A 2-benzyl substituted quinoline derivative and a method for preparing the same

Abstract

The application discloses a 2-position benzyl-substituted quinoline derivative and a preparation method thereof, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: under the condition that a base exists, a benzylating reagent shown in formula III and quinoline N-oxide shown in formula II are added into a solvent to perform a coupling reaction shown in the following formula, so as to obtain a C2-position benzyl-substituted quinoline derivative shown in formula I. The application realizes a mild and efficient benzylization reaction of quinoline N-oxide without transition metal participation, and has the advantages of easy availability of raw materials, mild conditions, efficient reaction, good functional group compatibility, good substrate universality and the like.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a 2-benzyl-substituted quinoline derivative and its preparation method. Background Technology

[0002] Nitrogen-containing heterocyclic compounds, as an important class of organic skeletons, have been widely used in the synthesis of bioactive molecules, advanced materials, and pesticide intermediates. In recent years, nitrogen-containing aromatic heterocyclic drugs have been the most common among FDA-approved drugs. Among them, C2-alkylated quinolines and their derivatives have high medicinal value, particularly in antibacterial and antiviral activity. For example, quinoline C2-alkyl derivatives A and B can inhibit the transformation of HTLV-1 virus cells in vivo; flometoquin can be used to control pests resistant to existing insecticides; bisacodyl is a stimulant laxative that primarily acts on the large intestine and is clinically used to treat acute and chronic constipation; betostine is a selective and orally active second-generation histamine H1 receptor antagonist used to treat allergic rhinitis, allergic conjunctivitis, and urticaria / pruritus; P2X3 receptor antagonists can be used to treat refractory chronic cough in the respiratory field. Representative nitrogen-containing heterocyclic drugs are shown below:

[0003]

[0004] Quinolines are heterocyclic organic compounds formed by the fusion of benzene and pyridine rings, possessing certain unique properties. Introducing nitrogen-containing heterocycles into the drug skeleton can improve drug selectivity by altering its polarity, thereby enhancing its physiological activity. It can also prolong the duration of action and improve bioavailability through hydrogen bonding with target proteins or amino acids at active sites. The introduction of sterically hindered groups such as the quinoline ring can also improve the drug's metabolic stability. Quinoline derivatives can also be converted into bioactive hydrogenated quinolines through subsequent transformation reactions. Based on the unique properties of quinolines, the efficient synthesis of quinoline derivatives is of great significance in drug development and structural modification. However, due to the high electronegativity of the nitrogen atom on the pyridine ring, the π electron cloud shifts to the nitrogen atom, reducing the electron cloud density on the ring. Therefore, the aromaticity of the pyridine ring is weaker than that of the benzene ring. In summary, electrophilic or nucleophilic aromatic substitution reactions of the pyridine ring present certain challenges. Currently, the main approach is to introduce different substituents onto the nitrogen atom to enhance the reactivity of quinoline compounds. Among them, quinoline oxynitrides have advantages such as high reactivity, readily available raw materials, and the ability to undergo subsequent transformations, and are widely used in the synthesis of quinoline derivatives.

[0005] Due to the unique advantages and important roles of quinoline derivatives, the synthesis of functionalized quinoline compounds has attracted widespread attention from organic chemists. In particular, the synthesis of 2-functionalized quinoline derivatives has been extensively reported in recent years. Traditional methods for synthesizing 2-functionalized substituted quinoline derivatives require the use of equivalent metal reagents or activators (acid anhydrides or acyl chlorides), and these reactions often require high temperatures. These demanding reaction conditions result in poor substrate universality, low regioselectivity, and low yields. Therefore, developing mild and efficient 2-functionalization methods for quinolines is of great significance for biomedicine, advanced materials, and other related fields.

[0006] Organoboron compounds possess advantages such as chemical stability, unique reactivity, low toxicity, good functional group tolerance, and the ability to undergo various transformation reactions, leading to their increasingly widespread application in organic synthesis. Boron, located in Group IIIA of the second period of the periodic table, has three valence electrons in its outermost shell. Neutral boron atoms have six valence electrons and one empty p orbital, making them relatively electron-deficient and exhibiting Lewis acidity, allowing them to accept lone pairs of electrons to form complexes. The earliest synthesized organoboron compounds, B₂X₄ (X = F, Cl, Br, I), were highly sensitive to water and oxygen, and their preparation conditions were demanding, significantly limiting their application in organic synthesis methodologies. With increasingly in-depth research into organoboron chemistry, organic chemists have discovered a variety of more stable organoboron molecules that are insensitive to water and oxygen. Among these, organoboronate esters are easy to prepare and chemically stable, making them a research hotspot for organic chemists. Currently, commonly used organoboron reagents include: symmetrical structures such as B2pin2, B2neop2, B2dmpd2, B2dmp2, and B2cat2, and asymmetrical structures such as BpinBdan and BpinB(Mes)2. Organoboron reagents can be used as functional group transfer agents to achieve structural modification of various skeletal fragments, or they can directly introduce boron-containing groups into active molecules, thereby obtaining a series of active molecule analogs through various transformation reactions. Therefore, applying organoboron compounds to methodological research is of great significance for the mild and efficient synthesis of complex drug structural fragments.

[0007] Transition metal-catalyzed cross-coupling reactions are a powerful means of constructing C-C bonds. Traditional synthetic methods require noble metal catalysts or highly toxic organotin reagents to participate in the reaction, which does not conform to the development concept of green chemistry.

[0008] In the literature, the C2-position alkylation of nitrogen-containing heterocycles often requires the use of transition metal catalysis. However, the existing literature on the C2-position alkylation of pyridine or quinoline oxynitrides has its own limitations, such as the need for saturated metal reagents, pre-prepared reagents, strong oxidants or expensive metal catalysts, and the need for high temperatures and long reaction times. We need to further enrich the methods for the C2-position alkylation of quinoline oxynitrides.

