2-benzyl substituted quinoline derivative and preparation method thereof

Abstract

The invention 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: in the presence of alkali, adding a benzylation reagent as shown in a formula III and quinoline nitrogen oxide as shown in a formula II into a solvent, and carrying out a coupling reaction as shown in the specification to obtain the 2-position benzyl substituted quinoline derivative. The C2-position benzyl substituted quinoline derivative as shown in the formula I is obtained; the method realizes mild and efficient benzylation reaction of quinoline nitrogen oxide without transition metal participation, and has the advantages of easily available raw materials, mild conditions, efficient reaction, good functional group compatibility, good substrate universality and the like.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a 2-benzyl substituted quinoline derivative and a preparation method thereof. Background Art

[0002] As an important class of organic skeletons, nitrogen-containing heterocyclic compounds have been widely used in the synthesis of bioactive molecules, advanced materials and pesticide intermediates. In recent years, nitrogen-containing aromatic heterocyclic drugs are the most common drugs approved by the FDA. Among them, C2-alkylated quinoline and its derivatives have high medicinal value, especially antibacterial and antiviral activity. For example, quinoline C2-alkyl derivatives A and B can inhibit the transformation of HTLV-1 virus cells in the body; Flometoquin can be used to control pests that are resistant to existing insecticides; Bisacodyl is a stimulant laxative that mainly acts on the large intestine and is clinically used to treat acute and chronic constipation; Bepotastine is a second-generation histamine H1 receptor antagonist with selective and oral activity, which can be 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] Quinoline is a heterocyclic organic compound formed by the fusion of a benzene ring and a pyridine ring, and has certain special properties. When a nitrogen-containing heterocyclic ring is introduced into the drug skeleton structure, the drug can be improved in terms of its high selectivity to the target by changing its polarity, thereby achieving the goal of improving the physiological activity of the drug; it can also extend the duration of action of the drug and improve the availability of the drug in vivo by hydrogen bonding with the target protein or the amino acid at the active site; the introduction of large steric hindrance groups such as quinoline rings can also improve the metabolic stability of the drug. Quinoline derivatives can also be obtained by subsequent conversion reactions to obtain hydrogenated quinoline compounds with biological activity. Based on the special properties of quinoline compounds, efficient synthesis of quinoline derivatives is of great significance in drug development and structural modification. However, due to the large electronegativity of the nitrogen atom on the pyridine ring, the π electron cloud will transfer to the nitrogen atom, and the electron cloud density on the ring will decrease, so the aromaticity of the pyridine ring is weaker than that of the benzene ring. In summary, the electrophilic or nucleophilic aromatic substitution reaction of the pyridine ring is challenging. At present, the reactivity of quinoline compounds is mainly improved by introducing different substituents on the nitrogen atom. Among them, quinoline nitrogen oxide has the advantages of high reactivity, easy availability of raw materials, and subsequent transformation, and is widely used in the synthesis of quinoline derivatives.

[0005] Based on the unique advantages and important roles of quinoline derivatives, the synthesis of functionalized quinoline compounds has received extensive attention from organic chemists. In particular, the synthesis of 2-functionalized quinoline derivatives has been widely reported in recent years. The traditional method for synthesizing 2-functionalized substituted quinoline derivatives requires the use of an equivalent amount of metal reagents or activators (anhydrides or acyl chlorides), and such reactions often require higher temperatures. The harsh reaction conditions make the substrate universality of the reaction worse, and the regioselectivity and yield of the product are low. Therefore, the development of a mild and efficient quinoline 2-functionalization method is of great significance for biomedicine, advanced materials and other related fields.

