Method for preparing a polysubstituted 1,2,3,4-tetrahydroquinoline

Abstract

The present invention provides a method for preparing polysubstituted 1,2,3,4-tetrahydroquinoline, which relates to the technical field of the synthesis of chemical intermediates for medicines and natural compounds. In the present invention, o-N-acylphenyl MBH carbonate and an unsaturated olefin are used as raw materials, and under the action of a Lewis base catalyst, a [4+2] cycloaddition reaction occurs in an organic solvent to generate a polysubstituted 1,2,3,4-tetrahydroquinoline compound. The diastereoselectivity and regioselectivity of the product are high. Without the need for a metal catalyst, the reaction product can be obtained in one step. The reaction conditions are mild, and it only needs to be stirred at room temperature in an organic solvent. The raw materials are easily available, the cost is low, the process is stable and the yield is high. The operation and post-treatment are simple. Moreover, the product can be prepared in gram scale and further derivatized and transformed, providing a reference for drug research and development.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of pharmaceutical and natural compound chemical intermediates, and particularly relates to a preparation method of polysubstituted 1,2,3,4-tetrahydroquinoline. Background Art

[0002] Tetrahydroquinoline and its derivatives are an important class of alkaloids, widely present in natural products and drug molecules, and are the active skeletons of many natural products and drug molecules (Chem. Rev., 2019, 119, 5057 - 5191). Tetrahydroquinoline compounds usually have good biological activities, such as antibacterial, anti-inflammatory, antitumor, antiviral, etc. (Chem. Sci., 2022, 13, 3674 - 3687). Due to the importance of tetrahydroquinoline compounds, their efficient synthesis remains one of the hotspots in organic synthesis (Angew. Chem., Int. Ed., 2022, DOI: 10.1002 / anie.202207829). Therefore, it is of great research significance and application value to develop more efficient methods to synthesize such compounds with diverse structures.

[0003] Through literature research, it is found that the methods for synthesizing tetrahydroquinoline include the following several:

[0004] Method (1): Synthesizing tetrahydroquinoline by intramolecular cyclization reaction. Using arylamine derivatives as starting materials, new chemical bonds are formed through intramolecular cyclization reactions, involving all possible chemical bonds on the dihydropyridine ring, such as N - C2, C2 - C3, C3 - C4, C4 - C4a, N - C8a, etc. For example, in Route (1), using cyanamide as a raw material, through the Lewis acid - promoted intramolecular aminocyanation reaction of alkenes, first, the C - C double bond undergoes an intramolecular nucleophilic attack on the N - sulfonylcyanamide activated by the Lewis acid, causing the N - CN bond to break, and then double - bond addition to prepare 2,2 - disubstituted tetrahydroquinoline (Angew. Chem., Int. Ed. 2014, 53, 5170 - 5174).

[0005]

[0006] Method (2): Synthesizing tetrahydroquinoline by intermolecular addition reaction. For example, in Route (2), using 2 - aminoacetophenone and 4 - chlorobenzaldehyde as raw materials, in the presence of L - proline, an intermolecular aza - Michael / intramolecular Michael addition tandem reaction occurs. After obtaining a tetrahydroquinolinone derivative, it is reduced to obtain a tetrahydroquinoline derivative (Tetrahedron Lett. 2012, 53, 2269 - 2272).

[0007]

[0008] Method (3): Synthesis of tetrahydroquinoline by Povarov reaction. Under acid catalysis, an N-arylimine is formed from an aromatic amine and an aldehyde, and a [4+2] cycloaddition reaction occurs between the N-arylimine and an electron-rich alkene, which is called the Povarov reaction. For example, in route (3), it was discovered by the Russian chemist L.S. Povarov in the 1960s (Curr. Org. Synth. 2016, 13, 157-175). This method has become the most commonly used method for synthesizing tetrahydroquinoline.

[0009]

[0010] Method (4): Synthesis of tetrahydroquinoline by rearrangement reaction. For example, in route (4), Sc(OTF)3 is used as a catalyst, and an α-alkyl-α-diazoester attacks an isatin substrate. An intermediate state is formed through a 1,2-aryl migration pathway, and then an enantioselective ring expansion occurs to obtain 2-quinolone compounds with a yield of up to 94% and an ee value of up to 99% (Angew. Chem., Int. Ed. 2012, 51, 8644-8647).

[0011]

[0012] Method (5): Synthesis of tetrahydroquinoline by hydrogenation of quinoline. Using various transition metal catalysts such as Ru, Co, Rh, Ir, Ni, Pd, Pt, and Au, selective hydrogenation of quinoline compounds can be achieved to prepare tetrahydroquinoline derivatives. In addition, organic catalysts and boron reagents have also been used in the regioselective hydrogenation reactions of quinoline and other related N-heterocycles. For example, in route (5), under mild conditions, using Hantzsch ester as a hydrogen source and Fe(OTF)2 as a catalyst, selective hydrogenation of quinoline derivatives is carried out to obtain tetrahydroquinoline derivatives. This condition has good tolerance for other functional groups, such as chlorine and nitro substituents, and has a high yield.

[0013]

[0014] In summary, although there are many methods for synthesizing tetrahydroquinoline and great progress has been made, due to the important physiological activities of tetrahydroquinoline compounds and their wide applications in drug research and development, it is of great significance to develop new methods for the concise and efficient synthesis of substituted tetrahydroquinoline. In particular, a method with low cost, green and efficient, high yield, and high selectivity for synthesizing substituted tetrahydroquinoline compounds is needed. Summary of the Invention

[0015] The object of the present invention is to provide a method for preparing polysubstituted 1,2,3,4-tetrahydroquinolines. In the present invention, o-N-acylphenyl MBH carbonate and an unsaturated olefin are used as raw materials, and a [4+2] cycloaddition reaction occurs in an organic solvent under the action of a Lewis base catalyst to generate a polysubstituted 1,2,3,4-tetrahydroquinoline compound.

