A nickel-catalyzed C(sp) catalyst promoted by a binaphthylamine-derived chiral phosphooxy ligand 3 )-H bond asymmetric cyclization

Abstract

The application provides a simple and efficient synthesis method for synthesizing a novel binaphthol derivative skeleton phosphorus oxygen ligand, and realizes a method for realizing the enantioselective nickel catalytic aliphatic C(sp 3 )‑H activation of formamide by using a binaphthol derivative phosphorus oxygen ligand connected nickel-aluminum bimetallic catalyst, and belongs to the technical field of asymmetric catalysis application. The key to solving the problem of the application lies in that: 1. A novel binaphthol derivative phosphorus oxygen ligand which is efficient and specific in reaction activity, site selectivity and corresponding selectivity is found, and a method for nickel catalytic aliphatic C(sp 3 )‑H asymmetric activation of formamide is realized; 2. A bimetallic catalyst system is designed by using the characteristics of the ligand, so that the reaction activity is greatly improved, and the efficient preparation is more easy.

Description

Technical Field

[0001] This invention relates to an enantioselective nickel-catalyzed aliphatic C(sp) formamide reaction using a binaphthylamine-derived phosphorooxyligand (H8-BINAPO)-bridged nickel-aluminum bimetallic catalyst. 3 The )-H activation method provides a series of chiral nitrogen-containing heterocycles, belonging to the field of asymmetric catalysis application technology. Background Technology

[0002] Chiral compounds are widely found in pharmaceuticals, agrochemicals, and bioactive natural products. Enantioselective activation of CH via transition metals is one of the most convenient and economical methods for obtaining chiral molecules present in a large number of natural products and bioactive compounds (such as pharmaceuticals and pesticides). Currently, the widely explored CH bonds are C(sp) bonds in aromatic hydrocarbons, alkenes, aldehydes, imines, formamides, or alkynes. 2 C(sp)-H or C(sp)-H bond. In contrast, due to C(sp) 3 The steric hindrance and lack of activity around the -H bond, resulting in inactive C(sp) 3 Achieving enantioselective activation of the H-bond presents a significant challenge.

[0003]

[0004] Over the past two decades, noble metals such as Pd, Rh, and Ir have been able to catalyze enantioselective C(sp) catalysis using well-designed chiral ligands or chiral anions. 3 The activation of the 3d-H bond provides good yields and high ee. However, the same strategy is generally ineffective for most 3d transition metals that are highly sensitive to substrate and ligand structures. To date, only Matsunaga, Yoshino, and colleagues have reported a successful example. They used achiral Cp-Co(III) and amino acid derivatives as chiral anions to promote the primary C(sp)-H bond activation of thioamides. 3 Enantioselective amidation of C(sp)-H bonds. Considering the advantages of high terrestrial abundance, low cost, and low biotoxicity of 3d metals, we will develop 3d metal-catalyzed enantioselective amidation of C(sp)-H bonds. 3 The activation reaction of the -H bond is essential.

[0005]

[0006] In summary, although nickel-catalyzed CH bond activation and even enantioselective nickel-catalyzed carbon (sp) bond activation... 2 Significant progress has been made in the activation of )-H bonds, but enantioselective Ni-catalyzed aliphatic C(sp) bonds remains a challenge. 3 Activating the -H bond remains a difficult challenge. Summary of the Invention:

[0007] Enantioselectivity of formamide with nickel-catalyzed aliphatic C(sp) 3 The )-H activation reaction did not yield good results by trying dioxane-based phosphoroxane ligands and other dinitrogen phosphoroxane ligands, but good results were achieved by using pennaphthylamine-derived phosphoroxane ligands.

[0008] One of the key points of this invention is the preparation of a novel dinitrophosphoric precursor via a nucleophilic substitution reaction of binaphthylamine with acyl chloride. The method is characterized by the following specific steps:

[0009]

[0010] 1. A three-necked Schlenk flask was filled with 10 mL of dry THF containing the corresponding substituted diamine 5 (1.0 mmol, 1.0 equivalent). Under a nitrogen atmosphere at -78 °C, n-butyllithium was added to hexane (2.5 M, 0.8 mL, 2 mmol) over 10 minutes. The mixture was stirred at the same temperature for 0.5 h, then heated to room temperature for 0.5 h. The mixture was then cooled to room temperature, and freshly distilled PCl3 (95 μL, 1.0 mmol, 1.0 equivalent) was added dropwise again at -78 °C. The solution was heated to room temperature and stirred for 1 h. H2O (18 μL, 1.0 mmol, 1.0 equivalent) was added to the resulting solution and stirred for 0.5 h. The solvent was removed under reduced pressure, and the residue was purified by rapid chromatography to give pure secondary phosphine oxide L.

[0011] 2. The R involved in this invention can be Ph, tBu, etc., but is not limited to these groups;

[0012] The advantages of this invention are:

[0013] 1. This invention is simple to operate, and the target product can be obtained in one step.

[0014] 2. The product of this invention has a stable structure and can exist stably in air.

[0015] 3. The ligand structure involved in this invention is easily modified.

[0016] The present invention also aims to provide a simple and practical method, for the first time using a novel H8-bis(2-naphthylamine)-derived chiral phosphine oxide (H8-BINAPO) to achieve enantioselective nickel-catalyzed C(sp) oxidation of formamide. 3 H-H activation provides a series of nitrogen-containing heterocycles in yields of 40-95% and ee of 70-95%. H8-BINAPO-linked Ni-Al bimetallic catalysts may be suitable for activation of formyl C(sp...) 2 )-H bond activation and subsequent aliphatic C(sp) bond acceleration via directional nickel annealing3 It plays a key role in the activation of H-H.

[0017] The second key point of this invention is the nickel catalysis of C(sp) involving novel dinitrogen phosphorus oxygen ligands. 3 A method for asymmetric activation of H-bonds and its applications. The method is characterized by the following specific steps:

[0018]

[0019] 1. Under a nitrogen atmosphere, add the ligand, metal catalyst, raw material and solvent sequentially to the reaction flask, then add Lewis acid, stir at the specified temperature for 2-8 hours, cool to room temperature, dilute with ethyl acetate, wash with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separate the liquid, dry the organic phase with anhydrous sodium sulfate, and separate by column chromatography to obtain the target product 3.

[0020] 2. The metal catalyst involved in this invention is Ni(cod)2, and the amount of catalyst used is generally 5 mol%.

[0021] 3. The ligand involved in this invention is a chiral bis-N skeleton secondary phosphonooxy, and its dosage is generally 5 mol%.

[0022] 4. The Al involved in this invention i Bu3, a 1 mol / L hexane solution, is typically used in a volume of 40 mol%.

[0023] 5. The solvent used in this invention is toluene solution, and the amount used is 2.5 mL per millimole of raw material 1.

[0024] 6. R in raw material 1 used in this invention 2 Methyl, cyclohexyl, cycloheptyl; R 2 Hydrogen, cyclohexyl, cycloheptyl; R 3 R can be a substituent such as isopropyl, cyclohexyl, alkoxy, etc., but is not limited to these groups; R can be a substituent such as ethyl, phenyl, thiophene, etc., but is not limited to these groups.

[0025] The advantages of this invention are:

[0026] 1. Most of the reagents used in this invention are commercially available. The chiral ligands to be synthesized are widely available, inexpensive, and stable at room temperature and pressure. They are easy to handle and require no special treatment.

[0027] 2. The ligand synthesis involved in this invention is simple and easy to operate, avoiding the shortcomings of previous methods which involved lengthy ligand synthesis steps, and requires minimal equipment. This significantly reduces the production cost of synthesizing this type of compound.

