Green and mild trifluoromethylated pyrido [1, 2-a] indole, synthetic method and application

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and discloses green and mild trifluoromethylated pyridino [1, 2-a] indole, a synthetic method and application, the method comprises the following steps: taking trifluoromethylsulfonyl pyridinium salt as a fluoroalkylation reagent under photocatalysis, and reacting the reagent with N-substituted indole to obtain the trifluoromethylated pyridino [1, 2-a] indole. According to the method, high-temperature reaction is not needed, the condition is mild, and the tolerance to a reaction substrate is good. According to the method disclosed by the invention, a photosensitizer and a metal catalyst are not needed in the reaction process, the synthetic route is green and environment-friendly, and the trifluoromethylated pyrido [1, 2-a] indole derivative can be rapidly and efficiently synthesized.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and in particular relates to a green and mild trifluoromethylated pyrido[1,2-a]indole, a synthesis method and an application thereof. Background Art

[0002] Functionalized fused tricyclic indole derivatives are important nitrogen-containing heterocyclic structures. Pyrido[1,2-a]indole is widely found in biologically active natural products and pharmaceuticals, as well as in materials science. For example, compound A acts as a CRTH2 agonist, compound B as a CRTH2 antagonist, compound C as a PKCβ inhibitor, and compound D as an S1P1 agonist (structural formulas shown below).

[0003]

[0004] Compared to the parent core structure, the introduction of fluorinated groups has long been an important modification method for bioactive structures. This is due to the high electronegativity, small atomic radius, and good lipophilicity of fluorine atoms. Small organic molecules with the introduction of fluorine atoms often exhibit unique physical, chemical, and biological properties, such as lipophilicity, membrane permeability, metabolic stability, and bioactivity. Consequently, fluorinated functional molecules have been widely used in fields such as medicine, pesticides, life sciences, and materials science, playing a particularly important role in drug development. Among them, the trifluoromethyl group is a representative fluorinated group with significant applications in medicine and biochemistry and a recurring feature in bioactive compounds. Therefore, the introduction of a CF3 group into the pyrido[1,2-a]indole skeleton to form a trifluoromethylated pyrido[1,2-a]indole is of great significance in drug development.

[0005] Trifluoromethyl groups can be easily introduced into the molecular structure through free radical initiation. In 2015, Zhang Lantong's research group used cuprous iodide (CuI) as a catalyst and Togni reagent as a trifluoromethyl source to synthesize trifluoromethylated fused tricyclic indole (Scheme a). In 2022, Hu Yulai's research group developed a visible light-induced, iridium-catalyzed free radical trifluoromethylation / cyclization reaction, and successfully prepared trifluoromethylated tricyclic indole using gaseous trifluorobromomethane (CF3Br) as a trifluoromethylation reagent (Scheme b). In 2023, Li Jiangsheng's research group reported a visible light-driven difunctionalization reaction of unactivated olefins using sodium trifluoromethanesulfonate (CF3SO2Na) catalyzed by eosin Y-Na2 to achieve the synthesis of fused tricyclic indole (Scheme c). In 2024, Huang Qitong and Yang Min proposed using rhodamine 6G as a photocatalyst to realize the cyclization transformation of unactivated N-olefins connected to indole and CF3SO2Na through a photocatalytic cyclization cascade reaction (Scheme d). In the same year, Wu Yusheng's research group reported a visible light-promoted cascade trifluoromethylation / cyclization reaction of unactivated olefins, using trifluoromethyl trifluoromethanesulfonic acid thianthrenium salt as a CF3 source to construct a trifluoromethylated tricyclic indole skeleton (Scheme e). Recently, Sun Song's research group used 4CzIPN as a photocatalyst and Togni reagent as a trifluoromethyl source to develop a visible light-promoted trifluoromethylation / arylation reaction of unactivated olefins for the synthesis of trifluoromethylated pyrrolo[1,2-a]indole (Scheme f). The specific reaction formula is as follows:

[0006]

[0007] Based on the above research background, the related methods in the prior art still have the following defects:

[0008] The introduction of trifluoromethyl groups requires the use of transition metal catalysis or reliance on photosensitizer catalysis, which limits the applicability of these development methods. Therefore, it is necessary to explore the use of inexpensive and stable trifluoromethyl reagents that do not rely on transition metal and photosensitizer catalysis to synthesize trifluoromethyl-substituted pyrido[1,2-a]indoles. Summary of the Invention

[0009] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a green and mild trifluoromethylated pyrido[1,2-a]indole, a synthesis method and an application thereof.

[0010] The technical solution adopted by the present invention to solve its technical problem is:

[0011] A green and mild method for synthesizing trifluoromethylated pyrido[1,2-a]indole is disclosed. The method comprises the following steps: using trifluoromethylsulfonyl pyridinium salt as a fluoroalkylating agent under photocatalysis, and reacting the agent with N-substituted indole to obtain trifluoromethylated pyrido[1,2-a]indole.

[0012] Furthermore, the reaction formula of the method is as follows:

[0013]

[0014] Among them, R1=H, F, Br, Cl, CH3; R2=CN, CH3CO, CHO.

[0015] Furthermore, the reaction mechanism of the method is as follows:

[0016]

[0017] Furthermore, the trifluoromethylsulfonylpyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate.

