A preparation method of 2-monofluoromethylquinoline and its derivatives

Abstract

The present invention belongs to the field of chemical synthesis technology, and in particular to a method for preparing 2-fluoromethylquinoline and its derivatives. The method is achieved by the following steps: in the presence of bis(trimethylsilyl)potassium amide, in a solvent, 2-methylquinoline and its derivatives are subjected to heating reaction, and fluoro-2-methylquinoline and its derivatives are obtained by column chromatography. The method provided by the present invention is carried out in solutions such as benzene, and the substrate has good solubility and wide applicability; the reaction yield is high and the controllability is strong. The method provided by the present invention is green and environmentally friendly, has few side reaction products, and is green and efficient.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a preparation method of 2-monofluoromethylquinoline and its derivatives. Background Art

[0002] Fluorine substitution will have many effects on the physical and chemical properties of compounds, such as solubility, lipophilicity, stability, acidity and alkalinity, etc. It will not only increase the binding affinity of the compound to the target, but may also affect a series of properties of the compound such as absorption, distribution, metabolism, excretion and toxicity. The application prospects of fluorinated drugs are promising. 30% of new drug research and development are based on fluorinated chemicals. In 2019, the FDA approved 48 new drug applications, of which 11 drug molecules contained fluorine. The global annual sales of fluorinated drugs are about US$40 billion. Among the top 200 drugs sold worldwide, there are as many as 29 fluorinated drugs, with a total sales of US$32 billion. Fluorinated pharmaceutical intermediates are estimated to be US$4 billion.

[0003] Heterocyclic compounds have always played an important role and significance in the design of new pharmaceutical molecular entities. Quinoline and its derivatives are ubiquitous in natural products and drugs and have a wide range of biological activities. Quinoline and its derivatives are very important nitrogen-containing heterocyclic compounds, which can be widely used in the fields of drugs, fungicides, herbicides, corrosion inhibitors and functional materials. Nitrogen-containing heterocycles play a vital role in the design of pharmaceutical chemical structures. It is reported that quinoline and its derivatives have a wide range of biological activities such as anticancer, antibacterial, anti-inflammatory, and anti-HIV. So far, many quinoline compounds have been reported, which have very important application value, such as 8-aminoquinoline, which has extremely important value and application in pharmacy, biochemistry, organic synthesis and small molecule probe detection. In recent years, studies have found that quinoline compounds can treat AIDS. Many compounds containing quinoline rings have biological and pharmacological activities such as antibacterial, bactericidal, antiallergic, antimalarial, antitumor, antihypertensive, antidepressant and memory enhancement. In addition, quinoline heterocycles are often introduced into drug molecules as pharmaceutical or pesticide parent structures.

[0004] Monofluoromethyl (CH2F) is considered to be a bioisostere of methyl, in which the strong electron-withdrawing effect of fluorine can avoid metabolic oxidation of methyl. Monofluoromethyl is also considered to be a bioisostere of hydroxymethyl (CH2OH) and methoxymethyl (CH2OCH3). According to investigations, there is almost no real monofluoromethylation method, especially by generating monofluoromethyl free radicals. Monofluoromethylation is a very difficult and challenging research hotspot. Therefore, in the past few decades, people have been committed to the study of fluorination reactions. Pang et al. obtained 2-monofluoromethylquinoline derivatives by first iodination of the CH bond in 2-alkylquinoline and then substitution with AgF2 (RSC Adv., 2016, 6, 111713–111717). Since expensive AgF2 is used in the reaction process, its industrial application is severely limited. Therefore, it is urgent to develop a method for synthesizing 2-fluoromethylquinoline derivatives under mild conditions and economical and practical. Summary of the invention

[0005] In view of the problems existing in the prior art, the present invention provides a method for preparing 2-fluoromethylquinoline and its derivatives. The method has the advantages of simple operation, wide application range of substrates, high yield and strong applicability.

[0006] The technical solution adopted by the present invention to achieve the above-mentioned purpose is:

[0007] The present invention provides a method for preparing 2-monofluoromethylquinoline and its derivatives, comprising the following steps:

[0008] (1) Adding 2-methylquinoline and its derivatives and selectfluor to a solution containing potassium bis(trimethylsilyl)amide to obtain a mixed solution;

[0009] (2) sealing the mixed solution and heating it to obtain a reaction solution;

[0010] (3) The reaction solution is cooled to room temperature, extracted with ethyl acetate, washed, dried, concentrated and purified to obtain 2-fluoromethylquinoline and its derivatives.

[0011] The structural formula of 2-fluoromethylquinoline and its derivatives prepared by the present invention is as follows:

[0012] ;

[0013] In the formula, R is an alkyl, halogen, alkoxy, hydrogen or aromatic ring

[0014] Furthermore, in step (1), the molar ratio of 2-methylquinoline and its derivatives to Selectfluor is 1:1.0-1.2, and most preferably, the molar ratio of 2-methylquinoline and its derivatives to Selectfluor is 1:1.1; the molar ratio of 2-methylquinoline and its derivatives to potassium bis(trimethylsilyl)amide is 1:1.0-1.2; most preferably, the molar ratio of 2-methylquinoline and its derivatives to potassium bis(trimethylsilyl)amide is 1:1.1.