[0028] 3. This invention can obtain optically pure products in one step, and the post-processing is simple and convenient, avoiding the previous method of obtaining chiral products through a series of reactions, and greatly reducing the product reaction cost.

[0029] 4. The catalyst used in this invention is inexpensive and requires low amounts of metals and ligands. While maintaining good catalytic effect and reducing costs, it also facilitates post-processing and reduces environmental pollution.

[0030] 5. The reaction of this invention is completely atom-economical, meets the requirements of green chemistry, and will not produce other byproducts in large-scale production, thus achieving the requirements of simplifying the process, reducing costs, and reducing environmental pollution.

[0031] Specific implementation methods

[0032] The following examples of ligand synthesis will better illustrate the invention, but it should be emphasized that the invention is by no means limited to what is shown in these examples. The following examples illustrate different aspects of the invention. The data given include specific operations and reaction conditions and products. Product purity was determined by NMR.

[0033] Example 1: Synthesis of phosphooxyligand L1

[0034]

[0035] A three-necked Schlenk flask was filled with 10 mL of dry THF containing the corresponding substituted diamine (1.0 mmol, 1.0 equivalent). Under a nitrogen atmosphere at -78 °C, n-butyllithium was added to hexane (2.5 M, 0.8 mL, 2 mmol) over 10 minutes. The mixture was stirred at the same temperature for 0.5 h, then heated to room temperature for 0.5 h. The mixture was then cooled to room temperature, and freshly distilled PCl3 (95 μL, 1.0 mmol, 1.0 equivalent) was added dropwise again at -78 °C. The solution was heated to room temperature and stirred for 1 h. H2O (18 μL, 1.0 mmol, 1.0 equivalent) was added to the resulting solution and stirred for 0.5 h. The solvent was removed under reduced pressure, and the residue was purified by rapid chromatography to give pure secondary phosphine oxide L1 as a white solid in 50% yield. 1H NMR (400MHz, CDCl3) δ7.97 (d, J=8.7Hz, 1H), 7.87 (dd, J=12.8, 8.6Hz, 2H), 7.77 (d, J=8.2Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.65 (d, J=8.6Hz, 1H), 7.50 (d, JP-H=612.0Hz, 1H), 7.38 (t, J=7.4Hz, 1H), 7.30 (t, J= 7.4Hz, 1H), 7.02 (t, J=7.6Hz, 1H), 6.93 (t, J=7.6Hz, 1H), 6.73 (dd, J=16.6, 7.8Hz, 2H), 6.63-6.46 (m, 8H), 6.45-6.38 (m, 2H), 4.96 (dd, J=14.4, 7.6Hz, 1H), 4.78-4.58 (m, 2H), 4.44 (dd, J=14.4, 6.8Hz, 1H). 13 C NMR (100MHz, CDCl3) δ138.0, 136.9, 136.1, 136.1, 135.6, 132.8, 132.6, 132.3, 131.9, 131.4, 130.8, 129.8, 129.5, 128.1, 1 27.9, 127.9, 127.8, 127.7, 127.6, 127.5, 127.0, 126.6, 126.1, 125.9, 125.7, 125.2, 124.2, 123.6, 51.9, 51.9, 49.7, 49.6. 31 P NMR (162MHz, CDCl3) δ22.9.HRMS (ESI) m / z: [M+H] + calcd.for C 34 H 38 N2OP 511.1934, found 511.1926.

[0036] Example 2: Synthesis of phosphooxyligand L2

[0037]

[0038] A three-necked Schlenk flask was filled with 10 mL of dry THF containing the corresponding substituted diamine (1.0 mmol, 1.0 equiv.). Under a nitrogen atmosphere at -78 °C, n-butyllithium was added to hexane (2.5 M, 0.8 mL, 2 mmol) over 10 minutes. The mixture was stirred at the same temperature for 0.5 h, then heated to room temperature for 0.5 h. The mixture was then cooled to room temperature, and freshly distilled PCl3 (95 μL, 1.0 mmol, 1.0 equiv.) was added dropwise again at -78 °C. The solution was heated to room temperature and stirred for 1 h. H2O (18 μL, 1.0 mmol, 1.0 equiv.) was added to the resulting solution and stirred for 0.5 h. The solvent was removed under reduced pressure, and the residue was purified by rapid chromatography to give pure secondary phosphine oxide L20 as a white solid in 60% yield. 1 H NMR (400MHz, CDCl3) δ7.88-7.80 (m, 2H), 7.79-7.71 (m, 2H), 7.63 (d, J=8.8Hz , 1H), 7.52 (d, J=8.8Hz, 1H), 7.30-7.21 (m, 2H), 7.18-6.99 (m, 4H), 7.02 (d, J P-H =599.6Hz, 1H), 3.54-3.42 (m, 2H), 3.24 (dd, J=14.0, 7.6Hz, 1H), 3.12 (t, J=15.8Hz, 1H), 0.16 (s, 18H). 13 C NMR (100MHz, CDCl3) δ141.7, 139.5, 139.5, 132.5, 132.3, 131.7, 131.4, 130.8, 129.9, 129.8, 128.3, 128.3, 127. 8, 127.7, 126.3, 126.2, 125.5, 125.3, 123.5, 123.1, 59.2, 59.2, 57.4, 57.3, 33.9, 33.9, 33.5, 33.5, 27.5, 27.3. 31 P NMR (162MHz, CDCl3) δ27.0.HRMS (ESI) m / z: [M+H] + calcd.for C 30 H 36 N2OP 471.2560, found 471.2553.

[0039] Example 3: Synthesis of phosphooxyligand L3

[0040]

[0041] A three-necked Schlenk flask was filled with 10 mL of dry THF containing the corresponding substituted diamine (1.0 mmol, 1.0 equiv.). Under a nitrogen atmosphere at -78 °C, n-butyllithium was added to hexane (2.5 M, 0.8 mL, 2 mmol) over 10 minutes. The mixture was stirred at the same temperature for 0.5 h, then heated to room temperature for 0.5 h. The mixture was then cooled to room temperature, and freshly distilled PCl3 (95 μL, 1.0 mmol, 1.0 equiv.) was added dropwise again at -78 °C. The solution was heated to room temperature and stirred for 1 h. H2O (18 μL, 1.0 mmol, 1.0 equiv.) was added to the resulting solution and stirred for 0.5 h. The solvent was removed under reduced pressure, and the residue was purified by rapid chromatography to give pure secondary phosphine oxide L21 as a white solid in 38% yield. 1 H NMR (400MHz, CDCl3) δ7.30 (d, J P-H =597.6Hz, 1H), 7.27 (d, J = 9.2Hz, 1H), 7.21 (d, J = 8.4Hz, 1H), 7.12-6.94 (m, 8H), 6 .78 (d, J=7.6Hz, 2H), 6.70 (d, J=7.4Hz, 2H), 4.85 (dd, J=14.4, 8.0Hz, 1H), 4.59-4 .46 (m, 2H), 4.31 (dd, J=14.4, 6.8Hz, 1H), 2.76 (t, J=6.0Hz, 2H), 2.69 (t, J=6.0Hz , 2H), 2.23-2.03(m, 2H), 1.72-1.63(m, 2H), 1.62-1.54(m, 2H), 1.53-1.21(m, 6H). 13 C NMR (100MHz, CDCl3) δ138.5, 138.4, 137.7, 137.5, 137.4, 137.2, 136.8, 136.1, 136.0, 136.0, 135.2, 135.2, 134.7, 134.7, 134.6, 129.1, 128.7, 128.2, 127.9, 127.9, 127.3, 127.0, 123.1, 123.1, 122.6, 122.5, 51.9, 51.8, 49.8, 49.7, 29.8, 29.7, 27.4, 27.2, 22.8, 22.7, 22.6. 31 P NMR (162MHz, CDCl3) δ22.9.HRMS (ESI) m / z: [M+H] + calcd.forC 34 H 36 N2OP 519.2560, found 519.2555.