[0009] Based on a literature review, we found that heterocyclic compounds modified into nitrides exhibit higher reactivity. Traditional functionalization reactions at the C2 position of heterocyclic nitrides require transition metals and stringent reaction conditions. Currently, the development of C2-position alkylation reactions of heterocyclic nitrides is relatively limited; although alkyl nucleophiles have high reactivity, their stability is poor and they are prone to decomposition. Based on existing research, we found that organoboronates are mild and stable nucleophiles. Among them, arylboronates have made good progress in C-C bond coupling reactions catalyzed by transition metals, but due to the aforementioned reasons, reactions involving alkylboronates are still very limited. We discovered that alkylboronates can form 4-coordinate organoboron complexes under the activation of oxygen- or nitrogen-containing reagents. These complexes have high reactivity and hold promise for achieving C2-position alkylation reactions of heterocyclic nitrides without transition metal involvement. This could lead to the development of a simple and efficient method for the alkylation of nitrogen-containing heterocyclic compounds. Since transition metal catalysis often leaves behind toxic transition metal residues, it requires cumbersome post-processing and purification steps in the field of drug development. This project utilizes the mild chemical properties of organoboron compounds to achieve the alkylation reaction of nitrogen-containing heterocyclic compounds in the absence of transition metals. Summary of the Invention

[0010] This invention provides a 2-benzyl-substituted quinoline derivative and its preparation method. The proposed method does not require the use of transition metals, making it greener, more environmentally friendly, simpler, and more efficient. It will provide a more effective method for the diversified synthesis of heterocyclic skeletons such as pyridine or quinoline with potential pharmaceutical value. It realizes a mild and efficient benzylation reaction of quinoline oxynitrides without the participation of transition metals.

[0011] To achieve the above-mentioned objective, the present invention provides a method for preparing a 2-benzyl-substituted quinoline derivative, characterized by comprising the following steps: under the presence of a base, adding the benzylating reagent shown in Formula III and the quinoline oxynitride shown in Formula II to a solvent to carry out a coupling reaction as shown below, to obtain the C2-benzyl-substituted quinoline derivative shown in Formula I;

[0012]

[0013] In quinoline nitrogen oxides as shown in Formula II:

[0014] n1 is selected from any integer between 0 and [M-1], where M represents the maximum number of substitutions on ring α;

[0015] R1 may be the same or different, and each of them is independently selected from one or more of hydrogen atoms, halogens, C1-C4 straight-chain or branched alkyl groups, C1-C4 straight-chain or branched alkoxy groups, carbocyclic rings, aryl groups, and unsaturated aryl groups.

[0016] The α ring is a nitrogen oxide of a bicyclic or tricyclic quinoline ring;

[0017] In the benzylating reagents shown in Formula III:

[0018] n2 is selected from any integer between 0 and 5;

[0019] R2 may be the same or different, each independently selected from one or more of hydrogen atoms, halogens and C1-C6 straight-chain or branched alkyl groups;

[0020] R3 is selected from one or more of the following: hydrogen atom, C1-C6 straight-chain or branched alkyl group, halogen-substituted C1-C6 straight-chain or branched alkyl group, C1-C6 straight-chain or branched unsaturated hydrocarbon group, carbocyclic ring, carbon heterocyclic ring, aryl group and halogen-substituted aryl group.

[0021] Where n1 and n2 are 0, 1 or 2;

[0022] And / or, when either R1 or R2 is a halogen, the halogen is preferably fluorine, chlorine, bromine or iodine;

[0023] And / or, when either R1 or R2 is a C1-C6 straight-chain or branched alkyl group, the C1-C6 straight-chain or branched alkyl group is a C1-C4 straight-chain or branched alkyl group, preferably methyl, ethyl, propyl, isopropyl or tert-butyl.

[0024] And / or, when any of R1 is a C1-C6 straight-chain or branched alkoxy group, the C1-C6 straight-chain or branched alkoxy group is preferably a C1-C3 straight-chain or branched alkoxy group, preferably methoxy, ethoxy, propoxy or isopropoxy.

[0025] And / or, when any of R1 is a carbon ring, the carbon ring is selected from 3-10 membered rings, preferably benzene rings and naphthalene rings;

[0026] And / or, when n1 is 1, R1 is a hydrogen atom, a halogen, or a methyl group, wherein the halogen is fluorine, chlorine, bromine, or iodine;

[0027] And / or, when n2 is 1, R2 is a hydrogen atom, a halogen, a methyl group, or a tert-butyl group, wherein the halogen is fluorine, chlorine, bromine, or iodine.

[0028] The reaction equations for the coupling reaction are shown in any of the following examples:

[0029]

[0030] Wherein, the alkali is an organic alkali or an inorganic alkali, and the organic alkali is... t One or more of BuOK, DMAP, and MTBD, wherein the inorganic base is t BuONa, LiO t One or more of Bu, NaOMe, K3PO4, Na2CO3, NaHCO3, KOMe, K2CO3, and KHCO3.

[0031] The coupling reaction is carried out under the protection of an inert gas, which is one or more of nitrogen, helium, argon and neon.

[0032] The molar ratio of the quinoline nitrogen oxide as shown in Formula II to potassium tert-butoxide is 1:0.1-1:10, preferably 1:1-1:1.5;

[0033] The molar ratio of the quinoline nitride as shown in Formula II to the benzylating agent is preferably 1:0.1-1:10, more preferably 1:0.5-1:2.0, and even more preferably 1:1-1:2.0;

[0034] The solvent is one or more of aromatic solvents and ether solvents; the aromatic solvent is one or more of benzene, toluene, and xylene; the ether solvent is one or more of diethyl ether, 1,4-dioxane, and tetrahydrofuran; more preferably, the solvent is one or more of toluene, tetrahydrofuran, and 1,4-dioxane.

[0035] The molar volume ratio of the quinoline nitride as shown in Formula II to the solvent is 0.01 mmol / mL to 1.0 mmol / mL, more preferably 0.1 mmol / mL to 0.5 mmol / mL.

[0036] The reaction time of the coupling reaction is preferably 0.1-200 h, more preferably 1-6 h;

[0037] The reaction temperature of the coupling reaction can be 0℃-100℃, more preferably 0℃-50℃, and even more preferably 50℃;

[0038] After the coupling reaction, 1,4-benzoquinone is added to the reaction system and the reaction continues at room temperature for 1-2 hours, as shown in Formula II, with a molar ratio of quinoline nitride to 1,4-benzoquinone of 1:1-1:3.

[0039] The present invention also provides a 2-benzyl-substituted quinoline derivative, which is prepared by the above-described method.

[0040] Compared with the prior art, the present invention has the following beneficial technical effects:

[0041] This invention uses compounds containing O or N as activating reagents to activate alkyl borate esters to form free radicals or carbanion intermediates. Nitrogen-containing heterocyclic nitride molecules contain electrophilic imine ion intermediates that are readily attacked by these active intermediates, thereby achieving a mild and efficient benzylation reaction of pyridine or quinoline nitrides.

