CN117586310A - Binaphthyl amine derived chiral phosphine oxide ligand promoted nickel catalysis C (sp 3 ) Asymmetric cyclization of the-H bond - Google Patents

Binaphthyl amine derived chiral phosphine oxide ligand promoted nickel catalysis C (sp 3 ) Asymmetric cyclization of the-H bond Download PDF

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CN117586310A
CN117586310A CN202210964711.5A CN202210964711A CN117586310A CN 117586310 A CN117586310 A CN 117586310A CN 202210964711 A CN202210964711 A CN 202210964711A CN 117586310 A CN117586310 A CN 117586310A
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叶萌春
王银霞
张凤萍
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Nankai University
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Abstract

The invention provides a simple and efficient synthesis method, synthesizes a novel binaphthol-derived skeleton phosphorus-oxygen ligand, utilizes the newly developed phosphorus-oxygen ligand, realizes that the binaphthol-derived phosphorus-oxygen ligand is used for connecting a nickel-aluminum bimetallic catalyst to realize the enantioselective nickel catalytic aliphatic C (sp) 3 ) A method for activating H, which belongs to the technical field of asymmetric catalysis application. The key of the invention for solving the problems is that: 1. find a novel binaphthol-derived phosphorus-oxygen ligand which is efficient and specific to reactivity, site selectivity and corresponding selectivity, and realize nickel catalysis of aliphatic C (sp) of formamide 3 ) -a method of asymmetric H activation; 2. by utilizing the ligand characteristic, the bimetallic catalytic system is designed, so that the reaction activity is greatly improved, and the preparation is easier and more efficient.

Description

Binaphthyl amine derived chiral phosphine oxide ligand promoted nickel catalysis C (sp 3 ) Asymmetric cyclization of the-H bond
Technical Field
The present invention relates to a method for preparing a phosphorus oxide ligand (H) derived by using binaphthyl amine 8 Implementation of enantioselective nickel-catalyzed aliphatic C (sp) of formamide with BINAPO bridged nickel-aluminum bimetallic catalyst 3 ) The method for activating H provides a series of chiral nitrogen-containing heterocycles, and belongs to the technical field of asymmetric catalysis application.
Background
Chiral compounds are widely found in pharmaceuticals, agrochemicals and biologically active natural products. The method of achieving C-H enantioselective activation by transition metals is one of the most convenient and economical ways to obtain chiral molecules present in large amounts of natural products and bioactive compounds such as pharmaceuticals and pesticides. Currently, widely explored C-H bonds are C (sp 2 ) -H or C (sp) -H bonds. In contrast, due to C (sp 3 ) Sterically hindered and inactive around H bond, non-activated C (sp 3 ) The achievement of enantioselective activation of the H bond presents a great challenge.
Noble metals such as Pd, rh and Ir have been able to catalyze widely enantioselective C (sp 3 ) H bond activation reaction, providing good yields and high ee. However, the same strategy is generally ineffective for most 3d transition metals that are very sensitive to substrate and ligand structures. To date, only Matsunaga, yoshino and its colleagues have reported a successful example. They use achiral Cp-Co (III) and amino acid derivatives as chiral anions to promote primary C (sp) of thioamides 3 ) Enantioselective amidation of the H bond. In view of the high earth abundance, low cost and low biotoxicity advantages of 3d metals, 3d metal catalyzed enantioselective C (sp 3 ) An H bond activation reaction is very necessary.
In summary, although nickel-catalyzed C-H bond activation even enantioselective nickel-catalyzed carbon (sp 2 ) The activation of the H bond has progressed considerably, but enantioselective Ni-catalyzed aliphatic C (sp 3 ) H-bond activation remains a difficult challenge to achieve.
The invention comprises the following steps:
enantioselective nickel catalyzed aliphatic C (sp 3 ) The H activation reaction did not give good results by trying both the dioxy backbone phosphorus-oxygen ligand and other dinitrogen phosphorus-oxygen ligands, and good results could be achieved with binaphthyl-amine derived phosphorus-oxygen ligands.