[0006] Organic boron compounds have the advantages of stable chemical properties, special reaction properties, low toxicity, good functional group tolerance and the ability to undergo a variety of transformation reactions, making them more and more widely used in the field of organic synthesis. Boron is located in the second period of the periodic table, group IIIA, with three valence electrons in the outermost layer. The neutral boron atom has six valence electrons and an empty P orbital, making the boron atom relatively electron-deficient and Lewis acidic, and can accept external lone pairs of electrons to form complexes. The earliest synthesized organic diboron compound B 2 X 4 (X=F, Cl, Br, I) is sensitive to water and oxygen, and the preparation conditions are relatively harsh, which greatly limits its application in organic synthesis methodology. With the increasingly in-depth research on organoboron chemistry, organic chemists have discovered a variety of more stable organic diboron molecules that are insensitive to water and oxygen. Among them, organic borate ester compounds are easy to prepare and have stable chemical properties, which is a research hotspot for organic researchers. At present, commonly used organic diboron reagents include: B with symmetrical structure 2 pin 2 , B 2 neop 2 , B 2 dmpd 2 , B 2 dmp 2 , B 2 cat 2 and asymmetric structures of BpinBdan and BpinB(Mes) 2 Organoboron reagents can be used as functional group transfer reagents to achieve structural modification of various skeleton fragments, and can also directly introduce boron-containing groups into active molecules, thereby obtaining a series of active molecular analogs through various transformation reactions. Therefore, the application of organoboron compounds in methodological research is of great significance for the mild and efficient synthesis of complex drug structure fragments.

[0007] Transition metal-catalyzed cross-coupling reactions are a powerful means of constructing CC bonds. Traditional synthesis methods require precious metal catalysts or highly toxic organotin reagents to participate in the reaction, which is not in line with the development concept of green chemistry.

[0008] The C2-alkylation reaction of nitrogen-containing heterocycles often requires the use of transition metal catalysis in the work reported in the literature. The existing literature on the 2-alkylation reaction of pyridine or quinoline nitrogen oxides has its own limitations, such as the need for equivalent metal reagents, pre-prepared reagents, strong oxidants or expensive metal catalysts, and the reaction requires higher temperatures and longer times. We need to further enrich the methods for the C2-alkylation of quinoline nitrogen oxides.

[0009] According to literature research, we found that heterocyclic compounds have higher reactivity when modified into nitrogen oxides. Traditional functionalization reactions at the C2 position of heterocyclic nitrogen oxides require the participation of transition metals and harsh reaction conditions. At present, the development of C2-position alkylation reactions of heterocyclic nitrogen oxides is relatively limited. Although alkyl nucleophiles have high activity, their stability is poor and they are easy to decompose. Based on existing research, we found that organic borate compounds are mild and stable nucleophiles. Among them, the CC bond coupling reaction of aromatic borate compounds under transition metal catalysis has made good progress, but due to the above reasons, the reactions involving alkyl borate compounds are still very limited. We found that alkyl borate compounds can form a 4-coordinated organic boron complex under the activation of oxygen-containing reagents or nitrogen-containing reagents. The complex has high reactivity and is expected to achieve C2-position alkylation reactions of heterocyclic nitrogen oxides without the participation of transition metals. A simple and efficient method can be developed to achieve the alkylation reaction of nitrogen-containing heterocyclic compounds. Since transition metal catalysis is often prone to leaving toxic transition metal residues, tedious post-processing and purification steps are required 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] The present invention provides a 2-benzyl substituted quinoline derivative and a preparation method thereof. The scheme proposed in the present invention does not require the use of transition metals and is more green, environmentally friendly, simple and efficient. It will provide a more effective method for the diversified synthesis of heterocyclic skeletons such as pyridine or quinoline with potential medicinal value; and realizes a mild and efficient benzylation reaction of quinoline nitrogen oxide without the participation of transition metals.

[0011] To achieve the above-mentioned object of the invention, the present invention provides a method for preparing a 2-benzyl-substituted quinoline derivative, which is characterized by comprising the following steps: in the presence of a base, adding a benzylation agent represented by formula III and a quinoline nitrogen oxide represented by formula II to a solvent, and performing a coupling reaction as shown below to obtain a C2-benzyl-substituted quinoline derivative represented by formula I;

[0012]

[0013] In the quinoline nitrogen oxide shown in formula II:

[0014] n 1 Any integer selected from 0-[M-1], where M represents the maximum number of substitutions on ring α;

[0015] R 1 are the same or different, and are independently selected from one or more of a hydrogen atom, a halogen, a C1-C4 straight chain or branched chain alkyl group, a C1-C4 straight chain or branched chain alkoxy group, a carbocyclic ring, an aryl group, and an unsaturated aryl group;

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

[0017] In the benzylation reagent shown in Formula III:

[0018] n 2 Any integer selected from 0-5;

[0019] R 2 are the same or different, and are independently selected from one or more of a hydrogen atom, a halogen, and a C1-C6 straight or branched alkyl group;

[0020] R3 is selected from one or more of a hydrogen atom, a C1-C6 straight chain or branched alkyl group, a halogen-substituted C1-C6 straight chain or branched alkyl group, a C1-C6 straight chain or branched unsaturated hydrocarbon group, a carbocycle, a carboheterocycle, an aryl group and a halogen-substituted aryl group.