[0018] Furthermore, the N-substituted indole includes 1-(1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5- Methoxy-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-bromo-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(6-methyl-1-(pent-4-en-1-yl) -1H-indol-3-yl)ethanone, 1-(6-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(6-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(7-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(pent-4-en-1-yl)-1H-indole-3-carbaldehyde, 1-(pent-4-en-1-yl) )-1H-indole-3-carbonitrile, 1-(3-acetyl-1H-indol-1-yl)pent-4-en-1-one, 1-(1-(but-3-en-1-yl)-1-H-indol-3-yl)ethanone, 1-(but-3-en-1-yl)-1H-indole-3-carbonitrile, 1-(1-(pent-4-en-1-yl)-1-H-indol-3-yl)ethanone, 1-(pent-4-en-1-yl)-1H-indole-3-carbonitrile;

[0019] Its structural formula is as follows:

[0020]

[0021]

[0022]

[0023] Further, the method comprises the following steps:

[0024] Under the condition of no water and no oxygen, N-substituted indole, trifluoromethylsulfonyl pyridine salt reagent, p-toluenesulfonic acid are added, and the reaction is carried out under the irradiation of a purple light with a power of 12 W and a wavelength of 390-395 nm, the temperature is controlled at 20-30 degrees Celsius, and the reaction is carried out for 10 hours; after the reaction is completed, extraction, washing, drying, column chromatography separation and purification are carried out, and finally trifluoromethylated pyrido[1,2-a]indole is obtained.

[0025] Further, the specific steps are as follows:

[0026] First, the Schlenk tube is treated under the condition of no water and no oxygen, the residual water in the reaction tube wall, the tube opening and the tube is removed by high temperature of the torch, the inert gas and the air in the reaction tube are replaced by double-tube, and a water-free and oxygen-free environment is created; after the Schlenk tube is cooled in the inert gas atmosphere, N-substituted indole, trifluoromethylsulfonyl pyridine salt reagent, p-toluenesulfonic acid are sequentially added to the reaction tube, the molar ratio of N-substituted indole: trifluoromethylsulfonyl pyridine salt reagent: p-toluenesulfonic acid is 0.30:0.90:0.60, and anhydrous dichloromethane is taken by a long needle syringe under the protection of double-tube inert gas, the ratio of anhydrous dichloromethane: p-toluenesulfonic acid is 3:0.6 mL: mmol, and is added to the reaction tube, the reactants are dissolved under stirring, and the reaction is carried out under the irradiation of a purple LED light with a power of 12 W and a wavelength of 390-395 nm for 10 hours; after the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, ethyl acetate is used for extraction 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, and the residue is purified by silica gel column chromatography to obtain the product;

[0027] The mobile phase system is petroleum ether: ethyl acetate, and the volume ratio of the two is 15:1-10:1.

[0028] Alternatively, the solvent is dichloromethane; and the inert gas is nitrogen or argon.

[0029] The application of the synthetic method as described above in the synthesis of trifluoromethylated pyrido[1,2-a]indole.

[0030] The trifluoromethylated pyrido[1,2-a]indole synthesized by the synthetic method as described above.

[0031] Further, the structural formula is as follows:

[0032]

[0033]

[0034] The advantages and positive effects achieved by the present invention are:

[0035] 1. The present invention utilizes trifluoromethylsulfonylpyridinium salt reagent as the source of fluoroalkyl, avoiding the use of expensive photosensitizers, and the reaction conditions are green and mild.

[0036] 2. The present invention avoids the use of transition metal catalysts, reduces reaction costs, and the synthesis route is green and environmentally friendly.

[0037] 3. The raw materials used in the present invention are cheap and easily available. The solvents used are common organic solvents and do not require special treatment. The post-treatment is simple, and the products can be separated by simple column chromatography. The pyrido[1,2-a]indole derivatives can be trifluoromethylated quickly and efficiently, and are suitable for the preparation and synthesis of fine chemicals or drug molecule precursors.

[0038] 4. The trifluoromethylated pyrido[1,2-a]indole derivatives prepared by the present invention are new compounds, which provide a new solution for preparing drug molecular structures with biological activity.

[0039] 5. The present method involves the reaction of a trifluoromethylsulfonylpyridinium salt as a fluoroalkylating agent with an N-substituted indole under photocatalysis to produce a trifluoromethylated pyrido[1,2-a]indole. This method does not require high temperatures, operates under mild reaction conditions, and exhibits good substrate tolerance. The reaction process does not require a photosensitizer or metal catalyst, resulting in an environmentally friendly synthetic route that allows for the rapid and efficient synthesis of trifluoromethylated pyrido[1,2-a]indole derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 : is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 1 of the present invention;

[0041] Figure 2 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 2 of the present invention;

[0042] Figure 3 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 3 of the present invention;

[0043] Figure 4 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 4 of the present invention;

[0044] Figure 5This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 5 of the present invention;

[0045] Figure 6 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 6 of the present invention;

[0046] Figure 7 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 7 of the present invention;

[0047] Figure 8 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 8 of the present invention;

[0048] Figure 9 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 9 of the present invention;

[0049] Figure 10 : is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 10 of the present invention;

[0050] Figure 11 : is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 11 of the present invention;

[0051] Figure 12 is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 12 of the present invention;

[0052] Figure 13 : is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 13 of the present invention;

[0053] Figure 14 : is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 14 of the present invention;

[0054] Figure 15 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 15 of the present invention;

[0055] Figure 16 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 16 of the present invention;

[0056] Figure 17 : is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 17 of the present invention;

[0057] Figure 18This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 18 of the present invention.