[0015] The concentration of the above potassium bis(trimethylsilyl)amide solution is 0.055 mol / L; the solvent of the potassium bis(trimethylsilyl)amide solution is benzene, tetrahydrofuran, dioxane, toluene, and n-hexane; most preferably, the solvent is benzene.

[0016] Furthermore, in step (2), the heating reaction is performed at 70-90°C for 24-48 hours; most preferably, the heating is performed at 80°C for 36 hours.

[0017] Furthermore, in step (3), the specific steps of washing, drying, concentrating and then purifying are: extracting the reaction solution with ethyl acetate, then washing with saturated brine, drying with anhydrous sodium sulfate, concentrating and purifying with silica gel column chromatography.

[0018] The present invention adopts n-hexane / ethyl acetate = 95 / 5 for silica gel column chromatography.

[0019] The beneficial effects of the present invention are:

[0020] (1) The method provided by the present invention is carried out in a solution containing potassium bis(trimethylsilyl)amide, and the substrate has good solubility and wide applicability; the reaction yield is high and the controllability is strong.

[0021] (2) The method provided by the present invention is environmentally friendly, has few side reaction products, and is green and efficient. DETAILED DESCRIPTION

[0022] The following examples further illustrate the technical solution of the present invention, but are not intended to limit the scope of protection of the present invention.

[0023] Example 1

[0024] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (152 mg, 95%).

[0025] The structural formula of compound 3a is:

[0026] ;

[0027] 1 H NMR (400 MHz, CDCl3) δ8.10 (d, J =8.5 Hz, 1 H), 8.02 (d, J =8.2 Hz, 1H), 7.73 (d, J =8.2 Hz, 1 H), 7.66 (dd, J = 8.5, 6.9 Hz, 1 H), 7.51- 7.45 (m, 2H), 5.61 (d, J =47.0 Hz, 2 H); 13 C NMR (101 MHz, CDCl3) δ156.7 (d, J =21.7 Hz),147.3 (d, J =1.8 Hz), 137.0, 130.0, 129.0, 127.7, 127.6, 126.6, 118.1 (d, J =5.1Hz), 85.0 (d, J =170.3 Hz); 19 F NMR (376 MHz, CDCl3) δ-221.20 (t, J =47.0 Hz); HRMS(EI) m / z: [M+H] + Calculated for C 10 H9FN: 162.0635; Found: 162.0632.

[0028] Example 2

[0029] In a glove box, 1.0 mmol of 2,4-dimethylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3b as a light yellow solid (158 mg, 90%).

[0030] The structural formula of compound 3b is:

[0031] ;

[0032] 1 H NMR (400 MHz, CDCl3) δ 8.01–7.92 (m, 1 H), 7.87 (dd, J = 8.4, 1.0Hz,1 H), 7.60 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.45 (ddd, J = 8.2, 6.9, 1.2Hz, 1H), 7.31 (s, 1H), 5.50 (d, J = 47.1 Hz, 2 H), 2.61 (s, 3 H); 13 C NMR (101 MHz, CDCl3) δ 156.49 (d, J = 21.2 Hz), 147.3, 145.6,129.6, 127.7, 126.6, 123.9,119.0 (d, J = 4.9 Hz), 85.1 (d, J = 170.0 Hz), 18.9; 19 F NMR (376 MHz, CDCl3)δ= –221.22 (t, J = 46.9 Hz); HRMS: m / z [M + H] + Calculate for C 11 H 12 FN: 177.0948; found:177.0950.

[0033] Example 3

[0034] In a glove box, 1.0 mmol of 6-chloro-2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3c as a light yellow solid (175 mg, 90%).

[0035] The structural formula of compound 3c is:

[0036]

[0037] 1 H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.5 Hz, 1 H), 7.95 (d, J =9.0Hz, 1 H), 7.76 (d, J = 2.0 Hz, 1 H), 7.67–7.53 (m, 2 H), 5.61 (d, J = 46.9 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ = 157.2 (d, J = 21.9 Hz), 145.8, 136.3,132.6,131.0, 130.7, 128.3, 126.4, 119.2 (d, J = 5.2 Hz); 19 F NMR (376 MHz, CDCl3): δ =–221.81 (t, J = 46.9 Hz);HRMS: m / z [M + H] + Calculate for C 10 H8ClFN: 196.0324; found:196.0322.

[0038] Example 4

[0039] In a glove box, 1.0 mmol of 6-bromo-2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3d as a tan solid (210 mg, 88%).

