Synthesis method and application of quinoxaline ketone derivatives substituted by hydroxyl fluoralkyl at C-3 position

Abstract

The application belongs to the technical field of organic synthesis chemistry, and discloses a synthesis method of a C-3 hydroxyl fluoralkyl substituted quinoxaline ketone derivative; the method is to react N-trifluoroethoxy phthalimide reagent as a hydroxyl fluoralkylating reagent with quinoxaline-2(1H)-ketone under photocatalysis to obtain a quinoxaline-2(1H)-ketone C-3 hydroxyl fluoralkylated derivative. In the method, high temperature and oxidants are not needed, the condition is mild, and the reaction substrate has good tolerance. In the method, photosensitizers and metal catalysts are not needed in the reaction process, the synthesis route is green and environmentally friendly, and the quinoxaline-2(1H)-ketone C-3 hydroxyl fluoralkylated derivative can be quickly and efficiently synthesized.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthetic chemistry, and particularly relates to a synthesis method and application of a quinoxaline-2(1H)-one derivative substituted with a hydroxyl fluoralkyl group at a C-3 position. BACKGROUND

[0002] Quinoxaline-2(1H)-one is an important nitrogen-containing heterocyclic structure, which is widely present in natural products and drugs with biological activity and material science. They have a wide range of biological activities, including antibacterial, anticancer, antithrombotic, protein kinase inhibition, benzodiazepine receptor agonist, etc. In the past decade, significant progress has been made in the direct functionalization of the C-3 position of quinoxaline-2(1H)-one, including arylation, alkylation, acylation, amination, sulfonation and phosphorylation.

[0003] Compared with the parent structure, the introduction of fluorine-containing groups has always been an important modification means for bioactive structures, because the fluorine atom has high electronegativity, small atomic radius and good lipophilicity, etc. Organic small molecules often exhibit unique physical, chemical and biological properties after introducing fluorine atoms, such as lipophilicity, membrane permeability, metabolic stability and biological activity. Therefore, fluorine-containing functional molecules have been widely used in the fields of medicine, pesticides, life science and material science, especially playing an important role in drug development. Among them, the secondary trifluoromethylmethanol is a unique and interesting trifluoromethyl group, which has significant applications in drugs and biochemistry, and is a repeatedly occurring feature in biologically active compounds. The introduction of a hydroxyl fluoralkyl group on the quinoxaline-2(1H)-one structure can obtain a series of new quinoxaline ketone derivatives, providing more possibilities for subsequent drug development. The hydroxyl fluoralkyl group can be easily introduced into the molecular structure through a free radical initiation method. In 2016, Liu Zhongquan and his colleagues developed a free radical-initiated dehydrogenative cross-coupling reaction of fluorinated alcohol with indole and pyrrole (Scheme a). In 2020, Shen Xia's group developed a method for directly transferring a trifluoroethanol group through an activated free radical of an organosilicon reagent (Scheme b). In 2023, Sharma and his team used an N-trifluoroethoxy phthalimide reagent to realize the hydroxyl fluoralkylation of isoquinoline (Scheme c). The specific reaction formula is shown in the following:

[0004]

[0005] Based on the above research background, the related methods in the prior art still have the following defects:

[0006] The introduction of the hydroxyl fluoralkyl group requires the use of transition metals, strong oxidants or high temperature conditions, which limits the applicability of these developed methods. Therefore, it is necessary to explore a new method for synthesizing quinoxaline ketone compounds substituted with a hydroxyl fluoralkyl group using a cheap and stable trifluoroethoxy reagent. SUMMARY

[0007] The present application aims at overcoming the deficiencies in the prior art, and provides a synthesis method and application of C-3 hydroxyl fluoralkyl substituted quinoxaline ketone derivatives.

[0008] The technical solution adopted by the present application to solve its technical problems is:

[0009] The present application provides a synthesis method of C-3 hydroxyl fluoralkyl substituted quinoxaline ketone derivatives, wherein the method is to react N-trifluoroethoxy phthalimide reagent as a hydroxyl fluoralkylating reagent with quinoxaline-2(1H)-ketone under photocatalysis to obtain quinoxaline-2(1H)-ketone C-3 hydroxyl fluoralkylated derivatives.

[0010] Further, the reaction formula of the method is as follows:

[0011]

[0012] wherein, R1=F, Br, Cl, CH3, C4H4; R2=H, CH3, C2H5, C3H7, C3H5, CH2Ph, C3H3, C4H5, CH2COOC2H5, CH2COOC(CH3)3, C8H9, CH2COPh, C7H 13 .

[0013] Further, the reaction mechanism of the method is as follows:

[0014]

[0015] Further, the N-trifluoroethoxy phthalimide reagent is 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione.

