Catalytic synthesis method of chiral polysubstituted hydroquinoline compound

Abstract

The invention discloses a catalytic synthesis method of a chiral polysubstituted hydroquinoline compound, and belongs to the field of organic synthesis. The method comprises the following steps: at 0-40 DEG C, respectively taking alcohol or halogenated hydrocarbon as a solvent, adding a metal copper catalyst and a chiral ligand, reacting for 0.5-2 hours under the protection of nitrogen, cooling to-60-0 DEG C, then sequentially adding o-aminophenyl nitrone, propargyl alcohol ester and alkali, and reacting for 6-48 hours to obtain the chiral polysubstituted hydroquinoline compound as shown in a formula 1 or 2. According to the present invention, the chiral polysubstituted hydroquinoline compound is synthesized by using the o-aminophenyl nitrone and the propargyl alcohol ester as the reactants through the catalysis of the cheap metal copper catalyst and the chiral ligand, and the method has advantages of simple operation, low cost, excellent enantioselectivity and excellent diastereoselectivity. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for synthesizing chiral multi-substituted hydrogenated quinoline compounds, and belongs to the field of organic synthesis. Background Art

[0002] Chiral multi-substituted hydrogenated quinoline compounds are widely present in pesticides, medicines, natural products and their derivatives. As one of the most important nitrogen heterocyclic skeletons in alkaloids in nature, they have attracted widespread attention from researchers.

[0003] Chirality is one of the most important properties of nature. The configuration of chiral drugs is directly related to the pharmacology, efficacy, toxic side effects, etc. of drug molecules, and asymmetric catalysis is the most direct and effective method to obtain chiral molecules. With the development of asymmetric catalysis, more and more methods for synthesizing chiral hydrogenated quinoline compounds have been developed, among which most of the research focuses on asymmetric Povarov reactions and asymmetric hydrogenation reactions of quinoline compounds. Among them, asymmetric Povarov reactions usually require expensive chiral phosphoric acid catalysts or precious metal catalysts, while asymmetric hydrogenation reactions require the use of precious metal catalysts or high-pressure hydrogen. Therefore, it is very valuable to develop a simple, efficient and low-cost method to obtain chiral multi-substituted hydrogenated quinoline compounds.

[0004] In 2011, Géraldine Masson's research group reported a three-component Povarov reaction of aldehydes, anilines and eneamines catalyzed by chiral phosphoric acid to generate trisubstituted tetrahydroquinolines with three consecutive stereocenters (Dagousset, G.; Zhu, J.; Masson, G. Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using enecarbamates as dienophiles: highly diastereo-and enantioselective synthesis of substituted 4-aminotetrahydroquinolines. J. Am. Chem. Soc. 2011, 133, 14804-14813.). This reaction has the characteristics of a wide substrate range, high yield, high diastereoselectivity and enantioselectivity, but it requires the use of expensive chiral phosphoric acid catalysts.

[0005]

[0006] In 2021, Liu Qiang's research group reported the asymmetric hydrogenation of quinoline catalyzed by cheap manganese (Liu, C.; Wang, M.; Liu, S.; Wang, Y.; Peng, Y.; Lan, Y.; Liu, Q. Manganese catalyzed asymmetric hydrogenation of quinolines enabled by π-π interaction. Angew. Chem. Int. Ed. 2021, 60, 5108-5113.). This method uses a new type of ligand, which can still achieve excellent yields and good enantioselectivity at a catalyst loading as low as 0.025 mol%. In addition, the reaction has a wide substrate range, good reaction selectivity (can tolerate halogens), high yield, and good enantioselectivity. Compared with precious metal catalysis, it is competitive, but it still requires the use of high-pressure hydrogen, and the new ligand used in the reaction is expensive.

[0007] Summary of the invention

[0008] In view of the above problems existing in the prior art, the object of the present invention is to provide a method for synthesizing polysubstituted hydroquinoline compounds by using a divergent asymmetric reaction catalyzed by a cheap metal copper catalyst and a commercially available cheap chiral ligand.

[0009] The present invention can obtain two products respectively through different reaction paths in different solvents. First, it reacts with propargyl alcohol ester under the action of a metal copper catalyst, a chiral ligand and a base to generate a copper allene intermediate I, and then reacts with a nitrone to generate a cyclization intermediate II, followed by ring opening to generate a highly active allenone intermediate III and an imine intermediate IV. In an alcohol solvent, the two intermediates undergo a [4+2] cyclization reaction / addition reaction / elimination reaction in series to obtain product 1; in a halogenated alkane solvent, the two intermediates undergo a [4+2] cyclization reaction / CH functionalization reaction in series to obtain product 2. The present invention is the first catalytic asymmetric reaction involving an allenone intermediate. By regulating the solvent, two chiral multi-substituted hydrogenated quinoline compounds with different skeletons can be obtained respectively, and the method is simple to operate, low in cost, and has excellent enantioselectivity and diastereoselectivity.

