A cobalt-catalyzed migratory asymmetric spirocyclization method of quinoline compounds

Abstract

This invention discloses a cobalt-catalyzed migration asymmetric spirocyclic cyclocyclization method for quinoline compounds. This method utilizes a cobalt and ligand combination catalysis to achieve migration asymmetric spirocyclic cyclocyclization of quinoline compounds, belonging to the fields of organic chemistry and medicinal chemistry. Under the influence of a cobalt source, chiral ligands, achiral ligands, reducing agents, and additives, this invention enables the reaction of aryl / alkenyl-substituted quinolines / intramolecularly migrating quinolines with different alkynes in organic solvents, yielding a series of spirocyclic chiral dihydroquinoline compounds with excellent enantioselectivity and good yields. This invention only requires different ligands to regulate the reaction, enabling migration asymmetric dearomatization spirocyclic cyclocyclization from aryl to aryl, migration asymmetric dearomatization spirocyclic cyclocyclization from aryl to alkenyl, and intramolecular migration asymmetric dearomatization spirocyclic cyclocyclization reactions. It has a wide substrate applicability and produces diverse product structures, providing a novel and universal method for the systematic synthesis of chiral spirocyclic dihydroquinoline compounds.

Description

Technical Field

[0001] The method of this invention belongs to the fields of organic chemistry and medicinal chemistry. It uses cobalt and different ligand combinations to catalyze the migration asymmetric dearomatization spirocyclization reaction of quinoline and alkyne, as well as the intramolecular migration asymmetric dearomatization spirocyclization reaction of quinoline, to obtain important enantiomeric enriched spirocyclic dihydroquinoline, which has a very wide range of applications. Background Technology

[0002] Chiral nitrogen-containing three-dimensional heterocycles (such as hydrogenated pyridine and hydrogenated (iso)quinoline) are widely found structural units in pharmaceuticals, agrochemicals, natural products, and organic materials. One of the most effective strategies for constructing such structures is the catalytic asymmetric dearomatization of planar nitrogen-containing aromatics. The intermolecular asymmetric 1,2-nucleophilic addition dearomatization of activated pyridinium or quinolineium salts catalyzed by transition metals has been extensively studied. Chiral spirocyclic skeletons, with their rigid structures, precise stereochemical recognition capabilities, and uniquely expandable three-dimensional chemical space, are highly valuable in ligand and catalyst design and drug development. However, their structural compactness and conformational constraints also present significant synthetic challenges, particularly in the synthesis of spirocyclic hydrogenated quinolines—a dominant skeleton among many bioactive molecules.

[0003] The reported synthetic methods for chiral spirocyclic dihydroquinoline compounds mainly include the following two:

[0004] In 2021, Zhaomin Hou's research group (S.-J. Lou, G. Luo, Z. Hou, J. Am. Chem. Soc. 2021, 143, 20462.) developed a novel method for synthesizing chiral spirocyclic dihydroquinoline compounds. They used chiral scandium complexes as catalysts to achieve the synthesis of chiral spirocyclic dihydroquinoline compounds via cyclization and dearomatization of quinoline and alkyne. However, the synthesis of this chiral scandium complex is cumbersome, difficult, and extremely sensitive to water and oxygen, thus hindering the widespread use of this method.

[0005] In 2022, Jia Yixia's research group (P. Yang, Q. Wang, B.-H. Cui, X.-D. Zhang, H. Liu, Y.-Y. Zhang, J.-L. Liu, W.-Y. Huang, R.-X. Liang, Y.-X. Jia, J. Am. Chem. Soc. 2022, 144, 1087.) developed a cobalt-catalyzed reductive alkyne dearomatic cyclization reaction of aryl halides and alkynes, achieving the synthesis of a series of chiral spirocyclic dihydroquinoline compounds. Although this method is easier to implement and apply than Hou's work, the limited product structures and the difficulty in synthesizing starting materials are undeniable drawbacks. Therefore, developing new universal synthetic methods to achieve the simplified synthesis of various types of chiral spirocyclic dihydroquinoline compounds is of great significance. Summary of the Invention

[0006] The purpose of this invention is to provide a cobalt-catalyzed 1,4-migration asymmetric dearomatization spirocyclic cyclocyclication method for quinoline compounds. Employing a ligand relay catalysis strategy, this method utilizes the migration dearomatization cyclization reaction of nitrogen-containing aromatic hydrocarbons as a novel pathway for the synthesis of enantiomeric enriched spirocyclic hydrogen quinolines. Through substrate design and optimization of reaction conditions, various types of chiral spirocyclic dihydroquinoline compounds can be constructed. This method uses inexpensive and readily available raw materials, is simple to operate, has a broad substrate range and good functional group compatibility, and exhibits excellent enantioselectivity and good yields. The cobalt-catalyzed 1,4-migration asymmetric dearomatization spirocyclic cyclo ... Chiral spirocyclic dihydroquinoline structures are widely found in many natural products and alkaloids, and are also the core skeleton of a class of highly efficient chiral ligands, which is of great significance and is expected to be used in the synthesis of natural products and drug molecules.

[0007] This invention uses inexpensive transition metal cobalt as a catalyst, with mild and simple conditions, good functional group compatibility, and easy operation.

[0008] One of the technical solutions adopted by the present invention to achieve the above-mentioned objectives is as follows: a cobalt-catalyzed migration asymmetric dearomatization spirocyclic method for quinoline compounds, comprising the following steps: in an inert gas atmosphere, dissolving a cobalt-based catalyst, a migrating ligand L, a chiral ligand L*, a reducing agent, and an additive in an organic solvent, and then adding a 2-aryl-substituted quinoline compound. Or 2-alkenyl-substituted quinoline compounds or intramolecular migration of dearomatic substrates aryl-substituted alkynes or alkyl-substituted alkynes As a substrate, a reaction mixture was obtained, which was then post-processed and purified to yield the target enantiomeric enriched aryl-to-aryl migrating spirocyclic chiral dihydroquinoline product. or its enantiomer ;

[0009] Aryl to alkenyl migration spirocyclic chiral dihydroquinoline products or its enantiomer ;

[0010] Intramolecular aryl-to-aryl migration spirocyclic chiral dihydroquinoline products or its enantiomer ;

[0011] Wherein, X is a leaving group, which is any one of bromine atom, iodine atom, or trifluoromethanesulfonate group;

[0012] Among them, R 1 R 2 It is a terminal substituent of an alkyne, and can be any one of hydrogen atom, alkyl, aryl, ester, amide, amino, protected amino, or silyl ether.

[0013] When Ar is aryl, the substituent on the aryl group is any one of chlorine atom, (hetero)aryl, (fluorine-containing)alkyl, (thio)ether, ketone, aldehyde, ester, amide, or cyano; when Ar is heteroaryl, it is any one of pyridine or pyrimidine, and the substituent on the heteroaryl group is any one of chlorine atom, fluorine atom, (fluorine-containing)alkyl, or alkoxy.

[0014] The non-chiral ligand L is any one of the following:

[0015]

[0016]

[0017]

[0018] The chiral ligand L* is any one of the following:

[0019]

[0020]

[0021] The preparation route of the cobalt-catalyzed migration asymmetric spirocyclization method for quinoline compounds can be any one of the following:

[0022] Preparation route 1:

[0023]

[0024] Preparation route 2:

[0025]

[0026] Preparation route 3:

[0027]

[0028] The chiral ligand L * 78 is a Phox ligand with the following structural formula: or its enantiomer or chiral ligand L * 81 for or its enantiomer or chiral ligand L * 82 for or its enantiomer .

[0029] Preferred preparation route 1:

[0030]

[0031] In Route 1, the molar ratio of quinoline 1 to alkyne 2 is 1:2, CoI2 is cobalt-based catalyst cobalt iodide, and the achiral migrating ligand L2 is... The chiral ligand L*78 is or its enantiomer Mn is the reducing agent manganese powder, NaI is the additive sodium iodide, and acetonitrile is the solvent;

[0032] The aryl-substituted quinoline 1 is specifically:

[0033]

[0034] The alkyne 2 is specifically:

[0035]

[0036] The product 3 is specifically:

[0037]

[0038] Preparation route 2:

[0039]

[0040] In route 2, the molar ratio of quinoline 1 to alkyne 2 is 1:2, CoI2 is cobalt-based catalyst cobalt iodide, and the achiral migrating ligand L2 is... The chiral ligand L*81 is or its enantiomer Mn is the reducing agent manganese powder, NaI is the additive sodium iodide, and acetonitrile is the solvent;

[0041] The alkenyl-substituted quinoline 4 is specifically:

[0042]

[0043] The alkyne 2 mentioned above is specifically:

[0044] Specifically, product 5 is:

[0045] Preparation route 3:

[0046]

[0047] In Route 3, quinoline 6 is 1.0 equivalent, CoI2 is cobalt iodide (a cobalt-based catalyst), and the chiral ligand L*82 is... or its enantiomer Mn is the reducing agent manganese powder, NaI and TMSCl are the additives sodium iodide and trimethylchlorosilane, and acetonitrile is the solvent.