[0058] Figure 19 This is the H spectrum of the trifluoromethylated pyrido[1,2-a]indole compound prepared in Example 19 of the present invention. DETAILED DESCRIPTION

[0059] The present invention will be further described below with reference to the following examples. The following examples are descriptive rather than restrictive, and the scope of protection of the present invention cannot be limited by the following examples.

[0060] The various experimental operations involved in the specific embodiments are all routine techniques in the field. For parts not specifically annotated in this document, ordinary technicians in this field can refer to various commonly used reference books, scientific literature or related instructions, manuals, etc. before the filing date of this invention to implement them.

[0061] In the following examples, the N-substituted indoles include 1-(1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5 -methoxy-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-bromo-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(6-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone )-1H-indol-3-yl)ethanone, 1-(6-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(6-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(7-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(pent-4-en-1-yl)-1H-indole-3-carbaldehyde, 1-(pent-4-en-1- 1-(1-(but-3-en-1-yl)-1H-indole-3-carbonitrile, 1-(1-(pent-4-en-1-yl)-1-H-indole-3-yl)ethanone, 1-(1-(pent-4-en-1-yl)-1-H-indole-3-carbonitrile, 1-(1-(pent-4-en-1-yl)-1-H-indole-3-yl)ethanone, 1-(pent-4-en-1-yl)-1H-indole-3-carbonitrile;

[0062] Its structural formula is as follows:

[0063]

[0064]

[0065] Specifically, the relevant preparation and detection are as follows:

[0066] Example 1

[0067]

[0068] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0069] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual moisture on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced by a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted for 10 hours under a purple 12 W LED light with a wavelength of 390-395 nm. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 85%. 1 H NMR (400MHz, CDCl3) δ7.91 (d, J = 7.2Hz, 1H), 7.37-7.27 (m, 3H), 4.34-4.30 (m, 1H), 4.25-4.22 (m, 1H), 3.9 5-3.88(m,1H),2.91-2.78(m,1H),2.71(s,3H),2.36-2.27(m,2H),2.21-2.15(m,2H),1.91-1.85(m,1H); 13C NMR(100MHz, CDCl3)δ193.8,147.1,136.2,126.6(q,J=277.0Hz,1C),126.1,122.7,122.3, 120.6,112.4,109.9,42.7,35.5(q,J=27.0Hz,1C),31.7,28.6(d,J=3.0Hz,1C),22.6,17.4; 19 F NMR (376MHz, CDCl3) δ-62.91. Figure 1 shown.

[0070] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0071] The solvent is dichloromethane.

[0072] Example 2

[0073]

[0074] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0075] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(4-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed that the reaction was complete, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over 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, with a volume ratio of 15:1). Yellow oily liquid, yield 50%. 1H NMR (400MHz, CDCl3) δ7.22-7.16(m,2H),7.07(d,J=6.4Hz,1H),4.31-4.27(m,1H),3.90-3.85(m,1H),3.83-3.79(m,1H), 2.96-2.84(m,1H),2.62(s,3H),2.56(s,3H),2.49-2.40(m,1H),2.28-2.25(m,1H),2.21-2.14(m,2H),1.95-1.88(m,1H); 13 C NMR (100MHz, CDCl3) δ197.5,142.2,136.5,130.2,126.6(q,J=277.0Hz,1C),125.1,124.4,122 .7,116.1,107.1,42.5,37.7(q,J=28.0Hz,1C),32.7,27.9(d,J=3.0Hz,1C),23.2,22.3,17.3; 19 F NMR (376MHz, CDCl3) δ-63.13; IR (neat, δcm -1 )2954,2362,1648,1506,1419,1253,1132,1078,956,748; HRMS(EI-TOF)m / z[M+Na] + calcd for C 17 H 18 F3NONa 332.1244,Found 332.1240. Figure 2 shown.

[0076] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0077] The solvent is dichloromethane.

[0078] Example 3

[0079]

[0080] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0081] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(4-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ7.23-7.18(m,1H),7.14-7.12(m,1H),6.98-6.93(m,1H),4.32-4.28(m,1H),4.11-4.08(m, 1H),3.92-3.84(m,1H),2.96-2.84(m,1H),2.69(s,3H),2.38-2.25(m,2H),2.22-2.15(m,2H),1.88-1.82(m,1H); 13 C NMR (100MHz, CDCl3) δ195.3,155.5(d,J=246.0Hz,1C),146.6,138.8(d,J=11.0H z,1C),126.6(q,J=277.0Hz,1C),123.1(d,J=9.0Hz,1C),114.0(d,J=19.0Hz,1C) ,111.7(d,J=2.0Hz,1C),108.6(d,J=23.0Hz,1C),105.8(d,J=4.0Hz,1C),43.1,3 6.0(q,J=28.0Hz,1C),31.8(d,J=17.0Hz,1C),28.5(d,J=3.0Hz,1C),22.6,17.1; 19 F NMR (376MHz,CDCl3)δ-62.72,-111.32. Figure 3 shown.

[0082] The trifluoromethylsulfonyl pyridine salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridine-1-trifluoromethanesulfonate;

[0083] The solvent is dichloromethane.

