Method for synthesizing alpha, alpha-disubstituted dihydroquinoline by dearomatization of quinoline salt under catalysis of asymmetric rhodium

Abstract

The invention discloses a method for synthesizing alpha, alpha-disubstituted dihydroquinoline by dearomatization of quinoline salt under the catalysis of asymmetric rhodium. The method is realized through asymmetric dearomatization arylation and alkenylation of rhodium-catalyzed 2-substituted quinoline salt and a boric acid reagent, and proper adjustment of counter ions of the 2-substituted quinoline salt is the key of success of the strategy. The method has the advantages of excellent enantioselectivity, wide substrate application range, convenience in product conversion, simplicity and feasibility in operation, low energy consumption, high efficiency and the like.

Description

Technical Field

[0001] The invention belongs to the field of asymmetric catalytic synthesis, relates to a method for realizing asymmetric rhodium-catalyzed dearomatization arylation and olefination reaction of 2-substituted quinoline salts by appropriately adjusting the counter ions of 2-substituted quinoline salts, and provides a new and efficient method for constructing chiral α,α-disubstituted dihydroquinoline. Technical Background

[0002] Nitrogen heterocycles are common structural units in our daily lives and are widely used in pharmaceuticals, pesticides, materials and other fields. Among them, α,α-disubstituted dihydroquinolines (including tetrahydroquinoline and dihydroquinoline) are an important class of nitrogen heterocyclic structural skeletons, which are widely present in natural products, drugs and bioactive molecules. (Reference 1: (a) J.Fotie,M.Kaiser,DADelfín,J.Manley,CSReid,J.Paris,T.Wenzler,L.Maes,KVMahasenan,C.Li and KAWerbovetz, J.Med.Chem., 2010, 53, 966-982; (b) CSReid, DAPatrick, S.He, J.Fotie, K.Premalatha, RRTidwell, MZWang, Q.Liu, P.Gershkovich, KMWasan, T.Wenzler, R.Brun and KAWerbovetz,Bioorg.Med.Chem.,2011,19,513-523.(c)J.Wuand ASC Chan, Acc. Chem. Res., 2006, 39, 711-720; (d) I. Muthukrishnan, V. Sridharan and JC Menéndez, Chem. Rev., 2019, 119, 5057-5191.) In addition, dihydroquinoline is a versatile starting material that can be efficiently converted into tetrahydroquinoline by reduction or functionalization.(Reference 1: (a) K. Kubota, Y. Watanabe and H. Ito, Adv. Synth. Catal., 2016, 358, 2379-2384; (b) D. Kong, S. Han, R. Wang, M. Li, G. Zi and G. Hou, Chem. Sci., 2017, 8, 4558-4564; (c) D. Kong, S. Han, G. Zi, G. Hou and J. Zhang, J. Org. Chem., 2018, 83, 1924-1932; (d) Q.-F. Xu-Xu, X. Zhang and S.-L.You,Org.Lett.,2019,21,5357-5362; (e)Q.-F.Xu-Xu,X.Zhang and S.-L.You, Org. Lett., 2020, 22, 1530-1534; (f) M.Jiao, J.Gao and X.Fang, Org.Lett., 2020, 22, 8566-8571.) Therefore, the economical and efficient asymmetric synthesis of dihydroquinolines has attracted widespread attention. However, the asymmetric synthesis of α,α-disubstituted dihydroquinolines is challenging due to the presence of steric hindrance.