[0021] Among them, n 1 and n 2 is 0, 1, or 2;

[0022] and / or, when R 1 , R 2 When any of is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine;

[0023] and / or, when R 1 , R 2 When any one of is a C1-C6 straight chain or branched chain alkyl group, the C1-C6 straight chain or branched chain alkyl group is a C1-C4 straight chain or branched chain alkyl group, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group;

[0024] and / or, when R 1 Any one of them is a C1-C6 straight chain or branched alkoxy group, wherein the C1-C6 straight chain or branched alkoxy group is preferably a C1-C3 straight chain or branched alkoxy group, preferably a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group;

[0025] and / or, when R 1 When any of is a carbocyclic ring, the carbocyclic ring is selected from a 3-10-membered ring, preferably a benzene ring and a naphthalene ring;

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

[0027] And / or, when n 2 When R 2 is a hydrogen atom, a halogen, a methyl group, or a tert-butyl group, wherein the halogen is fluorine, chlorine, bromine, or iodine.

[0028] Wherein, the reaction equation of the coupling reaction is shown as any one of the following:

[0029]

[0030] Wherein, the base is an organic base or an inorganic base, and the organic base is t One or more of BuOK, DMAP and MTBD, the inorganic base is t BuONa、LiO t Bu, NaOMe, K 3 PO 4 、Na 2 CO 3 、NaHCO 3 ,KOMe,K 2 CO 3 and KHCO 3 One or more of .

[0031] Wherein, the coupling reaction is carried out under the protection of an inert gas, and the inert protective gas 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 nitrogen oxide represented by formula II to the benzylation agent is preferably 1:0.1-1:10, more preferably 1:0.5-1:2.0, and further preferably 1:1-1:2.0;

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

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

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

[0037] The reaction temperature of the coupling reaction may be 0°C-100°C, more preferably 0°C-50°C, and further preferably 50°C;

[0038] After the coupling reaction, 1,4-benzoquinone is added to the reaction system and the reaction is continued at room temperature for 1-2 hours, as shown in formula II, and the molar ratio of quinoline nitrogen oxide to 1,4-benzoquinone is 1:1-1:3.

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

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

[0041] The invention uses an O- or N-containing compound as an activating agent to activate an alkyl borate ester compound to form a free radical or a carbon anion intermediate, and the electrophilic iminium ion intermediate contained in the nitrogen-containing heterocyclic nitrogen oxide molecule is easily attacked by these active intermediates, thereby realizing a mild and efficient benzylation reaction of pyridine or quinoline nitrogen oxide.

[0042] The present invention uses a cheap reaction system to realize the preparation of 2-benzylquinoline or quinoline N-oxide substituted with various functional groups, and has the advantages of readily available raw materials, mild conditions, high reaction efficiency, good functional group compatibility and substrate universality, etc. The preparation method provides better application prospects and use value for realizing the industrial synthesis of C2-functionalized quinoline or quinoline N-oxide. DETAILED DESCRIPTION

[0043] The present invention provides the following embodiments for a better understanding of the present invention, but is not limited to the best implementation mode described, and does not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0044] Embodiment 1:

[0045]

[0046] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was petroleum ether: ethyl acetate = 1:1. The product was obtained as a white solid of 72.1 mg with a yield of 76%. 1 H NMR (400 MHz, CDCl 3 ): 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 (100 MHz, CDCl 3 ): 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] Embodiment 2:

[0048]

[0049] In a glove box filled with helium, KO and tBu (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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 60.2 mg of a light yellow oil with a yield of 79%. 1 H NMR (400 MHz, CDCl 3 ): 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 (100 MHz, CDCl 3 ): 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 (376 MHz, CDCl 3 ):δ-115.8.