[0016] Further, the quinoxaline-2(lH)-one includes 1-methylquinoxaline-2(lH)-one, quinoxaline-2(lH)-one, 1-ethylquinoxaline-2(lH)-one, 1-propylquinoxaline-2(lH)-one, 1-(cyclohexylmethyl)quinoxaline-2(lH)-one, 1-allylquinoxaline-2(lH)-one, 1-(prop-2-ynyl)quinoxaline-2(lH)-one, 1-(but-2-ynyl)quinoxaline-2(lH)-one, ethyl (2-oxoquinoxalin-l-yl)acetate, prop-2-yl (2-oxoquinoxalin-l-yl)acetate, 1-benzylquinoxaline-2(lH)-one, 1-[(4-methylphenyl)methyl]quinoxaline-2(lH)-one, 1-(2-oxo-2-phenylethyl)quinoxaline-2(lH)-one, 6-fluoro-1-methylquinoxaline-2(lH)-one, 6-bromo-1-methylquinoxaline-2(lH)-one, 6-chloro-1-methylquinoxaline-2(lH)-one, 1,5-dimethylquinoxaline-2(lH)-one, 1,6,7-trimethylquinoxaline-2(lH)-one, 1-methylbenzo[2,l-g]quinoxaline-2(lH)-one.

[0017] Further, the quinoxaline-2(lH)-one derivative has the following structural formula:

[0018]

[0019]

[0020] Further, the method includes the following steps:

[0021] The quinoxaline-2(lH)-one, N-alkoxyphthalimide reagent, and trifluoroacetic acid are added under anhydrous and anaerobic conditions, and irradiated under a blue lamp with a power of 33 W and a wavelength of 440-450 nm, while controlling the temperature at 40-50 degrees Celsius for 12-24 hours. After the reaction is completed, the product is extracted, washed, dried, and separated and purified by column chromatography, and finally the quinoxaline-2(lH)-one derivative substituted with a hydroxyl fluoralkyl group at the C-3 position is obtained.

[0022] Further, the specific steps are as follows:

[0023] Firstly, the Schlenk tube is treated in anhydrous and anaerobic manner, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube is removed by high temperature of the oven gun, the inert gas and the air in the reaction tube are replaced by double-pipe, an anhydrous and anaerobic environment is created, after the Schlenk tube is cooled in the inert gas atmosphere, quinoxaline-2(1H)-one and its derivatives, N-alkoxy phthalimide reagent, trifluoroacetic acid are sequentially added into the reaction tube, the molar ratio of quinoxaline-2(1H)-one derivative:N-alkoxy phthalimide reagent:trifluoroacetic acid is 0.30:0.60:0.60, anhydrous N,N-dimethylacetamide is taken by a long needle syringe under the protection of double-pipe inert gas, the ratio of anhydrous N,N-dimethylacetamide:trifluoroacetic acid is 1.5:0.6 mL:mmol, and is added into the reaction tube, the reactants are dissolved under stirring, and the reaction is carried out under the light irradiation of a blue 33W LED lamp for 12-24 hours; after the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, ethyl acetate is extracted three times, a saturated sodium chloride solution is used for washing, the organic phase is dried with anhydrous sodium sulfate, the solvent is removed by rotary evaporation, and the residue is purified by silica gel column chromatography to obtain the product;

[0024] The mobile phase system is petroleum ether:ethyl acetate, and the volume ratio of the two is 10:1-3:1.

[0025] Further, the solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

[0026] The inert gas is nitrogen or argon.

[0027] The application of the synthetic method as described above in the synthesis of quinoxaline-2(1H)-one C-3 hydroxyl fluoralkylated derivatives.

[0028] The application has the following advantages and positive effects:

[0029] 1. The application uses N-trifluoroethoxy phthalimide reagent as the source of hydroxyl and fluoralkyl, avoids the use of strong oxidants and high temperature, and increases the substrate compatibility.

[0030] 2. The application avoids the use of transition metal catalysts and photosensitizers, reduces the reaction cost, and is green and environmentally friendly in the synthetic route.

[0031] 3. The raw materials used in the application are cheap and easy to obtain, the solvent used is a common organic solvent and does not need special treatment, the post-treatment is simple, the product can be separated by simple column chromatography, the C-3 hydroxyl fluoralkylated quinoxaline-2(1H)-one derivative can be synthesized quickly and efficiently, and the application is suitable for the preparation and synthesis of fine chemicals or drug molecule precursors.

[0032] 4. The quinoxaline ketone derivatives prepared by the application are new compounds, and provide a new scheme for preparing a drug molecule structure with biological activity. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 H spectrum of the compound of Example 1 in the application;

[0034] Figure 2 H spectrum of the compound of Example 2 in the application;

[0035] Figure 3 H spectrum of the compound of Example 3 in the application;

[0036] Figure 4 H spectrum of the compound of Example 4 in the application;

[0037] Figure 5 H spectrum of the compound of Example 5 in the application;

[0038] Figure 6 H spectrum of the compound of Example 6 in the application;

[0039] Figure 7 H spectrum of the compound of Example 7 in the application;

[0040] Figure 8 H spectrum of the compound of Example 8 in the application;

[0041] Figure 9 H spectrum of the compound of Example 9 in the application;

[0042] Figure 10 H spectrum of the compound of Example 10 in the application;

[0043] Figure 11 H spectrum of the compound of Example 11 in the application;

[0044] Figure 12 H spectrum of the compound of Example 12 in the application;

[0045] Figure 13 H spectrum of the compound of Example 13 in the application;

[0046] Figure 14 H spectrum of the compound of Example 14 in the application;

[0047] Figure 15 H spectrum of the compound of Example 15 in the application;

[0048] Figure 16 H spectrum of the compound of Example 16 in the application;

[0049] Figure 17 H NMR spectrum of the compound of Example 17 in the present application;

[0050] Figure 18 H NMR spectrum of the compound of Example 18 in the present application;

[0051] Figure 19 H NMR spectrum of the compound of Example 19 in the present application. DETAILED DESCRIPTION

[0052] The present application is further illustrated by the following examples, which are illustrative, but not limiting, and the scope of the present application is not limited by the following examples.