[0040] The structural formula of compound 3d is:

[0041]

[0042] 1 H NMR (400 MHz, CDCl3): δ =8.10 (d, J = 8.5 Hz, 1 H), 7.96 (d, J = 2.1Hz,1H), 7.89 (d, J = 9.0 Hz, 1 H), 7.76 (dd, J = 9.0, 2.2 Hz, 1 H), 7.59(dd, J = 8.5,0.9 Hz, 1 H), 5.61 (d, J = 46.9 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ =157.4 (d, J = 21.9 Hz), 146.0, 136.2,133.5, 130.8, 129.8, 128.8, 120.7, 119.1 (d, J = 5.2Hz), 84.9 (d, J = 170.8 Hz); 19 F NMR (376 MHz, CDCl3): δ =–221.94 (t, J = 47.0 Hz); HRMS: m / z [M + H] + Calculate for C 10 H8FN: 239.9819; found: 239.9818.

[0043] Example 5

[0044] In a glove box, 1.0 mmol of 6-iodo-2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 5) to obtain compound 3e as a yellow solid (228 mg, 80%).

[0045] The structural formula of compound 3e is:

[0046]

[0047] 1 H NMR (400 MHz, CDCl3): δ =8.19 (s, 1 H), 8.08 (d, J =8.5 Hz, 1 H),7.93 (dd, J = 8.9, 2.0 Hz, 1 H), 7.75 (d, J =8.9 Hz, 1 H), 7.58 (d, J =8.5 Hz, 1H), 5.61 (d, J =46.9 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ =157.5 (d, J =21.9 Hz),146.4 (d, J =1.9 Hz), 138.8, 136.6, 136.0, 130.8, 129.4,118.9 (d, J =5.4 Hz),92.4, 84.9 (d, J =170.9 Hz); 19 F NMR (376 MHz, CDCl3): δ =-222.08 (t, J =46.8Hz); HRMS: m / z [M + H] + Calculate for C 10 H8FIN: 287.9602; Found: 287.9601.

[0048] Example 6

[0049] In a glove box, 1.0 mmol of 2,6-dimethylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 5) to obtain compound 3f as a tan solid (161 mg, 92%).

[0050] The structural formula of compound 3f is:

[0051]

[0052] 1 H NMR (400 MHz, CDCl3): δ =7.96 (d, J = 8.5 Hz, 1 H), 7.88 (d, J = 8.5Hz,1 H), 7.44 (m, 3 H), 5.56 (d, J = 47.1 Hz, 2 H), 2.42 (s, 3 H); 13 C NMR (101 MHz, CDCl3): δ =155.6 (d, J = 21.5 Hz), 145.8, 136.5,136.3, 132.1, 128.5, 127.6,126.4, 118.2 (d, J = 4.9 Hz), 85.0 (d, J = 169.8Hz), 21.4; 19 F NMR (376 MHz, CDCl3): δ =–220.30 (t, J = 47.0 Hz); HRMS: m / z [M + H] + Calculate for C 11 H 11 FN:176.0870; found: 176.0871.

[0053] Example 7

[0054] In a glove box, 1.0 mmol of 2,8-dimethylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 5) to obtain compound 3g as a yellow oily liquid (156 mg, 89%).

[0055] The structural formula of compound 3g is:

[0056]

[0057] 1 H NMR (400 MHz, CDCl3): δ =8.19 (d, J =8.4 Hz, 1 H), 7.68 (d, J =8.2 Hz,1 H), 7.58 (d, J =8.7 Hz, 2 H), 7.45 (t, J =7.6 Hz, 1 H), 5.67 (d, J =47.2 Hz, 2H), 2.79 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ =155.9 (d, J =21.3 Hz), 146.9,137.5, 130.3, 128.0, 126.8, 126.1, 118.51, 118.46,86.0 (d, J =168.7 Hz), 17.9; 19 F NMR (376 MHz, CDCl3): δ =-219.76 (t, J =47.2 Hz); HRMS: m / z [M + H] + calcdforC 11 H 11 FN: 176.0792; Found: 176.0795.

[0058] Example 8

[0059] In a glove box, 8-methoxy-2-methylquinoline 1.0 mmol and selectfluor 1.10 mmol were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 5) to obtain compound 3h as a white solid (170 mg, 89%).

[0060] The structural formula of compound 3h is:

[0061]

[0062] 1 H NMR (400 MHz, CDCl3): δ =8.18 (d, J =8.5 Hz, 1 H), 7.62 (d, J =8.5 Hz,1 H), 7.50- 7.33 (m, 2 H), 7.05 (d, J =7.6 Hz, 1 H), 5.71 (d, J =46.9 Hz, 2 H), 4.06 (s, 3 H); 13 C NMR (101 MHz, CDCl3): δ=156.0 (d, J =22.6 Hz), 155.1, 139.3(d, J =2.2 Hz), 137.2, 128.9, 126.9, 119.7,118.9 (d, J =5.5 Hz), 108.2, 85.3 (d, J =169.5 Hz), 56.2; 19 F NMR (376 MHz, CDCl3): δ=-221.24 (t, J =47.0 Hz); HRMS: m / z[M + H] + calcd forC11H11FNO: 192.0741; Found: 192.0737.