[0050] Embodiment 3:

[0051]

[0052] In a glove box filled with helium, KO tBu (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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 59.8 mg of a light yellow oil with a yield of 80%. 1 H NMR (400 MHz, CDCl 3 ): 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), 7.5 8 (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 (100 MHz, CDCl 3 ): 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] Embodiment 4:

[0054]

[0055] In a glove box filled with argon, KO and t Bu (3.37 mg, 0.03 mmol), THF (30 mL), 1a (43.5 mg, 0.3 mmol) and 2d (459 mg, 3 mmol). After the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 60.0 mg of a light yellow oil with a yield of 85%. 1 H NMR (400 MHz, CDCl 3): δ8.80 (d, J=8.8Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 7.75 (t, J=7.2Hz, 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 (100 MHz, CDCl 3 ): 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] Embodiment 5:

[0057]

[0058] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was petroleum ether: ethyl acetate = 1:1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 6.07 mg of a light yellow oil with a yield of 64%. 1 H NMR (400 MHz, CDCl 3 ): δ8.67 (d, J=9.2Hz, 1H), 7.96 (d, J=2.0Hz, 1H), 7.79 (dd, J 1 =9.2Hz, J 2 =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 (100 MHz, CDCl 3 ): 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] Embodiment 6:

[0060]

[0061] In a glove box filled with nitrogen, 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 to a 4 mL sample bottle in sequence. After the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 29.4 mg of a light yellow oil with a yield of 78%. 1 H NMR (400 MHz, CDCl 3 ): 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=8.0 Hz, 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). 13 C NMR (100 MHz, CDCl 3 ): 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] Embodiment 7:

[0063]

[0064] In a glove box filled with neon, 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 to a 4 mL sample bottle in sequence. After the lid was closed, the glove box was removed and placed at 100 ° C for 1 h. After that, 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 48.7 mg of the product as a light yellow oil with a yield of 65%. 1 H NMR (400 MHz, CDCl 3 ): δ8.62 (s, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.42 (d, J = 8.0 Hz, 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 (100 MHz, CDCl 3 ): 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] Embodiment 8:

[0066]

[0067] In a glove box filled with nitrogen, add 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 the lid was closed, the glove box was removed and placed at 0°C for reaction 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 27.2 mg of a light yellow oil with a yield of 34%. 1 H NMR (400 MHz, CDCl 3): δ8.75 (d, J=7.2Hz, 1H), 7.97 (d, J=7.6Hz, 1H), 7.67-7.64 (m, 2H), 7.39-7.26 (m, 5H), 7.15 (dd, J 1 =8.8Hz, J 2 =2.0Hz, 1H), 4.46 (s, 2H). 13 CNMR (100MHz, CDCl 3 ): 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] Embodiment 9:

[0069]

[0070] In a glove box filled with nitrogen, LiO 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 the lid was closed, the glove box was removed and placed at 50°C for reaction 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 chromatographed on a silica gel plate. The eluent was petroleum ether: ethyl acetate = 1:1. The crude product was further chromatographed on a plate (eluent: dichloromethane: methanol = 100:1) to obtain 17.4 mg of a white solid product with a yield of 19%. 1 H NMR (400 MHz, CDCl 3 ): 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=8.4H z, 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 (100 MHz, CDCl 3 ): 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 JC-F =3.8Hz), 125.2, 124.1(q, 1 J C-F =270.3Hz), 121.9, 119.7, 37.3. 19 F NMR (376 MHz, CDCl 3 ): 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 NOF 3 304.0944; Found 304.0938.

[0071] Embodiment 10:

[0072]

[0073] In a glove box filled with nitrogen, NaOMe (19.4 mg, 0.36 mmol), ether (1.5 mL), 1a (43.5 mg, 0.3 mmol) and 2f (151.5 mg, 0.6 mmol) were added to a 4 mL sample bottle in sequence. The glove box was removed after the lid was closed and placed at 50 °C for 3 h. 1,4-benzoquinone (64.9 mg, 0.6 mmol) was added to the reaction system after the lid was opened 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 chromatographed on a silica gel plate (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 61.7 mg of the product as a light yellow oil with a yield of 76%. 1 H NMR (400 MHz, CDCl 3 ): 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 (100 MHz, CDCl 3 ): 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] Embodiment 11:

[0075]

[0076] In a glove box filled with nitrogen, K 3 PO4 (76.4 mg, 0.36 mmol), THF (1.5 mL), 1a (43.5 mg, 0.3 mmol) and 2g (160.9 mg, 0.6 mmol). After the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel plate. The eluent was dichloromethane: methanol = 70: 1. The crude product was further chromatographed on a plate (eluent: dichloromethane: methanol: petroleum ether = 100: 1: 20) to obtain a white solid product of 67.7 mg, with a yield of 79%. 1 H NMR (400 MHz, CDCl 3 ): 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 (100 MHz, CDCl 3 ): δ147.8, 141.4, 133.9, 132.6, 132.1, 130.3, 128.8, 128.7, 128.4, 128. 1, 127.9, 127.8, 126.4, 125.9, 125.6, 124.9, 124.0, 121.4, 119.6, 34.6.