[0048] The intramolecular migration-substituted quinoline 6 specifically refers to:

[0049]

[0050] Product 7 is specifically:

[0051]

[0052] Preferably, the cobalt salt is any one of cobalt iodide, cobalt bromide, cobalt bromide ethylene glycol dimethyl ether complex, cobalt chloride, cobalt chloride ethylene glycol dimethyl ether complex, cobalt trifluoromethanesulfonate, and cobalt tetrafluoroborate.

[0053] The reducing agent is any one of manganese powder, zinc powder, indium powder, and magnesium powder.

[0054] The additives are one or more of the following: lithium chloride, sodium chloride, lithium bromide, potassium bromide, magnesium bromide, magnesium bromide hydrate, lithium iodide, sodium iodide, zinc iodide, magnesium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, sodium acetate, potassium acetate, methanol, isopropanol, tert-butanol, lithium hexafluorophosphate, and trimethylchlorosilane.

[0055] The solvent is one or more of acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, chloroform, and N-methylpyrrolidone.

[0056] Beneficial effects:

[0057] 1. The reaction does not require the use of highly active metal reagents, the reactants are readily available, the functional groups are highly compatible, and the product can be obtained with excellent yield and enantioselectivity.

[0058] 2. The alkynes mentioned are inexpensive, commercially available, or have simple synthetic routes.

[0059] 3. The cobalt-catalyzed migration asymmetric spirocyclization method for quinoline compounds described above can achieve the synthesis of various types of chiral spirocyclic dihydroquinoline compounds through substrate design, with a range far exceeding that of existing synthetic methods.

[0060] 4. This reaction activation mode utilizes two structurally simple ligands with different functions: one promotes 1,4-cobalt / hydrogen migration, and the other drives subsequent asymmetric dearomatization and spirocyclic cyclication. The ligands are single-function and highly efficient. The role of the achiral ligand L is to coordinate with metallic cobalt, achieving 1,4-Co / H migration during the reaction. The chiral ligand L... * Its function is to coordinate with metallic cobalt, control chirality during the reaction, and achieve enantioselective spirocyclization through ligand relay migration in 1,4-Co / H in a two-step reaction.

[0061] 5. By regulating the ligands, asymmetric spirocyclization from aryl to aryl, asymmetric spirocyclization from aryl to alkenyl, and intramolecular asymmetric spirocyclization from aryl to aryl can be achieved, with a wide range of applications.

[0062] 6. All reducing agents mentioned are manganese powder; other reducing agents are not ideal. In routes 1-3, when zinc powder (Zn) and indium powder (In) are used,

[0063] No target product was generated.

[0064] 7. As can be seen from Example 1, both the migrating ligand L2 and the chiral ligand L*78 are essential; using only one ligand cannot yield the product. Replacing the migrating ligand L2 with other racemic ligands, such as L3 and L43, reduces the yield. Replacing the chiral ligand L*78 with other ligands, such as L*85 and L*93, reduces both the yield and the ee value. Replacing cobalt iodide with cobalt chloride reduces the yield. Using zinc powder as a reducing agent does not yield the product. Without sodium iodide, only a small amount of product is obtained. Attached Figure Description

[0065] The present invention will be further described below with reference to the accompanying drawings.

[0066] Figure 1 The H spectrum is that of the product in Example 1;

[0067] Figure 2 The C spectrum is that of the product of Example 1;

[0068] Figure 3This is the H spectrum of the product from Example 2;

[0069] Figure 4 The C spectrum is that of the product in Example 2;

[0070] Figure 5 The H spectrum is that of the product in Example 3;

[0071] Figure 6 This is the C spectrum of the product from Example 3;

[0072] Figure 7 The H spectrum is that of the product in Example 4;

[0073] Figure 8 This is the C spectrum of the product from Example 4;

[0074] Figure 9 This is the H spectrum of the product from Example 5;

[0075] Figure 10 This is the C spectrum of the product from Example 5;

[0076] Figure 11 The H spectrum is that of the product in Example 6;

[0077] Figure 12 The C spectrum is that of the product in Example 6;

[0078] Figure 13 The H spectrum is that of the product in Example 7;

[0079] Figure 14 The C spectrum is that of the product in Example 7;

[0080] Figure 15 The H spectrum is that of the product in Example 8;

[0081] Figure 16 The C spectrum is that of the product in Example 8;

[0082] Figure 17 The H spectrum is that of the product in Example 9;

[0083] Figure 18 The C spectrum is that of the product in Example 9;

[0084] Figure 19 This is the H spectrum of the product from Example 10;

[0085] Figure 20 The C spectrum of the product in Example 10;

[0086] Figure 21 This is the H spectrum of the product from Example 11;

[0087] Figure 22 The C spectrum of the product in Example 11;

[0088] Figure 23 This is the F-spectrum of the product of Example 11;

[0089] Figure 24 This is the H spectrum of the product from Example 12;

[0090] Figure 25 This is the C spectrum of the product from Example 12;

[0091] Figure 26 This is the H spectrum of the product from Example 13;

[0092] Figure 27 The C spectrum of the product in Example 13;

[0093] Figure 28 The F spectrum of the product in Example 13;

[0094] Figure 29 This is the H spectrum of the product from Example 14;

[0095] Figure 30 The C spectrum of the product in Example 14;

[0096] Figure 31 The F spectrum of the product in Example 14;

[0097] Figure 32 This is the C spectrum of the product from Example 15;

[0098] Figure 33 This is the H spectrum of the product from Example 15;

[0099] Figure 34 This is the H spectrum of the product from Example 16;

[0100] Figure 35 The C spectrum of the product in Example 16;

[0101] Figure 36 This is the H spectrum of the product from Example 17;

[0102] Figure 37 The C spectrum of the product in Example 17;

[0103] Figure 38 This is the H spectrum of the product from Example 18;

[0104] Figure 39 The C spectrum of the product in Example 18;

[0105] Figure 40 This is the F-spectrum of the product of Example 18;

[0106] Figure 41 This is the H spectrum of the product from Example 19;

[0107] Figure 42 The C spectrum of the product in Example 19;

[0108] Figure 43 This is the H spectrum of the product from Example 20;

[0109] Figure 44 This is the C spectrum of the product from Example 20;

[0110] Figure 45 This is the H spectrum of the product from Example 21;

[0111] Figure 46 This is the C spectrum of the product of Example 21;

[0112] Figure 47 This is the H spectrum of the product from Example 22;

[0113] Figure 48 This is the C spectrum of the product of Example 22;

[0114] Figure 49 This is the H spectrum of the product from Example 23;

[0115] Figure 50 The C spectrum of the product in Example 23;

[0116] Figure 51 This is the H spectrum of the product from Example 24;

[0117] Figure 52 This is the C spectrum of the product of Example 24;

[0118] Figure 53 This is the H spectrum of the product from Example 25;

[0119] Figure 54 The C spectrum of the product in Example 25; Detailed Implementation

[0120] The features and advantages of the present invention will be further understood through the following detailed description. The provided embodiments are merely illustrative of the method of the present invention and do not limit the rest of the content disclosed herein in any way.

[0121] In the following examples, CoI2 refers to cobalt iodide, dppe refers to 1,2-bis(diphenylphosphine)ethane, Mn refers to manganese powder, NaI refers to sodium iodide, CH3CN refers to acetonitrile, equiv refers to equivalent number, and L * ligands are or , or , or One of them.

[0122] Example 1

[0123]

[0124] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and the achiral ligand L2 were added to the reaction tube. (2.0 mg, 2.5 mol%), chiral ligand L78 * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (43.1 mg, yellow oily liquid, yield 75%) was obtained by column chromatography. The ee value of the target product was determined (97%). 1 H NMR (500 MHz, CDCl3) δ 7.52 – 7.44(m, 1H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.11 (td,J = 7.5, 1.0 Hz, 1H), 6.95 – 6.91 (m, 2H), 6.59 – 6.55 (m, 2H), 6.32 (d, J =8.0 Hz,1H), 5.02 (d, J = 9.5 Hz, 1H), 3.67 (s, 1H), 2.52 – 2.39 (m, 4H), 1.19(t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H) ppm; 13 C NMR (126 MHz, CDCl3) δ153.1, 151.4, 143.9, 142.1, 136.9, 128.6, 128.3, 127.1, 126.5, 125.7, 125.6,124.0, 118.8, 118.6, 116.9, 112.1, 70.7, 18.7, 18.6, 15.2, 13.6 ppm; HRMS(ESI) calcd. for C 21 H 22 N + [M+H] +m / z 288.1747, found 288.1740; IR (neat, cm -1 )3384, 2909, 1665, 1466, 737, 512, 447; [α] D 25 = +144.3 (c = 1.0, CHCl3); 97%ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 254 nm UV detector, t R (major) = 9.9 min, t R (minor) = 9.1 min.