[0042] Example 4: Synthesis of phosphooxyligand L4

[0043]

[0044] A three-necked Schlenk flask was filled with 10 mL of dry THF containing the corresponding substituted diamine (1.0 mmol, 1.0 equiv.). Under a nitrogen atmosphere at -78 °C, n-butyllithium was added to hexane (2.5 M, 0.8 mL, 2 mmol) over 10 minutes. The mixture was stirred at the same temperature for 0.5 h, then heated to room temperature for 0.5 h. The mixture was then cooled to room temperature, and freshly distilled PCl3 (95 μL, 1.0 mmol, 1.0 equiv.) was added dropwise again at -78 °C. The solution was heated to room temperature and stirred for 1 h. H2O (18 μL, 1.0 mmol, 1.0 equiv.) was added to the resulting solution and stirred for 0.5 h. The solvent was removed under reduced pressure, and the residue was purified by rapid chromatography to give pure secondary phosphine oxide L22 as a white solid in 35% yield. 1 H NMR (400MHz, CDCl3) δ7.26 (d, J=8.0Hz, 1H), 7.16 (d, J=8.0Hz, 1H), 7.10 (d, J=8.0Hz, 2H), 6.87 (d, J P-H =594.0Hz, 1H), 3.53-3.33(m, 2H), 3.24-3.13(m, 1H), 3.13-3.03(m, 1H), 2.93-2.73(m, 4H), 2.6 9-2.54 (m, 2H), 2.34-2.20 (m, 2H), 1.90-1.66 (m, 6H), 1.55-1.36 (m, 2H), 0.46 (d, J=4.8Hz, 18H). 13 C NMR (100MHz, CDCl3) δ141.1, 138.4, 138.4, 138.0, 137.1, 135.6, 135.5, 135.0, 134.9, 134.7, 133.8, 133.8, 129.0, 129.0, 128.8, 1 28.7, 122.3, 122.3, 122.0, 121.9, 59.0, 58.9, 57.4, 57.3, 33.8, 33.7, 33.4, 33.3, 29.2, 28.2, 27.7, 27.5, 22.7, 22.6, 22.5, 22.4. 31 P NMR (162MHz, CDCl3) δ27.1.HRMS (ESI) m / z: [M+H] + calcd.for C 30 H44 N2OP 479.3186, found 479.3180.

[0045] The following formamide enantioselectivity C(sp) 3 Examples of the )-H activation reaction will better illustrate the invention, but it should be emphasized that the invention is by no means limited to what is shown in these examples. The following examples illustrate different aspects of the invention. The data given include specific operations and reaction conditions and products. Product purity was determined by NMR. Product chirality was detected by chiral high-performance liquid chromatography.

[0046] Example 1: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2(1H)-one

[0047]

[0048] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3a, a yellow oily liquid with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ4.80-4.67 (m, 1H), 3.64-3.54 (m, 1H), 2.57-2.43 (m, 2H), 2.23-2.0 5 (m, 3H), 1.92 (d, J=16.4, 1H), 1.49-1.32 (m, 4H), 1.21-1.09 (m, 9H), 0.96-0.87 (m, 6H). 13 C NMR (100MHz, CDCl3) δ164.3, 142.0, 130.3, 44.8, 44.4, 35.9, 35.8, 28.6, 23.2, 21.3, 20.7, 20.6, 20.2, 14.4, 14.3.HRMS (ESI) m / z: [M+H] + calcd.for C 15 H 28NO 238.2165, found 238.2172.HPLC condition: Chiralpak IAcolumn, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-minor =8.1min,t r-major = 9.9 min, 91% ee. 111.1 (c 1.0, CHCl3).

[0049] Example 2: Synthesis of (R)-3,4-Diethyl-1-isopropyl-6-methyl-5,6-dihydropyridin-2(1H)-one

[0050]

[0051] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2b (32.8 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3b, a colorless oily liquid with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ4.82-4.66 (m, 1H), 3.67-3.53 (m, 1H), 2.59-2.39 (m, 2H), 2.29-2.17 (m, 2 H), 2.13-2.02 (m, 1H), 1.91 (d, J=16.4Hz, 1H), 1.14 (dd, J=12.0, 6.4Hz, 9H), 1.05-0.93 (m, 6H). 13 C NMR (100MHz, CDCl3) δ164.3, 142.9, 131.0, 44.6, 44.3, 35.3, 26.5, 21.3, 20.6, 20.1, 19.6, 14.6.11.9. HRMS (ESI) m / z: [M+H] + calcd.for C 13 H 24NO 210.1852, found 210.1855.HPLC condition: ChiralpakIA column, n-hexane / i-PrOH=99:1, 1.0mL / min, 254nm, t r-minor =14.0min,t r-major =15.4min, 93%ee. 110.0 (c 1.0, CHCl3).

[0052] Example 3: Synthesis of (R)-3,4-Dihexyl-1-isopropyl-6-methyl-5,6-dihydropyridin-2(1H)-one

[0053]

[0054] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2c (88.9 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3c, a colorless oily liquid with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ4.81-4.65 (m, 1H), 3.63-3.53 (m, 1H), 2.56-2.42 (m, 2H), 2.23-2.0 2 (m, 3H), 1.91 (d, J=16.4, 1H), 1.42-1.22 (m, 16H), 1.19-1.10 (m, 9H), 0.92-0.79 (m, 6H). 13 C NMR (100MHz, CDCl3) δ164.3, 142.0, 130.3, 44.7, 44.4, 35.8, 33.8, 31.8, 31.8, 30.0, 2 9.7, 29.5, 27.3, 26.6, 22.8, 22.7, 21.3, 20.6, 20.2, 14.2, 14.2.HRMS (ESI) m / z: [M+H] + calcd.for C 21 H 40NO 322.3104, found322.3111.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=99:1, 1.0mL / min, 254nm, t r-minor =11.6min,t r-major =12.5min, 93%ee. 96.0 (c 1.0, CHCl3).

[0055] Example 4: Synthesis of (R,E)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(4-phenylbut-3-en-2-yl)pyridine

[0056]

[0057] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2d (66.5 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3d, a colorless oily liquid with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ4.86-4.67 (m, 1H), 3.73-3.52 (m, 1H), 2.52 (dd, J=16.8, 6.4Hz, 1H), 2.47-2.37 (m, 1H), 2.25-2.12 (m, 2H), 2.09-1.98 (m, 1H), 1.90 (d, J=16.4Hz, 1H), 1.65-1.45 (m, 2H), 1-33-1.21 (m, 4H), 1.15 (q, J=6.6Hz, 9H), 0.91 (d, J=6.8Hz, 12H). 13 C NMR (100MHz, CDCl3) δ164.3, 142.1, 131.2, 44.6, 44.3, 39.2, 36.5, 35.9, 31.7, 28.6, 28.4, 24.6, 22.6, 22.5, 21.4, 20.6, 20.2.HRMS (ESI) m / z: [M+H] + calcd.for C 19 H36 NO 294.2791, found 294.2787.HPLC condition: Chiralpak IAcolumn, n-hexane / i-PrOH=99:1, 1.0mL / min, 254nm, t r-minor =12.2min, tr -major =15.7min, 93%ee. 93.9 (c 1.0, CHCl3).

