，s)，6.34(2H，s)；¹³C NMR(125MHz，DMSO)：δ180.1，148.8，148.1，147.3，141.8，133.6，128.7，127.9，125.2，115.8， 103.3，98.2；HRMS(ESI)：Calcd.for C₁₂H₉N₂O₂[M+H]⁺m/z 213.0659，Found m/z 213.0661.

Example 2: preparation of 2-amino-1, 9-dimethyl-3H-phenoxazin-3-one

A20 mL three-necked flask was charged with magneton, 2-amino-3-methylphenol (0.5mmol), TEMPO (0.05mmol) and nBu4NBF4(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time is over, the reaction solution is extracted by ethyl acetate (50mL x 3) and water, an organic phase is collected, and a pure target product is obtained by silica gel column chromatography with the yield of 80%.¹H NMR(500MHz，DMSO)：δ7.34-7.20(3H，m)，6.37(2H，s)，6.23(1H， s)，2.59(3H，s)，2.22(3H，m)；¹³C NMR(125MHz，DMSO)：δ179.5，148.7，145.8，143.6，141.8， 136.6，131.6，128.3，125.8，113.2，105.6，102.0，16.3，9.6；HRMS(ESI)：Calcd.for C₁₄H₁₃N₂O₂ [M+H]⁺m/z 241.0972，Found m/z 241.0971.

Example 3: preparation of 2-amino-4, 6-dimethyl-3H-phenoxazin-3-one

A20 mL three-necked flask was charged with magneton, 2-amino-6-methylphenol (0.5mmol), TEMPO (0.05mmol) and nBu4NBF4(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time is over, the reaction solution is extracted by ethyl acetate (50mL x 3) and water, an organic phase is collected, and pure target product is obtained by silica gel column chromatography, wherein the yield is 79%.¹H NMR(500MHz，DMSO)：δ7.46(1H，d，J＝7.5Hz)，7.26(1H，d，J＝7.5 Hz)，7.21(1H，t，J＝7.5Hz)，6.68(2H，s)，6.26(1H，s)，2.40(3H，s)，2.04(3H，m)；¹³C NMR(125 MHz，DMSO)：δ180.3，148.2，147.1，145.1，140.9，133.7，130.1，126.0，125.3，124.7，111.6，98.0， 14.8，8.0；HRMS(ESI)：Calcd.for C₁₄H₁₃N₂O₂[M+H]⁺m/z 241.0972，Found m/z 241.0976.

Example 4: preparation of 2-amino-1, 9-dimethoxy-3H-phenoxazin-3-one

Magnetitum, 2-amino-3-methoxyphenol (0.5mmol), TEMPO (0.05mmol) and nBu4NBF4(0.5mmol) were added to a 20mL three-necked flask. Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time was over, the reaction solution was extracted with ethyl acetate (50mL × 3) and water, the organic phase was collected and purified by silica gel column chromatography to give the pure desired product in 68% yield.¹H NMR(400MHz，DMSO)：δ7.45(1H，t，J＝8.4Hz)，7.08(1H，d，J＝8.4 Hz)，7.03(1H，d，J＝8.4Hz)，6.30(2H，s)，6.25(1H，s)，3.98(3H，s)，3.87(3H，s)；¹³C NMR(100 MHz，DMSO)：δ179.9，155.4，147.0，142.6，140.7，137.6，132.1，129.5，123.9，107.7，107.3，101.4， 59.9，56.4；HRMS(ESI)：Calcd.for C₁₄H₁₃N₂O₄[M+H]⁺m/z 273.0870，Found m/z 273.0877.