One of the key points of the invention for solving the problems is that the binaphthyl amine and acyl chloride are subjected to nucleophilic substitution reaction to prepare a novel dinitrogen phosphorus oxide precursor. The method is characterized by comprising the following specific steps:
1: a three-necked Schlenk flask was charged with the corresponding substituted diamine 5 (1.0 mmol,1.0 equiv.) in dry THF (10 mL) under N 2 N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) at-78deg.C in 10 minutes under an atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L.
2. R in the invention can be Ph, tBu and the like, but is not limited to the groups;
the invention has the advantages that:
1. the method is simple and convenient to operate, and the target product can be obtained through one-step reaction.
2. The product of the invention has stable structure and can exist in air stably.
3. The ligand structure related by the invention is easy to modify.
The invention also aims to provide a simple and practical method, which uses a novel H for the first time 8 -bis (2-naphthylamine) derived chiral phosphine oxide (H) 8 BINAPO to achieve enantioselective Nickel catalyzed C (sp) of formamide 3 ) Activation of H provides a series of nitrogen-containing heterocycles in 40-95% yields with ee of 70-95%. H 8 The BINAPO linked Ni-Al bimetallic catalyst may be activated with formyl C (sp 2 ) H bond activation and subsequent acceleration of aliphatic C (sp 3 ) -H activation plays a key role.
The second point of the invention to solve the problem is that the novel diazo-phospho-oxide ligand participates in nickel catalysis C (sp 3 ) -a method for asymmetric activation of H-bonds and use thereof. The method is characterized by comprising the following specific steps:
1. sequentially adding a ligand, a metal catalyst, raw materials and a solvent into a reaction bottle in a nitrogen atmosphere, then adding Lewis acid, stirring for 2-8 hours at a specified temperature, cooling to room temperature, adding ethyl acetate for dilution, adding 2mL of 5% ethylene diamine tetraacetic acid disodium salt aqueous solution for washing, separating liquid, drying an organic phase with anhydrous sodium sulfate, and separating by column chromatography to obtain a target product 3;
2. the metal catalyst of the invention is Ni (cod) 2 The catalyst is generally used in an amount of 5mol%.
3. The ligand involved in the invention is chiral bi-N framework secondary phosphine oxide, and the dosage of the ligand is generally 5mol percent.
4. Al according to the present invention i Bu 3 The amount of the n-hexane solution having a concentration of 1mol/L is generally 40mol%.
5. The solvent used in the present invention was toluene solution in an amount of 2.5mL per millimole of 1 starting material.
6. R in the raw material 1 used in the present invention 2 Methyl, cyclohexyl, cycloheptyl; r is R 2 Is hydrogen, cyclohexyl, cycloheptyl; r is R 3 Substituents such as isopropyl, cyclohexyl and alkoxy, but not limited to these groups; r is a substituent group such as ethyl, phenyl, thiophene, etc., but is not limited to these groups.
The invention has the advantages that:
1. most of the reagents used in the invention are commercially available, the chiral ligand to be synthesized has wide sources of raw materials and low cost, can exist stably at normal temperature and normal pressure, and is convenient to operate and process without special treatment.
2. The ligand synthesis method is simple in ligand synthesis and convenient to operate, the defect of long ligand synthesis steps used in the traditional method is avoided, and the requirement on equipment is simple. Greatly reduces the production cost for synthesizing the compounds.
3. The invention can obtain the optically pure product in one step, and the post-treatment is simple and convenient, thereby avoiding the method that the chiral product can be obtained only by relay reaction before, and greatly reducing the reaction cost of the product.
4. The catalyst used in the invention is cheap, the dosage of metal, ligand and the like is low, and the requirements of good catalytic effect, cost reduction, convenient post-treatment process, environmental pollution reduction and the like are maintained.
5. The reaction of the invention is completely atom economical, meets the requirement of green chemistry, does not have other byproducts in mass production, and meets the requirements of simplifying the process, reducing the cost, reducing the environmental pollution and the like.
Detailed description of the preferred embodiments
The following examples of ligand synthesis will better illustrate the invention, but it will be emphasized that the invention is in no way limited to the examples presented. The following examples show different sides of the invention. The data presented include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism.