[0042] This invention utilizes an inexpensive reaction system to prepare 2-benzylquinoline or quinoline oxynitrides with various functional group substitutions. It offers advantages such as readily available raw materials, mild reaction conditions, high reaction efficiency, functional group compatibility, and good substrate universality. This preparation method provides better application prospects and practical value for the industrial synthesis of C2-functionalized quinoline or quinoline oxynitrides. Detailed Implementation

[0043] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described herein. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0044] Example 1:

[0045]

[0046] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2a (178.2 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent, yielding 72.1 mg of a white solid, with a yield of 76%. 1H NMR (400MHz, CDCl3): δ8.78 (d, J=8.8Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.75 (t, J=7.6Hz, 1H), 7.63 -7.58 (m, 2H), 7.45 (d, J=8.0Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 7.09 (d, J=8.8Hz, 1H), 4.42 (s, 2H). 13 C NMR (100MHz, CDCl3): δ147.1, 141.4, 135.5, 131.8, 131.2, 130.4, 129.1, 128.00, 127.95, 125.1, 121.8, 120.8, 119.6, 36.8.

[0047] Example 2:

[0048]

[0049] In a helium-filled glove box, add KO gas sequentially to a 4 mL sample vial. t Bu (33.67 mg, 0.3 mmol), THF (3 mL), 1a (43.5 mg, 0.3 mmol), and 2b (70.9 mg, 0.3 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (32.5 mg, 0.3 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 60.2 mg of a pale yellow oil, with a yield of 79%. 1 H NMR (400MHz, CDCl3): δ8.79 (d, J=8.8Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.78-7.74 (m, 1H), 7.63 -7.58(m, 2H), 7.33-7.30(m, 2H), 7.09(d, J=8.8Hz, 1H), 7.03(t, J=8.8Hz, 2H), 4.45(s, 2H). 13 C NMR (100MHz, CDCl3): δ161.8(d, 1 J C-F =244.5Hz), 147.7, 141.4, 132.1(d, 4 J C-F =3.0Hz), 131.0(d, 3 J C-F=7.6Hz), 130.4, 129.1, 127.98, 127.97, 125.2, 121.8, 120.0, 115.6 (d, 2 J C-F =21.2Hz), 36.6. 19 F NMR (376MHz, CDCl3): δ-115.8.

[0050] Example 3:

[0051]

[0052] In a helium-filled glove box, KO was added sequentially to a 4 mL sample vial. t Bu (50.5 mg, 0.45 mmol), THF (0.6 mL), 1a (43.5 mg, 0.3 mmol), and 2c (139.3 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (97.4 mg, 0.9 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 59.8 mg of a pale yellow oil, with a yield of 80%. 1 H NMR (400MHz, CDCl3): δ8.79 (d, J=8.4Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.73 (t, J=7.2Hz, 1H), 7.63 (d, J=8.4Hz , 1H), 7.58 (t, J=6.8Hz, 1H), 7.35-7.33 (m, 4H), 7.26-7.20 (m, 2H), 5.39-5.36 (m, 1H), 1.74 (d, J=7.2Hz, 3H). 13 C NMR (100MHz, CDCl3): δ152.3, 142.3, 141.5, 130.3, 128.8, 128.6, 127.92, 127.86, 126.8, 125.1, 120.3, 119.9, 38.7, 18.2.

[0053] Example 4:

[0054]

[0055] In a glove box filled with argon, KO gas was added sequentially to a 4 mL sample vial. tBu (3.37 mg, 0.03 mmol), THF (30 mL), 1a (43.5 mg, 0.3 mmol), and 2d (459 mg, 3 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 60.0 mg of a pale yellow oil, with a yield of 85%. 1 H NMR (400MHz, CDCl3): δ8.80 (d, J=8.8Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.75 (t, J=7.2H z, 1H), 7.59 (t, J=8.0Hz, 2H), 7.34-7.27 (m, 5H), 7.05 (d, J=8.4Hz, 1H), 4.48 (s, 2H). 13 C NMR (100MHz, CDCl3): δ148.0, 141.4, 136.4, 130.3, 129.6, 129.0, 128.8, 127.92, 127.86, 126.9, 125.0, 121.8, 119.6, 37.3.

[0056] Example 5:

[0057]

[0058] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (336.7 mg, 3.0 mmol), THF (0.3 mL), 1b (67.2 mg, 0.3 mmol), and 2d (6.5 mg, 0.03 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 6.07 mg of a pale yellow oil, with a yield of 64%. 1H NMR (400MHz, CDCl3): δ8.67 (d, J=9.2Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.79 (dd, J1=9.2Hz, J2 =2.0Hz, 1H), 7.48 (d, J = 8.8Hz, 1H), 7.38-7.27 (m, 5H), 7.07 (d, J = 8.4Hz, 1H), 4.44 (s, 2H). 13 C NMR (100MHz, CDCl3): δ148.4, 140.3, 136.1, 133.5, 130.2, 129.9, 129.6, 128.9, 127.1, 123.6, 123.1, 122.2, 121.8, 37.3.

[0059] Example 6:

[0060]

[0061] In a nitrogen-filled glove box, DMAP (44.0 mg, 0.36 mmol), benzene (1.5 mL), 1c (47.8 mg, 0.3 mmol), and 2d (32.7 mg, 0.15 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 29.4 mg of a pale yellow oil, with a yield of 78%. 1 H NMR (400MHz, CDCl3): δ8.87 (d, J=8.8Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.75 (t, J=7.6Hz, 1H), 7.61 (t, J=8.0Hz, 1H), 7.36-7.35(m, 4H), 7.29-7.27(m, 1H), 6.90(s, 1H), 4.48(s, 2H), 2.55(s, 3H). 13C NMR (100MHz, CDCl3): δ147.2, 140.8, 136.6, 133.5, 129.9, 129.6, 128.7, 128.5, 127.6, 126.8, 124.5, 122.3, 120 .2, 37.2, 18.2.IR (neat): 3022, 2980, 2923, 1563, 1381, 1361, 1338, 1307, 1228, 1097, 1020, 759, 773, 728, 705cm - 1 HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 16 NO 250.1226; Found 250.1232.