[0063] Example 9

[0064] In a glove box, 1.0 mmol of 2-isopropylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 5) to obtain compound 3i as a colorless oily liquid (150 mg, 80%).

[0065] The structural formula of compound 3i is:

[0066]

[0067] 1 H NMR (400 MHz, CDCl3): δ =8.18 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.8 Hz,1H), 7.82 (dd, J = 1.2, 8.0 Hz,1H), 7.69-7.73 (m, 2H), 7.52 (ddd, J = 1.2, 6.9,8.0 Hz, 1H), 1.83 (d, J = 22.2 Hz, 6H); 13 C NMR (101 MHz, CDCl3): δ =164.2 (d, J =26.4 Hz), 147.2, 129.4, 129.3, 127.5, 127.2, 126.3, 116.6, 116.5, 97.5 (d, J =167.9 Hz), 27.8 (d, J = 25.2 Hz); 19 F NMR (376 MHz, CDCl3): δ =–143.1; HRMS: m / z[M + H] + Calculate for C 12 H 13 NF: 190.10320; found: 190.10325.

[0068] Example 10

[0069] In a glove box, 1.0 mmol of 2-ethylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 5) to obtain compound 3j as a colorless oily liquid (157 mg, 90%).

[0070] The structural formula of compound 3j is:

[0071]

[0072] 1 H NMR (400 MHz, CDCl3): δ =8.22 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz,1H), 7.83 (d, J = 8.4 Hz, 1H),7.72 (ddd, J = 2.5, 6.9, 8.4 Hz, 1H), 7.62 (dd, J =1.0, 8.6 Hz, 1H), 7.54 (ddd, J = 1.2, 6.9, 8.0 Hz, 1H),5.85 (qd, J = 6.5, 48.2Hz, 1H), 1.77 (dd, J = 6.5, 24.5 Hz, 3H); 13 C NMR (101 MHz, CDCl3): δ =161.0 (d, J = 26.4 Hz), 147.3, 137.1, 129.8, 129.1, 127.6, 127.6, 126.6, 117.1 (d, J = 6.0Hz), 92.1 (d, J = 170.3Hz), 21.8 (d, J = 24.0 Hz); 19 F NMR (376 MHz, CDCl3): δ =–177.7 (m); HRMS: m / z [M + H] +Calculate for C 11 H 11 NF: 176.08755; found: 176.8747.

[0073] Embodiment 11

[0074] In a glove box, 1-isopropyl-isoquinoline 1.0 mmol and selectfluor 1.10 mmol were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 5) to obtain compound 3k as a yellow oily liquid (160 mg, 85%).

[0075] The structural formula of compound 3k is:

[0076]

[0077] 1 H NMR (400 MHz, CDCl3): δ =8.71 (d, J = 8.8 Hz, 1H), 8.43 (d, J = 5.7 Hz,1H), 7.84 (d, J = 8.0 Hz, 1H),7.67 (t, J = 7.6 Hz, 1H), 7.57-7.61 (m, 2H), 1.97(d, J = 21.8 Hz, 6H); 13 C NMR (101 MHz, CDCl3): δ =161.3 (d, J = 25.2 Hz), 140.4,137.3, 129.6, 127.5, 127. 1(d, J = 15.6 Hz), 126.9, 125.6, 121.2,100.0 (d, J =166.7 Hz), 28.3 (d, J = 24.0 Hz); 19 F NMR (376 MHz, CDCl3): δ =–135.9; HRMS: m / z[M + H] +Calculate for C 12 H 13 NF: 190.10320; found: 190.10322.

[0078] Example 12

[0079] In a glove box, 1-ethyl-isoquinoline 1.0 mmol and selectfluor 1.10 mmol were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, taken out of the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3l as a yellow oily liquid (158 mg, 90%).

[0080] The structural formula of compound 31 is:

[0081]

[0082] 1 H NMR (400 MHz, CDCl3): δ =8.51 (d, J = 5.7, 1H), 8.38 (d, J = 8.4 Hz,1H), 7.86 (d, J = 8.4 Hz, 1H) 7.70(ddd, J = 1.2, 6.9, 8.3 Hz, 1H), 7.62-7.65 (m,2H), 6.34 (dq, J = 6.5, 47.8 Hz, 1H), 1.92 (dd, J = 6.5, 24.0,3H); 13 C NMR (101 MHz, CDCl3): δ =157.7 (d, J = 20.4 Hz), 141.4, 136.8, 130.0, 127.4, 126.0, 125.1,125.1, 121.4, 91.0 (d, J = 167.9 Hz), 20.3 (d, J = 23.99 Hz); 19F NMR (376 MHz, CDCl3): δ =–169.8 (m); HRMS: m / z [M + H] + Calculate for C 11 H 11 NF: 176.08755; found:176.08755.