[0003] Asymmetric dearomatization of readily available quinoline and its derivatives is the most efficient and direct method for constructing chiral dihydroquinolines, and asymmetric dearomatization reactions via quinoline hydrogenation or nucleophilic addition to activated quinoline have been widely reported. Despite these advances, the quinoline hydrogenation strategy has not been able to access chiral α,α-disubstituted dihydroquinolines because one of the introduced substituents is hydrogen. (Reference 1: (a) D.-S. Wang, Q.-A. Chen, S.-M. Lu and Y.-G. Zhou, Chem. Rev., 2012, 112, 2557-2590; (b) S. Park and S. Chang, Angew. Chem., Int. Ed., 2017, 56, 7720-7738.) On the other hand, the asymmetric nucleophilic addition of activated quinoline, such as the Reissert-type nucleophilic addition of N-acylquinoline generated in situ, the metal-catalyzed nucleophilic addition of N-alkylquinoline salts and the dearomatization [3+2] cycloaddition, the product types are limited to chiral α-monosubstituted dihydroquinoline. (Reference 1: (a) M. Takamura, K. Funabashi, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2000, 122, 6327-6328; (b) J. Preindl, S. Chakrabarty and J. Waser, Chem. Sci., 2017, 8, 7112-7118; (c) H.-J. Miao, L.-L. Wang, H.-B. Han, Y.-D. Zhao and Q.-L. Wang, Chem. Sci., 2020, 11, 1418-1424.) Moreover, in many cases, the removal of N-protecting groups is difficult, which limits their practicality to a certain extent. So far, only a few asymmetric synthesis methods of α,α-disubstituted dihydroquinolines have been reported. In 2021, Yang's group developed a strategy for synthesizing α,α-disubstituted dihydroquinolines by chiral phosphoric acid-catalyzed kinetic resolution. (Reference 1: (a) Y. Chen, C. Zhu, Z. Guo, W. Liu and X. Yang, Angew. Chem. Int. Ed., 2021, 60, 5268-5272; (b) C. Zhu, W. Liu, F. Zhao, Y. Chen, H. Tao, Y.-P. He and X. Yang, Org. Lett., 2021, 23, 4104-4108.) Recently, Hou and Jia's groups obtained a series of chiral spiro-dihydroquinolines through scandium- and cobalt-catalyzed dearomatization [3+2] cyclization reactions of quinoline and alkyne, respectively.(Reference 1: (a) S.-J. Lou, G. Luo, S. Yamaguchi, K. An, M. Nishiura and Z. Hou, J. Am. Chem. Soc., 2021, 143, 20462-2047; (b) P. Yang, Q. Wang, B.-H. Cui, X.-D. Zhang, H. Liu, Y.-Y. Zhang, J.-L. Liu, W.-Y. Huang, R.-X. Liang and Y.-X. Jia, J. Am. Chem. Soc., 2022, 144, 1087-1093.) It can be seen that the development of a fast and direct synthetic method to construct chiral α,α-disubstituted dihydroquinolines is still very much needed.

[0004] Asymmetric catalytic nucleophilic addition of 2-substituted quinoline salts is an attractive method for constructing chiral α,α-disubstituted dihydroquinolines. In 2016, Wang's group reported the only example of asymmetric rhodium-catalyzed dearomatization of iodinated N-ethyl-2-methylquinoline by phenylboronic acid. Although this example provided N-protected α,α-disubstituted dihydroquinoline with high enantioselectivity, the yield was only 38%. (Reference 1: Y.Wang, Y.Liu, D.Zhang, H.Wei, M.Shi and F.Wang, Angew.Chem., Int.Ed., 2016, 55, 3776-3780.) Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing α,α-disubstituted dihydroquinoline by asymmetric rhodium-catalyzed dearomatization arylation and alkenylation of 2-substituted quinoline salts. Appropriate adjustment of the counterion of the 2-substituted quinoline salt is the key to the success of the strategy, which can effectively enhance its reactivity, thereby promoting the asymmetric nucleophilic addition of boric acid to the 2-substituted quinoline salt. The present invention has the advantages of simple and practical operation, high efficiency, easy availability of raw materials, low energy consumption, environmental friendliness, high yield and excellent enantioselectivity.

[0006] To achieve the above purpose, the present invention uses [Rh(COD)Cl]2 and a chiral ligand as a catalytic system, an organic base as a base, ethanol as a solvent, a 2-substituted quinoline salt I as a substrate, and an organic boronic acid II as a nucleophilic reagent to synthesize an α,α-disubstituted dihydroquinoline compound III through a dearomatization reaction of catalytic asymmetric nucleophilic addition.

[0007] The technical solution of the present invention is as follows:

[0008] The invention provides a highly efficient synthesis method for chiral α,α-disubstituted dihydroquinoline. The method uses [Rh(COD)Cl]2 or Rh(COD)2BF4 and a chiral ligand as a catalytic system, an organic base as a base, 2-substituted quinoline salt I as a substrate, and an organic boronic acid II (including an aryl boronic acid or an alkenyl boronic acid) or a vinyl pinacol borate IV as a nucleophilic reagent. By catalyzing the asymmetric nucleophilic addition reaction of the organic boronic acid or the vinyl pinacol borate IV to the 2-substituted quinoline salt, challenging dearomatization arylation and alkenylation of the 2-substituted quinoline salt are completed, and a series of optically active α,α-disubstituted dihydroquinoline compounds III or V are synthesized.