[0125] Product 3a from Example 1 is a chiral spirocyclic dihydroquinoline compound. This type of structure can serve as the core framework for chiral ligands and is applicable to various metal-catalyzed asymmetric coupling reactions. Therefore, we prepared compound 11a and used it as a ligand for iridium-catalyzed asymmetric allyl amination reactions. Its application in a specific reaction, preparing chiral allylamine 13 with high enantioselectivity, is detailed below:

[0126]

[0127] According to known literature, under a nitrogen atmosphere, 3a (0.2 mmol, 57.4 mg) was dissolved in THF (1 mL) and heated at -78°C. o C drip in n BuLi (0.2 mmol, 1 equiv) was stirred for 30 minutes, then phosphorus trichloride (PCl3, 0.2 mmol, 27.4 mg) was added, and the mixture was slowly brought to room temperature and reacted for 3 hours. The reaction solution was then cooled to -78°C. o C. Add a toluene solution (0.4 mL) of R-1,1'-bi-2-naphthol [(R)-BINOL, 0.2 mmol, 57.2 mg], slowly restore to room temperature, then stir overnight, add water to quench the reaction, extract with ethyl acetate, concentrate under reduced pressure to remove the reaction solvent, and separate and purify by column chromatography to obtain the target product 11a, which is a novel chiral phosphine ligand. 1H NMR (500 MHz, CDCl3) δ 7.88 – 7.79 (m, 3H), 7.71(d, J = 8.8 Hz, 1H), 7.43 – 7.34 (m, 3H), 7.28 (q, J = 8.3, 7.8 Hz, 3H), 7.24– 7.07 (m, 6H), 6.89 (dd, J = 7.4, 1.7 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H),6.57 (td, J = 7.4, 1.0 Hz, 1H), 6.49 (d, J = 9.7 Hz, 1H), 5.97 (ddd, J = 8.7,7.4, 1.7 Hz, 1H), 5.06 (dd, J = 9.7, 5.0 Hz, 1H), 2.79 – 2.66 (m, J = 7.4 Hz,2H), 2.54 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H), 1.19 (t, J = 7.6 Hz,3H) ppm; 13 C NMR (126 MHz, CDCl3) δ 153.2 – 152.5 (m), 150.3 (d, J = 6.4 Hz),149.9, 142.1 (d, J = 1.5 Hz), 140.2 (d, J = 4.1 Hz), 139.0 (d, J = 8.6 Hz),133.0 – 132.9 (m), 132.7 (m), 131.6, 130.7, 130.6, 130.3, 128.4, 128.2 (d, J= 2.5 Hz), 128.0 (d, J = 6.3 Hz), 127.4, 127.3, 127.1, 127.1, 126.2, 126.2,125.7, 125.7, 125.1, 124.6, 124.6, 123.9 (d, J = 2.5 Hz), 123.2, 122.4, 122.3(d, J = 2.3 Hz), 121.2 (d, J = 1.9 Hz), 121.0 (d, J = 2.1 Hz), 120.9, 119.2,74.3 (d, J = 40.4 Hz), 20.2 (d, J = 8.8 Hz), 18.9, 15.2, 13.2 ppm; 31P NMR (202MHz, CDCl3) δ 146.7 ppm; IR (neat, cm -1 ) 2965, 1486, 1226, 944, 749; [α] D 25 = –147.6 (c = 1.0, CHCl3); HRMS (ESI) calcd. for C 41 H 33 NO2P + [M+H] + m / z 602.2243, found 602.2240.

[0128]

[0129] The synthesized novel chiral phosphine ligand was applied to an asymmetric allyl amination reaction. Following existing literature, under a nitrogen atmosphere, 1,5-cyclooctadiene iridium chloride dimer (3.4 mg, 2.5 mol%), chiral phosphine ligand 11a (6.0 mg, 5 mol%), propylamine (0.5 mL), and THF (0.5 mL) were added to a reaction tube. The reaction mixture was heated to 50 °C. o Heating at C for 30 minutes, then removing the volatile solvent under vacuum, yielded a yellow solid. Allyl propyl carbonate (44.1 mg, 0.20 mmol), aniline (37.3 mg, 0.40 mmol), and THF (1 mL) were added to the reaction tube, and heated at 50 °C. o The mixture was stirred at C for 12 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product was obtained by column chromatography (26.4 mg, yellow oily liquid, yield 63%). The ee value of the target product was measured (88%). 1 H NMR (400 MHz, CDCl3) δ 7.47 – 7.21(m, 5H), 7.13 (dd, J = 8.6, 7.3 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.59 (d, J= 7.8 Hz, 2H), 6.07 – 5.99 (m, 1H), 5.31 – 5.17 (m, 2H), 4.93 (d, J = 5.9 Hz,1H), 4.02 (br, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ 147.3, 142.0, 139.2, 129.2,128.9, 127.6, 127.3 117.8, 116.2, 113.7, 61.0 ppm; IR (neat, cm -1 ) 3410, 1600,1501, 748, 692; [α] D 25 = +10.2 (c = 1.0, CHCl3); 88% ee; HRMS (ESI) calcd. forC 15 H 16 N + [M+H] + m / z 210.1277, found 210.1280; HPLC analysis: CHIRALCEL ® OD-H column, 2% i PrOH in n-hexane, 0.8 mL / min, 254 nm UV detector, t R (major) = 12.0 min, t R (minor) = 11.2 min.

[0130]

[0131] Both the migrating ligand L2 and the chiral ligand L*78 are essential; using either ligand alone will not yield the product. Replacing the migrating ligand L2 with other racemic ligands, such as L3 or L43, reduces the yield. Replacing the chiral ligand L*78 with other ligands, such as L*85 or L*93, reduces both the yield and the ee value. Replacing cobalt iodide with cobalt chloride reduces the yield. Using zinc powder as a reducing agent will not yield the product. Without sodium iodide, only a small amount of product can be obtained.

[0132] Example 2

[0133]

[0134] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * (7.5 mg, 10 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2b, 21.6 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (37.3 mg, yellow oily liquid, yield 72%) was obtained by column chromatography. The ee value of the target product was determined (95%). 1 H NMR (500 MHz, CDCl3) δ 7.47 (dt, J = 7.8, 1.1Hz, 1H), 7.25 (tt, J = 7.5, 1.1 Hz, 1H), 7.11 (t, J = 7.2 Hz, 2H), 6.92 (t, J= 7.1 Hz, 2H), 6.60 – 6.54 (m, 2H), 6.33 (d, J = 7.9 Hz, 1H), 4.97 (d, J =10.3 Hz, 1H), 3.65 (s, 1H), 1.96 (s, 3H), 1.93 (s, 3H) ppm; 13 C NMR (126 MHz, CDCl3) δ 152.6, 146.5, 143.9, 143.4, 130.1, 128.6, 128.4, 127.1, 126.9,125.5, 125.3, 123.8, 118.8, 118.4, 117.0, 112.2, 70.3, 10.5, 10.3 ppm; HRMS(ESI) calcd. for C 19 H 18 N + [M+H] + m / z 260.1434, found 260.1428; IR (neat, cm -1 )3389, 2909, 1601, 1466, 737, 447; [α] D 25 = +223.8 (c = 1.0, CHCl3); 95% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% iPrOH in n-hexane, 0.5 mL / min, 220nm UV detector, t R (major) = 11.5 min, t R (minor) = 10.6 min.