[0058] Example 5: Synthesis of (R)-1-Isopropyl-3,4-bis(3-methoxypropyl)-6-methyl-5,6-dihydropyridin-2(1H)-one

[0059]

[0060] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2e (68.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3e, a colorless oily liquid with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ4.82-4.67 (m, 1H), 3.69-3.59 (m, 1H), 3.42-3-35 (m, 4H), 3.32 (d, J=5.2Hz, 6H) , 2.62-2.46 (m, 2H), 2.36-2.16 (m, 3H), 1.94 (d, J=16.8Hz, 1H), 1.76-1.60 (m, 4H), 1.23-1.09 (m, 9H). 13 C NMR (100MHz, CDCl3) δ164.1, 141.9, 130.1, 72.7, 72.3, 58.8, 58.5, 44.9, 44.5, 35.9, 30.3, 29.7, 27.4, 23.1, 21.3, 20.6, 20.2.HRMS (ESI) m / z: [M+H] + calcd.for C 17 H 32NO3 298.2377, found298.2370.HPLC condition: Chiralpak OD-H column, n-hexane / i-PrOH=97:3, 1.0mL / min, 254nm, t r-minor =10.3min,t r-major = 11.2 min, 90% ee. 36.7 (c 0.5, CHCl3).

[0061] Example 6: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-diphenyl-5,6-dihydropyridin-2(1H)-one

[0062]

[0063] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2f (71.2 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3f, a white solid with a yield of 67%. 1 H NMR (400MHz, CDCl3) δ7.24-7.07(m, 8H), 7.06-6.94(m, 2H), 4.93-4.73(m, 1H), 3.94-3.80(m, 1H), 3.16 (dd, J=16.8, 5.8Hz, 1H), 2.51 (d, J=16.8Hz, 1H), 1.48 (d, J=6.4Hz, 3H), 1.28 (d, J=6.4Hz, 6H). 13 C NMR (100MHz, CDCl3) δ163.6, 142.8, 140.7, 140.5, 136.4, 132.7, 131.5, 131.1, 128.4, 128.1, 127.6, 127.5, 126.8, 126.7, 125.3, 45.4, 45.1, 38.3, 21.4, 20.6, 20.4.HRMS (ESI) m / z: [M+H] + calcd.forC 21 H 24NO 306.1852, found 306.1853.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=96:4, 1.0mL / min, 254nm, t r-minor =11.4min,t r-major =14.4min, 92%ee. 124.0 (c 1.0, CHCl3).

[0064] Example 7: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-di-p-tolyl-5,6-dihydropyridin-2(1H)-one

[0065]

[0066] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5. mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2 g (82.4 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 3 g of the target product as a white solid, with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.09-6.95 (m, 6H), 6.94-6.87 (m, 2H), 4.92-4.76 (m, 1H), 3.93-3.76 (m, 1H), 3.1 1 (dd, J=16.4, 6.4Hz, 1H), 2.47 (d, J=16.4, 1H), 2.26 (s, 6H), 1.44 (d, J=6.4, 3H), 1.26 (d, J=6.4, 6H). 13 C NMR (100MHz, CDCl3) δ163.9, 142.2, 137.7, 137.3, 136.2, 133.6, 132.1, 130.9, 128. 8, 128.4, 128.3, 45.3, 45.0, 38.3, 21.4, 213, 21.3, 20.6, 20.3.HRMS (ESI) m / z: [M+H] + calcd.for C 23 H 28NO334.2165, found 334.2160.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor =10.4min,t r-major =16.4min, 94%ee. 111.7 (c 1.0, CHCl3).

[0067] Example 8: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-di-m-tolyl-5,6-dihydropyridin-2(1H)-one

[0068]

[0069] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2h (82.4 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3h, a white solid with a yield of 62%. 1 H NMR (400MHz, CDCl3) δ7.07-6.99 (m, 2H), 6.98-6.88 (m, 3H), 6.87-6.81 (m, 2H), 6.78 (d, J=7.6Hz, 1H), 4.92-4.78 (m, 1H), 3.87-3.78 (m, 1H), 3.13 (dd, J=16.4, 6.0Hz, 1H), 2.48 (d, J=16.4, 1H), 2.23 (s, 3H), 2.20 (s, 3H), 1.46 (d, J=6.4Hz, 3H), 1.46 (d, J=6.8Hz, 6H). 13 C NMR (100MHz, CDCl3) δ163.8, 142.6, 140.5, 137.5, 136.9, 136.4, 132.7, 131.6, 128.9, 128.2, 128.1 , 127.8, 127.5, 127.4, 125.5, 45.3, 45.0, 38.3, 21.5, 21.4, 21.4, 20.6, 20.4.HRMS (ESI) m / z: [M+H]+ calcd.for C 23 H 28 NO334.2165, found 334.2160.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=96:4, 1.0mL / min, 254nm, t r-minor = 9.7min, t r-major = 11.4 min, 91% ee. 90.6 (c 1.0, CHCl3).

[0070] Example 9: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-di-o-tolyl-5,6-dihydropyridin-2(1H)-one

[0071]

[0072] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2i (82.4 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3i, a white solid with a yield of 69%. 1 H NMR (400MHz, CDCl3) δ7.24-6.79(m, 7H), 6.77-6.62(m, 1H), 4.96-4.62(m, 1H), 3.99-3.77( m, 1H), 3.33-3.10 (m, 1H), 2.53-2.11 (m, 6H), 1.92 (s, 1H), 1.53 (s, 3H), 1.36-1.23 (m, 6H). 13 C NMR (100MHz, CDCl3) δ163.4, 144.5, 140.8, 136.5, 134.3, 131.8, 130.4, 130.3, 129.6, 127.3, 127.1 , 125.8, 125.4, 125.2, 124.8, 45.9, 45.6, 38.2, 29.8, 21.5, 21.2, 20.9, 20.3.HRMS (ESI) m / z: [M+H] + calcd.for C23 H 28 NO334.2165, found 334.2159.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor = 8.6min, t r-major =10.0min, 90%ee. -165.6 (c 1.0, CHCl3).

[0073] Example 10: Synthesis of (R,E)-N-Methyl-N-(6-(4-phenylbut-3-en-2-yl)pyridin-3-yl)benzamide

[0074]

[0075] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2j (116.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3j, a white solid with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ7.16 (t, J=8.0Hz, 4H), 7.05 (d, J=8.4Hz, 2H), 6.95 (d, J=8.4Hz, 2H), 4.91-4.74 (m, 1H), 3.9 1-3.78 (m, 1H), 3.11 (dd, J=16.8, 6.0Hz, 1H), 2.52 (d, J=16.4Hz, 1H), 1.45 (d, J=6.4Hz, 3H), 1.30-1.18 (m, 24H). 13 C NMR (100MHz, CDCl3) δ164.0, 150.5, 149.3, 142.1, 137.6, 133.6, 132.2, 130.7, 128.3, 124. 8, 124.5, 45.3, 45.1, 38.2, 34.6, 34.5, 31.4, 31.3, 21.4, 20.6, 20.4.HRMS (ESI) m / z: [M+H] + calcd.for C29 H 40 NO 418.3104, found 418.3099.HPLC condition: ChiralpakIA column, n-hexane / i-PrOH=96:4, 1.0mL / min, 254nm, t r-minor = 8.3min, t r-major = 11.4 min, 90% ee. 99.2 (c 1.0, CHCl3).