[0016] In order to achieve the above object of the present invention, the following technical solution is specifically adopted:

[0017] A method for preparing a polysubstituted 1,2,3,4-tetrahydroquinoline shown in Formula 3, comprising the following steps:

[0018]

[0019] The MBH (Morita-Baylis-Hillman) carbonate compound shown in Formula 1, the olefin compound shown in Formula 2 and a Lewis base catalyst undergo an addition reaction in an organic solvent, and after separation and purification, a polysubstituted 1,2,3,4-tetrahydroquinoline compound shown in Formula 3 is obtained;

[0020] Wherein, in Formula 1, PG is selected from a Boc protecting group, an Ac protecting group, a Ts protecting group, a Cbz protecting group, an alkyl protecting group (such as methyl, ethyl), and a benzyl protecting group;

[0021] EWG is selected from an ester group (such as methyl ester, ethyl ester, tert-butyl ester), a cyano group, a ketone carbonyl group, a nitro group, and a sulfone group;

[0022] In Formula 2, R is selected from a substituted or unsubstituted C1-C6 straight-chain or branched-chain alkyl group, a substituted or unsubstituted C2-C6 straight-chain or branched-chain alkenyl group, a substituted or unsubstituted C6-C12 aryl group, a 5-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and a substituted or unsubstituted C3-C6 cyclic alkyl group; the substituents of the substituted group are selected from a cyano group, a nitro group, an amino group, a hydroxyl group, a mercapto group, a halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a C2-C6 alkenyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, a phenyl group, and a C1-C6 alkyl-substituted phenyl group;

[0023] R 1 is selected from an ester group, a Ts group, a Bz group, and a substituted or unsubstituted sulfone group; the substituents of the substituted group are selected from a cyano group, a nitro group, an amino group, a hydroxyl group, a mercapto group, a halogen, a phenyl group, a halogenated phenyl group, a C1-C6 straight-chain or branched-chain alkyl group, a C3-C6 cyclic alkyl group, and a C2-C6 straight-chain or branched-chain alkenyl group.

[0024] In some embodiments, in Formula 2, R is selected from substituted or unsubstituted C1-C6 straight-chain or branched alkyl, substituted or unsubstituted C6-C12 aryl, 5-10 membered heteroaryl containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur; the substituents of the substitution are selected from halogen, cyano, nitro, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy; R is further preferably methyl, ethyl, phenyl, naphthyl, furyl, thienyl, indolyl, substituted phenyl (i.e., R 3 、R 4 、R 5 、R 6 and R 7 each independently selected from H, F, Cl, Br, cyano, nitro, methyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy); R is particularly preferably methyl, phenyl, benzyl, naphthyl, thienyl, furyl (such as 1-naphthyl, 2-naphthyl, 2-furyl, 3-thienyl), m-dichlorophenyl, trifluoromethylphenyl, (o-, p-, m-) chlorophenyl, (o-, p-, m-) bromophenyl, p-fluorophenyl, p-tert-butylphenyl, p-methylphenyl, nitrophenyl, cyanophenyl, p-trifluoromethoxyphenyl, p-methoxyphenyl, etc.

[0025] In some embodiments, in Formula 2, R 1 is selected from ester group, Ts group, Bz group, phenylsulfonyl group, halophenylsulfonyl group.

[0026] In some embodiments, the Lewis base catalyst is selected from one of 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triphenylphosphine, tricyclohexylphosphine.

[0027] In some embodiments, the molar ratio of the MBH carbonate compound shown in Formula 1, the olefin compound shown in Formula 2, and the Lewis base catalyst is 1-2∶1-1.2∶0.1-0.5, preferably 1.2∶1∶0.2.

[0028] In some embodiments, the organic solvent is selected from at least one of acetonitrile, toluene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetone, diethyl ether, dioxane, xylene, benzene, dimethyl sulfoxide, and formamide, preferably one of dichloromethane, toluene, ethyl acetate, and tetrahydrofuran.

[0029] In some embodiments, the addition reaction conditions include: a temperature of 25 - 100 °C, preferably 25 °C (e.g., 20, 30, 40, 50, 60, 65, 70, 75, 80, 85, 90, 95, 100 °C), and / or a time of 1 - 24 h (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 18, 20, 24 h).

[0030] In some embodiments, the reaction product is separated and purified by column chromatography.

[0031] In some embodiments, the solvent used in the separation and purification process is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate can be 10∶1 to 5∶1.

[0032] Beneficial effects:

[0033] 1. The present invention uses a Lewis base to catalyze the [4+2] cycloaddition reaction of MBH carbonate with olefins, and the reaction mechanism is as follows:

[0034]

[0035] First, under the action of a Lewis base (LB) catalyst, MBH carbonate 1 leaves CO2 and tert-butoxy anion (t-BuO - ), then the tert-butoxy anion abstracts the hydrogen on N to generate an zwitterionic intermediate II; subsequently, intermediate II undergoes nucleophilic addition with olefin substrate 2 to form intermediate III, and finally intermediate III undergoes nucleophilic addition to complete intramolecular cyclization. With the departure of the Lewis base catalyst, a polysubstituted 1,2,3,4-tetrahydroquinoline product 3 is obtained.

[0036] 2. The beneficial effects of the present invention are that the diastereoselectivity and regioselectivity of the product are high, no metal catalyst is required, the reaction product can be obtained in one step, avoiding the process of multiple-step reactions. The reaction process is simple, the reaction conditions are very mild and only require stirring at room temperature in an organic solvent. The raw materials are easily available, the cost is low, the process is stable and the yield is high. The operation and post-treatment are simple, and the product can be obtained only by column chromatography separation after the reaction, which is conducive to the application of the inventive method in green industrial production (the purity is preliminarily determined by NMR to be at least over 98%, and dr > 99∶1). The product can be prepared in gram scale and further derivatized and transformed, providing a reference for drug research and development. Specific embodiments

[0037] The following examples are used to further illustrate the present invention. It should be noted that the following examples are provided for illustrative purposes only and do not constitute a limitation on the scope of protection required by the present invention.

[0038] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are all conventional raw materials, reagents, and methods in this field.