[0053] The various experimental operations involved in the specific examples are all conventional techniques in the art, and the parts not specially noted herein can be implemented by referring to various commonly used tool books, scientific and technical literature or related instructions, manuals, etc. before the filing date of the present application.

[0054] A method for synthesizing quinoxaline-2(lH)-one derivatives substituted with hydroxyfluoroalkyl at C-3 position, the method is that under photocatalysis, a N-trifluoroethoxy phthalimide reagent is used as a hydroxyfluoroalkylating reagent, the reagent is reacted with quinoxaline-2(lH)-one to obtain a quinoxaline-2(lH)-one C-3 position hydroxyfluoroalkylated derivative.

[0055] Preferably, the reaction of the method is as follows:

[0056]

[0057] wherein, R1=F, Br, Cl, CH3, C4H4; R2=H, CH3, C2H5, C3H7, C3H5, CH2Ph, C3H3, C4H5, CH2COOC2H5, CH2COOC(CH3)3, C8H9, CH2COPh, C7H 13 .

[0058] Preferably, the reaction mechanism of the method is as follows:

[0059]

[0060] Preferably, the N-trifluoroethoxy phthalimide reagent is 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione.

[0061] More preferably, the quinoxaline-2(lH)-one includes 1-methylquinoxaline-2(lH)-one, quinoxaline-2(lH)-one, 1-ethylquinoxaline-2(lH)-one, 1-propylquinoxaline-2(lH)-one, 1-(cyclohexylmethyl)quinoxaline-2(lH)-one, 1-allylquinoxaline-2(lH)-one, 1-(prop-2-ynyl)quinoxaline-2(lH)-one, 1-(but-2-ynyl)quinoxaline-2(lH)-one, ethyl (2-oxoquinoxalin-l-yl)acetate, prop-2-yl (2-oxoquinoxalin-l-yl)acetate, 1-benzylquinoxaline-2(lH)-one, 1-[(4-methylphenyl)methyl]quinoxaline-2(lH)-one, 1-(2-oxo-2-phenylethyl)quinoxaline-2(lH)-one, 6-fluoro-1-methylquinoxaline-2(lH)-one, 6-bromo-1-methylquinoxaline-2(lH)-one, 6-chloro-1-methylquinoxaline-2(lH)-one, 1,5-dimethylquinoxaline-2(lH)-one, 1,6,7-trimethylquinoxaline-2(lH)-one, 1-methylbenzo[2,l-g]quinoxaline-2(lH)-one.

[0062] More preferably, the quinoxaline-2(lH)-one derivative has the following structural formula:

[0063]

[0064]

[0065] More preferably, the method includes the following steps:

[0066] The quinoxaline-2(lH)-one, the N-alkoxyphthalimide reagent, and the trifluoroacetic acid are added under anhydrous and anaerobic conditions, and irradiated under a blue lamp with a power of 33 W and a wavelength of 440-450 nm while controlling the temperature at 40-50 degrees Celsius for 12-24 hours. After the reaction is completed, the product is extracted, washed, dried, and separated and purified by column chromatography to obtain the quinoxaline-2(lH)-one derivative substituted with a hydroxyl fluorinated alkyl group at the C-3 position.

[0067] More preferably, the specific steps are as follows:

[0068] Firstly, the Schlenk tube is treated in anhydrous and anaerobic way, the residual moisture in the reaction tube wall, tube opening and tube is removed by high temperature of the oven gun, the inert gas and air in the reaction tube are replaced by double-tube, an anhydrous and anaerobic environment is created, after the Schlenk tube is cooled in the inert gas atmosphere, quinoxaline-2(1H)-one and its derivatives, N-alkoxy phthalimide reagent, trifluoroacetic acid are sequentially added into the reaction tube, the molar ratio of quinoxaline-2(1H)-one derivative:N-alkoxy phthalimide reagent:trifluoroacetic acid is 0.30:0.60:0.60, anhydrous N,N-dimethylacetamide is taken by a long needle syringe under the protection of double-tube inert gas, the ratio of anhydrous N,N-dimethylacetamide:trifluoroacetic acid is 1.5:0.6 mL:mmol, which is added into the reaction tube, the reactants are dissolved under stirring, the reaction is carried out under the illumination of blue 33W LED light for 12-24 hours; after the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, ethyl acetate is extracted three times, saturated sodium chloride solution is used for washing, the organic phase is dried with anhydrous sodium sulfate, the solvent is removed by rotary evaporation, the residue is purified by silica gel column chromatography to obtain the product;

[0069] The mobile phase system is petroleum ether: ethyl acetate, and the volume ratio of the two is 10:1-3:1.