[0009] The reaction formula of the method is as follows:

[0010]

[0011] Where:

[0012] X may be a trifluoromethanesulfonate anion, a tetrafluoroborate anion, a hexafluorophosphate anion or a bromide anion;

[0013] R 1 Can be methyl or benzyl;

[0014] R 2 It can be phenyl, benzyl, phenylpropyl or C1-C 20 At least one of the alkyl groups;

[0015] Ar can be an unsubstituted aromatic ring (preferably a benzene ring) or an aromatic ring containing a substituent (preferably a benzene ring), wherein the substituent in the aromatic ring containing a substituent (preferably a benzene ring) is methyl, methoxy or halogen;

[0016] R can be 2-naphthyl, 3-thienyl, an unsubstituted aromatic ring (preferably a benzene ring) containing a substituent, an unsubstituted vinyl, or a vinyl containing an aromatic (preferably a phenyl) substituent, the substituent in the aromatic ring containing a substituent is a halogen, a methoxy group or a methyl group, and the aromatic substituent in the vinyl containing an aromatic substituent is a phenyl, p-methylphenyl, p-chlorophenyl or p-methoxyphenyl group.

[0017] Based on the above technical solution, preferably, X is a trifluoromethanesulfonate anion, R 1 and R 2 is methyl, Ar is phenyl, and R is phenyl.

[0018] Based on the above technical scheme, preferably, the chiral ligand used in the method is (R)-SegPhos, (R)-BINAP, (R)-P-Phos, (S)-DifluorPhos or (R,R)-Ph-BPE, preferably (R)-SegPhos, (R)-BINAP, (R)-P-Phos, and more preferably (R)-SegPhos.

[0019] Based on the above technical scheme, preferably, the organic base used in the method is triethylamine (Et3N), N,N-diisopropylethylamine (DIPEA), sodium carbonate (Na2CO3) or cesium carbonate (Cs2CO3), preferably triethylamine or N,N-diisopropylethylamine, more preferably triethylamine.

[0020] Based on the above technical scheme, preferably, the reaction solvent is ethanol (EtOH), 1,2-dichloroethane (DCE), tetrahydrofuran (THF) or toluene (PhMe), preferably ethanol (EtOH).

[0021] Based on the above technical solution, preferably, the reaction temperature of the method is 40-80°C, preferably 40°C.

[0022] Based on the above technical scheme, preferably, the amount of [Rh(COD)Cl]2 or Rh(COD)2BF4 used in the method is 1.25-5.0% of the molar amount of 2-substituted quinoline salt I, preferably 2.5%; the amount of chiral ligand used is 5.0-6.0% of the molar amount of 2-substituted quinoline salt I.

[0023] Based on the above technical solution, preferably, the concentration of the 2-substituted quinoline salt I in the solvent is 0.05-0.07 mol / L.

[0024] Based on the above technical scheme, preferably, the molar ratio of the 2-substituted quinoline salt I, the organic boronic acid II or the vinyl pinacol borate ester IV and the organic base in the method is 1:2.5:2.5.

[0025] Based on the above technical solution, preferably, the specific steps of the method are:

[0026] Under nitrogen protection, [Rh(COD)Cl]2 or Rh(COD)2BF4, chiral ligand and solvent are added to an ampoule bottle and stirred at room temperature for 0.5-1h to prepare a catalytic system; in addition, 2-substituted quinoline salt I, organic boronic acid II or vinyl pinacol borate IV and organic base are added to a reaction sealed tube. Under nitrogen protection, the stirred catalytic system is transferred to the reaction sealed tube, and then the residual catalytic system in the ampoule bottle is washed and transferred with a solvent. Finally, the reaction is placed in a 40-80℃ oil bath and stirred for 24-72h to obtain chiral α,α-disubstituted dihydroquinoline product III or V.