[0039] Example 1: Synthesis of Compound 3a

[0040] The synthetic route is as follows:

[0041]

[0042] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 28.3 mg (1.0 equiv) of alkene 2a, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3a (54.3 mg, 95% yield) is obtained; 1 HNMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.30 - 7.26 (m, 9H), 7.15 (t, J = 7.2 Hz, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 6.08 (s, 1H), 4.53 (s, 1H), 3.71 (s, 3H), 2.44 (s, 3H), 1.37 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl3) δ 166.2, 152.1, 146.8, 138.3, 137.0, 134.2, 132.5, 130.7, 129.8, 129.0, 128.79, 128.75, 128.7, 128.0, 126.5, 125.8, 116.4, 82.6, 74.7, 58.2, 52.4, 45.8, 28.1, 21.8 ppm. ESI-HRMS: C 32 H 32 N2O6S+H + 573.2054, found 573.2049.

[0043] Example 2: Synthesis of Compound 3b

[0044] The synthetic route is as follows:

[0045]

[0046] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 29.7 mg (1.0 equiv) of alkene 2b, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3b (55.1 mg, 94% yield), was obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 3H), 7.27 (d, J = 6.8 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.58 (s, 1H), 6.50 (s, 1H), 6.10 (s, 1H), 4.50 (s, 1H), 3.72 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.40 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.2, 152.1, 146.7, 138.5, 137.1, 135.4, 134.1, 132.5, 130.7, 129.81, 129.76, 129.0, 128.9, 128.8, 128.5, 126.6, 125.7, 116.5, 82.5, 74.8, 57.9, 52.4, 45.7, 28.1, 21.8, 21.3 ppm. ESI-HRMS: C 33 H 34 N2O6S + H + 587.2210, found 587.2202.

[0047] Example 3: Synthesis of compound 3c

[0048] The synthetic route is as follows:

[0049]

[0050] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 31.3 mg (1.0 equiv) of alkene 2c, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3c (55.4 mg, 92% yield), was obtained; 1HNMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.32 - 7.29 (m, 5H), 7.14 (t, J = 7.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 6.48 (s, 1H), 6.08 (s, 1H), 4.49 (s, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H), 1.39 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.2, 159.7, 152.1, 146.8, 137.0, 134.1, 132.5, 130.7, 130.5, 129.9, 129.8, 129.0, 128.82, 128.79, 126.6, 125.8, 116.5, 113.4, 82.5, 74.9, 57.7, 55.2, 52.4, 45.7, 28.1, 21.8 ppm. ESI-HRMS: C 33 H 34 N2O7S + H + 603.2159, found 603.2153.

[0051] Example 4: Synthesis of Compound 3d

[0052] The synthesis route is as follows:

[0053]

[0054] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 33.9 mg (1.0 equiv) of alkene 2d, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3d (58.4 mg, 93% yield) is obtained; 1 HNMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.17 (d, J = 5.2 Hz, 6H), 7.08 (t, J = 7.2 Hz, 1H), 6.48 (s, 1H), 6.33 (s, 1H), 5.97 (s, 1H), 4.56 (s, 1H), 3.66 (s, 3H), 2.35 (s, 3H), 1.30 (s, 9H), 1.19 (s, 9H) ppm.13 C NMR (100 MHz, CDCl3) δ 166.3, 152.2, 151.5, 146.5, 137.1, 134.9, 134.4, 132.7, 130.7, 129.9, 129.7, 129.0, 128.9, 128.7, 128.4, 126.6, 125.7, 124.9, 116.5, 82.5, 74.6, 58.0, 52.5, 45.7, 34.6, 31.3, 28.1, 21.8 ppm. ESI-HRMS: C 36 H 40 N2O6S + H + 629.2680, found 629.2675.

[0055] Example 5: Synthesis of Compound 3e

[0056] The synthesis route is as follows:

[0057]

[0058] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 30.1 mg (1.0 equiv) of alkene 2e, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask, stir the reaction at room temperature for 12 h, monitor the end point of the reaction by TLC, and obtain the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3e (55.5 mg, 94% yield) after column chromatography separation and purification; 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.39 - 7.35 (m, 3H), 7.31 (d, J = 8.0 Hz, 3H), 7.16 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 8.4 Hz, 2H), 6.55 (s, 1H), 6.50 (s, 1H), 6.05 (s, 1H), 4.48 (s, 1H), 3.72 (s, 3H), 2.46 (s, 3H), 1.39 (s, 9H) ppm. 1313C NMR (100 MHz, CDCl3) δ 166.1, 162.7 (d, J = 246.6 Hz), 152.0, 147.0, 136.7, 134.4 (d, J = 3.3 Hz), 134.1, 132.3, 130.6, 130.64, 130.57, 130.49, 129.9, 129.8, 129.1, 128.8 (d, J = 14.8 Hz), 126.6, 126.0, 116.3, 115.1 (d, J = 21.7 Hz), 82.8, 74.7, 57.4, 52.5, 45.7, 28.1, 21.8 ppm. ESI-HRMS: C 32 H 31 FN2O6S + H + 591.1960, found 591.1952.

[0059] Example 6: Synthesis of Compound 3f

[0060] The synthetic route is as follows:

[0061]

[0062] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 31.7 mg (1.0 equiv) of alkene 2f, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3f (57.6 mg, 95% yield) is obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 - 6.98 (m, 6H), 6.99 (d, J = 7.6 Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 6.28 (s, 1H), 6.20 (s, 1H), 5.76 (s, 1H), 4.21 (s, 1H), 3.45 (s, 3H), 2.20 (s, 3H), 1.12 (s, 9H) ppm. 1313C NMR (100 MHz, CDCl3) δ 166.1, 152.0, 147.1, 137.0, 136.7, 134.7, 134.0, 132.2, 130.6, 130.1, 129.9, 129.8, 129.1, 128.8, 128.7, 128.3, 126.6, 126.0, 116.3, 82.9, 74.6, 57.5, 52.5, 45.7, 28.1, 21.9 ppm. ESI-HRMS: C 32 H 31 ClN2O6S+H + 607.1664, found 607.1660.

[0063] Example 7: Synthesis of Compound 3g

[0064] The synthetic route is as follows:

[0065]

[0066] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 36.0 mg (1.0 equiv) of alkene 2g, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3g (59.2 mg, 91% yield) is obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.2 Hz, 2H), 7.38 - 7.32 (m, 3H), 7.25 (d, J = 4.0 Hz, 1H), 7.19 - 7.08 (m, 4H), 6.99 (s, 1H), 6.73 (s, 1H), 6.28 (s, 1H), 4.54 (s, 1H), 3.72 (s, 3H), 2.49 (s, 3H), 1.45 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.3, 152.4, 146.8, 137.9, 137.3, 133.8, 133.5, 132.3, 131.3, 131.1, 130.3, 129.9, 129.1, 128.65, 128.61, 128.2, 127.5, 126.0, 125.3, 124.9, 116.1, 83.1, 72.1, 56.3, 52.4, 44.8, 28.3, 21.9 ppm. ESI-HRMS: C 32 H 31 BrN2O6S+H+ 651.1159( 79 Br), 653.1138( 81 Br) found 651.1152, 653.1136.