Example 5: preparation of 2-amino-4, 6-difluoro-3H-phenoxazin-3-one

A20 mL three-necked flask was charged with magneton, 2-amino-6-fluorophenol (0.5mmol), TEMPO (0.05mmol) and nBu4NBF4(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time was over, the reaction solution was extracted with ethyl acetate (50mL × 3) and water, the organic phase was collected and purified by silica gel column chromatography to give the pure desired product in 62% yield.¹H NMR(500MHz，DMSO)：δ7.55(1H，d，J＝8.0Hz)，7.47-7.44(1H，m)， 7.40-7.23(1H，m)，7.09(2H，s)，6.32(1H，s)；¹³C NMR(125MHz，DMSO)：δ172.2(d，²J_C-F＝ 16Hz)，149.2(d，¹J_C-F＝248Hz，)，147.3，146.6(d，⁴J_C-F＝2Hz)，138.7(d，¹J_C-F＝252Hz)，135.2， 132.5(d，³J_C-F＝6Hz)，129.5(d，³J_C-F＝11Hz)，124.5(d，³J_C-F＝7Hz)，123.7(d，⁴J_C-F＝2Hz)， 115.2(d，²J_C-F＝17Hz)，96.4；HRMS(ESI)：Calcd.for C₁₂H₇F₂N₂O₂[M+H]⁺m/z 249.0471，Found m/z 249.0477.

Example 6: preparation of 2-amino-4, 6-dichloro-3H-phenoxazin-3-one

A20 mL three-necked flask was charged with magneton, 2-amino-6-chlorophenol (0.5mmol), TEMPO (0.05mmol) and nBu₄NBF₄(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time is over, the reaction solution is extracted by ethyl acetate (50mL x 3) and water, an organic phase is collected, and pure target product is obtained by silica gel column chromatography with the yield of 69%.¹H NMR(500MHz，DMSO)：δ7.67(1H，d，J＝8.0Hz)，7.61(1H，d，J＝8.0 Hz)，7.40(1H，t，J＝8.0Hz)，7.10(2H，s)，6.38(1H，s)；¹³C NMR(125MHz，DMSO)：δ174.2， 147.3，147.1，143.8，137.6，134.8，128.8，126.8，125.6，119.8，109.6，97.5；HRMS(ESI)：Calcd.for C₁₂H₇Cl₂N₂O₂[M+H]⁺m/z 280.9879，Found m/z 280.9877.

Example 7: preparation of 2-amino-4, 6-dibromo-3H-phenoxazin-3-one

A20 mL three-necked flask was charged with magneton, 2-amino-6-bromophenol (0.5mmol), TEMPO (0.05mmol) and nBu4NBF4(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time is over, the reaction solution is extracted by ethyl acetate (50mL x 3) and water, an organic phase is collected, and pure target product is obtained by silica gel column chromatography with the yield of 71%.¹H NMR(500MHz，DMSO)：δ7.78(1H，d，J＝8.0Hz)，7.73(1H，d，J＝8.0 Hz)，7.37(1H，t，J＝8.0Hz)，7.13(2H，s)，6.40(1H，s)；¹³C NMR(125MHz，DMSO)：δ174.4， 147.6，147.1，146.0，139.0，135.0，131.8，127.3，126.3，108.7，101.1，97.6；HRMS(ESI)：Calcd.for C₁₂H₇B_r2_N2O₂[M+H]⁺m/z 368.8869，Found m/z 368.8867.

Example 8: preparation of dimethyl 2-amino-3-oxo-3H-phenoxazine-4, 6-dicarboxylic acid disalt

A20 mL three-necked flask was charged with magneton, methyl 3-amino-2-hydroxybenzoate (0.5mmol), TEMPO (0.05mmol) and nBu4NBF4(0.5 mmol). Graphite and platinum sheets were fixed to an electrode holder, which was then mounted in a three-necked flask, and DMF (5ml), a reaction solvent, was added to the three-necked flask. The reaction was stirred at room temperature and a constant current of 10mA was applied until the reaction was complete. After the reaction time is over, the reaction solution is extracted by ethyl acetate (50mLx 3) and water, an organic phase is collected, and a pure target product is obtained by silica gel column chromatography, wherein the yield is 64%.¹H NMR(400MHz，DMSO)：δ7.96(2H，t，J＝8.0Hz)，7.53(1H，t，J＝8.0 Hz)，7.07(2H，s)，6.44(1H，s)，3.91(6H，s)；¹³C NMR(100MHz，DMSO)：δ176.6，164.1，163.3， 147.0，146.3，144.9，140.0，134.3，132.5，130.5，125.1，118.7，110.2，98.4，52.3，52.2；HRMS(ESI)： Calcd.for C₁₆H₁₃N₂O₆[M+H]⁺m/z 329.0769，Found m/z 329.0773。