[0084] Example 4

[0085]

[0086] The synthesis method of the green mild trifluoromethylation pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0087] First, the 10 mL Schlenk tube is treated with anhydrous oxygen-free, the reaction tube wall, the mouth and the residual moisture in the tube are removed by high temperature of the oven gun, the argon and the air in the reaction tube are replaced by double-tube, an anhydrous oxygen-free environment is created, after the Schlenk tube is cooled in the argon atmosphere, 1-(4-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonyl pyridine salt (0.90 mmol), p-toluenesulfonic acid (0.60 mmol) are sequentially added to the reaction tube, 3 mL of anhydrous dichloromethane is taken by a long needle syringe under the protection of double-tube argon, and is added to the reaction tube. The reactants are dissolved under stirring, and the reaction is carried out under the light irradiation of a purple 12W LED lamp with a wavelength of 390-395 nm for 10 hours. After the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, and the product is extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and 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 (the mobile phase system is petroleum ether: ethyl acetate, the ratio is 15:1 by volume. Yellow solid, yield 62%. 1 H NMR (400 MHz, CDCl3) δ 7.26-7.22 (m, 2H), 7.19-7.15 (m, 1H), 4.31-4.27 (m, 1H), 3.90-3.83 (m, 1H), 3.76-3.72 (m, 1H), 3.04-2.90 (m, 1H), 2.64 (s, 3H), 2.48-2.33 (m, 1H), 2.27-2.23 (m, 1H), 2.21-2.12 (m, 2H), 1.92-1.83 (m, 1H); 13C NMR(100MHz, CDCl3)δ197.9,143.3,137.5,126.4(q,J=277.0Hz,1C),125.5,123.4,123.4, 123.1,115.2,108.3,42.8,37.4(q,J=27.3Hz,1C),33.9,27.8(d,J=2.8Hz,1C),23.0,17.3; 19 F NMR (376MHz, CDCl3) δ-63.05; IR (neat, δcm -1 )2956,2364,1652,1504,1423,1251,1128,1072,1014,954,738; HRMS(EI-TOF)m / z[M+Na] + calcd for C 16 H 15 ClF3NONa352.0697,Found 352.0695. Figure 4 shown.

[0088] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0089] The solvent is dichloromethane.

[0090] Example 5

[0091]

[0092] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0093] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(5-methoxy-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 39%. 1 H NMR (400MHz, CDCl3) δ7.35(s,1H),7.24(d,J=8.8Hz,1H),6.92(d,J=8.8Hz,1H),4.38-4.26(m,1H),4.28-4.18(m, 1H),3.91-3.84(m,4H),2.89-2.76(m,1H),2.66(s,3H),2.35-2.23(m,2H),2.19-2.13(m,2H),1.89-1.83(m,1H); 13 C NMR (100MHz, CDCl3) δ193.5,156.3,147.3,131.4,126.8,126.6(q,J=276.6Hz,1C),112.3,111 .1,110.4,103.9,56.0,42.6,35.5(q,J=27.2Hz,1C),31.5,28.6(d,J=2.0Hz,1C),22.4,17.3; 19 F NMR (376MHz, CDCl3) δ-62.91. Figure 5 shown.

[0094] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0095] The solvent is dichloromethane.

[0096] Example 6

[0097]

[0098] The synthesis method of the green mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0099] First, the 10 mL Schlenk tube is treated with anhydrous oxygen-free, the residual moisture on the wall of the reaction tube, the mouth of the tube and the tube is removed by high-temperature oven gun, argon and air in the reaction tube are replaced by double-tube to create an anhydrous oxygen-free environment, after the Schlenk tube is cooled in the argon atmosphere, 1-(5-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonyl pyridine salt (0.90 mmol), p-toluenesulfonic acid (0.60 mmol) are sequentially added to the reaction tube, 3 mL of anhydrous dichloromethane is taken by a long needle syringe under the protection of argon double-tube, and is added to the reaction tube. The reactants are dissolved under stirring, and the reaction is carried out under the light irradiation of a purple 12W LED lamp with a wavelength of 390-395 nm for 10 hours. After the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, extraction is carried out three times with ethyl acetate, washing is carried out with a saturated sodium chloride solution, 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 (the mobile phase system is petroleum ether: ethyl acetate, the ratio is 15:1 by volume. Yellow solid, yield 58%. 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 9.6 Hz, 1H), 7.29-7.26 (m, 1H), 7.05-7.01 (m, 1H), 4.31-4.28 (m, 1H), 4.24-4.21 (m, 1H), 3.95-3.88 (m, 1H), 2.89-2.77 (m, 1H), 2.66 (s, 3H), 2.36-2.26 (m, 2H), 2.22-2.16 (m, 2H), 1.91-1.85 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 193.4, 159.7 (d, J = 236.2 Hz, 1C), 148.3, 132.7, 126.7 (d, J = 10.1 Hz, 1C), 126.5 (q, J = 276.6 Hz, 1C), 112.6 (d, J = 4.1 Hz, 1C), 110.5 (d, J = 19.1 Hz, 1C), 110.5 (d, J = 37.7 Hz, 1C), 106.3 (d, J = 25.4 Hz, 1C), 42.8, 35.5 (q, J = 27.3 Hz, 1C), 31.4, 28.7 (d, J = 2.8 Hz, 1C), 22.3, 17.3; 19 F NMR (376 MHz, CDCl3) δ -62.91, -120.11. As Figure 6shown.

[0100] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0101] The solvent is dichloromethane.