[0070] Preferably, the solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

[0071] The inert gas is nitrogen or argon.

[0072] The application of the synthetic method as described above in the synthesis of quinoxaline-2(1H)-one C-3 hydroxyl fluoralkylated derivatives.

[0073] Specifically, the related preparation and detection are as follows:

[0074] Example 1

[0075]

[0076] Firstly, 10 mL Schlenk tube was treated with anhydrous and oxygen-free, the residual moisture in the reaction tube wall, tube opening and tube was removed by high temperature of the oven gun, the argon and air in the reaction tube was replaced by double-tube, to create a water and oxygen-free environment, after the Schlenk tube was cooled in the argon atmosphere, 1-methylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, 1.50 mL anhydrous N,N-dimethylacetamide was taken by long needle syringe under the protection of double-tube argon, added into the reaction tube, the reactants were dissolved under stirring, the reaction was carried out under the light of blue 33 W LED for 12 hours. After TLC confirmed that the reaction was complete, a large amount of water was added for washing, extracted with ethyl acetate for three times, washed with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was volume ratio 4:1. White solid, yield 75%. 1 H NMR (400 MHz, CDC13) δ 7.94 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.48 - 7.37 (m, 2H), 5.57 - 5.44 (m, 1H), 4.92 (d, J = 10.1 Hz, 1H), 3.76 (s, 3H); 13 CNMR (100 MHz, CDC13) δ 154.03, 150.83, 133.57, 132.16, 131.76, 130.55, 128.63 - 120.53 (m), 124.47, 114.08, 69.86 (q, J = 32.4 Hz), 29.31; 19 F NMR (376 MHz, CDC13) δ -76.27. As Figure 1 shown.

[0077] Example 2

[0078]

[0079] Firstly, 10 mL Schlenk tube was treated with anhydrous and oxygen-free, the residual moisture in the reaction tube wall, tube opening and tube was removed by high temperature of the oven gun, the argon and air in the reaction tube was replaced by double-tube, to create a water-free and oxygen-free environment, after the Schlenk tube was cooled in the argon atmosphere, quinoxaline-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, 1.50 mL anhydrous N,N-dimethylacetamide was taken by long needle syringe under the protection of double-tube argon, and added into the reaction tube, the reactants were dissolved under stirring, and the reaction was carried out under the light of blue 33 W LED for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate for three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was volume ratio 1:1. White solid, yield 78%. 1 H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.44-7.26 (m, 2H), 6.87 (d, J = 7.5 Hz, 1H), 5.64 (t, J = 7.0 Hz, 1H); 13 CNMR (100 MHz, DMSO) δ 154.39 (d, J = 8.9 Hz), 132.63, 131.97, 131.58, 129.51, 125.00 (d, J = 283.9 Hz), 124.23, 116.14, 66.88-65.13 (m); 19 FNMR (376 MHz, DMSO) δ -74.18. As Figure 2 shown.

[0080] Example 3

[0081]

[0082] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-ethylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 5:1 by volume. White solid, yield 89%. 1 H NMR (400 MHz, CDC13) δ 7.95 (dd, J = 8.3, 1.5 Hz, 1H), 7.72-7.64 (m, 1H), 7.46-7.40 (m, 2H), 5.55-5.44 (m, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.37 (t, 2H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 153.69, 150.88, 132.65, 130.93, 124.38, 123.93 (q, J = 285.83 Hz), 70.04 (q, J = 32.3 Hz), 37.80, 12.54; 19 F NMR (376 MHz, CDC13) δ -76.34. As Figure 3 shown.

[0083] Example 4

[0084]

[0085] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-propyl quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube in turn, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was volume ratio 6:1). White solid, yield 47%. 1 H NMR (400 MHz, CDC13) δ 7.94 (dd, J = 7.9, 1.5 Hz, 1H), 7.74 - 7.60 (m, 1H), 7.50 - 7.34 (m, 2H), 5.57 - 5.44 (m, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.31 - 4.17 (m, 2H), 1.95 - 1.74 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 153.85, 150.73, 132.77, 132.02 (d, J = 3.1 Hz), 130.76, 124.23, 123.82 (q, J = 286.84 Hz), 114.09, 69.95 (q, J = 32.2 Hz), 20.69, 11.29; 19 F NMR (376 MHz, CDC13) δ -76.35. As shown in Figure 4

[0086] Example 5

[0087]

[0088] ​A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1-cyclohexylmethyl quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added into the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 10:1 by volume). White solid, yield 57%. 1 H NMR (400 MHz, CDC13) δ 7.93 (dd, J = 8.0, 1.5 Hz, 1H), 7.69-7.61 (m, 1H), 7.47-7.31 (m, 2H), 5.56-5.43 (m, 1H), 4.99 (d, J = 10.1 Hz, 1H), 4.18 (dd, J = 7.5, 3.6 Hz, 2H), 1.89 (s, 1H), 1.78-1.60 (m, 3H), 1.18 (s, 2H); 13 C NMR (100 MHz, CDC13) δ 154.30, 150.72, 133.13, 132.02, 131.87, 130.73, 124.19, 123.84 (q, J = 284.8 Hz), 114.53, 69.97 (q, J = 32.3 Hz), 48.21, 36.60, 30.81, 30.74, 26.06, 25.71; 19 F NMR (376 MHz, CDC13) δ -76.21. As Figure 5 shown.