[0083] Example 13

[0084] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 5) to obtain compound 3m as a yellow solid (215 mg, 83%).

[0085] The structural formula of compound 3m is:

[0086]

[0087] 1 H NMR (400 MHz, CDCl3): δ =8.18 (d, J =8.5 Hz, 1 H), 8.01 (dd, J = 5.4,3.4 Hz, 2 H), 7.82 (dd, J = 8.8, 1.8 Hz,1 H), 7.65~7.53 (m, 3 H), 7.42~7.32 (m,3 H), 5.66 (d, J =46.9 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ =157.5 (d, J =21.9Hz), 146.9 (d, J =1.8 Hz), 136.9,132.8, 131.8, 131.1, 129.2, 128.7, 128.6,127.5, 123.0, 121.9, 119.0 (d, J =5.3 Hz), 91.0, 89.0, 84.9 (d, J=170.7 Hz); 19 FNMR (376 MHz, CDCl3): δ =-221.85 (t, J =46.9 Hz); HRMS: m / z [M + H] + calcdforC 18 H 13 FN: 262.0948; Found:262.0953.

[0088] Embodiment 14

[0089] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 5) to obtain compound 3n as a yellow solid (223 mg, 85%).

[0090] The structural formula of compound 3n is:

[0091]

[0092] 1 H NMR (400 MHz, CDCl3): δ =8.16 (d, J =8.5 Hz, 1 H), 8.06~7.91 (m, 2H), 7.79 (s, 1 H), 7.60~ 7.50 (m, 3 H),7.39 (t, J =7.6 Hz, 2 H), 7.29 (d, J =7.3Hz, 1H), 7.24 (s, 2H), 5.65 (d, J =47.0 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ =156.5 (d, J =21.7 Hz), 147.2, 137.1,137.0, 135.9, 130.4, 129.4, 128.9, 128.2,128.1, 127.83, 127.76, 126.8,125.9, 118.8 (d, J=5.2 Hz), 85.0 (d, J =170.2 Hz); 19 F NMR (376 MHz, CDCl3): δ =-221.00 (t, J =47.0 Hz); HRMS: m / z [M + H] + calcdforC 18 H 15 FN: 264.1105; Found:264.1099.

[0093] Embodiment 15

[0094] In a glove box, compound 1.0 mmol and selectfluor 1.10 mmol were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3o as a white solid (185 mg, 88%).

[0095] The structural formula of compound 3o is:

[0096]

[0097] 1 H NMR (400 MHz, CDCl3): δ =8.63 (d, J =8.5 Hz, 1 H), 8.55 (d, J =8.1 Hz,1 H), 8.32 (d, J =8.0 Hz, 1 H), 8.19(d, J =8.1 Hz, 1 H), 7.86 (dd, J = 8.3, 7.0 Hz,1 H), 7.80~ 7.63 (m, 3 H),6.01 (d, J =47.3 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ=154.9 (d, J=16.8 Hz), 143.2,133.3, 131.0, 130.4, 129.0, 127.9, 127.8, 126.3(d, J =4.2 Hz), 124.8,124.7, 122.5, 122.2, 85.6 (d, J =169.5 Hz); 19 F NMR (376MHz, CDCl3): δ =-212.89 (t, J =47.2 Hz); HRMS: m / z [M + H] + Calculate for C 14 H 11 FN:212.0792; Found:212.0791.

[0098] Example 16

[0099] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3p as a brown solid (183 mg, 87%).

[0100] The structural formula of compound 3p is:

[0101]

[0102] 1 H NMR (400 MHz, CDCl3): δ =8.92 (d, J = 8.6 Hz, 1 H), 8.58–8.49 (m,1H), 7.98–7.89 (m, 3 H), 7.72–7.61 (m, 3 H), 5.69 (d, J = 47.0 Hz, 2 H); 13 C NMR (101 MHz, CDCl3): δ =156.2 (d, J = 21.9 Hz), 147.5 (d, J= 1.7Hz), 131.8, 131.7,131.5, 129.5, 128.8, 127.8, 127.5, 127.3, 124.9 (d, J =0.9 Hz), 122.7, 118.4(d, J = 5.4 Hz), 84.9 (d, J = 170.0 Hz); 19 F NMR (376 MHz, CDCl3): δ =–221.30 (t, J =47.0 Hz); HRMS: m / z [M + H] + Calculate for C 14 H 11 FN: 212.0792; found: 212.0790.

[0103] Embodiment 17

[0104] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, taken out of the glove box, and heated at 80°C for 36 hours. The mixture was extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, cooled to room temperature, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3q as a yellow solid (200 mg, 82%).