[0102] Example 7

[0103]

[0104] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0105] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(5-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over 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 15:1 by volume). Yellow solid, yield 63%. 1 H NMR (400MHz, CDCl3) δ7.86(s,1H),7.28-7.22(m,2H),4.31-4.27(m,1H),4.23-4.20(m,1H),3.94-3. 87(m,1H),2.88-2.75(m,1H),2.67(s,3H),2.36-2.26(m,2H),2.22-2.15(m,2H),1.91-1.85(m,1H); 13C NMR (100MHz, CDCl3) δ193.4,148.1,134.6,128.6,127.1,126.5(q,J=276.5Hz,1C),122.6, 120.2,112.2,110.8,42.8,35.5(q,J=27.4Hz,1C),31.6,28.6(d,J=2.6Hz,1C),22.4,17.3; 19 FNMR (376MHz, CDCl3) δ-62.91. Figure 7 shown.

[0106] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0107] The solvent is dichloromethane.

[0108] Example 8

[0109]

[0110] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0111] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(5-bromo-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved with stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 39%. 1H NMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 4.31-4.27 (m, 1H), 4.22-4.20 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.73 (m, 1H), 2.66 (s, 3H), 2.33-2.27 (m, 2H), 2.21-2.15 (m, 2H), 1.91-1.85 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 193.4, 147.9, 134.9, 126.6 (q, J = 276.4 Hz, 1C), 127.7, 125.2, 123.2, 116.4, 112.1, 111.2, 42.8, 35.5 (q, J = 27.4 Hz, 1C), 31.6, 28.6 (d, J = 2.7 Hz, 1C), 22.4, 17.3; 19 F NMR (376 MHz, CDC13) δ -62.91. As Figure 8 shown.

[0112] wherein the trifluoromethylsulfonyl pyridine salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0113] the solvent is dichloromethane.

[0114] Example 9

[0115]

[0116] The above described method for the synthesis of green mild trifluoromethylated pyrido[1,2-a]indoles of the following structure comprises the following steps:

[0117] Firstly, 10 mL Schlenk tube was treated with anhydrous and anaerobic, 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, to create an anhydrous and anaerobic environment, after the Schlenk tube was cooled in the argon atmosphere, 1-(6-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonyl pyridine salt (0.90 mmol), p-toluenesulfonic acid (0.60 mmol) were added into the reaction tube, 3 mL anhydrous dichloromethane 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 irradiation of purple 12 W, wavelength 390-395 nm LED lamp for 10 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, extraction was carried out with ethyl acetate for three times, saturated sodium chloride solution was used for washing, the organic phase was 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 15:1 by volume. White solid, yield 78%. 1 H NMR (400 MHz, CDC13) δ 7.76 (d, J = 8.3 Hz, 1H), 7.14-7.12 (m, 2H), 4.29-4.19 (m, 2H), 3.89-3.82 (m, 1H), 2.89-2.77 (m, 1H), 2.68 (s, 3H), 2.50 (s, 3H), 2.34-2.24 (m, 2H), 2.19-2.10 (m, 2H), 1.88-1.82 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 193.8, 146.5, 136.6, 132.2, 126.6 (q, J = 276.6 Hz, 1C), 124.2, 123.8, 120.2, 112.2, 109.9, 42.5, 35.5 (q, J = 27.1 Hz, 1C), 31.5, 28.6 (d, J = 2.7 Hz, 1C), 22.5, 21.6, 17.4; 19 F NMR (376 MHz, CDC13) δ -62.91; IR (neat, δ cm -1 ) 2954, 2366, 1637, 1506, 1427, 1259, 1126, 1068, 950, 802, 734, 615; HRMS (EI-TOF) m / z [M + Na] + calcd for C 17 H 18 F3NONa 332.1244, Found 332.1240. As Figure 9 shown.

[0118] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0119] The solvent is dichloromethane.

[0120] Example 10

[0121]

[0122] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0123] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(6-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a white solid with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.83-7.80(m,1H),7.07-7.01(m,2H),4.25-4.18(m,2H),3.90-3.82(m, 1H),2.87-2.75(m,1H),2.67(s,3H),2.37-2.26(m,2H),2.22-2.13(m,2H),1.91-1.85(m,1H); 13C NMR (100MHz, CDCl3) δ193.5, 159.6 (d, J = 238.8Hz, 1C), 147.5 (d, J = 4.9Hz, 1C), 136.4 (d, J = 11.3Hz, 1C), 126.6 (q, J = 276.6Hz, 1C), 122.4, 121.4 (d,J=9.5Hz,1C),112.4,110.9(d,J=23.5Hz,1C),96.6(d,J=25.7Hz,1C),42.8,35.5(q,J=27.3Hz,1C),31.6,28.6(d,J=3.0Hz,1C),22.5,17.3; 19 FNMR (376MHz,CDCl3)δ-62.93,-119.70. Figure 10 shown.

[0124] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0125] The solvent is dichloromethane.

[0126] Example 11

[0127]

[0128] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0129] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(6-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 84%. 1H NMR (400MHz, CDCl3) δ7.80 (d, J = 8.6Hz, 1H), 7.34 (s, 1H), 7.27-7.25 (m, 1H), 4.28-4.20 (m, 2H), 3.92- 3.84(m,1H),2.87-2.75(m,1H),2.68(s,3H),2.37-2.27(m,2H),2.22-2.13(m,2H),1.91-1.85(m,1H); 13 C NMR (100MHz, CDCl3) δ193.5147.7,136.7,128.3,126.5(q,J=273.5Hz,1C),124.5,123.1,1 21.4,112.5,110.0,42.8,35.5(q,J=27.3Hz,1C),31.6,28.6(d,J=2.7Hz,1C),22.4,17.3; 19 F NMR (376MHz, CDCl3) δ-62.93; IR (neat, δcm -1 )2956,2360,1643,1504,1427,1257,1130,1080,952; HRMS(EI-TOF)m / z[M+Na] + calcd for C 16 H 15 ClF3NONa 352.0697,Found 352.0697. Figure 11 shown.