[0089] Example 6

[0090]

[0091] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1-allylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: dichloromethane: ethyl acetate, the ratio was 3:1:0.1 by volume). White solid, yield 57%. 1 H NMR (400 MHz, CDC13) δ 7.94 (dd, J = 8.1, 1.6 Hz, 1H), 7.73-7.59 (m, 1H), 7.53-7.31 (m, 1H), 6.03-5.83 (m, 1H), 5.58-5.45 (m, 1H), 5.31 (d, J = 10.5 Hz, 1H), 5.18 (d, J = 17.2 Hz, 1H), 5.01-4.85 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 153.61, 150.87 (d, J = 1.6 Hz), 132.81, 132.05, 131.93, 130.28 (d, J = 66.7 Hz), 124.43, 123.78 (d, J = 284.8 Hz), 114.62, 69.79 (q, J = 32.2 Hz), 44.69; 19 F NMR (376 MHz, CDC13) δ -76.34. As Figure 6 shown.

[0092] Example 7

[0093]

[0094] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1-(prop-2-ynyl)quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 24 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: dichloromethane: ethyl acetate, the ratio was 3:1:0.1 by volume). White solid, yield 34%. 1 H NMR (400 MHz, CDC13) δ 7.96 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 5.59-5.44 (m, 1H), 5.09 (qd, J = 17.5, 2.6 Hz, 2H), 4.75 (d, J = 10.1 Hz, 1H), 2.33 (t, J = 2.6 Hz, 1H); 13 C NMR (100 MHz, CDC13) δ 152.96, 150.94, 132.26, 132.09, 131.92, 130.67, 124.81, 128.68 (q, J = 284.82 Hz), 114.62, 76.02, 73.94, 69.54 (q, J = 32.3 Hz), 31.72; 19 F NMR (376 MHz, CDC13) δ -76.30. As Figure 7 shown.

[0095] Example 8

[0096]

[0097] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(but-2-ynyl)quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 24 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: dichloromethane: ethyl acetate, the ratio was 2:1:0.1 by volume). White solid, yield 75%. 1 H NMR (400 MHz, CDC13) δ 7.94 (dd, J = 8.1, 1.5 Hz, 1H), 7.74-7.67 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 5.58-5.43 (m, 1H), 5.09-4.96 (m, 2H), 4.83 (d, J = 10.1 Hz, 1H), 1.78 (t, J = 2.4 Hz, 3H); 13 C NMR (100 MHz, CDC13) δ 153.08, 150.88, 132.30, 132.14, 131.95, 130.51, 124.59, 123.73 (d, J = 284.9 Hz), 114.90, 81.91, 71.42, 69.70 (q, J = 32.5 Hz), 32.32, 3.58; 19 F NMR (376 MHz, CDC13) δ -76.29. As Figure 8 shown.

[0098] Example 9

[0099]

[0100] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, (2-oxoquinoxalin-1-yl) ethyl acetate (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were sequentially added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 24 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: dichloromethane: ethyl acetate, the ratio was volume ratio 3:1:0.1). White solid, yield 84%. 1 H NMR (400 MHz, CDC13) δ 7.97 (dd, J = 8.0, 1.6 Hz, 1H), 7.68-7.61 (m, 1H), 7.48-7.41 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 5.58-5.48 (m, 1H), 5.14-4.98 (m, 2H), 4.75 (d, J = 10.0 Hz, 1H), 4.30-4.21 (m, 2H), 1.29 (d, J = 7.1 Hz, 3H); 13 CNMR (100 MHz, CDC13) δ 166.46, 153.55, 150.90, 132.79, 132.31, 131.78, 130.85, 124.71, 123.68 (d, J = 284.6 Hz), 113.53, 72.56-66.17 (m), 62.39, 43.60, 29.71, 14.07; 19 FNMR (376 MHz, CDC13) δ -76.33. As Figure 9 shown.