[0062] Example 7:

[0063]

[0064] In a neon-filled glove box, MTBD (55.2 mg, 0.36 mmol), toluene (1.5 mL), 1d (47.8 mg, 0.3 mmol), and 2d (130.9 mg, 0.6 mmol) were added sequentially to 4 mL sample vials. After capping, the vials were removed from the glove box and reacted at 100 °C for 1 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 48.7 mg of a pale yellow oil, with a yield of 65%. 1 H NMR (400MHz, CDCl3): δ8.62 (s, 1H), 7.70 (d, J=8.0Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.35-7.27 (m, 5H), 7.00 (d, J=8.8Hz, 1H), 4.48 (s, 2H), 2.60 (s, 3H). 13 C NMR (100MHz, CDCl3): δ148.1, 141.44, 141.35, 136.7, 130.0, 129.7, 128.8, 127.7, 127.2, 126.9, 124.9, 120.9, 118.8, 37.4, 22.1.

[0065] Example 8:

[0066]

[0067] In a nitrogen-filled glove box, add the following to a 4 mL sample vial sequentially: t BuONa (34.6 mg, 0.36 mmol), xylene (1.5 mL), 1e (53.9 mg, 0.3 mmol), and 2d (130.9 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 0°C for 6 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 27.2 mg of a pale yellow oil, with a yield of 34%. 1 H NMR (400MHz, CDCl3): δ8.75 (d, J=7.2Hz, 1H), 7.97 (d, J=7.6Hz, 1H), 7.67-7.6 4(m, 2H), 7.39-7.26(m, 5H), 7.15(dd, J1=8.8Hz, J2=2.0Hz, 1H), 4.46(s, 2H). 13 CNMR (100MHz, CDCl3): δ148.7, 142.6, 136.1, 132.1, 129.8, 129.7, 128.9, 128.2, 127.4, 127.1, 122.6, 121.4, 119.0, 37.4.

[0068] Example 9:

[0069]

[0070] In a nitrogen-filled glove box, LiO2 was added sequentially to a 4 mL sample vial. t Bu (28.8 mg, 0.36 mmol), 1,4-dioxane (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2e (171.7 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent. The crude product was then subjected to plate chromatography again (eluent: dichloromethane:methanol = 100:1) to give 17.4 mg of a white solid, with a yield of 19%. 1H NMR (400MHz, CDCl3): δ8.79 (d, J=8.8Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.78 (t, J=8.0Hz, 1H), 7.65 ( t, J=8.4Hz, 2H), 7.60 (d, J=7.6Hz, 2H), 7.47 (d, J=8.0Hz, 2H), 7.15 (d, J=8.4Hz, 1H), 4.53 (s, 2H). 13 C NMR (100MHz, CDCl3): δ146.8, 141.6, 140.7, 130.6, 129.8, 129.28, 129.25 (q, 2 J C-F =32.1Hz), 128.2, 128.1, 125.7(q, 3 J C-F =3.8Hz), 125.2, 124.1(q, 1 J C-F =270.3Hz), 121.9, 119.7, 37.3. 19 F NMR (376MHz, CDCl3): δ-62.5.IR (neat): 2920, 2847, 1566, 1414, 1328, 1276, 1238, 1154, 1106, 1067, 1017, 910, 814, 758, 705cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 13 NOF3304.0944;Found 304.0938.

[0071] Example 10:

[0072]

[0073] In a nitrogen-filled glove box, NaOMe (19.4 mg, 0.36 mmol), diethyl ether (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2f (151.5 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 61.7 mg of a pale yellow oil, with a yield of 76%. 1H NMR (400MHz, CDCl3): δ8.78 (d, J=8.8Hz, 1H), 7.81 (d, J=8.4Hz, 1H), 7.77-7.73 ( m, 1H), 7.63-7.57 (m, 2H), 7.32-7.26 (m, 4H), 7.10 (d, J=8.8Hz, 1H), 4.43 (s, 2H). 13 C NMR (100MHz, CDCl3): δ147.2, 141.4, 135.0, 132.7, 130.8, 130.4, 129.1, 128.8, 128.0, 127.9, 125.1, 121.8, 119.6, 36.7.

[0074] Example 11:

[0075]

[0076] In a nitrogen-filled glove box, K3PO4 (76.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2 g (160.9 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with dichloromethane:methanol = 70:1 as the eluent. The crude product was then subjected to further plate chromatography (eluent: dichloromethane:methanol:petroleum ether = 100:1:20) to give 67.7 mg of a white solid, with a yield of 79%. 1 H NMR (400MHz, CDCl3): δ8.90 (d, J=8.8Hz, 1H), 7.93-7.78 (m, 5H), 7.61 (t, J=7.6Hz, 1H), 7.53-7.40 (m, 5H), 6.71 (d, J=8.8Hz, 1H), 4.94 (s, 2H). 13 C NMR (100MHz, CDCl3): δ147.8, 141.4, 133.9, 132.6, 132.1, 130.3, 128.8, 128.7, 12 8.4, 128.1, 127.9, 127.8, 126.4, 125.9, 125.6, 124.9, 124.0, 121.4, 119.6, 34.6.

[0077] Example 12:

[0078]

[0079] In a nitrogen-filled glove box, Na₂CO₃ (38.2 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2h (139.3 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After sealing, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent. The crude product was then subjected to further plate chromatography (eluent: dichloromethane: methanol: petroleum ether = 100:1:20) to obtain 45.7 mg of a pale yellow oil, with a yield of 61%. 1 H NMR (400MHz, CDCl3): δ8.81 (d, J=8.8Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.76 (t, J=7.2Hz, 1H ), 7.61-7.59(m, 2H), 7.24-7.16(m, 4H), 7.06(d, J=8.4Hz, 1H), 4.45(s, 2H), 2.35(s, 3H). 13 C NMR (100MHz, CDCl3): δ148.3, 141.5, 136.5, 133.4, 130.2, 129.53, 129.47, 129.0, 127.9, 127.8, 124.9, 121.8, 119.7, 36.9, 21.0.