[0067] Example 8: Synthesis of Compound 3h

[0068] The synthesis route is as follows:

[0069]

[0070] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 36.0 mg (1.0 equiv) of alkene 2h, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask, stir the reaction at room temperature for 12 h, monitor the end point of the reaction by TLC, and obtain the product polysubstituted 1,2,3,4-tetrahydroquinoline compound 3h (61.1 mg, 94% yield) after column chromatography separation and purification; 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.41 - 7.34 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.25 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.53 (s, 1H), 6.33 (s, 1H), 5.96 (s, 1H), 4.70 (s, 1H), 3.75 (s, 3H), 2.44 (s, 3H), 1.38 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.3, 152.0, 147.0, 140.3, 136.6, 134.4, 132.5, 132.4, 131.7, 130.7, 130.0, 129.8, 129.7, 129.2, 128.8, 128.6, 126.8, 126.5, 126.1, 121.6, 116.2, 82.9, 74.3, 57.8, 52.5, 45.6, 28.1, 21.9 ppm. ESI-HRMS: C 32 H 31 BrN2O6S + H + 651.1159( 79 Br), 653.1138( 81 Br) found 651.1151, 653.1133.

[0071] Example 9: Synthesis of Compound 3i

[0072] The synthetic route is as follows:

[0073]

[0074] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 36.0 mg (1.0 equiv) of alkene 2i, and the Lewis base catalyst DABCO (20 mol%) into the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3i (61.8 mg, 95% yield) is obtained; 1 HNMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.35 - 7.28 (m, 3H), 7.24 (d, J = 8.0 Hz, 3H), 7.18 (d, J = 7.6 Hz, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.48 (s, 1H), 6.38 (s, 1H), 5.95 (s, IH), 4.41 (s, 1H), 3.64 (s, 3H), 2.39 (s, 3H), 1.31 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl3) δ 166.1, 152.0, 147.1, 137.5, 136.7, 134.0, 132.2, 131.3, 130.6, 130.3, 129.9, 129.8, 129.1, 128.8, 128.7, 126.6, 126.0, 123.0, 116.3, 82.9, 74.5, 57.5, 52.5, 45.6, 28.1, 21.9 ppm. ESI-HRMS: C 32 H 31 BrN2O6S + H + 651.1159 ( 79 Br), 653.1138 ( 81 Br) found 651.1150, 653.1134.

[0075] Example 10: Synthesis of compound 3j

[0076] The synthetic route is as follows:

[0077]

[0078] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 35.1 mg (1.0 equiv) of alkene 2j, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3j (60.2 mg, 94% yield), was obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.61 - 7.53 (m, 5H), 7.42 (t, J = 7.6 Hz, 1H), 7.36 - 7.31 (m, 3H), 7.21 (t, J = 7.6 Hz, 1H), 6.59 (s, 1H), 6.54 (s, 1H), 6.04 (s, 1H), 4.55 (s, 1H), 3.75 (s, 3H), 2.48 (s, 3H), 1.40 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.1, 152.0, 147.2, 142.2, 136.6, 134.1, 132.1, 130.7 (q, J = 32.2 Hz), 130.6, 129.93, 129.89, 129.23, 129.19, 128.9, 128.8, 126.6, 126.2, 125.0 (q, J = 3.6 Hz), 123.9 (q, J = 270.5 Hz), 116.2, 83.0, 74.3, 57.6, 52.5, 45.6, 28.1, 21.8 ppm. ESI-HRMS: C 33 H 31 F3N2O6S+H + 641.1928, found 641.1922.

[0079] Example 11: Synthesis of compound 3k

[0080] The synthesis route is as follows:

[0081]

[0082] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 27.3 mg (1.0 equiv) of alkene 2k, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3k (50.0 mg, 89% yield), was obtained; 1HNMR(400MHz, CDCl3) δ 7.85 (d, J = 8.4Hz, 2H), 7.54 (d, J = 8.0Hz, 1H), 7.34 - 7.29 (m, 4H), 7.17 - 7.13 (m, 2H), 6.55 (s, 1H), 6.51 (s, 1H), 6.18 - 6.15 (m, 2H), 5.93 (s, 1H), 4.98 (s, 1H), 3.76 (s, 3H), 2.44 (s, 3H), 1.46 (s, 9H) ppm. 13 C NMR(100MHz, CDCl3) δ 166.4, 152.1, 149.8, 146.6, 142.2, 136.4, 135.1, 132.6, 131.2, 130.0, 129.6, 128.7, 128.6, 126.3, 125.7, 116.1, 110.7, 109.6, 82.8, 72.1, 53.7, 52.5, 45.1, 28.1, 21.8 ppm. ESI - HRMS: C 30 H 30 N2O7S + H + 563.1846, found 563.1839.

[0083] Example 12: Synthesis of Compound 3l

[0084] The synthetic route is as follows:

[0085]

[0086] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 28.9 mg (1.0 equiv) of alkene 2l, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4 - tetrahydroquinoline compound 3l (53.8 mg, 93% yield) is obtained; 1 HNMR(400MHz, CDCl3) δ 7.73 (d, J = 8.0Hz, 2H), 7.50 (d, J = 8.0Hz, 1H), 7.29 - 7.19 (m, 5H), 7.11 - 7.06 (m, 2H), 6.89 (d, J = 4.4Hz, 1H), 6.55 (s, 1H), 6.49 (s, 1H), 5.97 (s, 1H), 4.56 (s, 1H), 3.65 (s, 3H), 2.38 (s, 3H), 1.35 (s, 9H) ppm. 1313C NMR (100 MHz, CDCl3) δ 166.3, 152.1, 146.8, 138.3, 136.7, 134.4, 132.5, 130.8, 129.8, 129.7, 129.6, 128.9, 127.0, 126.4, 125.8, 125.4, 125.2, 116.6, 82.6, 73.7, 54.5, 52.4, 45.4, 28.1, 21.8 ppm. ESI-HRMS: C 30 H 30 N2O6S2 + H + 579.1618, found 579.1613.