Example 1: synthesis of Phosphonoxy ligand L1
A three-necked Schlenk flask was charged with the corresponding substituted diamine (1.0 mmol,1.0 equiv.) in dry THF (10 mL) and N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) over 10 minutes at-78deg.C under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L1 as a white solid in 50% yield. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )δ138.0，136.9，136.1，136.1，135.6，132.8，132.6，132.3，131.9，131.4，130.8，129.8，129.5，128.1，127.9，127.9，127.8，127.7，127.6，127.5，127.0，126.6，126.1，125.9，125.7，125.2，124.2，123.6，51.9，51.9，49.7，49.6. 31 P NMR(162MHz，CDCl 3 )δ22.9.HRMS(ESI)m/z：[M+H] + calcd.for C 34 H 38 N 2 OP 511.1934，found 511.1926.
Example 2: synthesis of phosphine oxide ligand L2
Into a three-necked Schlenk flask was charged the corresponding substituted diamine (1.0 mmol,1.0 eq)v.) dry THF (10 mL) and N-butyllithium was added to hexane (2.5 m,0.8mL,2 mmol) over 10 minutes at-78 ℃ under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L20 as a white solid in 60% yield. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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，CDCl 3 )δ27.0.HRMS(ESI)m/z：[M+H] + calcd.for C 30 H 36 N 2 OP 471.2560，found 471.2553.
Example 3: synthesis of Phosphonoxy ligand L3
A three-necked Schlenk flask was charged with the corresponding substituted diamine (1.0 mmol,1.0 equiv.) in dry THF (10 mL) and N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) over 10 minutes at-78deg.C under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirredAnd 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure phosphine oxide L21 as a white solid in 38% yield. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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，CDCl 3 )δ22.9.HRMS(ESI)m/z：[M+H] + calcd.for C 34 H 36 N 2 OP 519.2560，found 519.2555.
Example 4: synthesis of Phosphonoxy ligand L4
A three-necked Schlenk flask was charged with the corresponding substituted diamine (1.0 mmol,1.0 equiv.) in dry THF (10 mL) and N-butyllithium was added to hexane (2.5M, 0.8mL,2 mmol) over 10 minutes at-78deg.C under an N2 atmosphere. The mixture was stirred at the same temperature for 0.5 hours and then heated to room temperature for 0.5 hours. The mixture was then cooled to room temperature and freshly distilled PCl was added dropwise again at-78 ℃ 3 (95. Mu.L, 1.0mmol,1.0 equiv.). The solution was warmed to room temperature and stirred for 1 hour. H was added to the resulting solution 2 O (18. Mu.L, 1.0mmol,1.0 equiv.) and stirred for 0.5 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography to give pure secondaryPhosphine oxide L22, white solid, yield 35%. 1 H NMR(400MHz，CDCl 3 )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)，2.69-2.54(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，CDCl 3 )δ141.1，138.4，138.4，138.0，137.1，135.6，135.5，135.0，134.9，134.7，133.8，133.8，129.0，129.0，128.8，128.7，122.3，122.3，122.0，121.9，59.0，58.9，57.4，57.3，33.8，33.7，33.4，33.3，29.2，28.2，27.7，27.5，22.7，22.6，22.5，22.4. 31 P NMR(162MHz，CDCl 3 )δ27.1.HRMS(ESI)m/z：[M+H] + calcd.for C 30 H 44 N 2 OP 479.3186，found 479.3180.
The following carboxamide enantioselectivity C (sp 3 ) Examples of implementation of the H-activation reaction the invention will be better illustrated, but it will be emphasized that the invention is in no way limited to what is represented by these examples of implementation. The following examples show different sides of the invention. The data presented include specific operations and reaction conditions and products. The purity of the product was identified by nuclear magnetism. The chirality of the product is detected by chiral high performance liquid chromatography.