[0101] Example 10

[0102]

[0103] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, (2-oxoquinoxalin-1-yl)acetic acid prop-2-yl ester (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon, and then added into the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33 W LED lamp for 24 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 2:1 by volume). White solid, yield 49%. 1 H NMR (400 MHz, CDC13) δ 7.96 (dd, J = 8.1, 1.5 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.46 - 7.41 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.57 - 5.48 (m, 1H), 5.03 - 4.90 (m, 2H), 4.77 (d, J = 10.0 Hz, 1H), 1.45 (s, 9H); 13 C NMR (100 MHz, CDC13) δ 165.45, 153.55, 150.88, 132.86, 132.21, 131.74, 130.79, 124.61, 123.22 (q, J = 285.83 Hz), 113.55, 83.68, 69.47 (q, J = 32.4 Hz), 44.32, 27.92; 19 F NMR (376 MHz, CDC13) δ -76.35. As shown in Figure 10

[0104] Example 11

[0105]

[0106] ​A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1-benzylquinoxalin-2(lH)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-l,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added into the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 24 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: dichloromethane: ethyl acetate, the ratio was volume ratio 4:1:0.1). White solid, yield 91%. 1 H NMR (400 MHz, CDC13) δ 7.94 (dd, J = 8.1, 1.5 Hz, 1H), 7.58-7.52 (m, 1H), 7.43-7.28 (m, 5H), 7.24 (d, J = 7.3 Hz, 2H), 5.62-5.55 (m, 1H), 5.54 (s, 2H), 4.91 (d, J = 10.1 Hz, 1H); 13 C NMR (100 MHz, CDC13) δ 154.29, 151.13, 134.63, 133.03, 132.23, 132.15, 130.72, 129.25, 128.17, 127.01, 124.61, 123.94 (d, J = 284.6 Hz), 114.98, 69.95 (q, J = 32.3 Hz), 46.21; 19 F NMR (376 MHz, CDC13) δ -76.28. As shown in Figure 11

[0107] Example 12

[0108]

[0109] ​A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1-[(4-methylphenyl)methyl] quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added into the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33 W LED lamp for 24 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 10:1 by volume). White solid, yield 75%. 1 H NMR (400 MHz, CDC13) δ 7.93 (dd, J = 8.4, 1.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.41-7.35 (m, 2H), 7.13 (s, 4H), 5.61-5.53 (m, 1H), 5.49 (s, 2H), 4.93 (d, J = 10.1 Hz, 1H), 2.31 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 154.18, 150.97, 137.87, 132.93, 132.06, 132.04, 131.51, 130.62, 129.77, 126.93, 124.42, 128.56-119.17 (m), 114.88, 69.98 (q, J = 32.5 Hz), 45.88, 21.10; 19 F NMR (376 MHz, CDC13) δ -76.29. As shown in Figure 12

[0110] Example 13

[0111]

[0112] ​A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1-(2-oxo-2-phenylethyl) quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were sequentially added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was volume ratio 10:1). White solid, yield 49%. 1 H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 3H), 7.41 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.86-5.69 (m, 2H), 5.57-5.48 (m, 1H), 4.80 (d, J = 10.0 Hz, 1H); 13 CNMR (100 MHz, CDCl3) δ 190.39, 153.77, 150.67, 134.63, 134.25, 133.09, 132.20, 131.89, 130.77, 129.18, 128.21, 124.57, 123.75 (d, J = 284.7 Hz), 113.98, 69.50 (d, J = 32.4 Hz), 48.53; 19 F NMR (376 MHz, CDCl3) δ -76.29. As Figure 13 shown.

[0113] Example 14

[0114]

[0115] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 6-fluoro-1-methylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 5:1 by volume). White solid, yield 61%. 1 H NMR (400 MHz, CDC13) δ 7.64 (dd, J = 8.4, 2.8 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.38 (dd, J = 9.2, 4.8 Hz, 1H), 5.54 - 5.44 (m, 1H), 4.86 (d, J = 10.2 Hz, 1H), 3.75 (s, 3H); 13 C NMR (100 MHz, CDC13) δ 158.96 (d, J = 245.9 Hz), 153.68, 152.51, 132.27 (d, J = 11.3 Hz), 130.28, 123.68 (d, J = 284.8 Hz), 120.16 (d, J = 24.2 Hz), 115.89 (d, J = 22.8 Hz), 115.38 (d, J = 8.7 Hz), 70.00 (q, J = 32.4 Hz), 29.60; 19 F NMR (376 MHz, CDC13) δ -76.22, -117.17. As Figure 14 shown.

[0116] Example 15

[0117]

[0118] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 6-bromo-1-methylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was volume ratio 3:1). White solid, yield 46%. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 9.0, 2.3 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 5.53-5.45 (m, 1H), 4.78 (d, J = 10.2 Hz, 1H), 3.73 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 153.77, 152.47, 135.04, 132.98, 132.80, 132.57, 123.76 (d, J = 284.8 Hz), 117.25, 115.66, 69.93 (q, J = 32.4 Hz), 29.62; 19 F NMR (376 MHz, CDCl3) δ -76.20. As Figure 15 shown.