[0076] Example 11: Synthesis of (R,E)-N-methyl-N-(6-(4-phenylbut-3-en-2-yl)pyridin-3-yl)pivalamide

[0077]

[0078] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2k (95.2 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3k as a white solid with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ7.06 (d, J=8.4Hz, 2H), 6.97 (d, J=8.4Hz, 2H), 7.16 (t, J=8.0Hz, 4H), 4.91-4.75 (m, 1H), 3.91-3.79 (m, 1H), 3.78-3.67 (m, 6H), 3.09 (dd, J=16.8, 6.0Hz, 1H), 2.49 (d, J=16.4Hz, 1H), 1.44 (d, J=6.4Hz, 3H), 1.27 (d, J=6.4Hz, 6H). 13C NMR (100MHz, CDCl3) δ164.1, 158.8, 158.4, 141.7, 132.9, 132.3, 131.3, 129.9, 129.1 , 113.5, 113.2, 55.3, 45.3, 45.0, 38.3, 21.4, 20.6, 20.3. HPLCcondition: Chiralpak IA column, n-hexane / i-PrOH=80:20, 1.0mL / min, 254nm, t r-minor =7.7min,t r-major =10.5min, 92%ee. 116.4 (c 1.0, CHCl3).

[0079] Example 12: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-bis(4-(trifluoromethoxy)phenyl)-5,6-dihydropyridin-2(1H)-one

[0080]

[0081] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2k (138.4 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 3 μL of the target product, a white solid, with a yield of 54%. 1 H NMR (400MHz, CDCl3) δ7.13 (d, J=8.4Hz, 2H), 7.03 (d, J=7.2Hz, 6H), 4.87-4.71 (m, 1H), 3.97-3.82 (m, 1 H), 3.14 (dd, J=16.8, 6.0Hz, 1H), 2.49 (d, J=16.8Hz, 1H), 1.46 (d, J=6.4Hz, 3H), 1.28 (d, J=6.8Hz, 6H). 13C NMR (100MHz, CDCl3) δ163.0, 148.6 (q, J=13.8Hz), 148.3 (q, J=12.0Hz), 142.3, 138.6, 134.7, 132.6, 132.2 , 129.9, 121.7 (q, J=256.0Hz), 120.7, 120.2, 119.2 (q, J=256.0Hz), 45.7, 45.2, 38.3, 21.4, 20.6, 20.4.19F NMR (376MHz, CDCl3) δ-57.8, -57.9.HRMS (ESI) m / z: [M+H] + calcd.for C 23 H 22 F6NO3 474.1498, found 474.1492.HPLC condition: Chiralpak IAcolumn, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor = 8.6min, t r-major =13.2min, 92%ee. 91.1 (c 1.0, CHCl3).

[0082] Example 13: Synthesis of (R)-3,4-Bis(4-Fluorophenyl)-1-isopropyl-6-methyl-5,6-dihydropyridin-2(1H)-one

[0083]

[0084] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2m (85.6 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3m, a white solid with a yield of 63%. 11H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 6.87 (t, J = 7.8 Hz, 4H), 4.90 - 4.73 (m, 1H), 3.92 - 3.81 (m, 1H), 3.12 (dd, J = 16.8, 6.0 Hz, 1H), 2.47 (d, J = 16.8 Hz, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.8 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 163.4, 163.2 (d, J = 9.6 Hz), 160.8 (d, J = 7.2 Hz), 142.2, 136.2 (d, J = 3.2 Hz), 132.8 (d, J = 8.0 Hz), 132.1 (d, J = 3.2 Hz), 131.9, 130.2 (d, J = 8.0 Hz), 115.3 (d, J = 21.4 Hz), 114.7 (d, J = 21.2 Hz), 45.6, 45.1, 38.4, 21.4, 20.6, 20.4, 19F NMR (376 MHz, CDCl3) δ -113.4, -115.5. HRMS (ESI) m / z: [M + H] + calcd. for C 21 H 22 F2NO 342.1664, found 342.1660. HPLC condition: Chiralpak IA column, n - hexane / i - PrOH = 95∶5, 1.0 mL / min, 254 nm, t r-minor = 11.8 min, t r-major = 18.0 min, 95% ee. 147.4 (c 0.5, CHCl3).

[0085] Example 14: Synthesis of (R)-3,4 - Bis(3 - Fluorophenyl)-1 - isopropyl - 6 - methyl - 5,6 - dihydropyridin - 2(1H)-one

[0086]

[0087] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2n (85.6 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3n, a white solid with a yield of 53%. 1 H NMR (400MHz, CDCl3) δ7.18-7.08 (m, 2H), 6.95-6.80 (m, 4H), 6.77 (d, J=7.8Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 4.88-4.71 (m, 1 H), 3.94-3.80 (m, 1H), 3.13 (dd, J=16.8, 6.0Hz, 1H), 2.46 (d, J=16.8Hz, 1H), 1.46 (d, J=6.8Hz, 3H), 1.27 (d, J=6.8Hz, 6H). 13 C NMR (100MHz, CDCl3) δ163.6 (d, J=19.4Hz), 162.9, 161.2 (d, J=17.6Hz), 142.3 (d, J=1.6Hz), 14 2.2 (d, J=7.6Hz), 138.1 (d, J=8.2Hz), 132.3 (d, J=1.6Hz), 129.8 (d, J=8.2Hz), 129.1 (d, J=8.2 Hz), 126.8 (d, J=2.8Hz), 124.0 (d, J=2.8Hz), 118.0 (d, J=21.6Hz), 115.1 (d, J=21.8Hz), 114.8 (d, J=21.0Hz), 114.1 (d, J=21.0Hz), 45.6, 45.1, 38.2, 21.3, 20.5, 20.4. HRMS (ESI) m / z: [M+H] + calcd.for C 21 H 22 F2NO342.1664, found 342.1661. 19 F NMR (376MHz, CDCl3) δ-112.7, -114.3. HPLC condition: Chiralpak IA-3 column, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor=10.9min,t r-major =12.7min, 90%ee. 94.6 (c 1.0, CHCl3).

[0088] Example 15: Synthesis of (R)-3,4-Bis(2-Fluorophenyl)-1-isopropyl-6-methyl-5,6-dihydropyridin-2(1H)-one

[0089]

[0090] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 nmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2o (85.6 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3o, a white solid with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.19-7.09 (m, 2H), 7.08-7.02 (m, 1H), 7.01-6.85 (m, 5H), 4.88-4.75 (m, 1H), 3.92-3.8 1 (m, 1H), 3.18 (dd, J=16.8, 6.0Hz, 1H), 2.43 (d, J=16.8Hz, 1H), 1.50 (d, J=6.6Hz, 3H), 1.28 (d, J=6.8Hz, 6H). 13 C NMR (100MHz, CDCl3) δ162.3, 161.6, 160.7, 159.1, 158.2, 141.0, 132.8, 129.7 (d, J=7.9Hz), 129.1 (d, J=8.1Hz), 127.7 (d, J=15.2Hz), 124.0 (d, J=16 .2Hz), 123.8 (d, J=3.2Hz), 123.3 (d, J=2.7Hz), 115.7 (d, J=21.5Hz), 115. 0 (d, Jr=22.2Hz), 45.6, 45.5, 37.7, 21.3, 20.6, 20.0.HRMS (ESI) m / z: [M+H] + calcd.for C 21 H 22F2NO 342.1664, found342.1661. 19 F NMR (376MHz, CDCl3) δ-113.6, -114.1.HPLC condition: Chiralpak IA-3column, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor =12.0min,t r-major =14.1min, 91%ee. 25.2 (c 1.0, CHCl3).