[0087] Example 13: Synthesis of Compound 3m

[0088] The synthetic route is as follows:

[0089]

[0090] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 33.3 mg (1.0 equiv) of alkene 2m, and the Lewis base catalyst DABCO (20 mol%) to a reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3m (58.5 mg, 94% yield) is obtained; 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 4H), 7.51 (t, J = 7.6 Hz, 1H), 7.42 - 7.32 (m, 5H), 7.20 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 6.68 (s, 1H), 6.26 (s, 1H), 4.70 (s, 1H), 3.75 (s, 3H), 2.38 (s, 3H), 1.26 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.3, 152.4, 146.5, 137.4, 135.2, 134.3, 133.4, 132.2, 131.2, 130.5, 129.64, 129.57, 129.5, 128.8, 128.8, 128.6, 126.9, 126.5, 126.3, 125.8, 124.8, 124.7, 116.7, 82.8, 74.9, 52.5, 45.9, 28.1, 21.8 ppm. ESI-HRMS: C36 H 34 N2O6S + H + 623.2210, found 623.2201.

[0091] Example 14: Synthesis of Compound 3n

[0092] The synthesis route is as follows:

[0093]

[0094] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 33.3 mg (1.0 equiv) of alkene 2n, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3n (57.8 mg, 93% yield), is obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.80 - 7.71 (m, 5H), 7.65 (d, J = 8.0 Hz, 1H), 7.48 - 7.37 (m, 5H), 7.21 (t, J = 7.2 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 7.6 Hz, 2H), 6.08 (s, 1H), 4.70 (s, 1H), 3.75 (s, 3H), 2.32 (s, 3H), 1.36 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.3, 152.2, 146.7, 137.1, 135.2, 134.5, 133.2, 132.54, 132.48, 130.6, 130.1, 129.7, 129.10, 129.07, 128.85, 128.81, 128.3, 127.9, 127.7, 126.7, 126.5, 126.2, 126.0, 125.3, 116.5, 82.7, 74.5, 58.5, 52.5, 45.8, 28.1, 21.7 ppm. ESI-HRMS: C 36 H 34 N2O6S + H + 623.2210, found 623.2203.

[0095] Example 15: Synthesis of Compound 3o

[0096] The synthesis route is as follows:

[0097]

[0098] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 26.3 mg (1.0 equiv) of alkene 2o, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3o (50.9 mg, 92% yield) was obtained; 1 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.62 (t, J = 7.6 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.64 (s, 1H), 5.68 (s, 1H), 5.26 (s, 1H), 5.02 (s, 1H), 3.87 (s, 3H), 1.52 (s, 9H), 0.77 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.6, 153.9, 138.7, 137.1, 135.4, 135.0, 133.2, 132.4, 131.2, 128.9, 128.5, 127.5, 126.2, 125.5, 119.0, 81.7, 67.3, 61.6, 52.5, 45.8, 38.0, 28.3, 27.9 ppm. ESI-HRMS: C 30 H 36 N2O6S+H + 553.2367, found 553.2358.

[0099] Example 16: Synthesis of compound 3p

[0100] The synthesis route is as follows:

[0101]

[0102] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 26.9 mg (1.0 equiv) of alkene 2p, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3p (52.5 mg, 94% yield) was obtained; 1HNMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.32 - 7.28 (m, 3H), 7.23 - 7.18 (m, 4H), 7.08 (t, J = 7.6 Hz, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 6.01 (s, 1H), 4.44 (s, 1H), 3.63 (s, 3H), 1.30 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl3) δ 166.1, 152.1, 138.2, 137.0, 135.5, 135.4, 134.2, 130.6, 129.7, 129.2, 129.1, 128.84, 128.80, 128.6, 128.1, 126.6, 125.9, 116.3, 82.7, 74.7, 58.1, 52.5, 45.7, 28.1 ppm. ESI-HRMS: C 31 H 30 N2O6S + H + 559.1897, found 559.1895.

[0103] Example 17: Synthesis of Compound 3q

[0104] The synthetic route is as follows:

[0105]

[0106] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 30.3 mg (1.0 equiv) of alkene 2q, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3q (56.2 mg, 95% yield) is obtained; 1 HNMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.41 - 7.34 (m, 4H), 7.29 - 7.26 (m, 3H), 7.18 (t, J = 7.6 Hz, 1H), 6.57 (s, 1H), 6.44 (s, 1H), 6.04 (s, 1H), 4.67 (s, 1H), 3.75 (s, 3H), 1.38 (s, 9H) ppm. 1313C NMR (100 MHz, CDCl3) δ 166.2, 152.1, 142.4, 137.8, 136.9, 134.4, 134.0, 132.1, 129.6, 129.5, 129.1, 129.0, 128.9, 128.7, 128.1, 126.6, 125.9, 116.2, 82.8, 74.7, 58.2, 52.6, 45.7, 28.1 ppm. ESI-HRMS: C 31 H 29 ClN2O6S + H + 593.1508, found 593.1499.

[0107] Example 18: Synthesis of Compound 3r

[0108] The synthetic route is as follows:

[0109]

[0110] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 23.3 mg (1.0 equiv) of alkene 2r, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3r (47.0 mg, 90% yield) is obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.45 - 7.40 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.21 - 7.11 (m, 6H), 6.48 (s, 1H), 6.00 (s, 1H), 5.44 (s, 1H), 4.97 (s, 1H), 3.41 (s, 3H), 1.21 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 192.4, 166.3, 153.0, 139.4, 137.9, 136.3, 134.1, 133.2, 131.1, 129.9, 129.1, 128.5, 128.2, 128.1, 128.0, 127.3, 126.5, 125.4, 119.0, 82.1, 61.5, 60.0, 51.9, 48.0, 27.9 ppm. ESI-HRMS: C 32 H 30 N2O5 + H +523.2227, found 523.2222.