[0135] Example 3

[0136]

[0137] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2c, 44.1 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (39.7 mg, yellow oily liquid, yield 63%) was obtained by column chromatography. The ee value of the target product was determined (93%). 1 H NMR (400 MHz, CDCl3) δ 7.47 (dt, J = 7.6, 0.8Hz, 1H), 7.24 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (dt, J = 7.6, 0.8 Hz, 1H), 7.10(td, J = 7.2, 1.2 Hz, 1H), 6.96 –6.91 (m, 2H), 6.59 – 6.54 (m, 2H), 6.32 (d,J = 7.6 Hz, 1H), 5.02 (dd, J = 9.6, 2.0 Hz, 1H), 3.65 (s, 1H), 2.48 – 2.33(m, 4H), 1.66 – 1.53 (m, 4H), 1.00 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 153.0, 150.6, 144.0, 142.2, 136.0, 128.6,128.3, 127.0, 126.5, 126.0, 125.5, 123.9, 119.0, 118.6, 116.9, 112.2, 70.7,28.1, 27.6, 23.4, 22.0, 14.9, 14.5 ppm; HRMS (ESI) calcd. for C 23 H 26 N + [M+H] + m / z 316.2060, found 316.2052; IR (neat, cm -1 ) 3389, 2957, 1464, 740, 513; [α] D 25 =+93.2 (c = 1.0, CHCl3); 93% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 254 nm UV detector, t R (major) = 8.4 min, t R (minor) = 8.0 min.

[0138] Example 4

[0139]

[0140] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2d, 66.5 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (46.1 mg, yellow oily liquid, yield 62%) was obtained by column chromatography. The ee value of the target product was determined (97%). 1 H NMR (400 MHz, CDCl3) δ 7.47 (dt, J = 7.2, 0.8Hz, 1H), 7.24 (td, J = 7.6, 1.2 Hz, 1H), 7.15 (dt, J = 7.6, 1.2 Hz, 1H), 7.10(td, J = 7.6, 1.2 Hz, 1H), 6.95 – 6.91 (m, 2H), 6.59 – 6.55 (m, 2H), 6.32(dd, J = 7.6, 0.8 Hz, 1H), 5.01 (d, J = 9.6 Hz, 1H), 3.65 (s, 1H), 2.49 –2.31 (m, 4H), 1.59 – 1.50 (m, 4H), 1.40 – 1.35 (m, 4H), 1.27 – 1.21 (m, 4H), 0.93 – 0.90 (m, 3H), 0.85 – 0.81 (m, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 153.0,150.6, 144.0, 142.4, 136.0, 128.6, 128.3, 127.0, 126.5, 125.9, 125.5, 123.9,118.9, 118.7, 116.9, 112.2, 70.7, 32.5, 32.3, 29.8, 28.5, 25.9, 25.6, 22.7,22.5, 14.2, 14.1 ppm; HRMS (ESI) calcd. for C 27 H 34 N + [M+H] + m / z 372.2686, found372.2676; IR (neat, cm-1 ) 2856, 1636, 1466, 739, 513; [α] D 25 = +102.2 (c = 1.0,CHCl3); 97% ee; HPLC analysis: CHIRALCEL ® OJ-H column, 1% i PrOH in n-hexane,0.5 mL / min, 254 nm UV detector, t R (major) = 10.0 min, t R (minor) = 16.9 min.

[0141] Example 5

[0142]

[0143] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2e, 77.7 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (51.1 mg, yellow oily liquid, yield 64%) was obtained by column chromatography. The ee value of the target product was determined to be 91%. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.2 Hz,1H), 7.26 – 7.22 (m, 1H), 7.16 – 7.08 (m, 2H), 6.95 – 6.91 (m, 2H), 6.59 –6.55 (m, 2H), 6.32 (d, J = 8.0 Hz, 1H), 5.01 (dd, J = 9.6, 1.6 Hz, 1H), 3.65(s, 1H), 2.47 – 2.33 (m, 4H), 1.60 – 1.50 (m, 4H), 1.43 – 1.36 (m, 2H), 1.35– 1.30 (m, 4H), 1.27 – 1.19 (m, 6H), 0.93 – 0.88 (t, J = 6.8 Hz, 3H), 0.84(t, J = 6.8 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 153.0, 150.6, 144.0, 142.4,135.9, 128.6, 128.3, 127.0, 126.5, 125.9, 125.5, 123.9, 118.9, 118.7, 116.9,112.2, 70.7, 31.9, 31.7, 30.1, 30.0, 29.8, 28.8, 25.9, 25.6, 22.8, 22.7, 14.2ppm;HRMS (ESI) calcd. for C 29 H 38 N + [M+H] + m / z 400.2999, found 400.2990;IR(neat, cm -1 ) 3389, 2925, 1602, 1467, 741, 454;[α] D 25 = +102.7 (c = 1.0, CHCl3);91% e.e.;HPLC analysis: CHIRALPAK ® AD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 220 nm UV detector, t R (major) = 7.4 min, t R(minor) = 8.0 min.

[0144] Example 6

[0145]

[0146] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2f, 56.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (51.1 mg, yellow oily liquid, yield 52%) was obtained by column chromatography. The ee value of the target product was determined (97%). 1 H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 7.3 Hz, 1H), 7.17 (td, J = 7.2, 1.1 Hz, 1H), 7.12 (d, J = 7.0 Hz, 1H), 7.04 (td, J =7.3, 1.2 Hz, 1H), 6.86 (ddd, J = 10.1, 5.8, 2.0 Hz, 2H), 6.53 – 6.47 (m, 2H), 6.26 (d, J = 7.8 Hz, 1H), 4.92 (d, J = 9.7 Hz, 1H), 3.65 (s, 1H), 3.60 (t, J= 6.3 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 2.45 (ddd, J = 10.0, 7.8, 4.7 Hz,3H), 2.38 – 2.31 (m, 1H), 1.69 (ddt, J = 12.7, 10.3, 6.4 Hz, 4H), 0.85 (s,9H), 0.78 (s, 9H), 0.00 (s, 6H), -0.08 (d, J = 4.6 Hz, 6H) ppm; 13C NMR (126MHz, CDCl3) δ 153.1, 150.4, 143.9, 142.1, 135.7, 128.7, 128.3, 127.1, 126.6,125.7 125.6, 123.9, 119.0, 118.6, 117.0, 112.2, 70.8, 63.5, 62.9, 33.3, 31.9,26.2, 26.1, 26.1, 22.2, 21.7, 18.5, 18.4, -5.1, -5.2 ppm; HRMS (ESI) calcd.for C 23 H 26 NO2 + [M+H] + m / z 348.1958, found 348.1955; IR (neat, cm -1 ) 3378, 2925,1601, 1469, 1056, 746; [α] D 25 = +125.8 (c = 1.0, CHCl3); 97% ee; HPLC analysis: CHIRALPAK ® AD-H column, 20% i PrOH in n-hexane, 0.8 mL / min, 254 nm UVdetector, t R (major) = 29.1 min, t R (minor) = 16.2 min.

[0147] Example 7

[0148]

[0149] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * (7.5 mg, 10 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2 g, 34.4 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (26.8 mg, yellow oily liquid, yield 46%) was obtained by column chromatography. The ee value of the target product was determined (93%). 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.3 Hz,1H), 7.29 – 7.21 (m, 3H), 7.17 (td, J = 7.2, 1.6 Hz, 1H), 6.98 – 6.91 (m,2H), 6.64 – 6.55 (m, 2H), 6.34 (d, J = 7.8 Hz, 1H), 5.03 (d, J = 9.7 Hz, 1H), 4.61 (dd, J = 15.8, 4.2 Hz, 4H), 3.69 (br, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ152.2, 148.8, 143.2, 139.9, 137.2, 129.0, 128.8, 127.6, 127.3, 127.0, 124.2,124.0, 119.9, 118.6, 117.8, 112.8, 70.4, 57.4, 57.2 ppm; HRMS (ESI) calcd. forC 19 H 18 NO2 + [M+H] + m / z 292.1332, found 292.1327; IR (neat, cm -1 ) 3370, 2853, 1601,745, 458; [α] D 25 = +73.8 (c = 1.0, CHCl3); 93% ee; HPLC analysis: CHIRALCEL ® OD-H column, 15% iPrOH in n-hexane, 1.0 mL / min, 254 nm UV detector, t R (major) = 9.2 min, t R (minor) = 8.6 min.

[0150] Example 8

[0151]

[0152] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2i, 37.7 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (29.8 mg, yellow oily liquid, yield 50%) was obtained by column chromatography. The ee value of the target product was determined to be 83%. 1 H NMR (400 MHz, CDCl3) δ 7.48 (dt, J = 7.2, 0.8Hz, 1H), 7.29 – 7.21 (m, 2H), 7.14 (td, J = 7.2, 1.2 Hz, 1H), 6.95 – 6.89 (m,2H), 6.57 (td, J = 7.6, 1.2 Hz, 1H), 6.52 (d, J = 9.6 Hz, 1H), 6.32 (d, J =7.6 Hz, 1H), 5.14 – 5.11 (m, 2H), 4.97 – 4.96 (m, 1H), 3.80 (s, 1H), 2.56 (q,J = 7.6 Hz, 2H), 2.01 (dd, J = 1.6, 0.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H)ppm; 13C NMR (101 MHz, CDCl3) δ 153.1, 150.9, 143.6, 140.8, 140.4, 138.8,128.7, 128.4, 127.1, 126.4, 126.0, 125.9, 124.0, 119.7, 118.5, 116.9, 116.9,112.3, 70.8, 24.2, 19.5, 14.0 ppm; HRMS (ESI) calcd. for C 22 H 22 N + [M+H] + m / z300.1747, found 300.1741; IR (neat, cm -1 ) 3393, 2967, 1601, 1470, 896, 743; [α] D 25 = +186.4 (c = 1.0, CHCl3); 83% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 254 nm UV detector, t R (major) = 9.2min, t R (minor) = 10.1 min.