[0091] Example 16: Synthesis of (R,E)-N,N-Diisopropyl-6-(4-phenylbut-3-eh-2-yl)nicotinamide

[0092]

[0093] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2p (113.7 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3p as a white solid with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ7.46 (d, J=9.6Hz, 2H), 7.07 (d, J=8.4Hz, 1H), 7.04-6.75 (m, 5H), 6.34 (d, J=16.8Hz, 2H), 4.96-4.76 (m, 1H), 3.93 -3.81 (m, 1H), 3.66 (d, J=11.6, 6H), 3.23 (dd, J=16.8, 6.0Hz, 1H), 2.62 (d, J=16.4Hz, 1H), 1.51 (d, J=6.4Hz, 3H), 1.28 (d, J=6.4Hz, 6H). 13C NMR (100MHz, CDCl3) δ164.7, 142.7, 135.8, 135.7, 132.4, 132.1, 129.1, 128.2, 128.1, 128.0, 127.9, 125.3, 123.5 , 123.1, 120.6, 110.0, 108.6, 108.2, 101.2, 45.0, 44.9, 39.1, 32.8, 32.8, 21.4, 20.6, 20.3.HRMS (ESI) m / z: [M+H] + calcd.for C 27 H 30 N3O 412.2383, found 412.2380.HPLCcondition: Chiralpak IA column, n-hexane / i-PrOH=80:20, 1.0mL / min, 254nm, t r-minor =16.1min,t r-major =18.2min, 93%ee. 52.8 (c 1.0, CHCl3).

[0094] Example 17: Synthesis of (R)-1-Isopropyl-6-methyl-3,4-di(thiophen-3-yl)-5,6-dihydropyridin-2(1H)-one

[0095]

[0096] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2q (76.0 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3q, a yellow liquid with a yield of 40%. 11H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 3.2, 1.2 Hz, 1H), 7.18 (dd, J = 4.8, 3.2 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.89 (dd, J = 5.2, 1.2 Hz, 1H), 6.59 (dd, J = 5.2, 1.2 Hz, 1H), 4.91 - 4.77 (m, 1H), 3.89 - 3.80 (m, 1H), 3.00 (dd, J = 17.2, 6.0 Hz, 1H), 2.61 (d, J = 17.2, 1H), 1.42 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 7.0 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 163.5, 140.8, 137.2, 136.3, 130.1, 128.0, 126.7, 125.2, 125.0, 124.1, 123.5, 45.3, 44.9, 37.9, 21.3, 20.6, 20.4. HRMS (ESI) m / z: [M+H] + calcd. for C 17 H 20 NOS2 318.0981, found 318.0978. HPLC condition: Chiralpak IA - 3 column, n - hexane / i - PrOH = 90∶10, 1.0 mL / min, 254 nm, t r-minor = 10.0 min, t r-major = 14.9 min, 90% ee. 194.6 (c 1.0, CHCl3).

[0097] Example 18: Synthesis of (R)-4-Butyl-1-isopropyl-6-methyl-3-phenyl-5,6-dihydropyridin-2(1H)-one

[0098]

[0099] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2r (63.2 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3r, a white solid with a yield of 20%. 1 H NMR (400MHz, CDCl3) δ7.42-7.34 (m, 2H), 7.33-7.26 (m, 1H), 7.22-7.14 (m, 2H), 4.91-4.76 (m, 1H), 3.78-3.64 (m, 1H), 2.92 (dd, J=16.8Hz, 6.0Hz 1H), 2.58-2.46 (m, 1H), 2.24 (d, J=16.8Hz, 1H), 2.18-2.09 (m, 1H), 1.45-1.29 (m, 5H), 1.28-1.14 (m, 8H), 0.78 (t, J=7.2, 3H). 13 C NMR (100MHz, CDCl3) δ164.2, 141.2, 140.8, 132.4, 128.5, 127.5, 127.4, 44.9 , 44.6, 38.7, 31.8, 27.3, 22.9, 21.4, 20.6, 20.3, 14.0.HRMS(ESI)m / z: [M+H] + calcd.for C19H28NO 286.2165, found 286.2171.HPLCcondition: Chiralpak IA column, n-hexane / i-PrOH=96:4, 1.0mL / min, 254nm, t r-minor =7.6min,t r-major =10.3min, 87%ee. 113.2 (c 0.5, CHCl3).

[0100] Example 19: Synthesis of (R)-3-Butyl-1-isopropyl-6-methyl-4-phenyl-5,6-dihydropyridin-2(1H)-one

[0101]

[0102] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2r (63.2 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3r′, a white solid with a yield of 39%. 1 H NMR (400MHz, CDCl3) δ7.38-7.30 (m, 2H), 7.29-7.24 (m, 1H), 7.22-7.14 (m, 2H), 4.84-4.69 (m, 1H), 3.83-3.69 (m, 1H), 2.72 (dd, J=16.8Hz, 6.0Hz 1H), 2.13 (d, J=16.8Hz, 1H), 2.03 (t, J=7.8Hz, 2H), 1.45-1.30 (m, 5H), 1.28-1.12 (m, 8H), 0.78 (t, J=7.2, 3H). 13 C NMR (100MHz, CDCl3) δ163.5, 145.1, 136.6, 131.9, 130.1, 127.7, 126.8, 45.0 , 44.7, 35.6, 34.2, 29.4, 22.6, 21.3, 20.6, 20.3, 13.9.HRMS(ESI)m / z: [M+H] + calcd.for C 19 H 28 NO 286.2165, found 286.2171.HPLC condition: Chiralpak IAcolumn, n-hexane / i-PrOH=97:3, 1.0mL / min, 254nm, t r-minor =12.9min,t r-major =13.8min, 93%ee. 82.7 (c 1.0, CHCl3).

[0103] Example 20: Synthesis of (R)-3-(Tert-butyl)-1-isopropyl-4,6-dimethyl-5,6-dihydropyridin-2(1H)-one

[0104]

[0105] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a (25.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2s (63.2 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 3s, a colorless oily substance with a yield of 54%. 1 H NMR (400MHz, CDCl3) δ4.81-4.64(m, 1H), 3.64-3.50(m, 1H), 2.48-2.36(m, 1H ), 2.16 (d, J=17.0, 1H), 2.00 (d, J=2.0, 3H), 1.17 (s, 9H), 1.16-1.08 (m, 9H). 13 C NMR (100MHz, CDCl3) δ166.2, 147.6, 125.5, 44.6, 43.9, 36.4, 34.4, 29.3, 21.3, 20.4, 19.7, 15.5.HRMS (ESI) m / z: [M+H] + calcd.for C 14 H 26 NO 224.2009, found 224.2011.HPLC condition: Chiralpak IA-3 column, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor =7.3min,t r-major =8.1min, 89%ee. 132.4 (c 0.25, CHCl3).

[0106] Example 21: Synthesis of (R)-1-(tert-Butyl)-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2(1H)-one

[0107]

[0108] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1a′ (28.6 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4a, a colorless oily substance with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ3.96-3.84 (m, 1H), 2.58 (dd, J=16.8, 6.0Hz, 1H), 2.50-2.41 (m, 1H), 2.26-1.99 (m, 3H), 1.89 (d, J=16.8, 1H), 1.46 (s, 9H), 1.45-1.35 (m, 4H), 1.13 (d, J=6.4Hz, 3H), 0.93 (q, J=7.8Hz, 6H). 13 C NMR (100MHz, CDCl3) δ165.7, 141.4, 131.4, 56.7, 46.9, 36.2, 35.8, 29.4, 28.6, 23.3, 20.7, 19.9, 14.5, 14.4.HRMS (ESI) m / z: [M+H] + calcd.for C 16 H 30 NO 252.2322, found252.2319.HPLC condition: Chiralpak AD-H column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm,, t r-minor = 5.5min, t r-major =6.7min.90%ee. 59.4 (c 1.0, CHCl3).