[0010]

[0011] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0012] A catalytic synthesis method for chiral multi-substituted hydrogenated quinoline compounds comprises the following steps: at 0-40°C, using alcohol or halogenated alkane as solvent, adding a metal copper catalyst and a chiral ligand, reacting for 0.5-2 hours under nitrogen protection, cooling to -60-0°C, then sequentially adding o-aminophenyl nitrone, propargyl alcohol ester and a base, reacting for 6-48 hours, and obtaining a chiral multi-substituted hydrogenated quinoline compound as shown in formula 1 or 2:

[0013]

[0014] Wherein, R is selected from one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-naphthyl and 2-thienyl; R 1 is selected from the group consisting of hydrogen, 5-methyl, 5-bromo, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, and 4-methoxy; R 2 is selected from the group consisting of methyl, ethyl, isopropyl, 2,2,2-trifluoroethyl, and 1,1,1,3,3,3-hexafluoro-2-propyl; R 3 is selected from the group consisting of phenyl, 2-chlorophenyl, 2-methylphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-furyl, 3-thienyl, and 3-furyl; R 4 One selected from hydrogen, 4-fluoro, 4-chloro, 4-bromo, 3-fluoro, 3-chloro, and 2-methyl.

[0015] The metal copper catalyst includes but is not limited to divalent copper salt or monovalent copper salt, etc.; the divalent copper salt or monovalent copper salt is one of copper trifluoromethanesulfonate, copper acetate, copper perchlorate, cuprous iodide, cuprous thiophene-2-carboxylate, and cuprous tetraacetonitrile hexafluorophosphate.

[0016] The chiral ligand includes but is not limited to chiral Box ligand, chiral PyBox ligand, chiral PHOX ligand, chiral Phos ligand, etc.; the base is an inorganic base or an organic base, including but not limited to sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, 1-methylpiperidine, etc.

[0017] In terms of molar amount, the amount of the metal copper catalyst is 5-20% of that of o-aminophenylnitrone; the amount of the chiral ligand is 5-25% of that of o-aminophenylnitrone; the amount of the propargyl alcohol ester is 1-3 times that of o-aminophenylnitrone; and the amount of the base is 1-3 times that of o-aminophenylnitrone.

[0018] The halogenated alkane solvent includes, but is not limited to, dichloromethane, 1,2-dichloroethane or chloroform.

[0019] The alcohol solvent includes, but is not limited to, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, and 1,1,1,3,3,3-hexafluoro-2-propanol.

[0020] The chemical structural formula of the o-aminophenylnitrone is wherein R is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-naphthyl, and 2-thienyl; 1 is selected from the group consisting of hydrogen, 5-methyl, 5-bromo, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, and 4-methoxy; R 4 One selected from hydrogen, 4-fluoro, 4-chloro, 4-bromo, 3-fluoro, 3-chloro, and 2-methyl.

[0021] The chemical structural formula of the propargyl alcohol ester is Where R 3 is selected from the group consisting of phenyl, 2-chlorophenyl, 2-methylphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-furyl, 3-thienyl, and 3-furyl; R 5 One selected from acetyl, benzoyl, 3,5-dinitrobenzoyl and tert-butyloxycarbonyl (Boc).

[0022] In a preferred technical solution, the amount of the metallic copper catalyst used is 10% of the o-aminophenylnitrone in terms of molar amount.

[0023] In a preferred technical solution, the amount of the chiral ligand used is 12% of the o-aminophenylnitrone in molar amount.

[0024] In a preferred technical solution, the amount of the propargyl alcohol ester used is 2.0 times that of o-aminophenylnitrone on a molar basis.

[0025] In a preferred technical solution, the amount of the base used is 2.0 times that of o-aminophenylnitrone on a molar basis.

[0026] In the preferred technical solution, the chemical structures of the chiral Box ligand, chiral PyBox ligand, chiral PHOX ligand, and chiral Phos ligand are as follows:

[0027]

[0028] In the above technical solution, after the reaction is completed, the product can be separated by simple column chromatography (the eluent is preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 5:1:1) to obtain the target product.

[0029] The above reaction process is as follows:

[0030]

[0031] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0032] 1. The present invention realizes for the first time the synthesis of chiral multi-substituted hydroquinoline compounds using o-aminophenylnitrone and propargyl alcohol ester as reactants through the catalysis of cheap metal copper catalyst and chiral ligand. The method is simple to operate, low in cost, and has excellent enantioselectivity and diastereoselectivity.

[0033] 2. The method of the present invention does not involve a kinetic resolution process, and is a tandem reaction. Two products can be obtained separately by controlling the solvent used in the reaction.

[0034] 3. The compounds synthesized in the present invention have potential pharmaceutical activity, wherein the skeleton of product 2 is the first asymmetric synthesis. DETAILED DESCRIPTION

[0035] The present invention will be further described below in conjunction with specific embodiments.

