A nickel-catalyzed asymmetric hydroarylation method of olefins and its application

Abstract

The invention discloses a nickel-catalyzed asymmetric hydroarylation method and application of olefins, uses nickel and two types of ligands to relay and combine catalysis to realize the method for the migration asymmetric hydroarylation of nitrogen-containing olefins and its application in preparing nicotine (S)-Nicotine and small molecule inhibitors, and belongs to the field of organic chemistry and medicinal chemistry. The present invention, under the action of a metal nickel source, a chiral ligand, a base, a hydrogen source, an additive, etc., reacts nitrogen-containing olefins with an aryl bromide compound in an organic solvent, and obtains chiral α-(hetero)aryl-substituted amine compounds with excellent regioselectivity and enantioselectivity. The present invention uses easily available olefins and commercially available aryl bromides as raw materials, and produces abundant metal nickel as a catalyst. By combining a simple migration ligand and asymmetric coupling with a simple structure and function, the design and screening of a single chiral ligand with a complex structure is avoided, and the dual functions of migration and asymmetric coupling are achieved; the reaction conditions are mild, the functional group compatibility is good, and the operation is simple.

Description

Technical Field

[0001] The method of the invention belongs to the fields of organic chemistry and medicinal chemistry, uses nickel and a double ligand combination to catalyze the migratory asymmetric hydroarylation reaction of olefins to obtain important chiral α-(hetero)aryl substituted amine compounds, and has a wide range of applications. Background Art

[0002] Over the past two decades, inexpensive metal hydrogenation catalysts such as FeH, CoH, and CuH have begun to attract the attention of synthetic chemists. Nickel, being inexpensive and readily available, possesses a variety of oxidation states and has unique and widespread applications in coupling chemistry. The corresponding NiH catalysis enables diverse, high-value-added conversions of readily available olefins, yielding a range of high-value-added products.

[0003] Chiral α-(hetero)aryl substituted amines and their derivatives are widely present in various natural products, pharmaceuticals, and catalysts. In recent years, asymmetric hydroamination and hydroarylation using metal hydride catalysis, particularly CuH or NiH, have become two highly efficient methods for synthesizing these compounds from activated olefins.

[0004] The reported metal hydrogen-catalyzed asymmetric hydroaminations are mainly the following:

[0005] In 2013, the Buchwald group (S. Zhu, N. Niljianskul, S.L. Buchwald, J. Am. Chem. Soc. 2013, 135, 15746.) and the Miura group (Y. Miki, K. Hirano, T. Satoh, M. Miura, Angew. Chem. Int. Ed. 2013, 52, 10830.) respectively used a copper salt / chiral phosphine ligand combination to achieve copper-hydrogen-catalyzed asymmetric hydroalkylation of aromatic substituted alkenes to prepare chiral alkylamines.

[0006] a.

[0007]

[0008] b.

[0009] In 2021, Zhu Shaolin's research group used the simple, easily synthesized N,N-Biox ligand to achieve asymmetric hydroarylation, hydroalkylation, and hydroamidation of alkenes, respectively, with a wide range of substrates. (L. Meng, J. Yang, M. Duan, Y. Wang, S. Zhu, Angew. Chem. Int. Ed. 2021, 60, 23584.)

[0010] c.

[0011]

[0012] The reported asymmetric hydroarylation catalyzed by metal hydrogen mainly includes the following:

[0013] In 2021, the Zhu Shaolin group (Y.He, H.Song, S.Zhu, Nat.Commun. 2021, 12, 638.) and the Nevado group (S.Cuesta-Galisteo, J. X. Wei, E. Merino, C. Nevado, Angew. Chem. Int. Ed. 2021, 60, 1605.) successively reported a NiH-catalyzed highly regio- and enantioselective reductive hydroarylation reaction of N-acyl enamines with mild conditions and simple operation, thereby obtaining structurally diverse chiral benzylamines.

[0014] a.

[0015]

[0016]

[0017] In 2023, Professor Huo Haohua's research group used a halogen radical-mediated hydrogen atom transfer strategy to achieve the enantioselective asymmetric reductive coupling of α-amino acid derivatives and aromatic bromides.

[0018]

[0019] Although the above strategy can achieve specific chiral α-(hetero)aryl substituted amines, the disadvantage is that it requires the preparation of activated functionalized olefins. It would be more ideal if the reaction starting materials were commercially available or more easily prepared olefins.