[0109] Example 22: Synthesis of (6R)-1-((1S,2R,5R)-Adamantan-2-yl)-6-methyl-3,4-dipropyl-5,6-djhydropyridin-2(1H)-one

[0110]

[0111] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1b (44.2 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4b, a white solid with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ3.65 (s, 1H), 3.33 (s, 1H), 2.45-2.23 (m, 2H), 2.18-2.05 (m, 2H), 2.04-1.93 (m, 3H), 1.92-1.84 (m, 2H), 1.82-1.64 (m, 5H), 1.63-1.31 (m, 10H), 1.26 (d, J=6.4Hz, 3H), 0.95 (t, J=7.8Hz, 3H), 0.90 (d, J=7.8Hz, 3H). 13 C NMR (100MHz, CDCl3) δ167.9, 153.4, 131.3, 63.1, 45.2, 38.9, 37.9, 36.8, 36.5, 35.6, 30. 9, 30.5, 29.8, 29.6, 27.6, 27.0, 23.6, 23.5, 22.4, 22.3, 15.0, 14.6.HRMS (ESI) m / z: [M+H] + calcd.for C 22 H 36 NO 330.2791, found 330.2787.HPLC condition: Chiralpak IAcolumn, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-major = 5.8min, t r-minor = 6.9 min, 82% ee. 53.6 (c 0.5, CHCl3).

[0112] Example 23: Synthesis of (R)-1-(4,4-Dimethylcyclohexyl)-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2(1H)-one

[0113]

[0114] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1c (39.4 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-4 sodium disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4c, a colorless liquid with a yield of 56%. 1 H NMR (400MHz, CDCl3) δ4.38-4.14 (m, 1H), 3.73-3, 50 (m, 1H), 2.58-2.42 (m, 2H), 2.22-2.04 (m, 3H), 1.9 2 (d, J=16.4Hz, 1H), 1.70-1.54 (m, 3H), 1.51-1.27 (m, 9H), 1.15 (d, J=6.8Hz, 3H), 0.99-0.84 (m, 12H). 13 C NMR (100MHz, CDCl3) δ164.3, 141.9, 130.4, 53.7, 45.4, 38.9, 38.7, 35.9, 38.7, 35. 9, 35.8, 32.9, 29.7, 28.6, 27.1, 26.3, 24.2, 23.1, 20.7, 20.3.HRMS (ESI) m / z: [M+H] + calcd.for C 20 H 36 NO 306.2791, found 306.2788.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-minor =11.1min,t r-major =18.6min, 92%ee. 93.5 (c 1.0, CHCl3).

[0115] Example 24: Synthesis of R)-1-(2,2-Dimethyl-1,3-dioxan-5-yl)-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2(1H)-one

[0116]

[0117] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1d (40.2 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4d, a colorless liquid with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ4.31-4.16 (m, 2H), 4.11-3.94 (m, 4H), 2.69 (dd, J=16.8, 6.2Hz, 1H), 2.50-2.37 (m, 1H), 2.2 6-2.07 (m, 3H), 1.98 (d, J=16.8Hz, 1H), 1.52-1.31 (m, 10H), 1.25 (d, J=6.4Hz, 3H), 0.94 (dt, J=14.6, 7.2Hz, 6H). 13 C NMR (100MHz, CDCl3) δ165.2, 143.6, 129.7, 98.1, 62.6, 61.7, 49.8, 49.3, 36.0 , 35.6, 28.5, 24.8, 23.2, 23.2, 20.7, 19.4, 19.4, 14.3.HRMS (ESI) m / z: [M+Na] + calcd.forC 18 H 31 NNaO3332.2196, found 332.2189.HPLC condition: Chiralpak IA-3 column, n-hexane / i-PrOH=96:4, 1.0mL / min, 254nm, t r-minor = 8.9min, t r-major =12.6min, 92%ee. 75.7 (c 1.0, CHCl3).

[0118] Example 25: Synthesis of (R)-6-Methyl-3,4-dipropyl-1-(2,4,6-trimethylbenzyl)-5,6-dihydropyridin-2(1H)-one

[0119]

[0120] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1e (43.9 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4e, a colorless liquid with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ6.85 (s, 2H), 5.29 (d, J=14.8Hz, 1H), 4.16 (d, J=14.8Hz, 1H), 3.27-3.10 (m, 1H), 2.56-2.39 (m, 2H), 2.29 (s, 6H), 2.26 (s, 3H), 2.18-2.02 (m, 2H), 1.79 (d, J=16.8Hz, 2H), 1.50-1.35 (m, 4H), 1.09 (d, J=6.4Hz, 3H), 1.00-0.84 (m, 6H). 13 C NMR (100MHz, CDCl3) δ164.5, 142.9, 138.3, 137.0, 131.0, 129.3, 110.1, 46.6, 40.8 , 36.0, 34.6, 28.6, 23.3, 21.0, 20.8, 20.2, 17.3, 14.4, 14.3.HRMS(ESI)m / z: [M+H] + calcd.for C 22 H 34 NO 328.2635, found 328.2630.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-minor =11.5min,t r-major =12.3min, 74%ee. 66.6 (c 0.5, CHCl3).

[0121] Example 26: Synthesis of (R)-1-Benzhydryl-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2(1H)-one

[0122]

[0123] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1f (50.6 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-4 sodium disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4f, a colorless liquid with a yield of 45%. 1 H NMR (400MHz, CDCl3) δ7.34-7.28 (m, 6H), 7.27-7.20 (m, 3H), 7.14 (s, 1H), 3.71-3.55 (m, 1H), 2.88 (dd, J=16.8, 6.0Hz, 1H), 2.62-2.4 8 (m, 1H), 2.30-2.19 (m, 2H), 2.19-2.09 (m, 1H), 1.93 (d, J=16.8Hz, 1H), 1.55-1.37 (m, 4H), 1.02-0.88 (m, 6H), 0.56 (d, J=6.4Hz, 3H). 13 C NMR (100MHz, CDCl3) δ164.9, 143.3, 140.5, 140.0, 130.7, 130.3, 128.5, 128.4, 127.8, 127. 7, 126.9, 60.8, 46.9, 36.1, 35.7, 28.7, 23.2, 20.8, 18.9, 14.5, 14.4.HRMS (ESI) m / z: [M+H] + calcd.for C 15 H 32 NO 362.2478, found362.2472.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=96:4, 1.0mL / min, 254nm, t r-minor =15.4min,t r-major =20.1min, 93%ee. -100.0 (c 0.5, CHCl3).