[0036] Embodiment 1:

[0037]

[0038] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and diisopropylethylamine (25.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3a (34 mg), with a yield of 81% and ee = 91%. The product 3a was analyzed, and the results were as follows: Column Daicel Chiracel IC; iPrOH / Hexane = 30 / 70; flow rate = 1.0 mL / min; t R1 =9.56min,95.5%;t R2 =12.82min,4.5%; 1H NMR (400MHz, CDCl3): δ7.68(d,J=8.1Hz,1H),7.33(t,J=7.7Hz,1H),7.29(d,J=8.3Hz, 2H),7.25-7.13(m,8H),7.07(d,J=8.0Hz,2H),6.51(s,1H),3.74(s,3H),2.35(s,3H). 13 C NMR (101MHz, CDCl3): δ165.1,143.8,137.2,135.6,134.0,133.7,130.8,129.1,1 28.4,128.3,128.1,128.0,127.3,127.3,127.2,126.9,126.8,55.8,52.1,21.5.

[0039] Embodiment 2:

[0040]

[0041] Anhydrous copper acetate (1.8 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and chloroform (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and diisopropylethylamine (25.8 mg, 0.2 mmol) were added in sequence. The reaction was continued at this temperature for 8 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4a (29 mg), with a yield of 60% and ee = 91%. The product 4a was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =20.81min,95.5%;t R2 =22.91min,4.5%; 1H NMR (400MHz, DMSO-d6): δ7.97(d,J=8.3Hz,2H),7.70(d,J=3.8Hz,1H),7.58( d,J=6.7Hz,1H),7.46-7.36(m,6H),7.34-7.25(m,4H),7.10(t,J=8.0Hz,1H) ,6.92(t,J=7.5Hz,1H),6.80(d,J=8.2Hz,1H),6.58(t,J=7.2Hz,1H),6.46(d ,J=3.5Hz,1H),4.24-4.17(m,1H),3.63(dd,J=6.1,3.6Hz,1H),2.35(s,3H). 13 CNMR (101MHz, DMSO-d6): δ190.6,150.8,144.8,141.9,137.9,136.9,136.2,130.2,129.3,128.9,12 8.7,127.9,127.5,127.3,126.1,125.4,122.9,117.8,117.6,117.3,116.9,57.6,49.8,47.8,21.5.

[0042] Embodiment 3:

[0043]

[0044] Cuprous iodide (1.9 mg, 0.01 mmol), chiral ligand (7.0 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -10°C, and o-aminophenylnitrone 1b (35.2 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and diisopropylethylamine (25.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 8 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3b (30 mg), with a yield of 74% and ee = 92%. The product 3b was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1.0mL / min; t R1 =7.79min,96.0%;t R2 =10.26min,4.0%; 1H NMR (400MHz, CDCl3): δ7.69 (d, J = 8.1Hz, 1H), 7.50-7.45 (m, 1H), 7.43-7.39 (m, 2H), 7.37-7.32 (m, 1 H),7.29(d,J=7.5Hz,2H),7.26-7.18(m,7H),7.15(dd,J=7.6,1.6Hz,1H),6.52(s,1H),3.73(s,3H). 13 C NMR (101MHz, CDCl3): δ165.0,138.4,137.0,133.9,133.6,133.0,130.8,1 28.5,128.4,128.3,128.1,128.1,127.3,127.2,126.9,126.9,55.9,52.1.

[0045] Embodiment 4:

[0046]

[0047] Cupric perchlorate (3.7 mg, 0.01 mmol), chiral ligand (7.0 mg, 0.012 mmol) and dichloromethane (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -40°C, and o-aminophenylnitrone 5b (43.0 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and triethylamine (20.2 mg, 0.2 mmol) were added in sequence. The reaction was continued at this temperature for 40 hours. After the reaction was completed, the product was purified by simple column chromatography (preferably the eluent was petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4b (30 mg), with a yield of 55% and ee = 91%. The product 4b was analyzed, and the results were as follows: Column Daicel Chiracel IA; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =12.79min,4.4%; t R2 =14.04min,95.6%; 1H NMR (400MHz, CDCl3): δ7.91 (d, J = 2.3Hz, 1H), 7.85 (d, J = 8.1Hz, 1H), 7.70-7.64 (m, 2H), 7.57-7.52 (m, 1H), 7.43-7.26 (m, 7H), 7.21-7.1 6(m,3H),7.13-7.08(m,1H),6.27(d,J=8.7Hz,1H),5.68(d,J=7.7Hz,1H),4.47-4.39(m,1H),4.01(s,1H),2.97(dd,J=7.7,3.9Hz,1H). 13 C NMR (101MHz, CDCl3): δ189.0,148.0,141.6,139.2,138.0,137.2,132.8,130.5,130.0,128.8,1 28.7,127.8,127.7,127.5,127.2,126.3,124.7,123.3,119.0,117.8,111.0,58.0,53.7,51.9.