[0080] Example 13:

[0081]

[0082] In a nitrogen-filled glove box, NaHCO3 (30.2 mg, 0.36 mmol), THF (1.5 mL), 1f (67.2 mg, 0.3 mmol), and 2d (130.9 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with petroleum ether:ethyl acetate = 1:1 as the eluent. The crude product was then subjected to further plate chromatography (eluent: dichloromethane: methanol: petroleum ether = 100:1:20) to give 69.6 mg of a white solid, with a yield of 74%. 1H NMR (400MHz, CDCl3): δ8.98 (s, 1H), 7.64 (s, 2H), 7.53 (d, J=8.8Hz, 1H), 7.37-7.27 (m, 5H), 7.07 (d, J=8.8Hz, 1H), 4.45 (s, 2H). 13 C NMR (100MHz, CDCl3): δ148.8, 141.7, 136.1, 131.5, 129.5, 129.2, 128.8, 127.5, 127.0, 124.8, 124.5, 122.4, 122.2, 37.3.IR (neat): 3110, 3063, 3022, 1552, 1509, 1496, 1336, 1244, 1230, 1178, 1096, 878, 833, 718, 700cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 13 NOBr 314.0175; Found314.0177.

[0083] Example 14:

[0084]

[0085] In a nitrogen-filled glove box, KOMe (78.4 mg, 0.36 mmol), THF (1.5 mL), 1 g (62.9 mg, 0.3 mmol), and 2 d (130.9 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with dichloromethane:methanol = 70:1 as the eluent. The crude product was then subjected to further plate chromatography (eluent: n-pentane:ethyl acetate = 1:1) to give 76.8 mg of a white solid, with a yield of 85%. 1 H NMR (400MHz, CDCl3): δ8.17 (d, J=2.4Hz, 1H), 8.02 (t, J=8.8Hz, 1H), 7.37-7.28 (m, 6H), 6.99 (s, 1H), 4.44 (s, 2H), 4.01 (s, 3H). 13CNMR (100MHz, CDCl3): δ162.4, 148.7, 143.4, 135.9, 129.6, 128.9, 127.1, 126.3, 121.6, 121.5, 119.2, 98.7, 5 6.0, 37.4.IR (neat): 3053, 2956, 2920, 2852, 1615, 1456, 1274, 1216, 1022, 886, 842, 824, 734, 704, 690, 656cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 17 H 15 NO2Cl 300.0786; Found 300.0779.

[0086] Example 15:

[0087]

[0088] In a nitrogen-filled glove box, K₂CO₃ (49.8 mg, 0.36 mmol), THF (1.5 mL), 1 h (58.6 mg, 0.3 mmol), and 2 d (130.9 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to further plate chromatography (eluent: n-pentane:ethyl acetate = 1:1) to give 45.4 mg of a white solid, with a yield of 53%. 1 H NMR (400MHz, CDCl3): δ8.98 (d, J=8.4Hz, 1H), 8.51 (t, J=9.2Hz, 2H), 8.05 (d, J=8.0Hz, 1H), 7.76 (dt, J1=21.6Hz, J 2=7.2Hz, 2H), 7.68-7.60 (m, 2H), 7.36 (d, J=7.2Hz, 2H), 7.25 (t, J=7.6Hz, 2H), 7.17 (t, J=7.2Hz, 1H), 4.96 (s, 2H). 13C NMR (100MHz, CDCl3): δ145.1, 139.1, 137.0, 129.6, 128.9, 128.8, 128.7, 128.6, 126.6, 126.5, 125.7, 125.2, 122 .4, 121.0, 32.6.IR (neat): 3024, 3001, 2938, 2917, 1568, 1490, 1307, 1225, 1099, 1017, 781, 763, 748, 707, 671cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 16 NO 286.1226; Found 286.1224.

[0089] Example 16:

[0090]

[0091] In a nitrogen-filled glove box, KHCO3 (36.1 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2i (240.8 mg, 0.6 mmol) were added sequentially to a 4 mL sample vial. After capping, the vial was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with dichloromethane:methanol = 70:1 as the eluent, yielding 57.2 mg of a white solid, with a yield of 60%. 1 H NMR (400MHz, CDCl3): δ8.74 (d, J=8.4Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.72-7.68 ( m, 2H), 7.56 (t, J=7.2Hz, 1H), 7.51 (d, J=8.8Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.29 ( t, J=7.2Hz, 2H), 7.19 (t, J=7.2Hz, 1H), 5.07 (s, 1H), 4.13-4.07 (m, 2H), 2.74-2. 71(m, 2H), 2.45-2.38(m, 1H), 1.59-1.58(m, 2H), 1.43(s, 9H), 1.34-1.27(m, 2H). 13CNMR (100MHz, CDCl3): δ154.6, 149.2, 141.7, 139.1, 130.3, 128.8, 128.7, 128.6, 128.1, 127.8, 127.0, 125.0, 120.2, 120.1, 79.3, 49.6, 43.2, 38.8, 30.4, 28.3.IR (neat): 3058, 3024, 2920, 2847, 1683, 1426, 1364, 1166, 1123, 807, 769, 748, 732, 697cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 26 H 31 N2O3419.2329;Found 419.2332.

[0092] Example 17:

[0093]

[0094] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1i (66.4 mg, 0.3 mmol), and 2d (130.9 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. The reaction solution was then filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with petroleum ether:ethyl acetate (7:1) as the eluent. The product was a pale yellow oil, 28.8 mg, with a yield of 32%. 1 H NMR (400MHz, CDCl3): δ8.16 (d, J=8.4Hz, 1H), 7.85 (dd, J1=8.6Hz, J2=1.2Hz, 1H), 7.69 (ddd, J1=8.6Hz, J2=7.0Hz, J3 =1.2Hz, 1H), 7.46-7.40(m, 6H), 7.35-7.33(m, 2H), 7.30-7.26(m, 2H), 7.22-7.20(m, 1H), 7.17(s, 1H), 4.37(s, 2H). 13 C NMR (100MHz, CDCl3): δ160.7, 148.8, 148.3, 139.2, 138.1, 129.5, 129.4, 12 9.3, 129.2, 128.6, 128.4, 128.3, 126.4, 126.0, 125.6, 125.3, 121.6, 45.6.