[0105] The structural formula of compound 3q is:

[0106]

[0107] 1 H NMR (400 MHz, CDCl3): δ =8.57 (d, J = 8.2 Hz, 1H), 8.52 (s, 1H), 8.35(d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.7 Hz,1H), 7.90 (t, J = 7.5 Hz, 1H), 7.78 (t, J =7.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 5.99 (d,J = 47.3 Hz, 2H); 13 C NMR (101 MHz, CDCl3): δ =155.2 (d, J = 17.0 Hz), 141.7, 133.9, 132.3, 131.9, 131.4, 129.6,128.5, 126.4(d, J = 4.0 Hz), 125.8, 124.9, 122.6, 121.9, 85.4 (d, J = 169.8 Hz); 19 F NMR (376 MHz, CDCl3): δ =-213.38 (t, J = 47.3 Hz); HRMS: m / z [M + H] + calcdforC 14 H 10 ClFN: 246.0486; found: 246.0478.

[0108] Embodiment 18

[0109] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3r as a yellow solid (191 mg, 85%).

[0110] The structural formula of compound 3r is:

[0111]

[0112] 1 H NMR (400 MHz, CDCl3): δ =8.52 (d, J = 8.3 Hz, 1H), 8.26 - 8.17 (m,2H), 7.97 (d, J = 8.3 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.66 - 7.56 (m, 1H), 7.47(dd, J= 8.3, 1.7 Hz, 1H), 5.90(d, J = 47.4 Hz, 2H), 2.53 (s, 3H); 13 C NMR (101MHz, CDCl3): δ =153.77 (d, J = 16.7 Hz), 141.44,137.79, 132.91, 130.68, 130.62,130.02, 127.52, 126.12 (d, J = 4.0 Hz), 124.74, 124.39 (d, J = 1.3 Hz),122.36,121.70, 85.52 (d, J = 168.1 Hz), 22.05; 19 F NMR (376 MHz, CDCl3): δ =-212.30(t, J =47.3 Hz); HRMS: m / z [M + H] + Calculate for C 15 H 13 FN: 226.1032; found: 226.1029.

[0113] Embodiment 19

[0114] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3s as a yellow solid (217 mg, 88%).

[0115] The structural formula of compound 3s is:

[0116]

[0117] 1 H NMR (400 MHz, CDCl3): δ =8.48 (d, J = 8.3 Hz, 1H), 8.39 (d, J= 8.2 Hz, 1H), 7.99 – 7.87 (m, 2H), 7.85 – 7.77 (m, 1H), 7.31 – 7.21 (m, 1H), 6.01 (d, J = 47.3Hz, 2H); 13 C NMR (101 MHz, CDCl3): δ = 161.08 (dd, J = 247.4, 11.8 Hz), 159.41 (dd, J = 257.3, 13.5 Hz), 154.47 (d, J = 17.2 Hz), 132.06 (t, J = 3.6 Hz), 131.42, 129.97(dd, J = 10.4, 2.3 Hz), 128.99, 127.18(d, J = 9.1 Hz), 126.71 (d, J = 4.7 Hz), 125.23, 122.82, 104.38 (dd, J = 28.0, 23.3 Hz), 102.97 (dd, J = 22.6, 4.3Hz), 85.40 (d, J = 168.5 Hz); 19 F NMR (376 MHz, CDCl3): δ = -108.18 (dd, J = 8.3, 1.9 Hz), -118.46(dd, J = 7.9, 0.9 Hz), -212.10 (t, J = 47.3 Hz); HRMS: m / z [M + H] + calcd for C 14 H9F3N: 248.0687; found: 248.0680.

[0118] Example 20

[0119] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 5) to obtain compound 3t as a yellow solid (205 mg, 86%).

[0120] The structural formula of compound 3t is:

[0121]

[0122] 1 H NMR (400 MHz, CDCl3): δ =8.54 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 8.0 Hz,1H), 8.12 (s, 1H),7.74 (t, J = 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.35 (s,1H), 5.91 (d, J = 47.6 Hz,2H), 2.75 (s, 3H), 2.50 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ =151.21 (d, J = 7.0 Hz),139.22, 137.01, 136.13, 132.21, 130.29,129.25, 126.20, 125.08 (d, J = 4.1 Hz),123.62, 123.28, 121.54, 118.41, 85.13(d, J = 166.9 Hz), 20.98, 17.07; 19 F NMR (376 MHz, CDCl3): δ =-210.62(t, J = 47.3Hz); HRMS: m / z [M + H] + Calculate for C 16 H 15FN: 240.1189; found: 240.1181.

[0123] Embodiment 21

[0124] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 5) to obtain compound 3u as a yellow solid (192 mg, 80%).