[0119] Example 16

[0120]

[0121] Firstly, 10 mL Schlenk tube was treated with anhydrous and oxygen-free, the residual moisture in the reaction tube wall, tube opening and tube was removed by high temperature of the oven gun, the argon and air in the reaction tube was replaced by double-tube, to create a water-free and oxygen-free environment, after the Schlenk tube was cooled in the argon atmosphere, 6-chloro-1-methylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, 1.50 mL anhydrous N,N-dimethylacetamide was taken by long needle syringe under the protection of double-tube argon, added into the reaction tube, the reactants were dissolved under stirring, the reaction was carried out under the light of blue 33 W LED for 12 hours. After TLC confirmed that the reaction was complete, a large amount of water was added for washing, extracted with ethyl acetate for three times, washed with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed by rotary evaporation, the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was volume ratio 3:1). White solid, yield 89%. 1 H NMR (400 MHz, CDCI3) δ 7.94 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 9.0, 2.4 Hz, 1 H), 7.34 (d, J = 9.0 Hz, 1 H), 5.55-5.45 (m, 1 H), 4.79 (d, J = 10.2 Hz, 1 H), 3.74 (s, 3 H); 13 C NMR (100 MHz, CDCI3) δ 153.79, 152.54, 132.37, 132.33, 132.29, 130.09, 129.92, 123.76 (d, J = 284.4 Hz), 115.40, 69.98 (d, J = 32.4 Hz), 29.64; 19 F NMR (376 MHz, CDCI3) δ -76.22. As Figure 16 shown.

[0122] Example 17

[0123]

[0124] Firstly, 10 mL Schlenk tube was treated with anhydrous and oxygen-free, the residual moisture in the reaction tube wall, tube opening and tube was removed by high temperature of the oven gun, the argon and air in the reaction tube was replaced by double-tube, to create a water-free and oxygen-free environment, after the Schlenk tube was cooled in the argon atmosphere, 1, 5-dimethyl quinoxaline-2(1H)-ketone (0.30 mmol), 2-(2, 2, 2-trifluoroethoxy) isoindoline-1, 3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, 1.50 mL anhydrous N, N-dimethylacetamide was taken by long needle syringe under the protection of double-tube argon, and added into the reaction tube, the reactants were dissolved under stirring, and the reaction was carried out under the light of blue 33 W LED for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate for three times, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 5:1 by volume). White solid, yield 89%. 1 H NMR (400 MHz, CDCl3) δ 7.58-7.52 (m, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.55-5.45 (m, 1H), 4.95 (d, J = 9.9 Hz, 1H), 3.74 (s, 3H), 2.70 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 154.06, 148.97, 139.55, 133.89, 132.09, 130.51, 125.84, 123.93 (q, J = 284.8 Hz), 112.08, 69.99 (q, J = 32.2 Hz), 29.55, 17.58; 19 F NMR (376 MHz, CDCl3) δ -76.41. As Figure 17 shown.

[0125] Example 18

[0126]

[0127] A 10 mL Schlenk tube was first treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high-temperature oven gun, and the argon and air in the reaction tube were replaced by double-tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the argon atmosphere, 1,6,7-trimethylquinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added to the reaction tube in turn, and 1.50 mL of anhydrous N,N-dimethylacetamide was taken by a long needle syringe under the protection of double-tube argon and added to the reaction tube. The reactants were dissolved under stirring, and the reaction was carried out under the light of a blue 33W LED lamp for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 5:1 by volume). White solid, yield 55%. 1 H NMR (400 MHz, CDCl3) δ 7.58-7.52 (m, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.55-5.45 (m, 1H), 4.95 (d, J = 9.9 Hz, 1H), 3.74 (s, 3H), 2.70 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 154.26, 149.25 (d, J = 1.7 Hz), 142.66, 133.81, 131.72, 130.51, 130.41, 128.60-121.58 (m), 114.62, 70.08 (q, J = 32.2 Hz), 29.30, 20.93, 19.31; 19 F NMR (376 MHz, CDCl3) δ -76.47. As Figure 18 shown.

[0128] Example 19

[0129]

[0130] Firstly, 10 mL Schlenk tube was treated with anhydrous and oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube was removed by high temperature of the oven, the argon and air in the reaction tube was replaced by double-tube, an anhydrous and oxygen-free environment was created, after the Schlenk tube was cooled in the argon atmosphere, 1-methyl-benzo[2,1-g]quinoxalin-2(1H)-one (0.30 mmol), 2-(2,2,2-trifluoroethoxy)isoindoline-1,3-dione (0.60 mmol), trifluoroacetic acid (0.60 mmol) were added into the reaction tube, 1.50 mL anhydrous N,N-dimethylacetamide was taken by long needle syringe under the protection of double-tube argon, and then added into the reaction tube, the reactants were dissolved under stirring, and the reaction was carried out under the light of blue 33 W LED for 12 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, and the organic phase was extracted with ethyl acetate for three times, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. The solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography to obtain the product (the mobile phase system was petroleum ether: ethyl acetate, the ratio was 3:1 by volume). Yellow solid, yield 41%. 1 H NMR (400 MHz, CDCl3) δ 7.58-7.52 (m, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.55-5.45 (m, 1H), 4.95 (d, J = 9.9 Hz, 1H), 3.74 (s, 3H), 2.70 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 153.93, 151.67, 134.65, 131.17 (d, J = 53.4 Hz), 130.45, 129.98, 129.08, 128.90, 127.49, 126.13, 110.80, 69.87 (d, J = 32.0 Hz), 29.39; 19 F NMR (376 MHz, CDCl3) δ -76.16. As Figure 19 shown.