Example 1: synthesis of (R) -1-Isopropyl-6-methyl-3,4-dipropyl-5,6-dihydropyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, washing with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separating, and the organic phase was washed with anhydrous sulfurDrying sodium acid, concentrating, and separating by column chromatography to obtain the target product 3a, which is yellow oily liquid with a yield of 90%. 1 H NMR(400MHz，CDCl 3 )δ4.80-4.67(m，1H)，3.64-3.54(m，1H)，2.57-2.43(m，2H)，2.23-2.05(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，CDCl 3 )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 28 NO 238.2165，found 238.2172.HPLC condition：Chiralpak IA column，n-hexane/i-PrOH＝98∶2，1.0mL/min，254nm，t r-minor ＝8.1min，t r-major ＝9.9min，91％ee.111.1(c 1.0，CHCl 3 ).
Example 2: synthesis of (R) -3,4-Diethyl-1-isopropyl-6-methyl-5, 6-dihydroxyfridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2b (32.8 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 3b as a colorless oily liquid, yield 83%. 1 H NMR(400MHz，CDCl 3 )δ4.82-4.66(m，1H)，3.67-3.53(m，1H)，2.59-2.39(m，2H)，2.29-2.17(m，2H)，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，CDCl 3 )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 24 NO 210.1852，found 210.1855.HPLC condition：Chiralpak IA 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，CHCl 3 ).
Example 3: synthesis of (R) -3,4-Dihexyl-1-isopropyl-6-methyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2c (88.9 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product 3c by column chromatography, colorless oily liquid, yield 86%. 1 H NMR(400MHz，CDCl 3 )δ4.81-4.65(m，1H)，3.63-3.53(m，1H)，2.56-2.42(m，2H)，2.23-2.02(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，CDCl 3 )δ164.3，142.0，130.3，44.7，44.4，35.8，33.8，31.8，31.8，30.0，29.7，29.5，27.3，26.6，22.8，22.7，21.3，20.6，20.2，14.2，14.2.HRMS(ESI)m/z：[M+H] + calcd.for C 21 H 40 NO 322.3104，found 322.3111.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，CHCl 3 ).
Example 4: synthesis of (R, E) -5- (((tert-butyl methyl) oxy) methyl) -2- (4-phenylbut-3-en-2-yl) pyridine
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2d (66.5 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3d as a colorless oily liquid in 93% yield. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 H 36 NO 294.2791，found 294.2787.HPLC condition：Chiralpak IA column，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，CHCl 3 ).
Example 5: synthesis of (R) -1-Isopropyl-3,4-bis (3-methoxypropyl) -6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2e (68.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product 3e by column chromatography to obtain a colorless oily liquid with a yield of 48%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 32 NO 3 298.2377，found 298.2370.HPLC condition：Chiralpak OD-H column，n-hexane/i-PrOH＝97∶3，1.0mL/min，254nm，t r-minor ＝10.3min，t r-major ＝11.2min，90％ee.36.7(c 0.5，CHCl 3 ).
Example 6: synthesis of (R) -1-Isopropyl-6-methyl-3,4-diphenyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2f (71.2 mg,0.4 mmol) was added, triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate2mL of 5% ethylenediamine tetraacetic acid disodium salt aqueous solution is added for washing, the solution is separated, the organic phase is dried by anhydrous sodium sulfate, and the target product 3f is obtained by column chromatography separation after concentration, and the yield is 67%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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.for C 21 H 24 NO 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，CHCl 3 ).
Example 7: synthesis of (R) -1-isopopyyl-6-methyl-3, 4-di-p-tolyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5.mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2g (82.4 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain 3g of the objective product as a white solid in a yield of 81%. 1 H NMR(400MHz，CDCl 3 )δ7.09-6.95(m，6H)，6.94-6.87(m，2H)，4.92-4.76(m，1H)，3.93-3.76(m，1H)，3.11(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，CDCl 3 )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 28 NO 334.2165，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，CHCl 3 ).
Example 8: synthesis of (R) -1-isopopyyl-6-methyl-3, 4-di-m-tolyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then added 2h (82.4 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirred at 80℃for 2h, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to give the target product 3h as a white solid with a yield of 62%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 NO 334.2165，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 ＝11.4min，91％ee.90.6(c 1.0，CHCl 3 ).