[0153] Example 9

[0154]

[0155] Under a nitrogen atmosphere, aryl bromide (1a, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * The following ingredients were added: (7.5 mg, 10 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv). The mixture was dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2j, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped, and the reaction was carried out at 70 °C for 24 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the target product (21.8 mg, yellow oily liquid, yield 38%) was obtained by column chromatography. The ee value of the target product was determined (99%). 1 H NMR (500 MHz, CDCl3) δ 7.52 (dt, J = 7.5, 1.0Hz, 1H), 7.28 (td, J = 7.5, 1.5 Hz, 1H), 7.22 – 7.17 (m, 2H), 6.97 – 6.94 (m,2H), 6.62 (td, J = 7.5, 1.0 Hz, 1H), 6.55 (d, J = 10.0 Hz, 1H), 6.38 (dt, J =8.0, 1.0 Hz, 1H), 6.22 (t, J = 1.5 Hz, 1H), 5.17 (dd, J = 9.5, 1.5 Hz, 1H),3.82 (s, 1H), 2.45 – 2.42 (m, 2H), 1.66 – 1.60 (m, 2H), 1.46 – 1.39 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H) ppm; 13 C NMR (126 MHz, CDCl3) δ 153.5, 143.8, 142.4,142.2, 136.7, 128.5, 128.4, 127.1, 126.6, 126.5, 125.0, 124.0, 119.5, 119.4,117.5, 112.8, 68.2, 29.8, 27.0, 22.8, 14.1 ppm; HRMS (ESI) calcd. for C 21 H 22 N + [M+H] + m / z 288.1747, found 288.1742; IR (neat, cm -1 ) 3382, 2929, 1601, 1463,743; [α]D 25 = +67.2 (c = 1.0, CHCl3); 99% ee; HPLC analysis: CHIRALCEL ® OD-H column, 5% i PrOH in n-hexane, 0.4 mL / min, 254 nm UV detector, t R (major) = 13.0 min, t R (minor) = 13.6 min.

[0156] Example 10

[0157]

[0158] Under a nitrogen atmosphere, aryltrifluoromethanesulfonate (1kJ, 79.4 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to a reaction tube. * Manganese powder (7.5 mg, 10 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (43.3 mg, yellow oily liquid, yield 71%) was obtained by column chromatography. The ee value of the target product was determined (97%). 1H NMR (400 MHz, CDCl3) δ 7.45 (dt, J =7.5, 1.0 Hz, 1H), 7.26 (td, J = 7.5, 1.5 Hz, 1H), 7.17 (dt, J = 7.5, 1.0 Hz,1H), 7.11 (td, J = 7.5, 1.0 Hz, 1H), 6.68 – 6.62 (m, 2H), 6.50 (d, J = 10.0Hz, 1H), 6.24 (dd, J = 8.5, 4.5 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H), 3.60 (s,1H), 2.51 – 2.37 (m, 4H), 1.19 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H)ppm; 13 C NMR (101 MHz, CDCl3) δ 155.6 (d, J = 230.6 Hz), 152.7, 151.1, 142.1,140.1, 137.3, 128.5, 127.7, 125.9, 125.6, 123.9, 119.5 (d, J = 5.1 Hz),118.9, 114.7 (d, J = 25.0 Hz), 113.3 (d, J = 22.2 Hz), 112.4, 70.8, 18.7,18.6, 15.2, 13.6 ppm; 19 F NMR (471 MHz, CDCl3) δ -129.0 (s) ppm;HRMS (ESI)calcd. for C 21 H 21 FN + [M+H] + m / z 306.1653, found 306.1646;IR (neat, cm -1 ) 3396,2966, 1494, 1460, 1249, 752;[α] D 25 = +181.1 (c = 1.0, CHCl3); 97% e.e.;HPLCanalysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 220 nm UVdetector, tR (major) = 10.5 min, t R (minor) = 8.8 min.

[0159]

[0160] Dubamine is a class of alkaloids widely found in natural plants, possessing important anti-inflammatory and antibacterial activities. Recent studies have found that converting certain planar aromatic rings in bioactive molecules into three-dimensional unsaturated bonds can significantly enhance their metabolic stability and biological activity. This phenomenon is also an important direction in modern medicinal chemistry guiding drug structure modification and new drug development. Since the product 3k in Example 10 has a structure similar to the alkaloid Dubamine and possesses superior steric properties, it conforms to the basic characteristics of drug structure modification in modern medicinal chemistry, thus showing strong potential for application.

[0161] Example 11

[0162]

[0163] Under a nitrogen atmosphere, aryl bromide (1 L, 60.4 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (7.5 mg, 10 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (43.3 mg, yellow oily liquid, yield 71%) was obtained by column chromatography. The ee value of the target product was determined (97%). 1H NMR (400 MHz, CDCl3) δ 7.45 (dt, J =7.5, 1.0 Hz, 1H), 7.26 (td, J = 7.5, 1.5 Hz, 1H), 7.17 (dt, J = 7.5, 1.0 Hz,1H), 7.11 (td, J = 7.5, 1.0 Hz, 1H), 6.68 – 6.62 (m, 2H), 6.50 (d, J = 10.0Hz, 1H), 6.24 (dd, J = 8.5, 4.5 Hz, 1H), 5.11 (d, J = 10.0 Hz, 1H), 3.60 (s,1H), 2.51 – 2.37 (m, 4H), 1.19 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H)ppm; 13 C NMR (101 MHz, CDCl3) δ 155.6 (d, J = 230.6 Hz), 152.7, 151.1, 142.1,140.1, 137.3, 128.5, 127.7, 125.9, 125.6, 123.9, 119.5 (d, J = 5.1 Hz),118.9, 114.7 (d, J = 25.0 Hz), 113.3 (d, J = 22.2 Hz), 112.4, 70.8, 18.7,18.6, 15.2, 13.6 ppm; 19 F NMR (471 MHz, CDCl3) δ -129.0 (s) ppm;HRMS (ESI)calcd. for C 21 H 21 FN + [M+H] + m / z 306.1653, found 306.1646;IR (neat, cm -1 ) 3396,2966, 1494, 1460, 1249, 752;[α] D 25 = +181.1 (c = 1.0, CHCl3); 97% e.e.;HPLCanalysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 220 nm UVdetector, tR (major) = 10.5 min, t R (minor) = 8.8 min.

[0164] Example 12

[0165]

[0166] Under a nitrogen atmosphere, aryl bromide (1 mg, 63.7 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (42.5 mg, yellow oily liquid, yield 66%) was obtained by column chromatography. The ee value of the target product was determined (96%). 1 H NMR (500 MHz, CDCl3) δ 7.45 (dt,J = 7.5, 1.0 Hz, 1H), 7.26 (td, J = 7.0, 1.5 Hz, 1H), 7.17 (d, J = 7.0 Hz,1H), 7.12 (td, J = 7.0, 1.0 Hz, 1H), 6.90 – 6.86 (m, 2H), 6.49 (d, J = 10.0Hz, 1H), 6.24 (d, J = 8.5 Hz, 1H), 5.07 (dd, J = 10.0, 2.0 Hz, 1H), 3.69 (s,1H), 2.49 – 2.37 (m, 4H), 1.19 (t, J = 7.5 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H)ppm; 13C NMR (126 MHz, CDCl3) δ 152.7, 151.1, 142.4, 142.1, 137.3, 128.5,128.1, 127.2, 126.5, 125.7, 125.6, 124.0, 121.3, 119.9, 118.9, 113.0, 70.7,18.7, 18.5, 15.2, 13.6 ppm; HRMS (ESI) calcd. for C 21 H 21 ClN + [M+H] + m / z322.1357, found 322.1351; IR (neat, cm -1 ) 3394, 2965, 1483, 1454, 1304, 752,446; [α] D 25 = +109.7 (c = 1.0, CHCl3); 96% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 254 nm UV detector, t R (major) = 10.8 min, t R (minor) = 9.2 min.