[0048] Embodiment 5:

[0049]

[0050] Thiophene-2-carboxylic acid cuprous acid (1.9 mg, 0.01 mmol), chiral ligand (6.1 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -60°C, and o-aminophenylnitrone 1c (38.0 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and sodium carbonate (21.2 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 48 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3c (32 mg), with a yield of 74% and ee = 90%. The product 3c was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1.0mL / min; t R1 =10.55min,94.8%;t R2 =13.75min,5.2%; 1H NMR (400MHz, CDCl3): δ7.56(d,J=8.2Hz,1H),7.29(d,J=8.3Hz,2H),7.26-7.23(m,2H),7.21-7.17(m,4H),7.13(dd, J=8.2,1.6Hz,1H),7.07(d,J=8.1Hz,2H),6.94(d,J=1.6Hz,1H),6.48(s,1H),3.73(s,3H),2.35(s,3H),2.30(s,3H). 13 C NMR (101MHz, CDCl3): δ165.2,143.7,137.3,136.7,135.7,134.0,131.7,131.5,129 .1,128.7,128.4,128.0,127.8,127.2,127.1,127.1,127.0,55.9,52.1,21.5,20.9.

[0051] Embodiment 6:

[0052]

[0053] Thiophene-2-carboxylic acid cuprous acid (1.9 mg, 0.01 mmol), chiral ligand (6.1 mg, 0.012 mmol) and chloroform (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -60°C, and o-aminophenylnitrone 5c (45.8 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and sodium carbonate (21.2 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 48 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4c (35 mg), with a yield of 61% and ee = 88%. The product 4c was analyzed, and the results were as follows: Column Daicel Chiracel ID; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =16.57min,94.1%;t R2 =19.07min,5.9%; 1H NMR (400MHz, CDCl3): δ7.91(d,J=2.3Hz,1H),7.74(d,J=8.4Hz,1H),7.53(d, J=8.3Hz,2H),7.36(dd,J=8.7,2.4Hz,1H),7.33-7.25(m,4H),7.20-7.15(m,5 H),6.98-6.95(m,1H),6.22(d,J=8.7Hz,1H),5.58(d,J=8.0Hz,1H),4.43-4.3 7(m,1H),3.92(s,1H),2.92(dd,J=7.9,3.7Hz,1H),2.41(s,3H),2.30(s,3H). 13 C NMR (101MHz, CDCl3): δ189.2,148.1,143.4,141.8,137.9,136.3,134.6,134.5,130.7,130.5,129.4, 128.7,128.1,127.8,127.7,127.1,126.4,123.5,118.9,117.6,110.9,57.9,53.9,52.1,21.6,20.7.

[0054] Embodiment 7:

[0055]

[0056] Copper trifluoroacetate (2.9 mg, 0.01 mmol), chiral ligand (6.2 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -30°C, and o-aminophenylnitrone 1d (44.4 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and potassium carbonate (27.8 mg, 0.2 mmol) were added in sequence. The reaction was continued at this temperature for 30 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3d (39 mg), with a yield of 78% and ee = 87%. The product 3d was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1.0mL / min; t R1 =7.74min,93.6%;t R2 =9.82min,6.4%; 1H NMR (400MHz, CDCl3): δ7.56(d,J=8.6Hz,1H),7.43(dd,J=8.6,2.3Hz,1H),7.32(d,J=8.3Hz,2H),7.29(d,J =2.3Hz,1H),7.24-7.20(m,5H),7.17(s,1H),7.10(d,J=8.0Hz,2H),6.51(s,1H),3.74(s,3H),2.36(s,3H). 13 C NMR (101MHz, CDCl3): δ164.7,144.2,136.7,135.5,133.5,133.1,132.3,130.7,1 29.5,129.3,128.9,128.7,128.5,128.3,127.1,126.9,120.1,55.9,52.3,21.5.

[0057] Embodiment 8:

[0058]

[0059] Copper trifluoroacetate (2.9 mg, 0.01 mmol), chiral ligand (6.2 mg, 0.012 mmol) and dichloromethane (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -30°C, and o-aminophenylnitrone 5d (52.1 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and potassium carbonate (27.8 mg, 0.2 mmol) were added in sequence. The reaction was continued at this temperature for 30 hours. After the reaction was completed, the product was purified by simple column chromatography (preferably the eluent was petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4d (44 mg), with a yield of 69% and ee = 85%. The product 4d was analyzed, and the results were as follows: Column Daicel Chiracel IA; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =11.98min,7.5%;t R2 =13.17min,92.5%; 1H NMR (400MHz, CDCl3): δ7.90(d,J=2.3Hz,1H),7.71(d,J=8.3Hz,2H),7.66(d,J=8.9Hz,1H),7.39-7.36(m,2H),7.33-7.30(m,3H),7.28-7.26( m,1H),7.25-7.23(m,1H),7.23-7.19(m,3H),6.36(d,J=8.7Hz,1H),5. 96(d,J=6.3Hz,1H),4.45-4.35(m,2H),3.12-3.06(m,1H),2.41(s,3H). 13 C NMR (101MHz, CDCl3): δ188.6,147.6,144.1,141.2,138.2,136.7,136.0,132.5,130.4,129.8,129 .6,128.9,128.0,127.9,127.8,126.0,123.1,119.2,117.8,116.9,111.1,57.8,52.2,50.3,21.6.