[0095] Example 18:

[0096]

[0097] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2j (184.9 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with dichloromethane:methanol = 100:1 as the eluent, yielding 70.1 mg of a white solid, with a yield of 72%. 1 H NMR (400MHz, CDCl3): δ8.76 (d, J=8.8Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.73-7.69 (m, 1 H), 7.64 (d, J=8.8Hz, 1H), 7.56 (t, J=7.2Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 7.36 (d, J=7 .2Hz, 2H), 7.27 (t, J=7.2Hz, 2H), 7.23-7.16 (m, 5H), 7.12-7.09 (m, 1H), 5.56 (t, J=8 .4Hz, 1H), 3.57 (dd, J1=14.0Hz, J2=7.2Hz, 1H), 3.37 (dd, J1=13.8Hz, J2=8.8Hz, 1H). 13 C NMR (100MHz, CDCl3): δ150.4, 141.7, 140.0, 139.0, 130.3, 128.9, 128.8, 128.7, 128.5, 128.2, 128.0, 127.9, 126.9, 126.2, 1 25.0, 120.6, 119.9, 46.0, 38.7.IR (neat): 2917, 2849, 1454, 1356, 1345, 1283, 1244, 1071, 811, 787, 765, 749, 728, 695, 675cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 20 NO 326.1539; Found 326.1542.

[0098] Example 19:

[0099]

[0100] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2k (176.8 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with dichloromethane:methanol = 70:1 as the eluent, yielding 28.1 mg of a pale yellow oil, in 30% yield. 1 H NMR (400MHz, CDCl3): δ8.77 (d, J=8.8Hz, 1H), 7.81 (d, J=7.6Hz, 1H), 7.75 (dd d, J1=8.8Hz, J2=7.2Hz, J3=1.2Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.62-7.58 (m, 1 H), 7.42-7.40 (m, 2H), 7.35-7.32 (m, 3H), 7.26-7.23 (m, 1H), 5.25 (dd, J1=8. 6Hz, J2=6.4Hz, 1H), 3.62-3.58(m, 2H), 2.38-2.24(m, 2H), 1.91-1.84(m, 2H). 13 C NMR (100MHz, CDCl3): δ150.9, 141.6, 140.2, 130.5, 128.9, 128.8, 128.6, 128.1, 127.9, 127.1, 125.4, 120.2, 120.0, 44 .9, 43.7, 30.7, 30.2.IR (neat): 2975, 2925, 1720, 1643, 1598, 1494, 1453, 1385, 1234, 1087, 1046, 879, 834, 756, 702cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 19 NOCl 312.1150; Found312.1155.

[0101] Example 20:

[0102]

[0103] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2l (188.6 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with petroleum ether:ethyl acetate = 2:1 as the eluent, yielding 69.8 mg of a white solid, with a yield of 70%. 1 H NMR (400MHz, CDCl3): δ8.78 (d, J=8.4Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.70 (ddd, J1= 8.6Hz, J2=7.4Hz, J3=1.2Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.56-7.52 (m, 1H), 7.41-7. 39(m, 2H), 7.33-7.29(m, 3H), 7.23-7.19(m, 1H), 5.40(t, J=8.8Hz, 1H), 2.05-1.93( m, 3H), 1.76-1.58 (m, 4H), 1.12-1.09 (m, 1H), 1.06-1.02 (m, 3H), 0.99-0.98 (m, 2H). 13 C NMR (100MHz, CDCl3): δ151.5, 141.6, 141.1, 130.2, 128.7, 128.5, 127.79, 127.78, 126.7, 124.9, 120.4, 120.0, 41.3, 40.5, 35 .1, 33.7, 32.7, 26.4, 26.1, 26.0.IR (neat): 2928, 2915, 2852, 2831, 1355, 1340, 1243, 816, 796, 766, 746, 735, 725, 697, 675cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 26 NO 332.2009; Found 332.2004.

[0104] Example 21:

[0105]

[0106] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial.t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2m (201.8 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 5:1 as the eluent, yielding 68.8 mg of a white solid in 65% yield. 1 H NMR (400MHz, CDCl3): δ8.76 (d, J=8.8Hz, 1H), 7.74 (d, J=7.6Hz, 1H), 7.68 (t, J=7.2Hz, 1H), 7.58 (d, J=8.8Hz, 1H), 7.52 (t, J=7.2Hz, 1H), 7. 29 (t, J=7.6Hz, 2H), 7.27-7.20 (m, 4H), 7.18-7.11 (m, 3H), 5.26 (t, J=8.4Hz, 1H), 2.75-2.62 (m, 2H), 2.23-2.10 (m, 2H), 1.77-1.68 (m, 2H). 13 C NMR (100MHz, CDCl3): δ151.1, 141.9, 141.5, 140.7, 130.2, 128.7, 128.51, 128.45, 128.3, 128.2, 127.84, 127.76, 126.8, 125.6, 125. 0, 120.2, 119.9, 44.1, 35.5, 32.3, 29.2.IR (neat): 3066, 3027, 3003, 2933, 2860, 1558, 1352, 1238, 827, 819, 770, 747, 730, 700, 673cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 24 NO 354.1852; Found 354.1853.

[0107] Example 22:

[0108]

[0109] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. tBu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2n (195.7 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 5:1 as the eluent, yielding 60.4 mg of a colorless liquid, with a yield of 59%. 1 H NMR (400MHz, CDCl3): δ8.76 (d, J=8.8Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.55 (t, J=8.0Hz, 1H), 7.37-7.34 (m, 3H), 7.27 (t, J =7.2Hz, 2H), 7.21-7.15 (m, 3H), 6.86 (t, J = 8.4Hz, 2H), 5.50 (dd, J1 = 8.8Hz, J2 = 6.8 Hz, 1H), 3.55 (dd, J1=14.0Hz, J2=6.4Hz, 1H), 3.31 (dd, J1=14.0Hz, J2=9.2Hz, 1H). 13 C NMR (100MHz, CDCl3): δ161.3(d, 1 J C-F =242.7Hz), 150.3, 141.6, 139.6, 134.7(d, 4 J C-F =3.1Hz), 130.4, 130.2(d, 3 J C-F =7.6Hz), 128.8, 128.7, 128.5, 128.0, 127.9, 127.0, 125.0, 120.5, 119.8, 115.0 (d, 2 J C-F =21.2Hz), 46.3, 37.7. 19 FNMR (376MHz, CDCl3): δ-116.8.IR (neat): 3032, 3001, 2925, 2863, 1507, 1354, 1242, 1218, 821, 802, 768, 749, 723, 699, 675cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 19NOF344.1445; Found 344.1442.