[0027] Based on the above technical solution, preferably, when preparing the catalyst system, part of the solvent is added to the ampoule bottle, and the remaining solvent is used to transfer the catalyst system to wash and transfer the residual catalyst system in the ampoule bottle.

[0028] Based on the above technical solution, preferably, the volume ratio of the partial solvent to the remaining solvent is 1:5 to 1:2.

[0029] Based on the above technical solution, preferably, the residual catalyst system in the ampoule bottle is washed and transferred with a solvent in small amounts and multiple times.

[0030] Beneficial Effects

[0031] The present invention has the following advantages:

[0032] 1. Excellent enantioselectivity and high reaction activity (ee value can reach >99%, yield can reach 99%).

[0033] 2. It is one of the few convenient and efficient strategies for synthesizing chiral α,α-disubstituted dihydroquinolines.

[0034] 3. The synthesis of α,α-disubstituted dihydroquinolines plays an important role in drug development and the preparation of natural products.

[0035] 4. The substrate has a wide range of adaptability, simple and easy operation, convenient product conversion, environmentally friendly reaction, and high catalytic efficiency.

[0036] 5. Mild reaction conditions and low energy consumption.

[0037] Instruction Manual

[0038] Figure 1 Representative product spectra.

[0039] Figure 2 Representative product HPLC chart.

[0040] Figure 3 This is the X-ray diffraction single crystal pattern of the product (R)-3ha. DETAILED DESCRIPTION

[0041] The present invention is described in detail below by examples, but the present invention is not limited to the following examples.

[0042] The preparation of quinoline salts in the following examples is based on quinoline derivatives as raw materials. According to known literature [(a) Y. Wang, Y. Liu, D. Zhang, H. Wei, M. Shi and F. Wang, Angewandte Chemie International Edition, 2016, 55, 3776-3780; (b) DJ Robinson, SP Spurlin, JD Gorden and R. R. Karimov, ACS Catalysis, 2020, 10, 51-55.] procedures, quinoline salts 1a-o can be conveniently synthesized in 1-2 steps. Phenylboronic acid can be purchased from Aladdin or Alfa and used directly in the reaction without treatment.

[0043] Example 1

[0044] Counterion Screening:

[0045] Under nitrogen protection, [Rh(COD)Cl]2, (R)-BINAP and 1,2-dichloroethane (0.5 mL) were added to an ampoule bottle and stirred at room temperature for 0.5 h to prepare a catalytic system; 2-substituted quinoline salt 1, phenylboronic acid 2a and sodium carbonate were added to a reaction tube, and the stirred catalytic system was transferred to the reaction tube under nitrogen protection, and then 1,2-dichloroethane (2.5 mL in total) was used to wash and transfer the residual catalytic system in the ampoule bottle in small amounts and multiple times. Finally, the reaction was placed in a 60°C oil bath and stirred for 24 h to obtain the chiral α,α-disubstituted dihydroquinoline product 3.

[0046] The specific results of counterion screening are shown in Table 1.

[0047]

[0048] Table 1. Screening of counterions

[0049]

[0050] Example 2

[0051] Optimization of conditions: changing base, solvent, chiral ligand and temperature.

[0052] Under nitrogen protection, [Rh(COD)Cl]2, chiral ligand and solvent (0.5mL) were added to an ampoule bottle and stirred at room temperature for 0.5h to prepare a catalytic system; 2-substituted quinoline salt 1a, phenylboronic acid 2a and organic base were added to a reaction tube, and the stirred catalytic system was transferred to the reaction tube under nitrogen protection, and then the residual catalytic system in the ampoule bottle was washed and transferred with a small amount of solvent (2.5mL in total) several times. Finally, the reaction was placed in a 40 or 60℃ oil bath and stirred for 24h to obtain chiral α,α-disubstituted dihydroquinoline product 3aa.

[0053] Optimization of base, solvent, chiral ligand and temperature. The specific results are shown in Table 2.