[0111] Example 19: Synthesis of Compound 3s

[0112] The synthetic route is as follows:

[0113]

[0114] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 25.9 mg (1.0 equiv) of alkene 2s, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3s (49.9 mg, 91% yield), is obtained; 1 HNMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 15.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.39 - 7.32 (m, 4H), 7.24 - 7.18 (m, 7H), 6.45 (s, 1H), 5.94 (s, 1H), 5.43 (s, 1H), 4.75 (s, 1H), 3.65 (s, 3H), 1.25 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl3) δ 188.3, 166.4, 153.1, 147.4, 139.8, 138.0, 134.2, 133.8, 131.6, 130.5, 130.2, 129.2, 129.1, 129.0, 128.6, 128.4, 128.0, 127.1, 126.6, 125.5, 121.1, 119.0, 82.1, 62.9, 58.9, 52.2, 46.6, 28.0 ppm. ESI-HRMS: C 34 H 32 N2O5 + H + 549.2384, found 549.2379.

[0115] Example 20: Synthesis of Compound 3t

[0116] The synthetic route is as follows:

[0117]

[0118] Add 1 mL of CH2Cl2, 41.9 mg (1.2 equiv) of MBH carbonate 1b, 28.3 mg (1.0 equiv) of alkene 2a, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3t (48.3 mg, 94% yield), was obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 2H), 7.46 - 7.39 (m, 4H), 7.29 (d, J = 8.4 Hz, 7H), 6.94 (s, 1H), 6.57 (s, 1H), 6.07 (s, 1H), 4.51 (s, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 2.05 (s, 3H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 169.0, 165.9, 146.9, 137.8, 137.7, 133.6, 132.2, 131.3, 130.7, 129.8, 129.6, 129.0, 128.79, 128.77, 128.2, 127.5, 126.5, 116.4, 75.2, 57.3, 52.5, 46.6, 22.6, 21.8 ppm. ESI-HRMS: C 29 H 26 N2O5S+H + 515.1635, found 515.1627.

[0119] Example 21: Synthesis of compound 3u

[0120] The synthesis route is as follows:

[0121]

[0122] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 20.1 mg (1.0 equiv) of alkene 2u, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3u (39.2 mg, 80% yield), was obtained; 1HNMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.26 - 7.19 (m, 7H), 6.48 (s, 1H), 5.72 (s, 1H), 5.47 (s, 1H), 4.79 (s, 1H), 4.22 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 1.31 - 1.27 (m, 12H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.9, 165.6, 152.9, 139.1, 137.6, 134.6, 130.3, 130.0, 129.1, 128.6, 128.4, 128.3, 127.0, 126.5, 125.5, 116.8, 82.1, 64.0, 59.9, 57.8, 52.5, 46.7, 28.0, 13.7 ppm. ESI - HRMS: C 28 H 30 N2O6 + H + 491.2177, found 491.2176.

[0123] Example 22: Synthesis of Compound 3v

[0124] The synthetic route is as follows:

[0125]

[0126] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 21.5 mg (1.0 equiv) of alkene 2v, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4 - tetrahydroquinoline compound 3v (39.8 mg, 79% yield) is obtained; 1 HNMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.25 - 7.15 (m, 4H), 7.08 (d, J = 8.0 Hz, 2H), 6.47 (s, 1H), 5.70 (s, 1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.22 (q, J = 6.8 Hz, 2H), 3.80 (s, 3H), 2.30 (s, 3H), 1.31 - 1.28 (m, 12H) ppm. 1313C NMR (100 MHz, CDCl3) δ 166.8, 165.6, 152.9, 137.9, 137.6, 136.0, 134.6, 130.1, 130.0, 129.1, 129.0, 128.6, 126.9, 126.5, 125.5, 117.0, 82.0, 63.9, 59.7, 58.0, 52.4, 46.7, 28.0, 21.2, 13.7 ppm. ESI-HRMS: C 29 H 32 N2O6 + H + 505.2333, found 505.2330.

[0127] Example 23: Synthesis of Compound 3w

[0128] The synthetic route is as follows:

[0129]

[0130] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 21.9 mg (1.0 equiv) of alkene 2w, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the reaction endpoint by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3w (41.7 mg, 82% yield) is obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.29 - 7.20 (m, 4H), 6.99 (t, J = 8.4 Hz, 2H), 6.47 (s, 1H), 5.70 (s, 1H), 5.45 (s, 1H), 4.78 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 1.32 - 1.29 (m, 12H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.8, 165.5, 162.5 (d, J = 245.4 Hz), 152.8, 137.4, 135.0 (d, J = 3.0 Hz), 134.4, 130.3, 129.9, 129.1, 129.0, 128.9, 128.6, 126.5, 125.6, 116.7, 115.4 (d, J = 23.4 Hz), 82.3, 64.1, 59.2, 57.8, 52.5, 46.7, 28.0, 13.7 ppm. ESI-HRMS: C 28 H 29 FN2O6 + H+ 509.2082, found 509.2079.

[0131] Example 24: Synthesis of Compound 3x

[0132] The synthetic route is as follows:

[0133]

[0134] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 23.5 mg (1.0 equiv) of alkene 2x, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3x (42.4 mg, 81% yield), is obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.29 - 7.20 (m, 6H), 6.47 (s, 1H), 5.68 (s, 1H), 5.45 (s, 1H), 4.78 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.33 - 1.30 (m, 12H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.8, 165.4, 152.8, 137.7, 137.3, 134.4, 134.1, 130.3, 129.9, 129.2, 128.7, 128.6, 126.5, 125.7, 116.7, 82.4, 64.2, 59.3, 57.6, 52.5, 46.7, 28.0, 13.7 ppm. ESI-HRMS: C 28 H 29 ClN2O6 + H + 525.1787, found 525.1785.