[0110] Example 23:

[0111]

[0112] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2o (180.2 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with petroleum ether:ethyl acetate (eluent: 2:1) to give 57.5 mg of a white solid, yield 60%. 1 H NMR (400MHz, CDCl3): δ8.76 (d, J=8.8Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.70 (t, J=8.0Hz, 1H), 7. 64 (d, J=8.8Hz, 1H), 7.55 (t, J=7.2Hz, 1H), 7.40 (d, J=7.2Hz, 2H), 7.34-7.29 (m, 3H), 7.21 (t, J=7.2Hz, 1H), 5.81-5.71 (m, 1H), 5.22 (dd, J1=8.4Hz, J2=7.2Hz, 1H), 4.96 (dd, J1=17.4Hz, J2 =1.6Hz, 1H), 4.90 (d, J = 10.0Hz, 1H), 2.20-2.08 (m, 2H), 2.05-2.02 (m, 2H), 1.50-1.38 (m, 4H). 13 C NMR (100MHz, CDCl3): δ151.3, 141.6, 140.9, 138.7, 130.2, 128.7, 128.5, 128.49, 127.9, 127.8, 126.8, 125.1, 120.2, 120.0, 1 14.3, 44.2, 33.4, 32.8, 28.7, 27.1.IR (neat): 2925, 2855, 1561, 1356, 1346, 1244, 903, 828, 805, 796, 771, 746, 732, 697, 678cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 22 H24 NO 318.1852; Found 318.1847.

[0113] Example 24:

[0114]

[0115] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2p (181.3 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel plate chromatography with petroleum ether:ethyl acetate (2:1) as the eluent to give 39.8 mg of a pale yellow oil, with a yield of 42%. 1 H NMR (400MHz, CDCl3): δ8.11 (d, J=8.4Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 7.72 (d , J=8.0Hz, 1H), 7.68 (t, J=7.2Hz, 1H), 7.46 (t, J=8.0Hz, 3H), 7.32 (d, J=8.4H z, 1H), 7.27 (t, J=7.6Hz, 2H), 7.16 (t, J=7.6Hz, 1H), 3.95-3.88 (m, 3H), 3.42 (t, J=11.6Hz, 2H), 2.79-2.75(m, 1H), 1.51-1.42(m, 2H), 1.38-1.33(m, 2H). 13 C NMR (100MHz, CDCl3): δ162.5, 147.9, 141.5, 136.2, 129.3, 129.2, 128.6, 128.4, 127.4, 126.8, 126.6, 125.9, 121.8, 68.1, 6 7.9, 61.3, 38.8, 32.1, 31.7.IR (neat): 3061, 2946, 2915, 2842, 1596, 1503, 1135, 1090, 1017, 984, 876, 815, 751, 730, 700cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 22 NO 304.1696; Found 304.1692.

[0116] Example 25:

[0117]

[0118] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1j (73.6 mg, 0.3 mmol), and 2d (130.9 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate (2:1) as the eluent to give 71.3 mg of a white solid, with a yield of 71%. 1 H NMR (400MHz, CDCl3): δ8.70 (d, J=8.4Hz, 1H), 7.87 (s, 1H), 7.73 (d, J=7.6Hz, 1H), 7.67 (t, J=8.4Hz, 1H), 7.60 (d , J=7.2Hz, 2H), 7.56-7.52 (m, 3H), 7.38-7.37 (m, 3H), 7.27 (t, J=7.6Hz, 2H), 7.19 (t, J=7.2Hz, 1H), 4.78 (s, 2H). 13 C NMR (100MHz, CDCl3): δ148.3, 141.2, 136.7, 131.6, 130.7, 129.2, 129.1, 128.5, 128.4, 128.34, 128.30, 128.2, 127.7, 126.6, 122 .0, 119.9, 118.6, 95.3, 85.4, 35.4.IR (neat): 3076, 3061, 3024, 1490, 1347, 1330, 1281, 1224, 1072, 953, 848, 765, 749, 711, 686cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 18 NO 336.1383; Found 336.1379.

[0119] Example 26:

[0120]

[0121] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial.t Bu (67.3 mg, 0.6 mmol), THF (1.5 mL), 1k (47.8 mg, 0.3 mmol), 2d (130.9 mg, 0.6 mmol), and pyrrolidine (42.7 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at room temperature for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent. The crude product was then subjected to plate chromatography (eluent: petroleum ether:ethyl acetate = 1:1) to give 33.1 mg of a pale yellow solid, with a yield of 44%. 1 H NMR (400MHz, CDCl3): δ7.59 (d, J=7.2Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 7.43-7.3 5(m, 4H), 7.32-7.30(m, 3H), 6.90(d, J=8.8Hz, 1H), 4.38(s, 2H), 3.24(s, 3H). 13 C NMR (100MHz, CDCl3): δ149.3, 141.4, 136.8, 133.6, 133.3, 130.9, 129.8, 128.8, 127.3, 126.9, 126.8, 125.4, 121.5, 37.6, 25.3.

[0122] Example 27:

[0123]

[0124] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (67.3 mg, 0.6 mmol), THF (1.5 mL), 1 L (66.4 mg, 0.3 mmol), 2 D (130.9 mg, 0.6 mmol), and pyrrolidine (42.7 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at room temperature for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with dichloromethane:methanol = 100:1 as the eluent, yielding 43.4 mg of a white solid, with a yield of 46%. 1H NMR (400MHz, CDCl3): δ7.80 (dd, J1=7.8Hz, J2=1.2Hz, 1H), 7.59-7.54 (m, 2H), 7.52-7.5 0 (m, 1H), 7.42-7.34 (m, 7H), 7.26 (d, J=6.8Hz, 2H), 6.91 (d, J=8.8Hz, 1H), 4.32 (s, 2H). 13 C NMR (100MHz, CDCl3): δ149.4, 143.5, 139.0, 136.7, 136.1, 134.3, 130.4, 130.0, 128.8, 128.3, 127.9, 126.93, 126.87, 126. 7, 126.0, 124.8, 121.6, 37.4.IR (neat): 3076, 3050, 3019, 2923, 2849, 1492, 1362, 1245, 933, 832, 820, 758, 721, 697, 685cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 18 NO 312.1383; Found 312.1383.