[0060] Embodiment 9:

[0061]

[0062] Thiophene-2-carboxylic acid cuprous acid (1.9 mg, 0.01 mmol), chiral ligand (6.1 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -60°C, and o-aminophenylnitrone 1e (38.0 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and sodium bicarbonate (16.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 48 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3e (32 mg), with a yield of 74% and ee = 95%. The product 3e was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1.0mL / min; t R1 =8.97min,97.5%;t R2 =12.72min,2.5%; 1H NMR (400MHz, CDCl3): δ7.50 (s, 1H), 7.30 (d, J = 8.3Hz, 2H), 7.28-7.24 (m, 2H), 7.23-7.1 7(m,4H),7.09-7.02(m,3H),7.02-6.98(m,1H),6.48(s,1H),3.72(s,3H),2.35(m,6H). 13 C NMR (101MHz, CDCl3): δ165.2,143.8,141.5,137.4,135.7,133.9,133.9,129.0,128 .5,128.4,128.1,128.0,127.7,127.2,127.0,126.0,124.8,55.9,52.0,21.8,21.5.

[0063] Embodiment 10:

[0064]

[0065]

[0066] Thiophene-2-carboxylic acid cuprous acid (1.9 mg, 0.01 mmol), chiral ligand (6.1 mg, 0.012 mmol) and dichloromethane (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -60°C, and o-aminophenylnitrone 5e (45.8 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and sodium bicarbonate (16.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 48 hours. After the reaction was completed, the product was purified by simple column chromatography (preferably the eluent was petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4e (34 mg), with a yield of 59% and ee = 93%. The product 4e was analyzed, and the results were as follows: Column Daicel Chiracel IA; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =10.27min,96.5%;t R2 =13.24min,3.5%; 1H NMR (400MHz, CDCl3): δ7.90(d,J=2.3Hz,1H),7.67(s,1H),7.59(d,J=8.3Hz ,2H),7.37-7.26(m,4H),7.22-7.17(m,4H),7.04(d,J=7.7Hz,1H),6.90(d, J=7.7Hz,1H),6.25(d,J=8.7Hz,1H),5.70(d,J=7.5Hz,1H),4.40(d,J=3.3H z,1H),4.04(s,1H),2.95(dd,J=7.5,4.1Hz,1H),2.41(s,3H),2.35(s,3H). 13 C NMR (101MHz, CDCl3): δ189.2,148.0,143.6,141.7,140.0,137.9,137.1,136.3,130.5,129.4,128.7, 127.9,127.6,127.2,126.3,125.2,123.8,123.6,119.0,117.7,110.8,57.9,53.5,51.4,21.6,21.6.

[0067] Embodiment 11:

[0068]

[0069] Into a nitrogen-protected reaction flask, add copper tetraacetonitrile hexafluorophosphate (3.7 mg, 0.01 mmol), chiral ligand (4.3 mg, 0.012 mmol) and methanol (2 ml) in sequence, react at room temperature for 30 minutes, then cool to 0°C, add o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2b (53.2 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) in sequence, react at this temperature for 6 hours, after the reaction, the product can be obtained by simple column chromatography (eluent is preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3f (30 mg), with a yield of 66% and ee = 81%. The product 3f was analyzed, and the results are as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =7.65min,90.5%;t R2 =9.77min,9.5%; 1H NMR (400MHz, CDCl3): δ7.70 (d, J = 8.1Hz, 1H), 7.38-7.33 (m, 1H), 7.29-7.25 (m, 3H), 7.24-7. 19(m,2H),7.18-7.12(m,4H),7.07(d,J=8.0Hz,2H),6.47(s,1H),3.75(s,3H),2.34(s,3H). 13 C NMR (101MHz, CDCl3): δ164.8,144.0,139.4,135.4,134.3,134.1,133.8,131.0,129.7,1 29.1,128.5,128.3,128.0,127.3,127.1,127.0,126.9,126.5,125.5,55.3,52.2,21.5.