[0167] Example 13

[0168]

[0169] Under a nitrogen atmosphere, aryl bromide (1n, 70.4 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (44.7 mg, yellow oily liquid, yield 63%) was obtained by column chromatography. The ee value of the target product was determined (85%). 1 H NMR (400 MHz, CDCl3) δ 7.45 (d, J =7.3 Hz, 1H), 7.28 (td, J = 7.4, 1.1 Hz, 1H), 7.20 – 7.12 (m, 4H), 6.57 (d, J= 9.8 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.08 (dd, J = 9.8, 2.0 Hz, 1H), 3.97(s, 1H), 2.52 – 2.38 (m, 4H), 1.20 (t, J = 7.6 Hz, 3H), 1.12 (t, J = 7.6 Hz,3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 152.8, 151.0, 146.4, 142.1, 137.6, 128.7,126.8, 125.8 (q, J = 3.6 Hz), 125.6, 124.2 (q, J = 2.7 Hz), 119.0, 118.6 (q,J = 32.8 Hz), 117.9, 111.5, 70.8, 18.7, 18.6, 15.2, 13.6 ppm; 19 F NMR (471 MHz, CDCl3) δ -61.1 ppm; HRMS (ESI) calcd. for C 22 H 21 F3N + [M+H] + m / z 356.1621, found356.1614; IR (neat, cm -1 ) 2970, 1325, 1110, 1069, 754; [α] D 25= +236.6 (c = 1.0,CHCl3); 85% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane,0.5 mL / min, 254 nm UV detector, t R (major) = 10.6 min, t R (minor) = 8.7 min.

[0170] Example 14

[0171]

[0172] Under a nitrogen atmosphere, aryl bromide (10, 70.4 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (44.5 mg, yellow oily liquid, yield 60%) was obtained by column chromatography. The ee value of the target product was determined to be 92%. 1H NMR (500 MHz, CDCl3) δ 7.46 (dt, J =7.5, 1.0 Hz, 1H), 7.26 (td, J = 7.5, 1.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H),7.13 (td, J = 7.5, 1.0 Hz, 1H), 6.80 – 6.78 (m, 2H), 6.51 (d, J = 9.5 Hz,1H), 6.26 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 10.0 Hz, 1H), 3.73 (s, 1H), 2.51– 2.38 (m, 4H), 1.19 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H) ppm; 13 C NMR(126 MHz, CDCl3) δ 152.8, 151.1, 142.6, 142.1, 140.2 (q, J = 2.3 Hz), 137.4,128.6, 127.4, 125.7, 125.6, 124.0, 120.9 (q, J = 255.7 Hz), 121.5, 120.0,119.0, 119.0, 112.1, 70.8, 18.7, 18.6, 15.2, 13.6 ppm; 19 F NMR (471 MHz, CDCl3)δ -58.4 (s) ppm;HRMS (ESI) calcd. for C 22 H 21 F3NO + [M+H] + m / z 372.1570, found372.1562;IR (neat, cm -1 ) 2968, 1495, 1463, 1239, 1211, 751;[α] D 25 = +132.4 (c =1.0, CHCl3); 92% e.e.;HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 254 nm UV detector, t R (major) = 9.5 min, tR (minor) = 8.1min.

[0173] Example 15

[0174]

[0175] Under a nitrogen atmosphere, aryl bromide (1 p, 65.2 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (36.4 mg, yellow oily liquid, yield 55%) was obtained by column chromatography. The ee value of the target product was determined (98%). 1 H NMR (400 MHz, CDCl3) δ 7.47 (dt, J =7.6, 0.8 Hz, 1H), 7.24 (td, J = 7.6, 1.2 Hz, 1H), 7.16 (dt, J = 7.2, 0.8 Hz, 1H), 7.10 (td, J = 7.2, 1.2 Hz, 1H), 6.83 – 6.79 (m, 2H), 6.55 (d, J = 10.0Hz, 1H), 6.27 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 9.6 Hz, 1H), 3.58 (s, 1H), 2.81 – 2.74 (m, 1H), 2.51 – 2.40 (m, 4H), 1.23 – 1.17 (m, 9H), 1.12 (t, J =7.6 Hz, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 153.1, 151.5, 142.0, 141.9, 137.4,136.9, 128.3, 126.8, 126.5, 125.8, 125.5, 125.0, 124.0, 118.7, 118.4, 112.0,70.9, 33.3, 24.4, 24.4, 18.8, 18.6, 15.2, 13.6 ppm; HRMS (ESI) calcd. forC 24 H 28 N + [M+H] + m / z 330.2216, found 330.2209; IR (neat, cm -1 ) 3393, 2960, 1499,1455, 752, 723; [α] D 25 = +171.1 (c = 1.0, CHCl3); 98% ee; HPLC analysis:CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 254 nm UV detector,t R (major) = 8.0 min, t R (minor) = 7.6 min.

[0176] Example 16

[0177]

[0178] Under a nitrogen atmosphere, aryl bromide (1q, 62.8 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (31.1 mg, yellow oily liquid, yield 49%) was obtained by column chromatography. The ee value of the target product was determined (96%). 1 H NMR (400 MHz, CDCl3) δ 7.47 (dt, J =7.2, 0.8 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.17 (dt, J = 7.2, 0.8 Hz, 1H), 7.11(td, J = 7.2, 1.2 Hz, 1H), 6.59 – 6.53 (m, 3H), 6.31 – 6.29 (m, 1H), 5.11 (d,J = 9.6 Hz, 1H), 3.76 (s, 3H), 3.51 (s, 1H), 2.51 – 2.37 (m, 4H), 1.19 (t, J= 7.6 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 152.8,151.8, 151.3, 142.1, 138.2, 137.1, 128.3, 127.2, 126.5, 125.5, 123.8, 119.6,118.8, 114.4, 112.80, 112.76, 70.8, 56.1, 18.8, 18.6, 15.2, 13.6 ppm; HRMS(ESI) calcd. for C 22 H 24 NO + [M+H] + m / z 318.1852, found 318.1845; IR (neat, cm -1 )2921, 2360, 1497, 1464, 1259, 754; [α] D 25= +134.8 (c = 1.0, CHCl3); 96% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.8 mL / min, 254nm UV detector, t R (major) = 7.2 min, t R (minor) = 6.3 min.

[0179] Example 17

[0180]

[0181] Under a nitrogen atmosphere, aryl bromide (1r, 59.6 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (28.3 mg, yellow oily liquid, yield 47%) was obtained by column chromatography. The ee value of the target product was determined (92%). 1H NMR (500 MHz, CDCl3) δ 7.47 (dt, J =7.5, 1.0 Hz, 1H), 7.25 (td, J = 7.5, 1.0 Hz, 1H), 7.17 (dt, J = 7.5, 1.0 Hz,1H), 7.11 (td, J = 7.5, 1.0 Hz, 1H), 6.82 (d, J = 7.5 Hz, 1H), 6.55 (d, J =9.5 Hz, 1H), 6.41 (dd, J = 7.5, 0.5 Hz, 1H), 6.17 (s, 1H), 4.97 (d, J = 9.5Hz, 1H), 3.63 (s, 1H), 2.51 – 2.39 (m, 4H), 2.20 (s, 3H), 1.19 (t, J = 7.5Hz, 3H), 1.12 (t, J = 7.5 Hz, 3H) ppm; 13 C NMR (126 MHz, CDCl3) δ 153.1, 151.5,143.9, 142.1, 138.7, 136.9, 128.3, 126.9, 126.4, 125.5, 124.6, 124.0, 118.8,117.8, 116.1, 112.8, 70.7, 21.6, 18.8, 18.6, 15.2, 13.6 ppm;HRMS (ESI) calcd.for C 22 H 24 N + [M+H] + m / z 302.1903, found 302.1897;IR (neat, cm -1 ) 3388, 2920,1605, 1453, 1320, 709;[α] D 25 = +117.4 (c = 1.0, CHCl3); 92% e.e.;HPLCanalysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 220 nm UVdetector, t R (major) = 9.1 min, t R (minor) = 8.1 min。

[0182] Example 18

[0183]