[0135] Example 25: Synthesis of Compound 3y

[0136] The synthetic route is as follows:

[0137]

[0138] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 27.8 mg (1.0 equiv) of alkene 2y, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3y (46.6 mg, 82% yield), was obtained; 1 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 6.8 Hz, 1H), 7.41 (d, J = 5.6 Hz, 2H), 7.28 - 7.17 (m, 4H), 6.47 (s, 1H), 5.66 (s, 1H), 5.44 (s, 1H), 4.79 (s, 1H), 4.30 - 4.20 (m, 2H), 3.81 (s, 3H), 1.33 - 1.30 (m, 12H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 166.8, 165.4, 152.8, 141.5, 137.2, 134.5, 131.4, 130.5, 130.3, 130.1, 129.8, 129.2, 128.6, 126.5, 125.7, 125.6, 122.3, 116.5, 82.5, 64.2, 59.4, 57.5, 52.5, 46.7, 28.0, 13.8 ppm. ESI-HRMS: C 28 H 29 BrN2O6 + H + 569.1282 ( 79 Br), 571.1261 ( 81 Br) found 569.1277, 571.1259.

[0139] Example 26: Synthesis of compound 3z

[0140] The synthetic route is as follows:

[0141]

[0142] Add 1 mL of CH2Cl2, 48.8 mg (1.2 equiv) of MBH carbonate 1a, 27.8 mg (1.0 equiv) of alkene 2z, and the Lewis base catalyst DABCO (20 mol%) to the reaction flask. Stir the reaction at room temperature for 12 h. Monitor the end point of the reaction by TLC. After separation and purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3z (48.3 mg, 85% yield), was obtained; 1HNMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 1H), 7.48 - 7.42 (m, 3H), 7.23 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 5.67 (s, 1H), 5.45 (s, 1H), 4.78 (s, 1H), 4.23 (q, J = 6.8 Hz, 2H), 3.80 (s, 3H), 1.33 - 1.30 (m, 12H) ppm. 13 C NMR (100 MHz, CDCl3) δ 166.8, 165.4, 152.8, 138.2, 137.3, 134.4, 131.6, 130.3, 129.9, 129.2, 128.9, 128.6, 126.5, 125.7, 122.3, 116.6, 82.4, 64.2, 59.3, 57.6, 52.5, 46.7, 28.0, 13.7 ppm. ESI-HRMS: C 28 H 29 BrN2O6 + H + 569.1282 ( 79 Br), 571.1261 ( 81 Br) found 569.1278, 571.1257.

[0143] Example 27: Synthesis of Compound 3a under Different Conditions

[0144] To further verify the reaction conditions under different reactions, the following experiments were carried out:

[0145]

[0146] Reaction conditions:

[0147] (1) Using 1,2-dichloroethane (DCE) as the solvent (the other conditions are the same as in Example 1), the yield of product 3a was 87%.

[0148] (2) Using chloroform as the solvent (the other conditions are the same as in Example 1), the yield of product 3a was 90%.

[0149] (3) Using ethyl acetate as the solvent (the other conditions are the same as in Example 1), the yield of product 3a was 76%.

[0150] (4) Using acetonitrile as the solvent (the other conditions are the same as in Example 1), the yield of product 3a was 80%.

[0151] (5) Using dioxane as the solvent (the other conditions are the same as in Example 1), the yield of product 3a was 61%.

[0152] (6) Using tetrahydrofuran as the solvent (others are the same as in Example 1), the yield of product 3a was 58%.

[0153] (7) Using diethyl ether as the solvent (others are the same as in Example 1), the yield of product 3a was 48%.

[0154] (8) Using toluene as the solvent (others are the same as in Example 1), the yield of product 3a was 92%.

[0155] (9) Using 4-dimethylaminopyridine (DMAP) at 20 mol% as the catalyst (others are the same as in Example 1), the yield of product 3a was 91%.

[0156] (10) Using triethylamine (TEA) at 20 mol% as the catalyst (others are the same as in Example 1), the yield of product 3a was less than 5%.

[0157] (11) Using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 20 mol% as the catalyst (others are the same as in Example 1), the yield of product 3a was less than 56%.

[0158] Example 28: Gram-scale synthesis of compound 3a

[0159] The synthesis route is as follows:

[0160]

[0161] Add 10 mL of CH2Cl2, MBH carbonate 1a (0.977 g, 2.4 mmol, 1.2 equiv), alkene 2a (0.566 g, 2 mmol, 1.0 eq.), and the Lewis base catalyst DABCO (20 mol%) to the reaction flask (others are the same as in Example 1). After purification by column chromatography, the product, the polysubstituted 1,2,3,4-tetrahydroquinoline compound 3a (1.087 g, 95% yield, dr > 99:1), was obtained.

[0162] Example 29: Conversion of compound 3a to the polysubstituted dihydrophenanthridine compound 4

[0163] The synthesis route is as follows:

[0164]

[0165] Add 2 mL of CH3CN, 3a (0.2 mmol, 114.4 mg), and DBU (0.22 mmol, 32.8 μL) to the reaction flask. Stir at room temperature for 12 h and monitor the reaction endpoint by TLC. After the reaction stops, directly purify by column chromatography to obtain the polysubstituted dihydrophenanthridine compound 4 (80.1 mg, 88% yield). 11H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.26 - 7.18 (m, 6H), 7.06 - 7.00 (m, 3H), 6.69 (s, 1H), 4.62 (s, 2H), 3.81 (s, 3H), 1.57 (s, 9H) ppm. 13 13C NMR (100 MHz, CDCl3) δ 168.7, 147.0, 137.4, 136.2, 136.0, 134.5, 129.4, 128.9, 128.6, 128.1, 127.4, 126.8, 126.1, 125.4, 124.0, 116.6, 94.9, 82.3, 52.4, 28.4 ppm. ESI-HRMS: C 27 H 25 N3O4 + H + 456.1918, found 456.1914.