Example 9: synthesis of (R) -1-isopopyyl-6-methyl-3, 4-di-o-tolyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2i (82.4 mg,0.4 mmol) and triisobutylaluminum (1M, 80. Mu.L, 40 mol%) were added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase was dried over anhydrous sodium sulfate, and the desired product was isolated by column chromatography as a white solid in 69% yield. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 C 23 H 28 NO 334.2165，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，CHCl 3 ).
Example 10: synthesis of (R, E) -N-Methyl-N- (6- (4-phenyl-3-en-2-yl) pyridin-3-yl) benzamide
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2j (116.1 mg,0.4 mmol) was added, triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, the organic phase dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain the target product 3j as a white solid in 93% yield. 1 H NMR(400MHz，CDCl 3 )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)，3.91-3.78(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，CDCl 3 )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 C 29 H 40 NO 418.3104，found 418.3099.HPLC condition：Chiralpak IA column，n-hexane/i-PrOH＝96∶4，1.0mL/min，254nm，t r-minor ＝8.3min，t r-major ＝11.4min，90％ee.99.2(c 1.0，CHCl 3 ).
Example 11: synthesis of (R, E) -N-methyl-N- (6- (4-phenyl-3-en-2-yl) pyridin-3-yl) pivalamide
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2k (95.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3k as a white solid in 78% yield. 1 H NMR(400MHz，CDCl 3 )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). 13 C NMR(100MHz，CDCl 3 )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.HPLC condition：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，CHCl 3 ).
Example 12: synthesis of (R) -1-Isopropyl-6-methyl-3,4-bis (4- (trifluoromethyl) phenyl) -5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2k (138.4 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, added 2mL of 5% ethylenediamine tetraethyleneWashing the acid disodium salt aqueous solution, separating the solution, drying the organic phase by using anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain the target product 3l, white solid with the yield of 54%. 1 H NMR(400MHz，CDCl 3 )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，1H)，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). 13 C NMR(100MHz，CDCl 3 )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，CDCl 3 )δ-57.8，-57.9.HRMS(ESI)m/z：[M+H] + calcd.for C 23 H 22 F 6 NO 3 474.1498，found 474.1492.HPLC condition：Chiralpak IA column，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，CHCl 3 ).
Example 13: synthesis of (R) -3,4-Bis (4-Fluorophenyl) -1-isopropyl-6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2m (85.6 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to obtain the objective product of 3m as a white solid in 63% yield. 1 H NMR(400MHz，CDCl 3 )δ7.08(d，J＝8.4Hz，2H)，6.97(d，J＝7.2Hz，2H)，6.87(t，J＝7.8Hz，4H)，4.90-4.73(m，1H)，3.92-3.81(m，1H)，3.12(dd，J＝16.8，6.0Hz，1H)，2.47(d，J＝16.8Hz，1H)，1.45(d，J＝6.4Hz，3H)，1.27(d，J＝6.8Hz，6H). 13 C NMR(100MHz，CDCl 3 )δ163.4，163.2(d，J＝9.6Hz)，160.8(d，J＝7.2Hz)，142.2，136.2(d，J＝3.2Hz)，132.8(d，J＝8.0Hz)，132.1(d，J＝3.2Hz)，131.9，130.2(d，J＝8.0Hz)，115.3(d，J＝21.4Hz)，114.7(d，J＝21.2Hz)，45.6，45.1，38.4，21.4，20.6，20.4.19F NMR(376MHz，CDCl 3 )δ-113.4，-115.5.HRMS(ESI)m/z：[M+H] + calcd.for C 21 H 22 F 2 NO 342.1664，found 342.1660.HPLC condition：Chiralpak IA column，n-hexane/i-PrOH＝95∶5，1.0mL/min，254nm，t r-minor ＝11.8min，t r-major ＝18.0min，95％ee.147.4(c 0.5，CHCl 3 ).
Example 14: synthesis of (R) -3,4-Bis (3-Fluorophenyl) -1-isopropyl-6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2n (85.6 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3n as a white solid in 53% yield. 1 H NMR(400MHz，CDCl 3 )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，1H)，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，CDCl 3 )δ163.6(d，J＝19.4Hz)，162.9，161.2(d，J＝17.6Hz)，142.3(d，J＝1.6Hz)，142.2(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＝8.2Hz)，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 F 2 NO 342.1664，found 342.1661. 19 F NMR(376MHz，CDCl 3 )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，CHCl 3 ).