[0184] Under a nitrogen atmosphere, aryl bromide (1s, 64.0 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (36.2 mg, yellow oily liquid, yield 56%) was obtained by column chromatography. The ee value of the target product was determined (89%). 1 H NMR (400 MHz, CDCl3) δ 7.45 (dt,J = 7.2, 0.8 Hz, 1H), 7.28 (td, J = 7.6, 1.2 Hz, 1H), 7.19 (dt, J = 7.2, 0.8Hz, 1H), 7.14 (td, J = 7.6, 1.2 Hz, 1H), 6.63 – 6.57 (m, 1H), 6.55 – 6.50 (m,2H), 5.16 (dd, J = 9.6, 1.2 Hz, 1H), 3.76 (s, 1H), 2.53 – 2.34 (m, 4H), 1.20(t, J = 7.6 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H) ppm; 1313C NMR (101 MHz, CDCl3) δ153.8 (dd, J = 236.4, 12.1 Hz), 152.7, 150.8, 148.7 (dd, J = 240.4, 12.1 Hz),142.2, 137.6, 128.9, 128.6, 128.3 (dd, J = 12.4, 2.8 Hz), 125.7, 125.1 (dd, J= 4.2, 2.6 Hz), 123.9, 120.6 (dd, J = 9.0, 5.8 Hz), 119.0, 108.6 (dd, J =22.7, 3.2 Hz), 102.8 (dd, J = 26.9, 22.5 Hz), 69.9, 18.7, 18.6, 15.1, 13.6 ppm; 19 19F NMR (471 MHz, CDCl3) δ -127.6, -138.2 ppm;HRMS (ESI) calcd. for C 21 H 20 F2N + [M+H] + m / z 324.1558, found 324.1553;IR (neat, cm -1 ) 2968, 1491, 1305,981, 753;[α] D 25 = +244.6(c = 1.0, CHCl3); 89% e.e.;HPLC analysis: CHIRALCEL ® OD-H column, 1.5% i PrOH in n-hexane, 0.5 mL / min, 220 nm UV detector, t R (major) = 9.0 min, t R (minor) = 8.0 min.

[0185] Example 19

[0186]

[0187] Under a nitrogen atmosphere, aryl bromide (1 t, 63.7 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L78 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (30.2 mg, yellow oily liquid, yield 47%) was obtained by column chromatography. The ee value of the target product was determined (94%). 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J =7.6 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 6.97 –6.92 (m, 2H), 6.61 – 6.56 (m, 2H), 6.35 (d, J = 8.0 Hz, 1H), 4.98 (dd, J =10.0, 2.0 Hz, 1H), 3.65 (s, 1H), 2.52 – 2.38 (m, 4H), 1.18 (t, J = 7.6 Hz,3H), 1.12 (t, J = 7.6 Hz, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 153.2, 151.3,144.1, 143.6, 136.2, 134.3, 128.8, 127.2, 126.9, 125.3, 125.0, 124.9, 119.2,118.4, 117.2, 112.2, 70.4, 18.9, 18.5, 15.0, 13.5 ppm; HRMS (ESI) calcd. forC 21 H 21 ClN + [M+H] + m / z 322.1357, found 322.1353; IR (neat, cm-1 ) 3387, 2966, 1599,1468, 742; [α] D 25 = +237.3 (c = 1.0, CHCl3); 94% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 220 nm UV detector, t R (major) = 10.9 min, t R (minor) = 9.9 min.

[0188] Example 20

[0189]

[0190] Under a nitrogen atmosphere, aryl bromide (4a, 71.7 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), achiral ligand L2 (2.0 mg, 2.5 mol%), and chiral ligand L81 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (90 mg, 0.60 mmol, 3.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, the above-mentioned alkyne (2a, 32.9 mg, 0.40 mmol, 2.0 equiv) was added. The reaction tube was capped and reacted at 70 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (46.6 mg, yellow oily liquid, yield 66%) was obtained by column chromatography. The ee value of the target product was determined (91%). 11H NMR (400 MHz, CDCl3) δ 7.37 (d, J =7.6 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.0, 2.0 Hz, 1H), 6.97 –6.92 (m, 2H), 6.72 – 6.56 (m, 2H), 6.61 – 6.56 (m, 2H), 6.35 (d, J = 8.0 Hz,1H), 4.98 (dd, J = 10.0, 2.0 Hz, 1H), 3.65 (s, 1H), 2.52 – 2.38 (m, 4H), 1.18 (t, J = 7.6 Hz, 3H), 1.12 (t, J = 7.6 Hz, 3H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 153.2, 151.3, 144.1, 143.6, 136.2, 134.3, 128.8, 127.2, 126.9, 125.3, 125.0, 124.9, 119.2, 118.4, 117.2, 112.2, 70.4, 18.9, 18.5, 15.0, 13.5 ppm; HRMS (ESI) calcd. for C 21 H 21 ClN + [M+H] + m / z 322.1357, found 322.1353; IR (neat, cm -1 -1) 3387, 2966, 1599, 1468, 742; [α] D 25 D = +237.3 (c = 1.0, CHCl3); 91% e.e.; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.5 mL / min, 220 nm UV detector, t R (major) = 10.9 min, t R (minor) = 9.2 min.

[0191] Example 21

[0192]

[0193] Under a nitrogen atmosphere, aryl bromide (6a, 74.9 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and chiral ligand L82 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (60 mg, 0.40 mmol, 2.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. The mixture was stirred at 25 °C for 2 minutes, and then trimethylchlorosilane (21.7 mg, 0.20 mmol, 1.0 equiv) was added. The reaction tube was capped, and the reaction was carried out at 120 °C for 24 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the target product (30.7 mg, yellow oily liquid, yield 52%) was obtained by column chromatography. The ee value of the target product was determined to be 92%. 1 HNMR (400 MHz, CDCl3) δ 7.60 (ddt, J = 11.8, 7.6, 1.0 Hz, 2H), 7.51 (d, J =7.7 Hz, 1H), 7.48 – 7.44 (m, 1H), 7.34 (td, J = 7.5, 1.2 Hz, 1H), 7.23 (td, J= 7.4, 1.2 Hz, 1H), 7.17 (ddd, J = 7.7, 1.6, 0.8 Hz, 1H), 7.02 – 6.95 (m,2H), 6.72 – 6.56 (m, 2H), 6.35 (d, J = 7.8 Hz, 1H), 5.26 (d, J = 9.7 Hz, 1H), 4.02 (s, 1H), 2.35 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 152.4, 152.0, 143.1,138.6, 137.9, 135.3, 129.9, 129.0, 128.9, 128.0, 127.1, 126.4, 125.7, 125.4,119.8, 119.6, 118.9, 117.5, 112.6, 67.3, 21.7 ppm; HRMS (ESI) calcd. forC 22 H 18 N + [M+H] +m / z 296.1434, found 296.1431; IR (neat, cm -1 ) 3383, 2954, 1458,1257, 746; [α] D 25 = –77.4 (c = 1.0, CHCl3); 92% ee; HPLC analysis: CHIRALCEL ® OD-H column, 2% i PrOH in n-hexane, 0.8 mL / min, 254 nm UV detector, t R (major) = 9.7 min, t R (minor) = 10.9 min.

[0194] Example 22

[0195]

[0196] Under a nitrogen atmosphere, aryl bromide (6b, 78.1 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and chiral ligand L82 were added to the reaction tube. * (12.4 mg, 15 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (60 mg, 0.40 mmol, 2.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, trimethylchlorosilane (21.7 mg, 0.20 mmol, 1.0 equiv) was added. The reaction tube was capped and reacted at 120 °C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (29.9 mg, yellow oily liquid, yield 48%) was obtained by column chromatography. The ee value of the target product was determined to be 91%. 1HNMR (400 MHz, CDCl3) δ 7.59 (dt, J = 7.6, 0.8 Hz, 1H), 7.55 – 7.52 (m, 2H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.22 – 7.18 (m, 2H), 7.03 – 6.97 (m, 2H), 6.91 (dd, J = 8.4, 2.8 Hz, 1H), 6.66 (td, J = 7.2, 0.8 Hz, 1H), 6.61 (d, J = 9.6 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 5.28 (d, J = 9.6 Hz, 1H), 4.06 (s, 1H), 3.80 (s, 3H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 160.5, 154.1, 151.8, 143.0, 137.7, 130.8, 129.1, 129.0, 127.2, 127.2, 126.4, 125.6, 120.9, 119.2, 118.9, 117.6, 115.4, 112.7, 110.9, 67.4, 55.8 ppm; HRMS (ESI) calcd. for C 22 H 18 NO + [M+H] + m / z 312.1383, found 312.1379; IR (neat, cm -1 ) 3383, 2954, 1607, 1458, 1269, 746; [α] D 25 = –88.2 (c = 1.0, CHCl3); 91% e.e.; HPLC analysis: CHIRALPAK ® AD-H column, 5% i PrOH in n-hexane, 0.8 mL / min, 254 nm UV detector, t R (major) = 20.7 min, t R (minor) = 27.4 min.