[0124] Example 27: Synthesis of (R)-1-(1,3-Diphenylpropan-2-yl)-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2(1H)-one

[0125]

[0126] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1 g (56.2 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 4 g of the target product, a colorless liquid, with a yield of 55%. 1 H NMR (400MHz, CDCl3) δ7.42-6.86 (m, 10H), 3.36 (s, 2H), 3.01 (d, J=8.2Hz, 1H), 2.88-2.83 (m, 1H), 2.80-2.55 (m, 1H), 2.52-2.43 (m, 1H), 2.18-2.02 (m, 1H), 2.01-1.84 (m, 2H), 1.99-1.34 (m, 5H), 1.27-1.14 (m, 2H), 0.87 (t, J=7.8Hz, 3H), 0.78 (t, J=7.2Hz, 3H), 0.42 (s, 3H). 13 C NMR (100MHz, CDCl3) δ165.3, 142.2, 140.1, 130.2, 129.6, 129.4, 128.4, 128.3, 126.3, 126 .2, 39.3, 38.7, 35.7, 34.4, 30.4, 28.3, 23.1, 20.5, 18.2, 14.4, 14.1.HRMS (ESI) m / z: [M+H] + calcd.for C 27 H 36 NO 390.2791, found 390.2787.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-minor =12.4min,t r-major =13.5min, 90%ee. 38.6 (c 1.0, CHCl3).

[0127] Example 28: Synthesis of (S)-6,6,9a-Trimethyl-2,3-dipropyl-1,6,7,8,9,9a-hexahydro-4H-quinolizin-4-one

[0128]

[0129] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1h (33.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% ethylenediaminetetraacetic acid disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4h, a colorless liquid with a yield of 40%. 1 H NMR (400MHz, CDCl3) δ2.44-2.32 (m, 2H), 2.22-2.00 (m, 3H), 1.89 (d, J=16.8, 1H), 1.78-1.59 (m, 3H), 1.58 (s, 3H), 1.57-1.46 (m, 3H), 1.21 (s, 6H), 1.27-1.15 (m, 4H), 0.99-0.85 (m, 6H). 13 C NMR (100MHz, CDCl3) δ167.8, 142.7, 131.2, 55.5, 55.1, 46.3, 42.4, 40.0, 35. 5, 32.4, 28.7, 24.5, 24.1, 23.3, 20.6, 16.2, 14.4, 14.2.HRMS(ESI)m / z: [M+H] + calcd.for C 18 H 32 NO 278.2478, found 278.2473.HPLCcondition: Chiralpak AD-H column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-major = 5.7min, t r-minor = 6.2 min, 74% ee. -54.4 (c 0.5, CHCl3).

[0130] Example 29: Synthesis of (R)-9a-Methyl-7,8-dipropyl-3,4,9,9a-tetrahydropyrido[2,1-c][1,4]oxazin-6(1H)-one

[0131]

[0132] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1i (28.6 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4i, a white solid with a yield of 42%. 1 H NMR (400MHz, CDCl3) δ4.10-3.99 (m, 2H), 3.63 (d, J=11.2Hz, 1H), 3.56-3.45 (m, 1H), 3.29 (d, J=11.2Hz, 1H), 3.03-2.91 (m, 1H), 2.45-2. 35 (m, 1H), 2.34-2.19 (m, 3H), 2.18-2.09 (m, 1H), 1.91 (d, J=16.8Hz, 1H), 1.55-1.35 (m, 4H), 1.25 (s, 3H), 0.94 (dt, J=14.8, 7.2Hz, 6H). 13 C NMR (100MHz, CDCl3) δ165.8, 143.6, 129.1, 67.4, 53.7, 37.1, 37.4, 36.0, 28.6, 23.3, 20.8, 18.9, 14.4, 14.3.HRMS (ESI) m / z: [M+H] + calcd.for C 15 H 26 NO2 252.1958, found 252.1954.HPLC condition: Chiralpak IAcolumn, n-hexane / i-PrOH=95:5, 1.0mL / min, 254nm, t r-minor =9.2min,t r-major =11.9min, 70%ee. 62.7 (c 0.5, CHCl3).

[0133] Example 30: Synthesis of (4aR,8aR)-1-Cyclohexyl-3,4-dipropyl-4a,5,6,7,8,8a-hexahydroquinolin-2(1H)-one

[0134]

[0135] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1j (41.8 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-4-sodium disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4j, a colorless liquid with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ4.31-4.26 (m, 1H), 3.29-3.15 (m, 1H), 2.71-2.55 (m, 2H), 2.45-2.34 (m, 1H), 2.04-2.34 (m, 1H), 2.07-1. 93(m, 2H), 1.83-1.69(m, 3H), 1.68-1.59(m, 4H), 1.56-1.30(m, 10H), 1.29-1.14(m, 2H), 1.13-1.00(m, 2H), 0.94-0.84(m, 6H). 13 C NMR (100MHz, CDCl3) δ164.1, 145.2, 132.1, 53.2, 52.7, 37.7, 31.8, 31.4, 31.2, 28. 8, 28.5, 27.7, 26.2, 26.1, 25.7, 25.1, 23.3, 22.2, 22.1, 14.3.HRMS (ESI) m / z: [M+H] + calcd.for C 21 H 36 NO 318.2791, found 318.2798.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, t r-major = 8.7min, t r-minor = 9.9 min, 85% ee. -71.3 (c 1.0, CHCl3).

[0136] Example 31: Synthesis of (4aR,9aR)-1-Cycloheptyl-3,4-dipropyl-5,6,7,8,9,9a-hexahydro-1H-cyclohepta[b]pyridin-2(4aH)-one

[0137]

[0138] Under a nitrogen atmosphere, ligand H8-BINAPO (4.8 mg, 5 mol%), Ni(cod)2 (2.75 mg, 5 mol%), 1k (47.44 mg, 0.2 mmol), and toluene (0.5 mL) were added sequentially to the reaction flask. Then, 2a (44.1 mg, 0.4 mmol) and triisobutylaluminum (1 M, 80 μL, 40 mol%) were added. The mixture was stirred at 80 °C for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2 mL of 5% EDTA-disodium salt aqueous solution, separated, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target product 4k, a colorless liquid with a yield of 95%. 1 H NMR (400MHz, CDCl3) δ4.35-4.19 (m, 1H), 3.46-3.26 (m, 1H), 2.74 (q, J=6.8Hz, 1H), 2.60-2.47 (m, 1H), 2.36-2.23 (m, 1H), 2.19-2.0 9 (m, 1H), 2.08-1.98 (m, 1H), 1.97-1.91 (m, 1H), 1.90-1.80 (m, 2H), 1.78-1.54 (m, 11H), 1.53-1.18 (m, 12H), 0.89 (q, J=7.2Hz, 6H). 13 C NMR (100MHz, CDCl3) δ164.0, 146.6, 130.9, 57.0, 56.8, 40.5, 34.6, 32.9, 31.7, 30.1, 29.5, 2 8.7, 28.4, 27.7, 27.3, 26.2, 25.6, 25.5, 23.6, 23.3, 22.6, 14.4, 14.3.HRMS (ESI) m / z: [M+H] + calcd.for C 23 H 40 NO2 346.3104, found346.3101.HPLC condition: Chiralpak IA column, n-hexane / i-PrOH=98:2, 1.0mL / min, 254nm, tr-major =8.7min,t r-minor =9.9min,85%ee. -50.4(c 1.0, CHCl3).

Claims

1. A dinitrogen-phosphorus-oxygen ligand, characterized in that: The structure is Where R is t Bu, Ph, or Bn.

2. A method for preparing dinitrophosphoric ligands by nucleophilic substitution reaction of binaphthylamine with acyl chloride, characterized in that... The specific steps are as follows; 3. An application of the dinitrogen-phosphorus-oxygen ligand according to claim 1, characterized in that: The ligand is applied to the following nickel-catalyzed C(sp) 3 -H bond asymmetric activation, Where R 1 Methyl, cyclohexyl, cycloheptyl; R 2 Hydrogen, cyclohexyl, cycloheptyl; R 3 It is isopropyl, cyclohexyl, or alkoxy; R 4 R 5 It can be ethyl, phenyl, or thiophene.

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