Example 15: synthesis of (R) -3,4-Bis (2-Fluorophenyl) -1-isopropyl-6-methyl-5, 6-dihydroxymatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 nmol), toluene (0.5 mL), then 2o (85.6 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring for 2 hours at 80 ℃, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 3o as a white solid with a yield of 84%. 1 H NMR(400MHz，CDCl 3 )δ7.19-7.09(m，2H)，7.08-7.02(m，1H)，7.01-6.85(m，5H)，4.88-4.75(m，1H)，3.92-3.81(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，CDCl 3 )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 22 F 2 NO 342.1664，found 342.1661. 19 F NMR(376MHz，CDCl 3 )δ-113.6，-114.1.HPLC condition：Chiralpak IA-3 column，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，CHCl 3 ).
Example 16: synthesis of (R, E) -N, N-Diisopropyl-6- (4-phenylbut-3-eh-2-yl) nicotonamide
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2p (113.7 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 3p as a white solid with a yield of 48%. 1 H NMR(400MHz，CDCl 3 )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). 13 C NMR(100MHz，CDCl 3 )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 N 3 O 412.2383，found 412.2380.HPLC condition：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，CHCl 3 ).
Example 17: synthesis of (R) -1-Isopropyl-6-methyl-3,4-di (thiophen-3-yl) -5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2q (76.0 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to obtain the objective product 3q as a yellow liquid in 40% yield. 1 H NMR(400MHz，CDCl 3 )δ7.27(dd，J＝3.2，1.2Hz，1H)，7.18(dd，J＝4.8，3.2Hz，1H)，7.12-7.06(m，2H)，6.89(dd，J＝5.2，1.2Hz，1H)，6.59(dd，J＝5.2，1.2Hz，1H)，4.91-4.77(m，1H)，3.89-3.80(m，1H)，3.00(dd，J＝17.2，6.0Hz，1H)，2.61(d，J＝17.2，1H)，1.42(d，J＝6.4Hz，3H)，1.25(d，J＝7.0Hz，6H). 13 C NMR(100MHz，CDCl 3 )δ163.5，140.8，137.2，136.3，130.1，128.0，126.7，125.2，125.0，124.1，123.5，45.3，44.9，37.9，21.3，20.6，20.4.HRMS(ESI)m/z：[M+H] + calcd.for C 17 H 20 NOS 2 318.0981，found 318.0978.HPLC condition：Chiralpak IA-3 column，n-hexane/i-PrOH＝90∶10，1.0mL/min，254nm，t r-minor ＝10.0min，t r-major ＝14.9min，90％ee.194.6(c 1.0，CHCl 3 ).
Example 18: synthesis of (R) -4-Butyl-1-isopropyl-6-methyl-3-phenyl-5, 6-dihydroxyfridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2r (63.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography to obtain the objective product 3r as a white solid in 20% yield. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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.HPLC condition：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，CHCl 3 ).
Example 19: synthesis of (R) -3-Butyl-1-isopropyyl-6-methyl-4-phenyl-5, 6-dihydroxyfridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2r (63.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3r', as a white solid, yield 39%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 IA column，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，CHCl 3 ).
Example 20: synthesis of (R) -3- (Tert-butyl) -1-isopropyl-4,6-dimethyl-5, 6-dihydromatridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a (25.8 mg,0.2 mmol), toluene (0.5 mL), then 2s (63.2 mg,0.4 mmol) of triisobutylaluminum (1M, 80. Mu.L, 40 mol%) was added thereto, stirred at 80℃for 2 hours, cooled to room temperature, diluted with ethyl acetate, washed with 2mL of 5% aqueous disodium ethylenediamine tetraacetate, separated, and the organic phase was dried over anhydrous sodium sulfate, concentrated and then separated by column chromatography to obtain the objective product 3s as a colorless oil, yield 54%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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，CHCl 3 )./>
Example 21: synthesis of (R) -1- (tert-Butyl) -6-methyl-3,4-dipropyl-5, 6-dihydropyridine-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1a' (28.6 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, washing with 2mL of 5% aqueous disodium ethylenediamine tetraacetate,separating the solution, drying the organic phase with anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain the target product 4a as colorless oily substance, wherein the yield is 46%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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，found 252.2319.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，CHCl 3 ).