[0197] Example 23

[0198]

[0199] Under a nitrogen atmosphere, aryl bromide (6c, 87.3 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and chiral ligand L82 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (60 mg, 0.40 mmol, 2.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. The mixture was stirred at 25 °C for 2 minutes, and then trimethylchlorosilane (21.7 mg, 0.20 mmol, 1.0 equiv) was added. The reaction tube was capped, and the reaction was carried out at 120 °C for 24 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the target product (30.6 mg, yellow solid, yield 43%) was obtained by column chromatography. The ee value of the target product was determined to be 94%. 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 1.7 Hz, 1H), 7.72 – 7.58 (m, 6H), 7.43 – 7.26 (m, 5H), 7.06 – 6.94 (m, 2H), 6.69 – 6.59 (m, 2H), 6.37 (d, J = 7.8Hz, 1H), 5.31 (d, J = 9.7 Hz, 1H), 4.09 (s, 1H) ppm; 13 C NMR (101 MHz, CDCl3) δ153.01, 152.36, 143.00, 141.65, 141.00, 137.32, 137.24, 129.20, 129.01,128.91, 128.47, 128.13, 127.50, 127.24, 127.22, 126.13, 125.75, 125.66,124.61, 120.31, 120.04, 118.80, 117.57, 112.64, 67.53 ppm; HRMS (ESI) calcd.for C 27 H 20 N + [M+H] + m / z 358.1590, found 358.1589; IR (neat, cm -1 ) 3385, 1467,756, 733, 697; [α]D 25 = –92.6 (c = 1.0, CHCl3); 90% ee; HPLC analysis:CHIRALCEL ® OD-H column, 1% i PrOH in n-hexane, 0.8 mL / min, 254 nm UV detector,t R (major) = 13.1 min, t R (minor) = 14.0 min.

[0200] Example 24

[0201]

[0202] Under a nitrogen atmosphere, aryl bromide (6 d, 87.3 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and chiral ligand L82 were added to the reaction tube. * (12.4 mg, 15 mol%), manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv), and sodium iodide (60 mg, 0.40 mmol, 2.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. After stirring at 25 °C for 2 minutes, trimethylchlorosilane (21.7 mg, 0.20 mmol, 1.0 equiv) was added. The reaction tube was capped and reacted at 120 °C for 24 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the target product (37.2 mg, yellow solid, yield 52%) was obtained by column chromatography. The ee value of the target product was determined to be 93%. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 1.7 Hz, 1H), 7.74 – 7.61 (m, 5H), 7.54 – 7.43 (m, 3H), 7.42 – 7.28 (m, 3H), 7.10 – 6.98 (m, 2H), 6.72 – 6.61 (m,2H), 6.39 (d, J = 7.8 Hz, 1H), 5.33 (d, J = 9.7 Hz, 1H), 4.06 (s, 1H) ppm; 13CNMR (101 MHz, CDCl3) δ 152.4, 150.9, 143.1, 142.6, 141.3, 138.5, 137.8,129.2, 129.0, 129.0, 128.6, 127.7, 127.6, 127.4, 127.2, 126.2, 126.0, 125.8,125.7, 120.0, 119.1, 118.8, 117.7, 112.8, 67.2 ppm; HRMS (ESI) calcd. forC 27 H 20 N + [M+H] + m / z 358.1590, found 358.1586; IR (neat, cm -1 ) 2953, 1467, 1269,770, 454; [α] D 25 = –68.1 (c = 1.0, CHCl3); 93% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.8 mL / min, 254 nm UV detector, t R (major) = 16.7 min, t R (minor) = 19.8 min.

[0203] Example 25

[0204]

[0205] Under a nitrogen atmosphere, aryl bromide (6e, 83.7 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and chiral ligand L82 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (60 mg, 0.40 mmol, 2.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. The mixture was stirred at 25 °C for 2 minutes, and then trimethylchlorosilane (21.7 mg, 0.20 mmol, 1.0 equiv) was added. The reaction tube was capped, and the reaction was carried out at 120 °C for 24 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the target product (38.0 mg, yellow solid, yield 56%) was obtained by column chromatography. The ee value of the target product was determined to be 93%. 1 H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 15.5, 7.4 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.31 (td, J = 7.4, 1.1 Hz, 1H), 7.24 – 7.18 (m, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.94 (ddd, J = 15.5, 7.7, 1.5 Hz, 2H), 6.75 (dd, J = 8.3, 2.3 Hz, 1H), 6.60 (td, J = 7.4, 1.1 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 6.31 (d, J = 7.9Hz, 1H), 5.24 (dd, J = 9.7, 2.0 Hz, 1H), 4.56 (m, 1H), 3.98 (d, J = 2.0 Hz, 1H), 1.33 (s, 3H), 1.32 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 159.2, 152.9,144.5, 143.2, 139.4, 137.8, 129.0, 128.8, 128.5, 127.1, 126.6, 126.5, 125.7,125.4, 119.8, 119.0, 117.5, 115.9, 112.7, 107.4, 70.4, 66.8, 22.2 ppm; HRMS(ESI) calcd. for C 24 H 22 NO + [M+H] + m / z 340.1696, found 340.1690; IR (neat, cm-1 )3382, 1603, 1470, 1195, 1109, 746; [α] D 25 = –59.8 (c = 1.0, CHCl3); 93% ee; HPLC analysis: CHIRALCEL ® OD-H column, 3% i PrOH in n-hexane, 0.8 mL / min, 254nm UV detector, t R (major) = 10.8 min, t R (minor) = 12.1 min.

[0206] Example 26

[0207]

[0208] Under a nitrogen atmosphere, aryl bromide (6f, 81.7 mg, 0.20 mmol, 1.0 equiv), cobalt iodide (6.2 mg, 10 mol%), and chiral ligand L82 were added to the reaction tube. * Manganese powder (33.0 mg, 0.60 mmol, 3.0 equiv) and sodium iodide (60 mg, 0.40 mmol, 2.0 equiv) were dissolved in 2.0 mL of dry acetonitrile. The mixture was stirred at 25 °C for 2 minutes, and then trimethylchlorosilane (21.7 mg, 0.20 mmol, 1.0 equiv) was added. The reaction tube was capped, and the reaction was carried out at 120 °C for 24 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the target product (29.0 mg, yellow solid, yield 44%) was obtained by column chromatography. The ee value of the target product was determined (94%). 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.57 (m, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.43(s, 1H), 7.35 (td, J = 7.5, 1.2 Hz, 1H), 7.27 – 7.23 (m, 1H), 7.18 (d, J =7.6 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 6.54(d, J = 9.7 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 5.31 (dd, J = 9.7, 2.0 Hz,1H), 4.04 (s, 1H), 2.37 (s, 3H) ppm; 13 C NMR (101 MHz, CDCl3) δ 152.0, 151.6,141.6, 138.7, 138.0, 135.3, 130.1, 129.2, 128.4, 128.0, 127.8, 126.6, 126.3,125.6, 124.5, 121.9, 120.2, 119.9, 119.8, 113.6, 67.3, 21.7 ppm;HRMS (ESI)calcd. for C 22 H 17 ClN + [M+H] + m / z 330.1044, found 330.1040;IR (neat, cm -1 ) 3388,1483, 14583, 733, 709;[α] D 25 = –87.1 (c = 1.0, CHCl3); 94% e.e.;HPLC analysis:CHIRALCEL ® OD-H column, 5% i PrOH in n-hexane, 0.8 mL / min, 254 nm UV detector,t R (major) = 8.0 min, t R (minor) = 8.7 min。

Claims

1. A cobalt-catalyzed migration asymmetric spirocyclization method for quinoline compounds, characterized in that, Includes the following steps: In an inert gas atmosphere, a cobalt catalyst, achiral ligand L and chiral ligand L*, a reducing agent, and additives are dissolved in an organic solvent, and then an aryl-substituted quinoline is added. , substituted alkynes As a substrate, a reaction mixture was obtained, which was then post-treated and purified to give the target compound: ; The preparation route of the cobalt-catalyzed migration asymmetric spirocyclization method for quinoline compounds is as follows: Preparation route 1: ； The molar ratio of quinoline 1 to alkyne 2 is 1:2, the cobalt catalyst is CoI2, and the achiral ligand L is L2. The chiral ligand L* is L*78, and L*78 is... The reducing agent is Mn, the additive is sodium iodide, and the solvent is acetonitrile; The aryl-substituted quinoline 1 is specifically: ； The alkyne 2 is specifically: ； The product 3 is specifically: 。 2. The cobalt-catalyzed migration asymmetric spirocyclic oxidation method for quinoline compounds according to claim 1, characterized in that: The specific preparation method and reaction route are as follows: 。

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