[0077] Embodiment 12:

[0078]

[0079] In a glove box filled with nitrogen, Na 2 CO 3(38.2mg, 0.36mmol), THF (1.5mL), 1a (43.5mg, 0.3mmol) and 2h (139.3mg, 0.6mmol). After the lid was closed, the glove box was removed and placed at 50°C for reaction for 3h. Then, 1,4-benzoquinone (64.9mg, 0.6mmol) was added to the reaction system and the reaction was continued at room temperature for 1.5h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and chromatographed on a silica gel plate. The eluent was petroleum ether: ethyl acetate = 1:1. The crude product was further chromatographed on a plate (eluent: dichloromethane: methanol: petroleum ether = 100: 1: 20) to obtain 45.7mg of the product as a light yellow oil with a yield of 61%. 1 H NMR (400 MHz, CDCl 3 ): 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 (100 MHz, CDCl 3 ): 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] Embodiment 13:

[0081]

[0082] In a glove box filled with nitrogen, NaHCO 3 (30.2mg, 0.36mmol), THF (1.5mL), 1f (67.2mg, 0.3mmol) and 2d (130.9mg, 0.6mmol). After the lid was closed, the glove box was removed and placed at 50°C for reaction for 3h. Then, 1,4-benzoquinone (64.9mg, 0.6mmol) was added to the reaction system and the reaction was continued at room temperature for 1.5h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and chromatographed on a silica gel plate. The eluent was petroleum ether: ethyl acetate = 1:1. The crude product was further chromatographed on a plate (eluent: dichloromethane: methanol: petroleum ether = 100: 1: 20) to obtain a product of 69.6mg of a white solid with a yield of 74%. 1 H NMR (400 MHz, CDCl 3): 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 (100 MHz, CDCl 3 ): 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] Embodiment 14:

[0084]

[0085] In a glove box filled with nitrogen, KOMe (78.4 mg, 0.36 mmol), THF (1.5 mL), 1g (62.9 mg, 0.3 mmol) and 2d (130.9 mg, 0.6 mmol) were added to a 4 mL sample bottle in sequence. After the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel plate. The eluent was dichloromethane: methanol = 70:1. The crude product was further chromatographed on a plate (eluent: n-pentane: ethyl acetate = 1:1) to obtain a white solid product of 76.8 mg, with a yield of 85%. 1 H NMR (400 MHz, CDCl 3 ): 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). 13 CNMR (100MHz, CDCl 3): δ162.4, 148.7, 143.4, 135.9, 129.6, 128.9, 127.1, 126.3, 121.6, 121.5, 119.2, 98.7, 56.0, 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 NO 2 Cl 300.0786; Found 300.0779.

[0086] Embodiment 15:

[0087]

[0088] In a glove box filled with nitrogen, K 2 CO 3 (49.8mg, 0.36mmol), THF (1.5mL), 1h (58.6mg, 0.3mmol) and 2d (130.9mg, 0.6mmol). After the lid was closed, the glove box was removed and placed at 50°C for reaction for 3h. Then, 1,4-benzoquinone (64.9mg, 0.6mmol) was added to the reaction system and the reaction was continued at room temperature for 1.5h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and chromatographed on a silica gel plate with an eluent of dichloromethane: methanol = 100:1. The crude product was further chromatographed on a plate (eluent: n-pentane: ethyl acetate = 1:1) to obtain a white solid product of 45.4mg with a yield of 53%. 1 H NMR (400 MHz, CDCl 3 ): δ8.98 (d, J=8.4Hz, 1H), 8.51 (t, J=9.2Hz, 2H), 8.05 (d, J=8.0Hz, 1H), 7.76 (dt, J 1 =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). 13 C NMR (100 MHz, CDCl 3): 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] Embodiment 16:

[0090]

[0091] In a glove box filled with nitrogen, KHCO 3 (36.1mg, 0.36mmol), THF (1.5mL), 1a (43.5mg, 0.3mmol) and 2i (240.8mg, 0.6mmol). After the lid was closed, the glove box was removed and placed at 50°C for reaction for 3h. Then, 1,4-benzoquinone (64.9mg, 0.6mmol) was added to the reaction system and the reaction was continued at room temperature for 1.5h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and chromatographed on a silica gel column with an eluent of dichloromethane: methanol = 70:1 to obtain 57.2mg of the product as a white solid with a yield of 60%. 1 H NMR (400 MHz, CDCl 3 ): 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=7.2H z, 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). 13 CNMR (100MHz, CDCl 3): 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 N 2 O 3 419.2329; Found 419.2332.