[0125] Example 28:

[0126]

[0127] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2q (180.2 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate (2:1) as the eluent to give a white solid of 55.2 mg, yield 58%. 1H NMR (400MHz, CDCl3): δ8.75 (d, J=8.8Hz, 1H), 7.74 (d, J=8.0Hz, 1H), 7.69-7.64 (m, 2H), 7.54-7.50 (m, 2H), 7.46 (d, J=7.2Hz, 2H), 7.29-7.25 (m, 2H), 7.18-7.14(m, 1H), 5.09(d, J=11.6Hz, 1H), 2.27-2.19(m, 1H), 1.69-1.59( m, 5H), 1.27-1.20 (m, 3H), 1.14 (t, J=12.4Hz, 1H), 1.05 (t, J=11.6Hz, 1H). 13 C NMR (100MHz, CDCl3): δ150.5, 141.7, 140.1, 130.1, 128.9, 128.6, 128.4, 127.8, 127.7, 126.6, 125.0, 120.4, 120.2, 50.1, 40.4, 31.34, 31.31, 26.3, 26.09, 26.07.IR (neat): 3056, 3030, 2928, 2842, 1558, 1355, 1346, 1242, 807, 765, 746, 734, 729, 699, 678cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 24 NO 318.1852; Found 318.1847.

[0128] Example 29:

[0129]

[0130] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol), and 2r (163.3 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 3:1 as the eluent, yielding 19.9 mg of a pale yellow oil, with a yield of 23%. 1H NMR (400MHz, CDCl3): δ8.75 (d, J=8.4Hz, 1H), 7.79 (d, J=8.4Hz, 1H), 7.71-7.67 (m, 2H), 7.55 (t, J=8.0Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 7.34 (d, J=7.2Hz, 2H), 7.26 (t, J=7.6Hz, 2H), 7.16 (t, J=7.2Hz, 1H), 5.19 (d, J=11.6Hz, 1H), 3 .15-3.11(m, 1H), 2.10-2.04(m, 2H), 1.95-1.89(m, 3H), 1.77-1.72(m, 1H). 13 C NMR (100MHz, CDCl3): δ150.0, 141.8, 140.0, 130.1, 128.9, 128.4, 128.3, 127.9, 127.8, 126.6, 124.9, 120.3, 120.0, 50. 9, 38.7, 27.2, 26.8, 17.7.IR (neat): 2975, 2951, 2920, 2849, 1555, 1355, 1339, 1243, 810, 798, 764, 743, 730, 695, 675cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 20 NO 290.1539; Found 290.1535.

[0131] Example 30:

[0132]

[0133] In a nitrogen-filled glove box, KO gas was added sequentially to a 4 mL sample vial. t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1 m (66.4 mg, 0.3 mmol), and 2 d (130.9 mg, 0.6 mmol). After capping, the mixture was removed from the glove box and reacted at 50 °C for 3 h. Then, 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system, and the reaction was continued at room temperature for 1.5 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 5:1 as the eluent, yielding 69.1 mg of a pale yellow oil, with a yield of 74%. 1H NMR (400MHz, CDCl3): δ8.80 (d, J=8.8Hz, 1H), 7.84 (d, J=8.0Hz, 1H), 7.77-7.73 (m, 1H), 7.65-7.61 ( m, 2H), 7.44-7.42 (m, 3H), 7.32-7.30 (m, 2H), 7.20-7.14 (m, 3H), 7.07 (d, J=7.2Hz, 2H), 4.50 (s, 2H). 13 C NMR (100MHz, CDCl3): δ146.9, 140.8, 138.0, 137.4, 137.2, 130.0, 129.1, 128.4, 128.34, 128.30, 128.26, 128.23, 127.9, 12 6.1, 125.6, 120.0, 34.5.IR (neat): 3058, 3022, 1734, 1567, 1491, 1444, 1373, 1333, 1237, 1130, 1098, 1046, 772, 699, 663cm -1 HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 18 NO 312.1383; Found 312.1383.

[0134] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a 2-benzyl-substituted quinoline derivative, characterized in that... Includes the following steps: In the presence of a base, the benzylating reagent shown in Formula III and the quinoline oxynitride shown in Formula II are added to a solvent to carry out a coupling reaction as shown below, to obtain the C2-benzyl-substituted quinoline derivative shown in Formula I; ； In quinoline nitrogen oxides as shown in Formula II: n1 is selected from any integer between 0 and [M-1], where M represents the maximum number of substitutions on ring α; R1 may be the same or different, each independently selected from one or more of hydrogen, halogen, methyl, ethyl, propyl, isopropyl or tert-butyl, methoxy, ethoxy, propoxy or isopropoxy; The α ring is a nitrogen oxide of a bicyclic or tricyclic quinoline ring; In the benzylating reagents shown in Formula III: n2 is selected from any integer between 0 and 5; R2 may be the same or different, each independently selected from hydrogen atom, halogen, methyl, tert-butyl, wherein the halogen is fluorine, chlorine, bromine or iodine; R3 is selected from one or more of the following: hydrogen atom, C1-C2 straight-chain alkyl, C3-C6 straight-chain or branched alkyl, halogen-substituted C1-C2 straight-chain alkyl, halogen-substituted C3-C6 straight-chain or branched alkyl, C2 straight-chain unsaturated hydrocarbon group, and C3-C6 straight-chain or branched unsaturated hydrocarbon group. The alkali is an organic alkali or an inorganic alkali, and the organic alkali is... t One or more of BuOK, DMAP, and MTBD, wherein the inorganic base is t BuONa, LiO t One or more of Bu, NaOMe, K3PO4, Na2CO3, NaHCO3, KOMe, K2CO3 and KHCO3; The coupling reaction is carried out under the protection of an inert gas, which is one or more of nitrogen, helium, argon and neon. The molar ratio of the quinoline nitrogen oxide as shown in Formula II to the base is 1:0.1-1:10; The molar ratio of the quinoline nitride as shown in Formula II to the benzylating agent is 1:0.1-1:10; The solvent is one or more of aromatic solvents and ether solvents; the aromatic solvent is one or more of benzene, toluene, and xylene; the ether solvent is one or more of diethyl ether, 1,4-dioxane, and tetrahydrofuran. The molar volume ratio of the quinoline nitride as shown in Formula II to the solvent is 0.01 mmol / mL to 1.0 mmol / mL; The reaction time for the coupling reaction is 0.1-200 h; The reaction temperature of the coupling reaction is 0℃-100℃.

2. The preparation method according to claim 1, characterized in that: The reaction equations for the coupling reaction are shown in any of the following: 。 3. The preparation method according to claim 1, characterized in that: After the coupling reaction, 1,4-benzoquinone was added to the reaction system, and the reaction was continued at room temperature for 1-2 h, with the molar ratio of quinoline nitride to 1,4-benzoquinone as shown in Formula II being 1:1-1:3.

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