[0054]

[0055] Table 2. Condition optimization

[0056]

[0057]

[0058] Example 3

[0059] Asymmetric rhodium-catalyzed dearomatization arylation of 2-substituted quinolinyl trifluoromethanesulfonate to synthesize α,α-disubstituted dihydroquinoline:

[0060] Under nitrogen protection, [Rh(COD)Cl]2 (0.005mmol), (R)-SegPhos (0.01mmol) and ethanol (0.5mL) were added to an ampoule bottle and stirred at room temperature for 0.5h to prepare a catalytic system; trifluoromethanesulfonic acid 2-substituted quinoline salt 1 (0.20mmol), arylboronic acid 2 (0.50mmol) and triethylamine (0.50mmol) were added to a reaction tube, and under nitrogen protection, the stirred catalytic system was transferred to the reaction tube, and then washed and transferred with ethanol (2.5mL) in small amounts and multiple times. Finally, the reaction was placed in a 40℃ oil bath and stirred for 24h, the system was cooled to room temperature, filtered with diatomaceous earth, the solution was recovered and the solvent was removed under reduced pressure to obtain a mixed system containing the product, and the mixed system was wet-loaded on a column for separation to obtain a chiral α,α-disubstituted dihydroquinoline product 3.

[0061] When the aryl boronic acid is 2a (Ar is Ph), changing the type of 2-substituted quinoline salt 1 in the reaction gives 8 different experimental groups of chiral α,α-disubstituted dihydroquinoline products 3; when the 2-substituted quinoline salt is 1j (R is Ph, R' is H) and the aryl boronic acid 2 is p-methylphenylboronic acid 2b, 1 different experimental group of chiral α,α-disubstituted dihydroquinoline product 3jb is obtained. When the 2-substituted quinoline salt is 1i (R is Me, R' is H, and there is a substituent at position 4 of quinoline, which is methyl), and the aryl boronic acid is 2a (Ar is Ph), no experimental group of product 3ia is obtained. And when the 2-substituted quinoline salt is 1a (R is Me, R' is H), changing the type of aryl boronic acid 2 in the reaction gives 8 different experimental groups of chiral α,α-disubstituted dihydroquinoline products 3. The specific types of changes are as follows:

[0062]

[0063] Absolute configuration is one of the most basic and important information of a chiral compound. Determining the absolute configuration of the product is also an important part of chiral synthesis, and is of great significance for understanding the properties and physiological activity of the compound. In order to determine the absolute configuration of the dearomatization arylation product of 2-substituted quinoline salt, the obtained solid product (+)-3ha was first dissolved in chloroform (0.3mL), and n-hexane (1.5mL) was slowly added to the system at room temperature, placed outdoors at a temperature of about 5°C, and waited for the solvent to slowly diffuse. A single crystal was obtained after five days. X-ray diffraction determined that the absolute configuration of (+)-3ha was (R)-type (see Figure 3 ). The CCDC number is 2246605. These details are available free of charge from the Cambridge Crystallographic Data Centre at www.ccdc.com.ac.uk / data_request / cif

[0064] Example 4

[0065] 2-Substituted Quinoline Salts and Temperature Screening:

[0066] Under nitrogen protection, [Rh(COD)Cl]2, (R)-SegPhos and ethanol (0.5 mL) were added to an ampoule bottle and stirred at room temperature for 0.5 h to prepare a catalytic system; 2-substituted quinoline salt 1, styryl boronic acid 4a and triethylamine were added to a reaction tube, and the stirred catalytic system was transferred to the reaction tube under nitrogen protection, and then washed with ethanol (2.5 mL in total) in small amounts and multiple times to transfer the residual catalytic system in the ampoule bottle. Finally, the reaction was placed in a 60 or 80 ° C oil bath and stirred for 24 h, the system was cooled to room temperature, filtered with diatomaceous earth, the solution was recovered and the solvent was removed under reduced pressure to obtain a mixed system containing the product, and the mixed system was wet loaded on a column for separation to obtain a chiral α, α-disubstituted dihydroquinoline product 5.

[0067] 2-Substituted quinoline salt and temperature screening, the specific results are shown in Table 3.