[0092] Embodiment 17:

[0093]

[0094] In a glove box filled with nitrogen, KO and 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 the lid was closed, the mixture was removed from the glove box and placed at 50°C for reaction for 3 h. The reaction solution was filtered through a short silica gel column, washed with EA, concentrated, and chromatographed on a silica gel plate (eluent: petroleum ether: ethyl acetate = 7:1) to obtain 28.8 mg of the product as a light yellow oil with a yield of 32%. 1 H NMR (400 MHz, CDCl 3 ): δ8.16(d, J=8.4Hz, 1H), 7.85(dd, J 1 =8.6Hz, J 2 =1.2 Hz, 1H), 7.69 (ddd, J 1 =8.6Hz, J 2 =7.0Hz, J 3 =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 (100 MHz, CDCl 3): δ160.7, 148.8, 148.3, 139.2, 138.1, 129.5, 129.4, 129.3, 129.2, 128.6, 128.4, 128.3, 126.4, 126.0, 125.6, 125.3, 121.6, 45.6.

[0095] Embodiment 18:

[0096]

[0097] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel plate. The eluent was dichloromethane: methanol = 100: 1. The product was obtained as a white solid of 70.1 mg with a yield of 72%. 1 H NMR (400 MHz, CDCl 3 ): δ8.76 (d, J=8.8Hz, 1H), 7.77 (d, J=8.4Hz, 1H), 7.73-7.69 (m, 1H), 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, J 1 =14.0Hz, J 2 =7.2 Hz, 1H), 3.37 (dd, J 1 =13.8Hz, J 2 =8.8 Hz, 1H). 13 C NMR (100 MHz, CDCl 3): 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, 125.0, 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] Embodiment 19:

[0099]

[0100] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel plate. The eluent was dichloromethane: methanol = 70: 1. The product was obtained as a light yellow oil of 28.1 mg, with a yield of 30%. 1 H NMR (400 MHz, CDCl 3 ): δ8.77 (d, J=8.8Hz, 1H), 7.81 (d, J=7.6Hz, 1H), 7.75 (ddd, J 1 =8.8Hz, J 2 =7.2Hz, J 3 =1.2Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.62-7.58 (m, 1H), 7.42-7.40 (m, 2H), 7.35-7.32 (m, 3H), 7.26-7.23 (m, 1H), 5.25 (dd, J 1 =8.6Hz, J 2 =6.4Hz, 1H), 3.62-3.58(m, 2H), 2.38-2.24(m, 2H), 1.91-1.84(m, 2H).13 C NMR (100 MHz, CDCl 3 ): 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] Embodiment 20:

[0102]

[0103] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel plate. The eluent was petroleum ether: ethyl acetate = 2:1. The product was obtained as a white solid of 69.8 mg with a yield of 70%. 1 H NMR (400 MHz, CDCl 3 ): δ8.78 (d, J=8.4Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.70 (ddd, J 1 =8.6Hz, J 2 =7.4Hz, J 3=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 (100 MHz, CDCl 3 ): 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] Embodiment 21:

[0105]

[0106] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was petroleum ether: ethyl acetate = 5:1. The product was obtained as a white solid of 68.8 mg with a yield of 65%. 1 H NMR (400 MHz, CDCl 3): 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 (100 MHz, CDCl 3 ): 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] Embodiment 22:

[0108]