[0125] The structural formula of compound 3u is:

[0126]

[0127] 1 H NMR (400 MHz, CDCl3): δ =8.53 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 9.0 Hz,1H), 8.28 (d, J =8.2 Hz, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H),7.58 (d, J = 2.6 Hz, 1H),7.32 (dd, J = 9.0, 2.6 Hz, 1H), 5.99 (d, J = 47.3 Hz, 2H),3.98 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ =160.25, 155.19 (d, J = 16.5 Hz),144.81, 133.40, 130.96, 126.59,126.08 (d, J = 3.8 Hz) 123.71, 123.26, 121.93,118.93, 118.59 (d, J = 1.5 Hz), 109.96,85.33 (d, J= 168.7 Hz), 55.63; 19 F NMR (376MHz, CDCl3): δ =-213.19(t, J = 47.3 Hz); HRMS: m / z [M + H] + Calculate for C 15 H 13 FNO:242.0981; found: 242.0974.

[0128] Embodiment 22

[0129] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3v as a yellow solid (210 mg, 86%).

[0130] The structural formula of compound 3v is:

[0131]

[0132] 1 H NMR (400 MHz, CDCl3): δ =8.46 (d, J = 8.3 Hz, 1H), 8.41 (d, J = 2.1 Hz,1H), 8.25 (d, J = 8.2 Hz, 1H),8.01 (d, J = 8.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H),7.68 (t, J = 7.6 Hz, 1H), 7.60 (dd, J = 8.7, 2.2 Hz, 1H), 5.90 (d, J = 47.3 Hz,2H); 13 C NMR (101 MHz, CDCl3): δ =153.99(d, J= 16.8 Hz), 140.51, 132.69, 131.11,130.77, 130.14, 128.39, 127.32, 125.20 (d, J = 4.2 Hz), 124.55 (d, J = 1.3 Hz) ,123.73, 121.40, 120.71, 84.26 (d, J = 168.8 Hz); 19 F NMR (376 MHz, CDCl3): δ =-213.27(t, J = 47.3 Hz); HRMS: m / z [M + H] + Calculate for C 14 H 10 ClFN: 246.0486; found:246.0478.

[0133] Embodiment 23

[0134] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 100 / 5) to obtain compound 3w as a yellow solid (250 mg, 85%).

[0135] The structural formula of compound 3w is:

[0136]

[0137] 1 H NMR (400 MHz, CDCl3): δ =8.69 (d, J = 9.1 Hz, 1H), 8.53 (d, J = 8.8 Hz,1H), 8.22 –8.13 (m, 2H), 7.82 – 7.69 (m, 3H), 5.98 (d, J = 47.3 Hz, 2H); 13 C NMR (101 MHz, CDCl3): δ =154.13 (d, J= 17.3 Hz), 148.02, 143.19, 131.71, 130.56,129.36, 128.32,125.45, 124.73, 124.35, 123.78, 122.03, 120.56 (q, J = 256.8 Hz)117.55 (d, J = 4.9Hz), 85.49 (d, J = 168.7 Hz); 19 F NMR (376 MHz, CDCl3): δ =-57.69, -212.95; HRMS: m / z [M + H] + Calculate for C 15 H 10 F4NO: 296.0699; found:296.0692.

[0138] Embodiment 24

[0139] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3x as a yellow solid (215 mg, 89%).

[0140] The structural formula of compound 3x is:

[0141]

[0142] 1 H NMR (400 MHz, CDCl3): δ =8.47 (d, J = 9.1Hz, 1H), 8.40 (dd, J = 6.8,2.7 Hz, 1H), 8.08 (dd, J = 8.1, 5.8 Hz, 1H), 7.66 – 7.54 (m,3H), 7.42 (dd, J =9.1, 2.6 Hz, 1H), 5.90 (d, J= 47.4 Hz, 2H), 3.92 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ =158.87, 153.88 (d, J = 16.9 Hz), 142.37, 130.29, 127.89, 127.81,127.62, 126.09, 124.68, 124.06, 121.71, 121.58, 106.01 (d, J = 4.8 Hz), 85.84(d, J =168.1 Hz), 55.60; 19 F NMR (376 MHz, CDCl3): δ =-213.30; HRMS: m / z [M + H] + Calculate for C 15 H 13 FNO: 242.0981; found: 242.0979.

[0143] Embodiment 25

[0144] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3y as a yellow solid (258 mg, 90%).

[0145] The structural formula of compound 3y is:

[0146]

[0147] 1 H NMR (400 MHz, CDCl3): δ =8.71 (d, J = 8.6 Hz, 1H), 8.58 (d, J = 7.8 Hz,1H), 8.52 (s, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.11(dd, J= 8.6, 1.3 Hz, 1H), 7.79– 7.67 (m, 4H), 7.53 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.3Hz, 1H), 6.05 (d, J =47.3 Hz, 2H); 13 C NMR (101 MHz, CDCl3): δ =154.92 (d, J = 6.8Hz), 143.16, 140.57,140.18, 132.21, 130.41, 130.23, 129.11, 128.90, 128.02, 127.89,127.53,125.11, 124.43 (d, J = 1.3 Hz), 124.24, 124.20, 123.03, 122.12, 85.60 (d, J =168.5 Hz); 19 F NMR (376 MHz, CDCl3): δ =-212.61; HRMS: m / z [M + H] + calcdforC 20 H 15 FN: 288.1189; found: 288.1183.