[0070] Embodiment 12:

[0071]

[0072] Into a nitrogen-protected reaction flask, add copper tetraacetonitrile hexafluorophosphate (3.7 mg, 0.01 mmol), chiral ligand (4.3 mg, 0.012 mmol) and 1,2-dichloroethane (2 ml) in sequence, react at room temperature for 30 minutes, then cool to 0°C, add o-aminophenylnitrone 5a (44.4 mg, 0.1 mmol), propargyl alcohol ester 2b (53.2 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) in sequence, react at this temperature for 6 hours, after the reaction, the product can be obtained by simple column chromatography (eluent is preferably petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4f (30 mg), with a yield of 51% and ee = 86%. The product 4f was analyzed, and the results are as follows: Column Daicel Chiracel IA; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =10.50min,7.0%;t R2 =13.96min,93.0%; 1HNMR (400MHz, CDCl3): δ7.93-7.84(m,2H),7.53(d,J=8.1Hz,2H),7.41-7.36(m,2H),7.24(d,J=4.7Hz,2H),7.21-7.10(m,5H),7 .08-7.04(m,1H),6.23(d,J=8.7Hz,1H),5.55(d,J=8.0Hz,1H),4.48-4.40(m,1H),3.94(s,1H),2.94-2.88(m,1H),2.42(s,3H). 13 C NMR (101MHz, CDCl3): δ188.7,148.0,143.8(2C),138.0,136.9,135.9,134.5,130.5,130.1,129.9,129. 5,128.0,127.8,127.6,127.0,126.5,124.9,124.8,123.6,118.7,117.7,111.0,57.5,53.6,51.9,21.6.

[0073] Embodiment 13:

[0074]

[0075] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (5.8 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2c (49.2 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3g (35 mg), with a yield of 81% and ee = 91%. The product 3g was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =10.33min,95.7%;t R2 =15.04min,4.3%; 1H NMR (400MHz, CDCl3): δ7.67(d,J=8.1Hz,1H),7.35-7.27(m,3H),7.24(s,1H),7.22-7.15(m,2H),7.13(d,J=7 .9Hz,2H),7.06(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),6.48(s,1H),3.73(s,3H),2.34(s,3H),2.24(s,3H). 13 CNMR (101MHz, CDCl3): δ165.1,143.8,137.8,135.7,134.1,134.0,133.6,130.7,129 .1,129.1,128.3,128.0,127.4,127.4,127.1,126.9,126.7,55.7,52.1,21.5,21.0.

[0076] Embodiment 14:

[0077]

[0078] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (5.8 mg, 0.012 mmol) and dichloromethane (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 5a (44.4 mg, 0.1 mmol), propargyl alcohol ester 2c (49.2 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4g (39 mg), with a yield of 68% and ee = 94%. The product 4g was analyzed, and the results were as follows: Column Daicel Chiracel ID; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =16.89min,97.0%;t R2 =18.90min,3.0%; 1H NMR (400MHz, CDCl3): δ7.90(d,J=2.1Hz,1H),7.83(d,J=8.3Hz,1H),7.57(d,J=8.1Hz,2H),7.37-7.32(m,2H),7.20-7.15(m,3H),7.1 4-7.05(m,5H),6.25(d,J=8.7Hz,1H),5.65(d,J=7.6Hz,1H),4.48-4.40(m,1H),4.06(s,1H),2.96(m,1H),2.41(s,3H),2.31(s,3H). 13 C NMR (101MHz, CDCl3): δ189.1,148.0,143.6,138.7,137.9,137.3,136.3,130.5,129.8,129.4,129 .4,127.8,127.4,126.9,126.2,124.4,123.1,119.0,117.7,110.8,57.7,53.6,51.7,21.6,21.1.

[0079] Embodiment 15:

[0080]

[0081] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2d (56.4 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3h (26 mg), with a yield of 55% and ee = 90%. The product 3h was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =10.07min,5.1%;t R2 =11.09min,94.9%; 1H NMR (400MHz, CDCl3): δ7.78-7.72(m,2H),7.69-7.64(m,2H),7.61(dd,J=8.6,1.8Hz,1H),7.49(s,1H),7.43-7. 37(m,2H),7.36-7.27(m,4H),7.21-7.16(m,2H),7.09(d,J=8.0Hz,2H),6.68(s,1H),3.75(s,3H),2.36(s,3H). 13 C NMR (101MHz, CDCl3): δ165.1,143.9,135.6,134.4,134.1,133.9,133.0,132.8,130.8,129.1,128. 4,128.3,128.0,127.5,127.4,127.1,127.0,126.9,126.1,126.0,125.9,125.7,56.0,52.2,21.5.