[0130] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0131] The solvent is dichloromethane.

[0132] Example 12

[0133]

[0134] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0135] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(7-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ7.76 (d, J = 8.2Hz, 1H), 7.16-7.12 (m, 1H), 6.99-6.97 (m, 1H), 4.83-4.78 (m, 1H), 4.32-4.24 (m, 2H), 2.90-2.83(m,1H),2.79(s,3H),2.68(s,3H),2.37-2.28(m,1H),2.21-2.15(m,2H),2.08-2.04(m,1H),1.88-1.80(m,1H); 13 C NMR (100MHz, CDCl3) δ193.9,147.1,135.5,127.0,126.6(q,J=276.7Hz,1C),125.8,122.4,122 .1,118.6,112.8,46.5,36.1(q,J=27.1Hz,1C),32.0,28.9(d,J=2.6Hz,1C),22.1,21.1,18.4; 19 F NMR (376MHz, CDCl3) δ-62.85; IR (neat, δcm -1 )2956,2366,1635,1504,1407,1251,1126,1072,962,781,744; HRMS(EI-TOF)m / z[M+Na] + calcdfor C 17 H 18 F3NONa 332.1244,Found 332.1249. Figure 12 shown.

[0136] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0137] The solvent is dichloromethane.

[0138] Example 13

[0139]

[0140] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0141] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual moisture on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(pent-4-en-1-yl)-1H-indole-3-carbaldehyde (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted for 10 hours under a purple 12 W LED light with a wavelength of 390-395 nm. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 10:1). The product was obtained as a yellow solid with a yield of 54%. 1 H NMR(400MHz, CDCl3)δ10.26(s,1H),8.13-8.11(m,1H),7.34-7.29(m,3H),4.33-4.27(m,1H),4.11-4.07(m,1H),3 .98-3.90(m,1H),2.82-2.69(m,1H),2.56-2.42(m,1H),2.27-2.22(m,1H),2.20-2.15(m,2H),2.04-1.95(m,1H); 13C NMR (100MHz, CDCl3) δ183.4,147.3,136.2,126.3(q,J=277.0Hz,1C),126.6,123 .4,123.2,119.7,112.0,109.7,42.6,37.9(q,J=28.0Hz,1C),27.4,23.1,17.7; 19 F NMR (376MHz, CDCl3) δ-63.4. Figure 13 shown.

[0142] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0143] The solvent is dichloromethane.

[0144] Example 14

[0145]

[0146] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0147] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual moisture on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced by a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(pent-4-en-1-yl)-1H-indole-3-carbonitrile (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted for 10 hours under a purple 12 W LED light with a wavelength of 390-395 nm. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 68%. 1H NMR (400MHz, CDCl3) δ7.69 (d, J = 7.2Hz, 1H), 7.35-7.28 (m, 3H), 4.16-4.04 (m, 2H), 3.71- 3.69(m,1H),3.10-2.99(m,1H),2.56-2.42(m,1H),2.21-2.18(m,2H),2.13-1.98(m,2H); 13 C NMR (100MHz, CDCl3) δ145.9, 135.2, 127.5, 126.1 (q, J = 277.0Hz, 1C), 123.5, 122.7, 119 .2,116.0,109.9,83.0,42.7,37.7(q,J=28.0Hz,1C),28.7(d,J=3.0Hz,1C),24.6,19.5; 19 F NMR (376MHz, CDCl3) δ-63.16. Figure 14 shown.

[0148] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0149] The solvent is dichloromethane.

[0150] Example 15

[0151]

[0152] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0153] Firstly, 10 mL Schlenk tube was treated with anhydrous and anaerobic, the residual moisture on the wall of reaction tube, the mouth of tube and the tube was removed by high temperature of oven, the argon and air in the reaction tube was replaced by double-tube, an anhydrous and anaerobic environment was created, after the Schlenk tube was cooled in argon atmosphere, 1-(3-acetyl-1H-indol-1-yl)pent-4-en-1-one (0.30 mmol), trifluoromethylsulfonyl pyridine salt (0.90 mmol), p-toluenesulfonic acid (0.60 mmol) were added into the reaction tube, 3 mL anhydrous dichloromethane 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 irradiation of purple 12 W, wavelength 390-395 nm LED lamp for 10 hours. After the reaction was confirmed to be complete by TLC, a large amount of water was added for washing, extraction was carried out with ethyl acetate for three times, saturated sodium chloride solution was used for washing, the organic phase was 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 78%. 1 H NMR (400 MHz, CDC13) δ 8.58-8.56 (m, 1H), 7.88-7.86 (m, 1H), 7.41-7.39 (m, 2H), 4.38-4.35 (m, 1H), 3.02-2.86 (m, 2H), 2.73 (m, 4H), 2.47-2.39 (m, 1H), 2.38-2.33 (m, 1H), 2.25-2.22 (m, 1H); 13 C NMR (100 MHz, CDC13) δ 195.4, 169.0, 146.3, 134.9, 126.3, 126.1 (q, J = 276.6 Hz, 1C), 125.7, 125.2, 120.3, 117.4, 117.1, 34.3 (q, J = 28.0 Hz, 1C), 32.1, 29.5, 27.5 (q, J = 2.7 Hz, 1C), 22.6; 19 F NMR (376 MHz, CDC13) δ -63.29. Figure 15 as shown.