[0148] Embodiment 26

[0149] In a glove box, 1.0 mmol of the compound and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3z as a yellow solid (208 mg, 85%).

[0150] The structural formula of compound 3z is:

[0151]

[0152] 1 H NMR (400 MHz, CDCl3): δ =8.58 (d, J= 8.9 Hz, 1H), 8.52 (d, J = 7.9 Hz,1H), 8.32 (t, J = 1.9 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.85 – 7.67 (m, 3H), 5.96 (d, J = 47.3 Hz, 2H); 13 C NMR (101 MHz, CDCl3): δ =153.78 (d, J = 17.1 Hz),143.10, 133.70, 131.59, 131.52, 130.52, 129.24,128.22, 125.65, 125.60,124.16, 123.94, 121.96, 85.41 (d, J = 168.6 Hz); 19 F NMR (376 MHz, CDCl3): δ =-212.81; HRMS: m / z [M + H] + Calculate for C 14 H 10 ClFN:246.0486; found: 246.0478.

[0153] Embodiment 27

[0154] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a dioxane solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (110 mg, 69%).

[0155] Embodiment 28

[0156] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a toluene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (134 mg, 84%).

[0157] Embodiment 29

[0158] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a hexane solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (129 mg, 81%).

[0159] Comparative Example 1

[0160] In a glove box, 1.0 mmol of 2-methylquinoline and 0.9 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (123 mg, 77%).

[0161] Comparative Example 2

[0162] In a glove box, 1.0 mmol of 2-methylquinoline and 1.5 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (119 mg, 74%).

[0163] Comparative Example 3

[0164] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (390 mg, 1.50 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (142 mg, 88%).

[0165] Comparative Example 4

[0166] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (234 mg, 0.90 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (109 mg, 68%). Comparative Example 5

[0167] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 60°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (103 mg, 65%).

[0168] Comparative Example 6

[0169] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 100°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (131 mg, 82%).

[0170] Comparative Example 7

[0171] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 12 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (87 mg, 55%).

[0172] Comparative Example 8

[0173] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing potassium bis(trimethylsilyl)amide (286 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 60 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (137 mg, 87%).

[0174] Comparative Example 9

[0175] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing lithium bis(trimethylsilyl)amide (240 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (42 mg, 27%).

[0176] Comparative Example 10

[0177] In a glove box, 1.0 mmol of 2-methylquinoline and 1.10 mmol of selectfluor were added to a benzene solution (20 mL) containing sodium bis(trimethylsilyl)amide (263 mg, 1.10 mmol) in a 50 mL Schlenk tube. The Schlenk tube was sealed, removed from the glove box, and heated at 80°C for 36 hours. The mixture was cooled to room temperature, extracted with ethyl acetate, then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and directly purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5) to obtain compound 3a as a tan solid (112 mg, 72%).

Claims

1. A method for preparing 2-fluoromethylquinoline and its derivatives, characterized in that: The following steps are involved: (1) Adding 2-methylquinoline and its derivatives and selectfluor to a solution containing potassium bis(trimethylsilyl)amide to obtain a mixed solution; (2) sealing the mixed solution and heating it to obtain a reaction solution; (3) The reaction solution is cooled to room temperature, extracted with ethyl acetate, washed, dried, concentrated, and purified to obtain 2-fluoromethylquinoline and its derivatives; The structural formula of the 2-fluoromethylquinoline and its derivatives is as follows: ； In the formula, R is an alkyl group, a halogen group, an alkoxy group, a hydrogen group or an aromatic ring.

2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of the 2-methylquinoline and its derivatives to Selectfluor is 1:1.0-1.2; the molar ratio of the 2-methylquinoline and its derivatives to potassium bis(trimethylsilyl)amide is 1:1.0-1.

2.

3. The preparation method according to claim 2, characterized in that: The concentration of the solution of potassium bis(trimethylsilyl)amide is 0.055 mol / L.

4. The preparation method according to claim 3, characterized in that: The solvent of the solution of potassium bis(trimethylsilyl)amide is benzene, tetrahydrofuran, dioxane, toluene and n-hexane.

5. The preparation method according to claim 4, characterized in that: The solvent of the solution of potassium bis(trimethylsilyl)amide is benzene.

6. The preparation method according to claim 1, characterized in that: In step (2), the heating reaction is performed at 70-90° C. for 24-48 hours.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In step (3), the specific steps of washing, drying, concentrating and purifying are: extracting the reaction solution with ethyl acetate, then washing with saturated brine, drying with anhydrous sodium sulfate, concentrating and purifying with silica gel column chromatography.

8. The preparation method according to claim 7, characterized in that: Silica gel column chromatography was performed using n-hexane / ethyl acetate = 95 / 5.

Images