[0082] Embodiment 16:

[0083]

[0084] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and dichloromethane (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 5a (44.4 mg, 0.1 mmol), propargyl alcohol ester 2d (56.4 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) were added in sequence. The reaction was continued at this temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4h (33 mg), with a yield of 54% and ee = 85%. The product 4h was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =14.52min,7.6%;t R2 =18.86min,92.4%; 1H NMR (400MHz, DMSO-d6): δ7.98-7.90 (m, 4H), 7.82 (d, J = 3.3Hz, 1H), 7.80-7.74 (m,2H),7.64(d,J=2.2Hz,1H),7.55(d,J=8.5Hz,1H),7.53-7.47(m,3H),7.45 -7.38(m,4H),7.20(t,J=7.8Hz,1H),6.99(t,J=7.5Hz,1H),6.80(d,J=8.9Hz, 1H), 6.48 (d, J = 3.7Hz, 1H), 4.37-4.29 (m, 1H), 3.79-3.70 (m, 1H), 2.36 (s, 3H). 13 C NMR (101MHz, DMSO-d6): δ189.6,149.9,144.8,139.5,138.5,137.9,136.7,133.2,132.8,130.3,129.2,129.1,129.0,12 8.6,128.3,128.1,127.6,127.1,126.7,125.2,125.1,124.2,123.2,119.5,118.7,118.5,108.6,57.8,49.6,48.1,21.5.

[0085] Embodiment 17:

[0086]

[0087] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and methanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2e (44.4 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was purified by simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3i (25 mg), with a yield of 61% and ee = 91%. The product 3i was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =14.65min,95.5%;t R2 =29.40min,4.5%; 1H NMR (400MHz, CDCl3): δ7.71 (d, J = 8.1Hz, 1H), 7.39-7.34 (m, 1H), 7.30-7.26 (m, 3H), 7.24-7.20 (m, 1H), 7.19-7.1 4(m,2H),7.05(d,J=8.0Hz,2H),6.60(s,1H),6.14-6.11(m,1H),5.97(d,J=3.3Hz,1H),3.75(s,3H),2.33(s,3H). 13 C NMR (101MHz, CDCl3): δ164.6,149.7,143.9,143.2,135.5,134.1,133.9,130.8,1 29.1,128.5,127.5,126.9,126.9,126.8,125.3,110.1,108.7,52.1,51.0,21.5.

[0088] Embodiment 18:

[0089]

[0090]

[0091] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and dichloromethane (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 5a (44.4 mg, 0.1 mmol), propargyl alcohol ester 2e (44.4 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was purified by simple column chromatography (preferably the eluent was petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4i (29 mg), with a yield of 53% and ee = 84%. The product 4i was analyzed, and the results were as follows: Column Daicel Chiracel IA; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =12.28min,92.1%;t R2 =14.11min,7.9%; 1H NMR (400MHz, CDCl3): δ7.89(d,J=2.1Hz,1H),7.65(d,J=8.3Hz,1H),7.61(d,J=8.2Hz,2H),7.38-7.32(m,2H),7.25-7.15(m,4H),7. 08-7.02(m,1H),6.40-6.27(m,3H),5.98(d,J=6.9Hz,1H),4.60-4.51(m,1H),4.28(s,1H),3.40(dd,J=6.6,4.9Hz,1H),2.40(s,3H). 13 C NMR (101MHz, CDCl3): δ188.8,152.3,148.1,143.8,142.5,138.1,136.8,136.5,130.5,129.6,129 .5,127.9,127.1,126.3,124.3,122.5,119.0,117.7,110.9,110.6,108.9,51.9,51.4,49.3,21.6.

[0092] Embodiment 19:

[0093]

[0094] Copper trifluoromethanesulfonate (3.6 mg, 0.01 mmol), chiral ligand (4.0 mg, 0.012 mmol) and ethanol (2 ml) were added to a nitrogen-protected reaction bottle in sequence. After reacting at room temperature for 30 minutes, the temperature was lowered to -20°C, and o-aminophenylnitrone 1a (36.6 mg, 0.1 mmol), propargyl alcohol ester 2a (46.6 mg, 0.2 mmol) and diisopropylethylamine (25.8 mg, 0.2 mmol) were added in sequence. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate: dichloromethane = 20:1:1 to 10:1:1) to obtain the target product 3j (26 mg), with a yield of 60% and ee = 84%. The product 3j was analyzed, and the results were as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=1mL / min; t R1 =9.66min,92.1%;t R2 =12.54min,7.9%; 1H NMR (400MHz, CDCl3): δ7.69 (d, J = 8.1Hz, 1H), 7.36-7.28 (m, 3H), 7.27-7.24 (m, 2H), 7.24-7.13 (m, 6H), 7.06 (d, J = 8.0Hz, 2H), 6.51 (s, 1H), 4.20 (q, J = 7.1Hz, 2H), 2.34 (s, 3H), 1.27 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3): δ164.6,143.8,137.3,135.7,134.1,133.4,130.7,129.1,128 .4,128.3,128.1,128.0,127.8,127.4,127.2,126.9,126.8,60.9,55.8,21.5,14.3.