[0020] Zhu Shaolin's research group at Nanjing University has long been dedicated to nickel-hydrogen catalysis, achieving the (migratory) asymmetric hydrofunctionalization of a series of olefins, selectively introducing aryl and alkyl functional groups, and further tunable the enantioselectivity of the reaction through chiral ligands. The ligand relay strategy developed in this paper facilitates nickel-hydrogen-catalyzed asymmetric hydroarylation, providing a novel and efficient method for the synthesis of chiral amines and has been successfully applied to the synthesis of nicotine (S)-nicotine and the small molecule inhibitor MSC2530818. Summary of the Invention

[0021] The present invention aims to provide a nickel-catalyzed asymmetric hydroarylation method for olefins and its application. This method is a novel method for synthesizing chiral amine compounds. This method utilizes readily available, inexpensive raw materials, is simple to operate, has a broad substrate range, and exhibits good functional group compatibility. It exhibits good yields and excellent regio- and enantioselectivity. Furthermore, this method can be applied to the synthesis of nicotine (S)-Nicotine and the small molecule inhibitor MSC2530818. This method utilizes readily available olefins and commercially available aryl bromides as raw materials, and abundant nickel as a catalyst. By combining a structurally and functionally simple migrating ligand with asymmetric coupling, the method avoids the design and screening of complex single-chiral ligands, achieving the dual functions of migrating and asymmetric coupling. The reaction conditions are mild, the functional group compatibility is good, and the operation is simple.

[0022] The present invention achieves one of the above-mentioned purposes by adopting the following technical scheme: a nickel-catalyzed asymmetric migration arylation method for olefins, comprising the following steps: under the protection of inert gas, dissolving a metal nickel catalyst, a migration ligand L, a chiral ligand L*, a base, a hydrogen source, and an additive in an organic solvent, and then adding the olefin (Hetero)aryl compound (Het)Ar-Br, to obtain a reaction mixture, which is post-treated and purified to obtain the target enantiomerically enriched α-aryl substituted chiral amine product;

[0023] Among them, the migration ligand L is One of the following;

[0024] The chiral ligand L* is One of the following;

[0025] R 1 is a substituent in the nitrogen-containing chain olefin substrate, which is any of an alkyl group and an aryl group;

[0026] R 2 is any one of a hydrogen atom and an alkyl group;

[0027] When Ar is an aryl group, the substituent on the aryl group is any one of a chlorine atom, a (hetero)aryl group, a (fluorinated)alkyl group, a (thio)ether, a ketone, an aldehyde, an ester, an amide, and a cyano group; when Ar is a heteroaryl group, it is any one of pyridine and pyrimidine, and the substituent on the heteroaryl group is any one of a chlorine atom, a fluorine atom, a (fluorinated)alkyl group, and an alkoxy group;

[0028] The solvent is one or more of toluene, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, and diethyl ether;

[0029] Preparation route 1:

[0030]

[0031] or

[0032]

[0033] Preparation route 2:

[0034]

[0035] or

[0036]

[0037] Preferably,

[0038] Preparation route 1:

[0039]

[0040] or

[0041]

[0042] R in Preparation Scheme 1 1 is a substituent in the nitrogen-containing chain olefin substrate, which is any of an alkyl group and an aryl group,

[0043] R 2 is any one of a hydrogen atom and an alkyl group,

[0044] The nickel catalyst is nickel nitrate (II) hexahydrate Ni(NO3)2·6H2O, and the migration ligand L is The chiral ligand is L1* ent-L1* The hydrogen source is dimethoxymethylsilane (MeO)2MeSiH, the base is sodium carbonate Na2CO3, the additive is sodium iodide NaI, and the solvents are toluene and N-methylpyrrolidone;

[0045] Preparation route 2:

[0046]

[0047] or

[0048] The nickel catalyst in preparation route 2 is nickel nitrate (II) hexahydrate Ni(NO3)2·6H2O, and the migration ligand L is The chiral ligand is L2* ent-L2* The hydrogen source is one of dimethoxymethylsilane (MeO)2MeSiH or diethoxymethylsilane (EtO)2MeSiH, the base is sodium carbonate K2CO3, the additive is sodium iodide NaI, and the solvent is multiple of N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, and diethyl ether.