[0154] The trifluoromethylsulfonyl pyridine salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium trifluoromethanesulfonate;

[0155] The solvent is dichloromethane.

[0156] Example 16

[0157]

[0158] The synthesis method of the green mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0159] First, the 10 mL Schlenk tube is treated in anhydrous and anaerobic manner, the water remaining in the reaction tube wall, tube opening and tube is removed by high-temperature oven gun, and argon and air in the reaction tube are replaced by double-tube argon to create an anhydrous and anaerobic environment. After the Schlenk tube is cooled in the argon atmosphere, 1-(1-(but-3-en-1-yl)-1-H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonyl pyridine salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) are sequentially added to the reaction tube. 3 mL of anhydrous dichloromethane is taken by a long needle syringe under the protection of double-tube argon, and is added to the reaction tube. The reactants are dissolved under stirring, and the reaction is carried out under the light irradiation of a purple 12 W LED lamp with a wavelength of 390-395 nm for 10 hours. After the reaction is confirmed to be complete by TLC, a large amount of water is added for washing, and the product is extracted with ethyl acetate three times, washed with a saturated sodium chloride solution, and 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 (the mobile phase system is petroleum ether: ethyl acetate, the ratio is 15:1 by volume. Yellow oily liquid, yield 70%. 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 1H), 7.31-7.25 (m, 3H), 4.20-4.09 (m, 2H), 3.96-3.92 (m, 1H), 3.24-3.12 (m, 1H), 2.93-2.83 (m, 1H), 2.64 (m, 4H), 2.78-2.14 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 193.3, 153.0, 132.5, 130.0, 126.6 (q, J = 276.0 Hz, 1C), 122.3, 122.3, 121.1, 110.6, 110.3, 43.3, 35.7 (q, J = 27.5 Hz, 1C), 33.9 (d, J = 2.9 Hz, 1C), 32.1, 30.2; 19 F NMR (376 MHz, CDCl3) δ -64.16. As Figure 16 shown.

[0160] The trifluoromethylsulfonyl pyridine salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridine-1-trifluoromethanesulfonate;

[0161] The solvent is dichloromethane.

[0162] Example 17

[0163]

[0164] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0165] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced through a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(but-3-en-1-yl)-1H-indole-3-carbonitrile (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved with stirring, and the reaction was carried out under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ7.69-7.67(m,1H),7.32-7.25(m,3H),4.31-4.25(m,1H),4.12-4.06(m,1H) ,3.83-3.76(m,1H),3.26-3.13(m,1H),3.03-2.96(m,1H),2.57-2.47(m,1H),2.43-2.29(m,1H); 13 C NMR (100MHz, CDCl3) δ151.8,131.9,131.9,126.1(q,J=275.7Hz,1C),123.5,122.3,1 19.9,115.5,110.7,78.2,44.4,36.6(q,J=28.5Hz,1C),34.2,33.1(d,J=3.1Hz,1C); 19 F NMR (376MHz, CDCl3) δ-64.55. Figure 17 shown.

[0166] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0167] The solvent is dichloromethane.

[0168] Example 18

[0169]

[0170] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0171] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual water on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced by a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(1-(pent-4-en-1-yl)-1-H-indol-3-yl)ethanone (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted under purple 12 W LED light with a wavelength of 390-395 nm for 10 hours. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over 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, with a volume ratio of 15:1). It was a yellow liquid with a yield of 58%. 1 H NMR (400MHz, CDCl3) δ7.91-7.88(m,1H),7.37-7.35(m,1H),7.30-7.23(m,2H),5.21-5.19(m,1H),4.64-4.59(m,1H),3.92 -3.86(m,1H),2.71(s,3H),2.63-2.50(m,2H),2.18-2.10(m,2H),1.96-1.90(m,2H),1.79-1.72(m,1H),1.60-1.50(m,1H); 13 C NMR (100MHz, CDCl3) δ195.5, 149.2, 136.3, 127.9 (q, J = 276.3Hz, 1C), 125.9, 122.4, 12 1.9,121.0,114.1,109.6,44.9,34.6(q,J=27.9Hz,1C),32.1,29.3,28.8,28.2,24.1; 19 F NMR (376MHz, CDCl3) δ-64.18. Figure 18 shown.

[0172] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0173] The solvent is dichloromethane.

[0174] Example 19

[0175]

[0176] The synthesis method of the green and mild trifluoromethylated pyrido[1,2-a]indole of the above structural formula comprises the following steps:

[0177] First, a 10 mL Schlenk tube was treated to be anhydrous and oxygen-free. Residual moisture on the reaction tube wall, tube mouth, and inside the tube was removed by high-temperature drying with a drying gun. Argon gas and air in the reaction tube were replaced by a double-row tube to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in an argon atmosphere, 1-(pent-4-en-1-yl)-1H-indole-3-carbonitrile (0.30 mmol), trifluoromethylsulfonylpyridinium salt (0.90 mmol), and p-toluenesulfonic acid (0.60 mmol) were added to the reaction tube in sequence. 3 mL of anhydrous dichloromethane was taken using a long-needle syringe under the protection of double-row argon gas and added to the reaction tube. The reactants were dissolved under stirring and reacted for 10 hours under a purple 12 W LED light with a wavelength of 390-395 nm. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The residue was purified by silica gel column chromatography (the mobile phase system was petroleum ether:ethyl acetate, with a volume ratio of 15:1). The product was obtained as a yellow solid with a yield of 51%. 1 H NMR (400MHz, CDCl3) δ7.69 (d, J = 7.6Hz, 1H), 7.36-7.23 (m, 3H), 4.56-4.52 (m, 1H), 4.01-3.91 (m, 2 H),2.75-2.60(m,2H),2.08-2.04(m,2H),2.00-1.97(m,1H),1.95-1.84(m,2H),1.65-1.57(m,1H); 13 C NMR (100MHz, CDCl3) δ149.9, 136.3, 127.0, 126.1 (q, J = 276.0Hz, 1C), 123.6, 122.1 ,119.6,115.9,109.8,85.7,45.3,35.3(q,J=28.4Hz,1C),31.8,30.9,28.4,25.0; 19FNMR (376MHz, CDCl3) δ-64.39; IR (neat, δcm -1 )2923,2364,2215,1539,1461,1257,1141,1097,744; HRMS(EI-TOF)m / z[M+Na] + calcd for C 16 H 15 F3N2Na 315.1091,Found 315.1088. Figure 19 shown.

[0178] Wherein, the trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate;

[0179] The solvent is dichloromethane.

[0180] Although the embodiments of the present invention are disclosed for illustrative purposes, those skilled in the art will understand that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present invention and the appended claims. Therefore, the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims

1. A green and mild method for synthesizing trifluoromethylated pyrido[1,2-a]indole, characterized by: The method comprises the following steps: using trifluoromethylsulfonyl pyridinium salt as a fluoroalkylation reagent under photocatalysis; reacting the reagent with N-substituted indole to obtain trifluoromethylated pyrido[1,2-a]indole.

2. The synthesis method according to claim 1, wherein: The general reaction formula of the method is as follows: Among them, R1=H, F, Br, Cl, CH3,; R2=CN, CH3CO, CHO.

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

4. The synthesis method according to claim 1, wherein: The trifluoromethylsulfonyl pyridinium salt reagent is 4-(dimethylamino)-1-((trifluoromethyl)sulfonyl)pyridinium-1-trifluoromethanesulfonate.

5. The synthesis method according to claim 1, wherein: The N-substituted indoles include 1-(1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(4-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-methoxy- 1-(Pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(5-bromo-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(6-methyl-1-(pent-4-en-1-yl)-1H -indol-3-yl)ethanone, 1-(6-fluoro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(6-chloro-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(7-methyl-1-(pent-4-en-1-yl)-1H-indol-3-yl)ethanone, 1-(pent-4-en-1-yl)-1H-indole-3-carbaldehyde, 1-(pent-4-en-1-yl) -1H-indole-3-carbonitrile, 1-(3-acetyl-1H-indol-1-yl)pent-4-en-1-one, 1-(1-(but-3-en-1-yl)-1-H-indol-3-yl)ethanone, 1-(but-3-en-1-yl)-1H-indole-3-carbonitrile, 1-(1-(pent-4-en-1-yl)-1-H-indol-3-yl)ethanone, 1-(pent-4-en-1-yl)-1H-indole-3-carbonitrile; Its structural formula is as follows:

6. The synthesis method according to any one of claims 1 to 5, characterized in that: The method comprises the following steps: adding N-substituted indole, trifluoromethylsulfonyl pyridinium salt reagent and p-toluenesulfonic acid under anhydrous and oxygen-free conditions, irradiating under a purple lamp with a power of 12W and a wavelength of 390-395nm, controlling the temperature at 20-30 degrees Celsius to react for 10 hours, and after the reaction, extracting, washing, drying, and separating and purifying by column chromatography to finally obtain trifluoromethylated pyrido[1,2-a]indole.

7. The synthesis method according to claim 6, characterized in that: The specific steps are as follows: First, the Schlenk tube was treated to be anhydrous and oxygen-free. The residual water on the reaction tube wall, tube mouth and inside the tube was removed by high temperature drying gun. The inert gas and air in the reaction tube were replaced by double-row tubes to create an anhydrous and oxygen-free environment. After the Schlenk tube was cooled in the inert gas atmosphere, N-substituted indole, trifluoromethylsulfonyl pyridinium salt reagent and p-toluenesulfonic acid were added to the reaction tube in sequence. The molar ratio of N-substituted indole: trifluoromethylsulfonyl pyridinium salt reagent: p-toluenesulfonic acid was 0.30:0.90:0.

60. Anhydrous dichloromethane was taken with a syringe under the protection of a double-row inert gas. The ratio of anhydrous dichloromethane to p-toluenesulfonic acid was 3:0.6 in mL:mmol. The mixture was added to a reaction tube, and the reactants were dissolved under stirring. The mixture was allowed to react for 10 hours under a purple 12W LED light with a wavelength of 390-395nm. After TLC confirmed the completion of the reaction, a large amount of water was added for washing, and the mixture was extracted three times with ethyl acetate and washed with a saturated sodium chloride solution. The organic phase was dried over 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 is petroleum ether:ethyl acetate, and the volume ratio of the two is 15:1 to 10:1; Alternatively, the solvent is dichloromethane; and the inert gas is nitrogen or argon.

8. Use of the synthesis method according to any one of claims 1 to 7 in the synthesis of trifluoromethylated pyrido[1,2-a]indole.

9. Trifluoromethylated pyrido[1,2-a]indole synthesized by the method according to any one of claims 1 to 7.

10. The trifluoromethylated pyrido[1,2-a]indole according to claim 9, characterized in that: Its structural formula is shown below:

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