[0068] Table 3.2 - Screening of substituted quinoline salts and temperature

[0069]

[0070]

[0071] Example 5

[0072] Asymmetric rhodium-catalyzed dearomatization of 2-substituted quinolinyl tetrafluoroborates to synthesize α,α-disubstituted dihydroquinolines:

[0073] Under nitrogen protection, [Rh(COD)Cl]2 (0.005mmol), (R)-SegPhos (0.01mmol) and ethanol (0.5mL) were added to an ampoule bottle and stirred at room temperature for 0.5h to prepare a catalytic system; in addition, 1,2-dimethylquinolinium tetrafluoroborate 1k (0.20mmol), alkenylboronic acid 4 (0.50mmol) and triethylamine (0.50mmol) were added to a reaction tube, and under nitrogen protection, the stirred catalytic system was transferred to the reaction tube, and then washed and transferred with ethanol (2.5mL) in small amounts and multiple times. The residual catalytic system in the ampoule bottle was finally placed in a 60℃ oil bath and stirred for 24h, the system was cooled to room temperature, filtered with diatomaceous earth, the solution was recovered and the solvent was removed under reduced pressure to obtain a mixed system containing the product, and the mixed system was wet-loaded on a column for separation to obtain a chiral α,α-disubstituted dihydroquinoline product 5.

[0074] The 2-substituted quinoline salt is 1k. By changing the type of alkenyl boronic acid 4 in the reaction, four different chiral α,α-disubstituted dihydroquinoline products 5 are obtained. The specific types of changes are as follows:

[0075]

[0076] Example 6

[0077] Asymmetric rhodium-catalyzed dearomatization of 2-substituted quinolinium tetrafluoroborates 1k with vinyl pinacol borate 4e to synthesize α,α-disubstituted dihydroquinolines 5ke:

[0078] Under nitrogen protection, [Rh(COD)Cl]2 (0.005mmol), (R)-SegPhos (0.01mmol) and ethanol (0.5mL) were added to an ampoule bottle and stirred at room temperature for 0.5h to prepare a catalytic system; in addition, 1,2-dimethylquinolinium tetrafluoroborate 1k (0.20mmol), vinyl pinacol borate 4e (0.50mmol) and triethylamine (0.50mmol) were added to a reaction tube, and under nitrogen protection, the stirred catalytic system was transferred to the reaction tube, and then washed with ethanol (2.5mL) in small amounts and multiple times to transfer the residual catalytic system in the ampoule bottle. Finally, the reaction was placed in a 60℃ oil bath and stirred for 24h, the system was cooled to room temperature, filtered with diatomaceous earth, the solution was recovered and the solvent was removed under reduced pressure to obtain a mixed system containing the product, and the mixed system was wet-loaded on a column for separation to obtain a chiral α,α-disubstituted dihydroquinoline product 5ke.

[0079]

[0080] Example 7

[0081] Temperature screening:

[0082] Under nitrogen protection, [Rh(COD)Cl]2, (R)-SegPhos and ethanol were added to an ampoule bottle and stirred at room temperature for 0.5h to prepare a catalytic system; N-benzyl 2-methylquinoline salt 1n, phenylboronic acid 2a and triethylamine were added to a reaction tube, and the stirred catalytic system was transferred to the reaction tube under nitrogen protection, and then washed with ethanol in small amounts and multiple times and the residual catalytic system in the ampoule bottle was transferred. Finally, the reaction was placed in a 40 or 60°C oil bath and stirred for 24h, the system was cooled to room temperature, filtered with diatomaceous earth, the solution was recovered and the solvent was removed under reduced pressure to obtain a mixed system containing the product, and the mixed system was wet-loaded on a column for separation to obtain a chiral α,α-disubstituted dihydroquinoline product 3.

[0083] Temperature screening, specific results are shown in Table 4.

[0084] Table 4. Temperature screening

[0085]

[0086]

[0087] Example 8

[0088] Asymmetric Rhodium-Catalyzed Dearomatization and Arylation of N-Benzyl 2-Methylquinolium Bromide to Synthesize α,α-Disubstituted Dihydroquinolines:

[0089] Under nitrogen protection, [Rh(COD)Cl]2 (0.005mmol), (R)-SegPhos (0.01mmol) and ethanol (0.5mL) were added to an ampoule bottle and stirred at room temperature for 0.5h to prepare a catalytic system; N-benzyl 2-methylquinoline salt 1n (0.20mmol), arylboronic acid 2 (0.50mmol) and triethylamine (0.50mmol) were added to a reaction tube, and the stirred catalytic system was transferred to the reaction tube under nitrogen protection, and then washed and transferred with ethanol (2.5mL) in small amounts and multiple times. The residual catalytic system in the ampoule bottle was finally placed in an 80℃ oil bath and stirred for 24h, the system was cooled to room temperature, filtered with diatomaceous earth, the solution was recovered and the solvent was removed under reduced pressure to obtain a mixed system containing the product, and the mixed system was wet-loaded on a column for separation to obtain a chiral α,α-disubstituted dihydroquinoline product 3.