[0049] Preferably, the nickel-catalyzed asymmetric migration arylation method for olefins in preparation route 1 comprises reacting the olefin and the aryl bromide at 25° C. in a solvent in the presence of a metal nickel catalyst, a chiral ligand L*, a migration ligand L, a hydrogen source, an additive, and a base for 1 to 24 hours; the molar ratio of the metal nickel catalyst, the migration ligand L, the chiral ligand L1* or ent-L1*, the hydrogen source, the additive, the base, the olefin, and the aryl bromide is (0-0.01):(0-0.012):(0-0.001):(0.2-0.6):(0-0.1):(0.2-0.4):(0.2-0.3):(0.2-0.3); and the reaction time is determined until the reaction is complete.

[0050] Preferably, the nickel-catalyzed asymmetric migration arylation method for olefins of Preparation Route 2 comprises reacting the olefin and the aryl bromide at 25° C. in a solvent in the presence of a metal nickel catalyst, a chiral ligand L*, a migration ligand L, a hydrogen source, an additive, and a base for 1 to 24 hours; the molar ratio of the metal nickel catalyst, the migration ligand L, the chiral ligand L*, the hydrogen source, the additive, the base, the olefin, and the aryl bromide is (0-0.02):(0-0.024):(0-0.002):(0.2-0.6):(0-0.4):(0.2-0.4):(0.2-0.3):(0.2-0.3); and the reaction time is determined until the reaction is complete.

[0051] Preferably, the metal nickel catalyst is a metal nickel salt, the hydrogen source is silicon hydride or borohydride pinacol, and the additive is an inorganic salt of iodine.

[0052] The present invention achieves one of the above-mentioned objectives by using the nickel-catalyzed asymmetric migration arylation method of olefins described in another technical solution below in the preparation of nicotine (S)-Nicotine. The specific preparation method reaction formula is as follows:

[0053]

[0054] In the first step, nickel (II) nitrate hexahydrate, chiral ligand ent-L2*, and potassium carbonate are added to a reaction tube under a nitrogen atmosphere, followed by the addition of dry N,N-dimethylformamide and an ether solution containing the migrating ligand L; after stirring at 25°C for 5 minutes, the above-mentioned olefin, heteroaryl bromide, and diethoxymethylsilane are added, the reaction tube is capped, and the reaction is carried out at 25°C for 24 hours; after the reaction is completed, the reaction solvent is removed by concentration under reduced pressure, and the pyrrolidine derivative is separated and purified by column chromatography;

[0055] In the second step, lithium aluminum hydride is dissolved in tetrahydrofuran under a nitrogen atmosphere, and then a pyrrolidine derivative is added to the solution at 0°C; the reaction is refluxed for six hours, and then quenched with water at 0°C; the mixture is filtered through diatomaceous earth, washed with dichloromethane, and rotary evaporated to obtain a crude material; then, the crude material is dissolved in methanol, and palladium carbon and sodium hydroxide are added; after the air is expelled, hydrogen is filled into the flask through a balloon; the reaction is stirred at room temperature for 4 hours; after the reaction is completed, the mixture is filtered through diatomaceous earth and concentrated; the crude product is purified by column chromatography to obtain the target product nicotine (S)-Nicotine.

[0056] The present invention achieves one of the above-mentioned objectives by using the nickel-catalyzed asymmetric migration arylation method of olefins described in another technical solution below. The nickel-catalyzed asymmetric migration arylation method of olefins is used in the preparation of the inhibitor MSC2530818. The specific preparation method reaction formula is as follows:

[0057]

[0058] In the first step, nickel nitrate (II) hexahydrate and chiral ligand ent-L2 were added to the reaction tube under nitrogen atmosphere. * , potassium carbonate, sodium iodide, followed by the addition of dry N,N-dimethylacetamide and a solution of ethylene glycol dimethyl ether containing the migration ligand L; stirring at 25°C for 5 minutes, then adding the above-mentioned olefin, aryl bromide and diethoxymethylsilane, covering the reaction tube, and reacting at 25°C for 24 hours; after the reaction is completed, concentrating under reduced pressure to remove the reaction solvent, and separating and purifying by column chromatography to obtain a pyrrolidine derivative;

[0059] In the second step, under a nitrogen atmosphere, a pyrrolidine derivative is added to dry dichloromethane, placed in an ice-water bath, and BBr3 is carefully added at 0°C; the reaction is stirred at room temperature for 5 hours; the excess BBr3 is quenched with methanol; the reaction mixture is then concentrated to obtain a crude product; the crude product is purified by column chromatography to obtain the target compound; then, the obtained product is dissolved in N,N-dimethylformamide, followed by the addition of 3-methyl-1H-pyrazolo[3,4-B]pyridine-5-carboxylic acid, N-(3-dimethylaminopropyl)-N'ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole; after stirring for a few minutes, N-methylmorpholine is added at room temperature, and the reaction mixture is stirred overnight at room temperature; after the reaction is completed, the reaction solution is diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate; the solvent is removed under reduced pressure to obtain a crude product; the crude product is purified by column chromatography to obtain the target product.