Example 22: synthesis of (6R) -1- ((1S, 2R, 5R) -Adamantan-2-yl) -6-methyl-3,4-dipropyl-5,6-djhydropyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1b (44.2 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4b as a white solid with a yield of 65%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 IA column，n-hexane/i-PrOH＝98∶2，1.0mL/min，254nm，t r-major ＝5.8min，t r-minor ＝6.9min，82％ee.53.6(c 0.5，CHCl 3 ).
Example 23: synthesis of (R) -1- (4, 4-dimethylchlorohexyl) -6-methyl-3,4-dipropyl-5, 6-dihydroxyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1c (39.4 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4c as a colorless liquid with a yield of 56%. 1 H NMR(400MHz，CDCl 3 )δ4.38-4.14(m，1H)，3.73-3，50(m，1H)，2.58-2.42(m，2H)，2.22-2.04(m，3H)，1.92(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，CDCl 3 )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，CHCl 3 ).
Example 24: synthesis of R) -1- (2, 2-Dimethyl-1, 3-dioxan-5-yl) -6-methyl-3,4-dipropyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1d (40.2 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4d, colorless liquid, yield 75%. 1 H NMR(400MHz，CDCl 3 )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)，2.26-2.07(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，CDCl 3 )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.for C 18 H 31 NNaO 3 332.2196，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，CHCl 3 ).
Example 25: synthesis of (R) -6-Methyl-3,4-dipropyl-1- (2, 4, 6-trimethylrenzyl) -5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1e (43.9 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 4e, colorless liquid, yield 46%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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，CHCl 3 ).
Example 26: synthesis of (R) -1-Benz-6-methyl-3, 4-dipropyl-5, 6-dihydopyridin-2 (1H) -one
In a nitrogen atmosphere, toLigand H is added into the reaction bottle in sequence 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1f (50.6 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4f, colorless liquid, yield 45%. 1 H NMR(400MHz，CDCl 3 )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)，2.62-2.48(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，CDCl 3 )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，found 362.2472.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，CHCl 3 ).
Example 27: synthesis of (R) -1- (1, 3-Diphenyl-2-yl) -6-methyl-3,4-dipropyl-5, 6-dihydopyridin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1g (56.2 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol) and triisobutylaluminum (1M, 80. Mu.L, 40 mol%) were added thereto, stirred at 80℃for 2 hours, cooled to room temperature, added withDiluting with ethyl acetate, adding 2mL of 5% ethylenediamine tetraacetic acid disodium salt aqueous solution for washing, separating liquid, drying an organic phase by using anhydrous sodium sulfate, concentrating, and separating by column chromatography to obtain a target product of 4g, colorless liquid, and the yield is 55%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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，CHCl 3 ).
Example 28: synthesis of (S) -6, 9a-Trimethyl-2,3-dipropyl-1,6,7,8, 9a-hexahydro-4H-quinolizin-4-one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1h (33.8 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2h, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4h, colorless liquid, yield 40%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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.HPLC condition：Chiralpak AD-H column，n-hexane/i-PrOH＝98∶2，1.0mL/min，254nm，t r-major ＝5.7min，t r-minor ＝6.2min，74％ee.-54.4(c 0.5，CHCl 3 ).
Example 29: synthesis of (R) -9a-Methyl-7,8-dipropyl-3,4,9 a-tetrahydrochyrido [2,1-c ] [1,4] oxazin-6 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1i (28.6 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating the target product by column chromatography to obtain 4i as a white solid with a yield of 42%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 NO 2 252.1958，found 252.1954.HPLC condition：Chiralpak IA column，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，CHCl 3 ).