[0166] Example 30: Transformation of Compound 3a into Polycyclic Compound 6

[0167] The synthetic route is as follows:

[0168]

[0169] Add 2 mL of CH2Cl2, 3a (0.2 mmol, 114.4 mg), chloroaldehyde hydrazone 5 (0.22 mmol, 50.6 mg, 1.1 equiv), and Cs2CO3 (71.5 mg, 0.22 mmol, 1.1 eq.) to the reaction flask. Stir at room temperature for 1 h. Monitor the reaction endpoint by TLC. After the reaction stops, directly separate and purify by column chromatography to obtain the polysubstituted polycyclic compound 6 (138.1 mg, 90% yield with dr > 25:1). 1 1H NMR (400 MHz, CDCl3) δ 7.65 (t, J = 7.2 Hz, 3H), 7.58 (d, J = 8.0 Hz, 2H), 7.38 - 7.27 (m, 10H), 7.25 - 7.21 (m, 6H), 7.04 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 6.00 (s, 1H), 5.22 (s, 1H), 4.07 (d, J = 17.6 Hz, 1H), 3.89 (d, J = 17.6 Hz, 1H), 3.43 (s, 3H), 2.40 (s, 3H), 1.22 (s, 9H) ppm. 1313C NMR (100 MHz, CDCl3) δ 169.9, 152.3, 148.6, 146.6, 143.6, 137.9, 137.6, 134.0, 131.9, 130.4, 129.7, 129.5, 129.3, 129.0, 128.8, 128.7, 128.4, 127.9, 126.0, 125.8, 124.8, 124.2, 122.8, 120.0, 115.9, 82.6, 74.5, 61.4, 52.3, 47.0, 43.3, 27.8, 21.8 ppm. ESI-HRMS: C 45 H 42 N4O6S+H + 767.2898, found 767.2891.

[0170] Example 31: Removal of the Boc protecting group of compound 3a to convert it into the polysubstituted tetrahydroquinoline compound 7

[0171] The synthetic route is as follows:

[0172]

[0173] Add TFA (0.1 ml), 2 mL of CH2Cl2, and 3a (0.2 mmol, 114.4 mg) to the reaction flask, stir at room temperature for 1 h, monitor the reaction end point by TLC. After the reaction stops, directly separate and purify by column chromatography to obtain the polysubstituted tetrahydroquinoline compound 7 (92.5 mg, 98% yield with dr > 25:1). 1 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.19 - 7.12 (m, 5H), 7.10 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.76 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 11.2 Hz, 2H), 5.69 (s, 1H), 5.29 (s, 1H), 5.21 (s, 1H), 4.00 (s, 1H), 3.87 (s, 3H), 2.30 (s, 3H) ppm. 1313C NMR (100 MHz, CDCl3) δ 167.3, 145.1, 142.1, 141.4, 135.8, 133.3, 132.1, 130.3, 130.0, 129.8, 129.4, 128.81, 128.76, 128.71, 120.3, 118.9, 116.3, 114.1, 67.5, 55.9, 52.5, 45.5, 21.6 ppm. ESI-HRMS: C 27 H 24 N2O4S + H + 473.1530, found 473.1525.

[0174] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing a polysubstituted 1,2,3,4-tetrahydroquinoline represented by Formula 3, characterized in that, It includes the following steps: ， The MBH carbonate compound shown in Formula 1, the olefin compound shown in Formula 2 and a Lewis base catalyst undergo an addition reaction in an organic solvent, and after separation and purification, a polysubstituted 1,2,3,4-tetrahydroquinoline compound shown in Formula 3 is obtained; the Lewis base catalyst is selected from one of 1,4-diazabicyclo[2.2.2]octane, 4-dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene; Wherein, in Formula 1, PG is selected from Boc protecting group, Ac protecting group, Ts protecting group, Cbz protecting group, alkyl protecting group, benzyl protecting group; EWG is selected from ester group, cyano group, ketone carbonyl group, nitro group, sulfone group; In Formula 2, R is selected from substituted or unsubstituted C1-C6 straight-chain or branched-chain alkyl group, substituted or unsubstituted C2-C6 straight-chain or branched-chain alkenyl group, substituted or unsubstituted C6-C12 aryl group, 5-10-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur, substituted or unsubstituted C3-C6 cyclic alkyl group; the substituents of the substituted ones are selected from cyano group, nitro group, amino group, hydroxyl group, mercapto group, halogen, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C2-C6 alkenyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group, phenyl group, C1-C6 alkyl-substituted phenyl group; R 1 selected from an ester group, a Ts group, a Bz group, a substituted or unsubstituted sulfone group; the substituent of the substitution is selected from a cyano group, a nitro group, an amino group, a hydroxyl group, a mercapto group, a halogen, a phenyl group, a halogenated phenyl group, a C1-C6 straight-chain or branched alkyl group, a C3-C6 cyclic alkyl group, a C2-C6 straight-chain or branched alkenyl group.

2. The preparation method according to claim 1, wherein In Formula 2, R is selected from substituted or unsubstituted C1-C6 straight-chain or branched-chain alkyl group, substituted or unsubstituted C6-C12 aryl group, 5-10-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, sulfur; the substituents of the substituted ones are selected from halogen, cyano group, nitro group, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group.

3. The preparation method according to claim 1, wherein In Formula 2, R is selected from methyl group, phenyl group, benzyl group, naphthyl group, thiophenyl group, furyl group, m-dichlorophenyl group, trifluoromethylphenyl group, chlorophenyl group, bromophenyl group, p-fluorophenyl group, p-tert-butylphenyl group, p-methylphenyl group, nitrophenyl group, cyanophenyl group, p-trifluoromethoxyphenyl group, p-methoxyphenyl group.

4. The preparation method according to claim 1, characterized in that, The Lewis base catalyst is 1,4-diazabicyclo[2.2.2]octane.

5. The preparation method according to claim 1, characterized in that, The molar ratio of the MBH carbonate compound shown in Formula 1, the olefin compound shown in Formula 2 and the Lewis base catalyst is 1-2:1-1.2:0.1-0.

5.

6. The preparation method according to claim 5, characterized in that, The molar ratio of the MBH carbonate compound shown in Formula 1, the olefin compound shown in Formula 2 and the Lewis base catalyst is 1.2:1:0.

2.

7. The preparation method according to claim 1, characterized in that, The organic solvent is selected from at least one of acetonitrile, toluene, dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, acetone, ether, dioxane, xylene, benzene, dimethyl sulfoxide and formamide.

8. The preparation method according to claim 7, characterized in that, The organic solvent is one of dichloromethane, toluene, ethyl acetate, tetrahydrofuran.

9. The preparation method according to claim 1, wherein, The addition reaction conditions include: the temperature is 25-100 °C, and / or, the time is 1-24 h.

10. The preparation method according to claim 9, wherein, The addition reaction temperature is 25 °C.

11. According to the preparation method described in claim 1, characterized in that, The reaction product is separated and purified by column chromatography.

12. The preparation method according to claim 11, wherein, The solvent used in the separation and purification process is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10:1 to 5:1.

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