[0095] Embodiment 20:

[0096]

[0097] Into a nitrogen-protected reaction bottle, add copper tetraacetonitrile hexafluorophosphate (3.7 mg, 0.01 mmol), chiral ligand (4.3 mg, 0.012 mmol) and 1,2-dichloroethane (2 ml) in sequence, react at room temperature for 30 minutes, then cool to 0°C, add o-aminophenylnitrone 5f (40.0 mg, 0.1 mmol), propargyl alcohol ester 2a (46.4 mg, 0.2 mmol) and 1-methylpiperidine (19.8 mg, 0.2 mmol) in sequence, react at this temperature for 6 hours, after the reaction, the product can be obtained by simple column chromatography (eluent is preferably petroleum ether: ethyl acetate: dichloromethane = 10:1:1 to 5:1:1) to obtain the target product 4j (28 mg), with a yield of 54% and ee = 87%. The product 4j was analyzed, and the results are as follows: Column Daicel Chiracel IC; i PrOH / Hexane=30 / 70; flow rate=0.5mL / min; t R1 =37.77min,6.6%;t R2 =41.15min,93.4%; 1HNMR (400MHz, CDCl3): δ7.87(d,J=8.3Hz,1H),7.75(d,J=8.5Hz,1H),7.55(d,J= 8.3Hz,2H),7.40-7.36(m,1H),7.34-7.27(m,3H),7.22-7.16(m,5H),7.16-7.10 (m,1H),6.73(dd,J=8.5,1.8Hz,1H),6.30(d,J=1.8Hz,1H),5.59(d,J=7.9Hz,1H ),4.47(d,J=3.5Hz,1H),3.92(s,1H),2.96(dd,J=7.8,4.0Hz,1H),2.44(s,3H). 13 C NMR (101MHz, CDCl3): δ189.3,149.7,143.7,141.8,141.5,137.2,136.3,130.0,129.8,129.5,128 .7,127.8,127.7,127.5,127.2,126.3,124.7,123.7,119.3,116.1,115.4,58.0,54.0,52.0,21.6.

[0098] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A catalytic synthesis method for chiral multi-substituted hydroquinoline compounds, characterized in that: The following steps are involved: At 0-40°C, alcohol or halogenated alkane is used as solvent, a copper catalyst and a chiral ligand are added, and the reaction is carried out for 0.5-2 hours under nitrogen protection, and then the temperature is lowered to -60-0°C, and then o-aminophenyl nitrone, propargyl alcohol ester and a base are added in sequence, and the reaction is carried out for 6-48 hours to obtain a chiral multi-substituted hydroquinoline compound represented by formula 1 or 2: The metal copper catalyst is one or more of divalent copper salts or monovalent copper salts; the chiral ligand is one or more of chiral Box ligands, chiral PyBox ligands, chiral PHOX ligands, and chiral Phos ligands.

2. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: The base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and 1-methylpiperidine.

3. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: The divalent copper salt or monovalent copper salt is one of copper trifluoromethanesulfonate, copper acetate, copper perchlorate, cuprous iodide, cuprous thiophene-2-carboxylate, and cuprous tetraacetonitrile hexafluorophosphate.

4. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: In terms of molar amount, the amount of the metal copper catalyst is 5-20% of that of o-aminophenylnitrone; the amount of the chiral ligand is 5-25% of that of o-aminophenylnitrone; the amount of the propargyl alcohol ester is 1-3 times that of o-aminophenylnitrone; and the amount of the base is 1-3 times that of o-aminophenylnitrone.

5. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: The chemical structural formula of the o-aminophenylnitrone is wherein R is selected from one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-naphthyl, and 2-thienyl; R 1 is selected from the group consisting of 5-methyl, 5-bromo, 4-methyl, 4-fluoro, 4-chloro, 4-bromo, 4-trifluoromethyl, and 4-methoxy; R 4 One selected from 4-fluoro, 4-chloro, 4-bromo, 3-fluoro, 3-chloro, and 2-methyl.

6. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: The chemical structural formula of the propargyl alcohol ester is Where R 3 is selected from the group consisting of 2-chlorophenyl, 2-methylphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 4-methoxyphenyl, 3,5-dimethylphenyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 2-furyl, 3-thienyl, and 3-furyl; R 5 One selected from acetyl, benzoyl, 3,5-dinitrobenzoyl and tert-butyloxycarbonyl.

7. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: The halogenated alkane solvent is one or more of dichloromethane, 1,2-dichloroethane or chloroform.

8. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: The alcohol solvent is one or more of methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, and 1,1,1,3,3,3-hexafluoro-2-propanol.

9. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 1, characterized in that: After the reaction is completed, the method further comprises the step of column chromatography separation and purification.

10. The catalytic synthesis method of chiral multi-substituted hydroquinoline compounds according to claim 9, characterized in that: The eluent of the column chromatography is petroleum ether:ethyl acetate:dichloromethane=20:1:1-5:1:1.

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