[0109] In a glove box filled with nitrogen, KO and t Bu (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 the lid was closed, the glove box was removed and placed at 50 ° C for reaction 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 chromatographed on a silica gel column. The eluent was petroleum ether: ethyl acetate = 5:1. The product was obtained as a colorless liquid of 60.4 mg with a yield of 59%. 1 H NMR (400 MHz, CDCl 3δ 8.76 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.37 - 7.34 (m, 3H), 7.27 (t, J = 7.2 Hz, 2H), 7.21 - 7.15 (m, 3H), 6.86 (t, J = 8.4 Hz, 2H), 5.50 (dd, J 1 = 8.8 Hz, J 2 = 6.8 Hz, 1H), 3.55 (dd, J 1 = 14.0 Hz, J 2 = 6.4 Hz, 1H), 3.31 (dd, J 1 = 14.0 Hz, J 2 = 9.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ):δ 161.3 (d, 1 J C-F = 242.7 Hz), 150.3, 141.6, 139.6, 134.7 (d, 4 J C-F = 3.1 Hz), 130.4, 130.2 (d, 3 J C-F = 7.6 Hz), 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 = 21.2 Hz), 46.3, 37.7. 19 F NMR (376 MHz, CDCl 3 ):δ -116.8. IR (neat): 3032, 3001, 2925, 2863, 1507, 1354, 1242, 1218, 821, 802, 768, 749, 723, 699, 675 cm -1 . HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 19 NOF 344.1445; Found 344.1442.

[0110] Example 23:

[0111]

[0112] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for reaction 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 chromatographed on a silica gel column (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 57.5 mg of the product as a white solid with a yield of 60%. 1 H NMR (400 MHz, CDCl 3 ): 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, J 1 =8.4Hz, J 2 =7.2 Hz, 1H), 4.96 (dd, J 1 =17.4Hz, J 2 =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 (100 MHz, CDCl 3 ): 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, 114.3, 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 H 24 NO 318.1852; Found 318.1847.

[0113] Embodiment 24:

[0114]

[0115] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel plate (the eluent was petroleum ether: ethyl acetate = 2:1) to obtain 39.8 mg of the product as a light yellow oil with a yield of 42%. 1 H NMR (400 MHz, CDCl 3 ): 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=8.4Hz, 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 (100 MHz, CDCl 3 ): 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, 67.9, 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] Embodiment 25:

[0117]

[0118] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column (the eluent was petroleum ether: ethyl acetate = 2:1) to obtain the product as a white solid of 71.3 mg with a yield of 71%. 1 H NMR (400 MHz, CDCl 3 ): 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 (100 MHz, CDCl 3 ): 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] Embodiment 26:

[0120]

[0121] In a glove box filled with nitrogen, KO and tBu (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 the lid was closed, the glove box was removed and the mixture was allowed to react for 3 h at room temperature. 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The crude product was further chromatographed on a plate (eluent: petroleum ether: ethyl acetate = 1: 1) to obtain 33.1 mg of a light yellow solid product with a yield of 44%. 1 H NMR (400 MHz, CDCl 3 ): δ7.59 (d, J=7.2Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 7.43-7.35 (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 (100 MHz, CDCl 3 ): 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] Embodiment 27:

[0123]

[0124] In a glove box filled with nitrogen, KO and t Bu (67.3 mg, 0.6 mmol), THF (1.5 mL), 1l (66.4 mg, 0.3 mmol), 2d (130.9 mg, 0.6 mmol) and pyrrolidine (42.7 mg, 0.6 mmol). After the lid was closed, the glove box was removed and the mixture was allowed to react for 3 h at room temperature. 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 chromatographed on a silica gel column. The eluent was dichloromethane: methanol = 100: 1. The product was obtained as a white solid (43.4 mg) with a yield of 46%. 1 H NMR (400 MHz, CDCl 3 ): δ7.80(dd, J 1 =7.8Hz, J 2=1.2Hz, 1H), 7.59-7.54 (m, 2H), 7.52-7.50 (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 (100 MHz, CDCl 3 ): 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] Embodiment 28:

[0126]

[0127] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column (the eluent was petroleum ether: ethyl acetate = 2:1) to obtain the product as a white solid of 55.2 mg with a yield of 58%. 1 H NMR (400 MHz, CDCl 3): 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), 7.18-7.1 4 (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 (100 MHz, CDCl 3 ): 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] Embodiment 29:

[0129]

[0130] In a glove box filled with nitrogen, KO and 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 the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was petroleum ether: ethyl acetate = 3:1. The product was obtained as a light yellow oil of 19.9 mg with a yield of 23%. 1 H NMR (400 MHz, CDCl 3): 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 (100 MHz, CDCl 3 ): 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, 2 7.2, 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] Embodiment 30:

[0132]

[0133] In a glove box filled with nitrogen, KO and t Bu (40.4 mg, 0.36 mmol), THF (1.5 mL), 1m (66.4 mg, 0.3 mmol) and 2d (130.9 mg, 0.6 mmol). After the lid was closed, the glove box was removed and placed at 50 ° C for 3 h. After that, 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 chromatographed on a silica gel column. The eluent was petroleum ether: ethyl acetate = 5:1. The product was obtained as a light yellow oil of 69.1 mg with a yield of 74%. 1 H NMR (400 MHz, CDCl 3): 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 (100 MHz, CDCl 3 ): 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, 126.1, 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 is only 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 aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein with equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a 2-benzyl substituted quinoline derivative, characterized in that The following steps are involved: In the presence of a base, a benzylation agent represented by formula III and a quinoline nitrogen oxide represented by formula II are added to a solvent to carry out a coupling reaction as shown below to obtain a C2-position benzyl-substituted quinoline derivative represented by formula I; In the quinoline nitrogen oxide 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 are the same or different, and are independently selected from one or more of a hydrogen atom, a halogen, a C1-C4 straight chain or branched alkyl group, a C1-C4 straight chain or branched alkoxy group, a carbocyclic ring, an aryl group, and an unsaturated aryl group; Ring α is a nitrogen oxide of a bicyclic quinoline ring or a tricyclic quinoline ring; In the benzylation reagent shown in Formula III: n2 is selected from any integer between 0 and 5; R2 are the same or different, and are independently selected from one or more of a hydrogen atom, a halogen, and a C1-C6 straight or branched alkyl group; R3 is selected from one or more of a hydrogen atom, a C1-C6 straight chain or branched alkyl group, a halogen-substituted C1-C6 straight chain or branched alkyl group, a C1-C6 straight chain or branched unsaturated hydrocarbon group, a carbocycle, a carboheterocycle, an aryl group and a halogen-substituted aryl group.

2. The preparation method according to claim 1, characterized in that: n1 and n2 are 0, 1 or 2; and / or, when either R1 or R2 is a halogen, the halogen is preferably fluorine, chlorine, bromine or iodine; And / or, when either R1 or R2 is a C1-C6 straight chain or branched chain alkyl group, the C1-C6 straight chain or branched chain alkyl group is a C1-C4 straight chain or branched chain alkyl group; And / or, when any one of R1 is a C1-C6 straight chain or branched chain alkoxy group, the C1-C6 straight chain or branched chain alkoxy group is a C1-C3 straight chain or branched chain alkoxy group; and / or, when any of R1 is a carbocyclic ring, the carbocyclic ring is selected from a 3-10 membered ring; 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; And / or, when n2 is 1, R2 is a hydrogen atom, a halogen, a methyl group, or a tert-butyl group, and the halogen is fluorine, chlorine, bromine, or iodine.

3. The preparation method according to claim 1, characterized in that: The reaction equation of the coupling reaction is shown in any of the following:

4. The preparation method according to claim 1, characterized in that: The base is an organic base or an inorganic base. The organic base is t One or more of BuOK, DMAP and MTBD, the inorganic base is t BuONa、LiO t One or more of Bu, NaOMe, K3PO4, Na2CO3, NaHCO3, KOMe, K2CO3 and KHCO3.

5. The preparation method according to claim 1, characterized in that: The coupling reaction is carried out under the protection of an inert gas, wherein the inert protective gas 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 nitrogen oxide as shown in formula II to the benzylation agent is 1:0.1-1:10; The solvent is one or more of an aromatic hydrocarbon solvent and an ether solvent; the aromatic hydrocarbon 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 nitrogen oxide represented by formula II to the solvent is 0.01 mmol / mL-1.0 mmol / mL; The reaction time of the coupling reaction is 0.1-200h; The reaction temperature of the coupling reaction is 0°C-100°C.

6. The preparation method according to claim 1, characterized in that: After the coupling reaction, 1,4-benzoquinone is added to the reaction system and the reaction is continued at room temperature for 1-2 hours, as shown in formula II, and the molar ratio of quinoline nitrogen oxide to 1,4-benzoquinone is 1:1-1:

3.

7. A 2-benzyl substituted quinoline derivative prepared by the preparation method according to any one of claims 1 to 6.

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