[0090] The 2-substituted quinoline salt is 1n, and the type of the arylboronic acid 2 in the reaction is changed to obtain 6 different chiral α,α-disubstituted dihydroquinoline products 3. The specific types of changes are as follows:

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

Claims

1. A method for preparing a chiral α,α-disubstituted dihydroquinoline, characterized in that: [Rh(COD)Cl]2 or Rh(COD)2BF4 and chiral ligands are used as catalyst systems, organic bases are used as bases, 2-substituted quinoline salts I are used as substrates, organic boronic acids II or vinyl pinacol borate esters IV are used as nucleophiles, and α,α-disubstituted dihydroquinoline compounds III or V are synthesized through asymmetric nucleophilic addition dearomatization reactions; The reaction formula is as follows: Where: X is a trifluoromethanesulfonate anion, a tetrafluoroborate anion, a hexafluorophosphate anion, or a bromide anion; R 1 is methyl or benzyl; R 2 is phenyl, benzyl, phenylpropyl or C1-C 20 At least one of the alkyl groups; Ar is an unsubstituted aromatic ring or an aromatic ring containing a substituent, wherein the substituent in the aromatic ring containing a substituent is methyl, methoxy or halogen; R is 2-naphthyl, 3-thienyl, an unsubstituted aromatic ring, an aromatic ring containing a substituent, an unsubstituted vinyl, or a vinyl containing an aromatic substituent, the substituent in the aromatic ring containing a substituent is a halogen, a methoxy group or a methyl group, and the aromatic substituent in the vinyl containing an aromatic substituent is a phenyl, p-methylphenyl, p-chlorophenyl or p-methoxyphenyl group.

2. The method according to claim 1, characterized in that: X is trifluoromethanesulfonate anion, R 1 and R 2 is methyl, R is phenyl, and Ar is phenyl.

3. The method according to claim 1, characterized in that The specific steps of the method are: Under nitrogen protection, [Rh(COD)Cl]2 or Rh(COD)2BF4, a chiral ligand and a solvent are added to an ampoule, and stirred at room temperature for 0.5-1h to prepare a catalytic system; in addition, 2-substituted quinoline salt I, organic boronic acid II or vinyl pinacol borate IV and an organic base are added to a reaction sealed tube, and under nitrogen protection, the stirred catalytic system is transferred to the reaction sealed tube, and then the residual catalytic system in the ampoule is washed and transferred with a solvent; finally, the reaction is placed in a 40-80°C oil bath and stirred for 24-72h to obtain a chiral α,α-disubstituted dihydroquinoline product.

4. The method according to claim 1 or 3, characterized in that: The amount of [Rh(COD)Cl]2 or Rh(COD)2BF4 used is 1.25-5.0% of the molar amount of 2-substituted quinoline salt I, and the amount of chiral ligand used is 5.0-6.0% of the molar amount of 2-substituted quinoline salt I.

5. The method according to claim 1 or 3, characterized in that: The concentration of the 2-substituted quinoline salt I in the solvent is 0.05-0.07 mol / L.

6. The method according to claim 1 or 3, characterized in that: The molar ratio of 2-substituted quinoline salt I, organic boronic acid II or vinyl pinacol borate IV and organic base is 1:2.5:2.

5.

7. The method according to claim 3, characterized in that The chiral ligand is (R)-SegPhos, (R)-BINAP, (R)-P-Phos, (S)-DifluorPhos or (R,R)-Ph-BPE.

8. The method according to claim 3, characterized in that The organic base is triethylamine, N,N-diisopropylethylamine, sodium carbonate or cesium carbonate.

9. The method according to claim 1, characterized in that: The reaction solvent is ethanol, 1,2-dichloroethane, tetrahydrofuran or toluene.

10. The method according to claim 3, characterized in that: The residual catalyst system in the ampoule was washed and transferred several times with solvent.

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