Example 30: synthesis of (4 aR,8 aR) -1-Cyclohexyl-3,4-dipropyl-4a,5,6,7, 8a-hexahydroquinolin-2 (1H) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1j (41.8 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4j as colorless liquid with a yield of 90%. 1 H NMR(400MHz，CDCl 3 )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，CDCl 3 )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 ＝9.9min，85％ee.-71.3(c 1.0，CHCl 3 ).
Example 31: synthesis of (4 aR,9 aR) -1-cyclopeptyl-3, 4-dipropyl-5,6,7,8,9 a-hexahydro-1H-cyclopepta [ b ] pyridin-2 (4 aH) -one
Ligand H is added into the reaction bottle in sequence in nitrogen atmosphere 8 -BINAPO(4.8mg，5mol％)，Ni(cod) 2 (2.75 mg,5 mol%), 1k (47.44 mg,0.2 mmol), toluene (0.5 mL), then 2a (44.1 mg,0.4 mmol), triisobutylaluminum (1M, 80. Mu.L, 40 mol%), stirring at 80℃for 2 hours, cooling to room temperature, diluting with ethyl acetate, adding 2mL of 5% aqueous solution of disodium ethylenediamine tetraacetate, washing, separating, drying the organic phase with anhydrous sodium sulfate, concentrating and separating by column chromatography to obtain the target product 4k, colorless liquid, yield 95%. 1 H NMR(400MHz，CDCl 3 )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)，2.19-2.09(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，CDCl 3 )δ164.0，146.6，130.9，57.0，56.8，40.5，34.6，32.9，31.7，30.1，29.5，28.7，28.4，27.7，27.3，26.2，25.6，25.5，23.6，23.3，22.6，14.4，14.3.HRMS(ESI)m/z：[M+H] + calcd.for C 23 H 40 NO 2 346.3104，found 346.3101.HPLC condition：Chiralpak IA column，n-hexane/i-PrOH＝98∶2，1.0mL/min，254nm，t r-major ＝8.7min，t r-minor ＝9.9min，85％ee.-50.4(c 1.0，CHCl 3 )。/>

Claims (8)

1. A novel dinitrogen phosphorus oxygen precursor is prepared by nucleophilic substitution reaction of binaphthyl amine and acyl chloride. The method is characterized by comprising the following specific steps:
2. r in the present invention may be Ph, t bu and the like, but are not limited to these groups.
3. The invention also provides application of the binaphthyl amine phosphorus oxide ligand to realize nickel catalysis of C (sp 3 ) -an asymmetric activation method of H bonds, characterized in that it comprises the specific steps of:
in nitrogen atmosphere, adding a ligand, a metal catalyst, raw materials and a solvent into a reaction bottle in sequence, then adding Lewis acid, stirring for 2 hours at a specified temperature, cooling to room temperature, adding ethyl acetate for dilution, adding 2mL of 5% ethylenediamine tetraacetic acid disodium salt aqueous solution for washing, separating liquid, drying an organic phase with anhydrous sodium sulfate, and separating by column chromatography to obtain a target product.
4. The metal catalyst of the invention is Ni (cod) 2 The catalyst is generally used in an amount of 5mol%.
5. The ligand involved in the invention is chiral bi-N framework secondary phosphine oxide, and the dosage of the ligand is generally 5mol percent.
6. Al according to the present invention t Bu 3 The amount of the n-hexane solution having a concentration of 1mol/L is generally 40mol%.
7. The solvent used in the present invention was toluene solution in an amount of 2.5mL per millimole of 1 starting material.
8. R in the raw material 1 used in the present invention 2 Methyl, cyclohexyl, cycloheptyl; r is R 2 Is hydrogen, cyclohexyl, cycloheptyl; r is R 3 Substituents such as isopropyl, cyclohexyl and alkoxy, but not limited to these groups; r is a substituent group such as ethyl, phenyl, thiophene, etc., but is not limited to these groups.
CN202210964711.5A 2022-08-12 2022-08-12 Binaphthyl amine derived chiral phosphine oxide ligand promoted nickel catalysis C (sp 3 ) Asymmetric cyclization of the-H bond Pending CN117586310A (en)

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