[0131] Although the embodiments of the present application are disclosed for illustrative purposes, those skilled in the art can understand that various alternatives, changes and modifications are possible without departing from the spirit and scope of the present application and the appended claims, therefore, the scope of the present application is not limited to the disclosed content of the embodiments.

Claims

1. A process for the synthesis of a quinoxaline ketone derivative substituted with a hydroxy fluoroalkyl group at C-3 position, characterized by: The method is that under photocatalysis, N-trifluoroethoxy phthalimide reagent is used as hydroxyl fluoralkylating reagent, which reacts with quinoxaline-2(1H)-one to obtain quinoxaline-2(1H)-one C-3 hydroxyl fluoralkylated derivative; The reaction formula of the method is as follows: wherein R1 = F, Br, CI, CH3, C4H4; R2 = H, CH3, C2H5, C3H7, C3H5, CH2Ph, C3H3, C4H5, CH2COOC2H5, CH2COOC(CH3)3, C8H9, CH2COPh, C7H 13 .

2. The method of synthesis of claim 1, wherein: The reaction mechanism of the method is as follows:

3. The method of synthesis of claim 1, wherein: The N-trifluoroethoxy phthalimide reagent is 2-(2,2,2-trifluoroethoxy) isoindoline-1,3-dione.

4. The method of synthesis of claim 1, wherein: The quinoxaline-2(1H)-one is 1-methyl quinoxaline-2(1H)-one, quinoxaline-2(1H)-one, 1-ethyl quinoxaline-2(1H)-one, 1-propyl quinoxaline-2(1H)-one, 1-(cyclohexylmethyl) quinoxaline-2(1H)-one, 1-allyl quinoxaline-2(1H)-one, 1-(prop-2-ynyl) quinoxaline-2(1H)-one, 1-(but-2-ynyl) quinoxaline-2(1H)-one, (2-oxo quinoxalin-1-yl) ethyl acetate, (2-oxo quinoxalin-1-yl) prop-2-yl acetate, 1-benzyl quinoxaline-2(1H)-one, 1-[(4-methylphenyl) methyl] quinoxaline-2(1H)-one, 1-(2-oxo-2-phenylethyl) quinoxaline-2(1H)-one, 6-fluoro-1-methyl quinoxaline-2(1H)-one, 6-bromo-1-methyl quinoxaline-2(1H)-one, 6-chloro-1-methyl quinoxaline-2(1H)-one, 1,5-dimethyl quinoxaline-2(1H)-one, 1,6,7-trimethyl quinoxaline-2(1H)-one, 1-methylbenzo[2,1-g] quinoxaline-2(1H)-one.

5. The method of synthesis of claim 1, wherein: The structural formula of the quinoxaline-2(1H)-one derivative is as follows:

6. The method of synthesis according to any one of claims 1 to 5, wherein: The method comprises the following steps: Under anhydrous and anaerobic conditions, quinoxaline-2(1H)-one, N-alkoxy phthalimide reagent, trifluoroacetic acid are added, and irradiation is carried out under a blue lamp with a power of 33 W and a wavelength of 440-450 nm, the temperature is controlled at 40-50 DEG C, and the reaction is carried out for 12-24 hours, after the reaction is completed, extraction, washing, drying, column chromatography separation and purification are carried out, and finally C-3 hydroxyl fluoralkyl substituted quinoxaline ketone derivative is obtained.

7. The method of synthesis of claim 6, wherein: The specific steps are as follows: Firstly, the Schlenk tube is treated in anhydrous and anaerobic way, the residual moisture in the reaction tube wall, tube opening and tube is removed by high temperature of the oven gun, the inert gas and air in the reaction tube are replaced by double-tube, an anhydrous and anaerobic environment is created, after the Schlenk tube is cooled in the inert gas atmosphere, quinoxaline-2(1H)-one and its derivatives, N-alkoxy phthalimide reagent, trifluoroacetic acid are sequentially added into the reaction tube, the molar ratio of quinoxaline-2(1H)-one derivative:N-alkoxy phthalimide reagent:trifluoroacetic acid is 0.30:0.60:0.60, anhydrous N,N-dimethylacetamide is taken by a long needle syringe under the protection of double-tube inert gas, the ratio of anhydrous N,N-dimethylacetamide:trifluoroacetic acid is 1.5:0.6 (mL:mmol), which is added into the reaction tube, the reactants are dissolved under stirring, the reaction is carried out under the illumination of blue 33W LED light for 12-24 hours; after the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, ethyl acetate is extracted three times, saturated sodium chloride solution is used for washing, the organic phase is dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation, the residue is purified by silica gel column chromatography to obtain the product; The mobile phase system is petroleum ether: ethyl acetate, and the volume ratio of the two is 10:1-3:

1.

8. The method of synthesis of claim 7, wherein: The solvent is N,N-dimethylformamide or N,N-dimethylacetamide; The inert gas is nitrogen or argon.

9. Use of the synthetic method according to any one of claims 1 to 7 for the synthesis of hydroxyl fluoralkylated derivatives of quinoxaline-2(1H)-one at C-3 position.

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