[0060] Preferably, the metal nickel salt is any one of nickel iodide, nickel iodide hydrate, nickel chloride, nickel chloride hexahydrate, nickel chloride glycol dimethyl ether complex, nickel bromide, nickel bromide trihydrate, nickel bromide diethylene glycol dimethyl ether complex, nickel bromide glycol dimethyl ether complex, bis-(1,5-cyclooctadiene) nickel complex, nickel nitrate hexahydrate, nickel perchlorate hexahydrate, and nickel tetrafluoroborate hexahydrate;

[0061] The hydrogen source is any one of polymethylhydrogensiloxane (PMHS), trimethoxysilane, triethoxysilane, dimethoxymethylsilane (DMMS), diethoxymethylsilane (DEMS), phenylsilane, diphenylsilane, triphenylsilane, triethylsilane, borane dimethyl sulfide, and pinacol borane;

[0062] The additive is one or more of lithium chloride, sodium chloride, lithium bromide, potassium bromide, magnesium bromide, magnesium bromide hydrate, lithium iodide, sodium iodide, zinc iodide, magnesium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, sodium acetate, potassium acetate, methanol, isopropanol, tert-butanol, hexafluoroisopropanol, benzyl alcohol, and acetonitrile;

[0063] The solvent is one or more of tetrahydrofuran, 1,4-dioxane, ethyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, toluene, xylene, trimethylbenzene, trifluorotoluene, 1,2-dichloroethane, chloroform, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropylene urea, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol and water.

[0064] The base, whose cation is Li + 、Na + , K + 、Cs + and Mg 2+ Any of the following, with anion [CO3] 2- , [HCO3] - , [PO4] 3- , [HPO4] 2- 、[H2PO4] - 、F - , [OH] - , [CH3COO] - 、[OMe] - and [O t Bu] - Any of .

[0065] Beneficial effects:

[0066] 1. The reaction temperature is 25°C, the reaction conditions are mild, the reaction effect is good, and the product can be obtained with good yield, excellent regioselectivity and enantioselectivity.

[0067] 2. The olefins are inexpensive, commercially available, or have a simple synthesis route.

[0068] 3. Application of the dual-ligand relay strategy nickel-catalyzed asymmetric hydroarylation of olefins in the preparation of nicotine (S)-Nicotine and the inhibitor MSC2530818. The above method has simple synthetic steps and uses a cheap and readily available metal nickel catalyst to obtain nicotine (S)-Nicotine and the inhibitor MSC2530818 precursors in good yields and excellent regio- and enantioselectivities.

[0069] 4. The role of the chiral ligand and migrating ligand: Ideally, the migrating ligand controls the chain walk, and the chiral ligand controls the asymmetric coupling. The asymmetric migrating arylation of the unactivated distal olefin is achieved through a ligand relay strategy to obtain chiral α-(hetero)aryl substituted amines.

[0070] 5. Comparative Example 1 shows that in the reaction of Example 1, the migration ligand replace The results showed that the regioselectivity was improved, but the yield and enantioselectivity were significantly reduced.

[0071] 6. Comparative Example 2 shows that in the reaction of Example 1, without adding the additive NaI, the enantioselectivity is improved, but the regioselectivity and yield are significantly reduced.

[0072] 7. Comparative Example 3 shows that in the reaction of Example 1, aryl iodide is used instead of aryl bromide. The results show that the enantioselectivity remains basically unchanged, but the regioselectivity is reduced and the yield is significantly reduced.

[0073] 8. Comparative Example 4 shows that in the reaction of Example 1, potassium carbonate is used instead of sodium carbonate. The results show that the regioselectivity and yield remain basically unchanged, but the enantioselectivity is significantly reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] The present invention will be further described below with reference to the accompanying drawings.

[0075] Figure 1 is the H spectrum of the product of Example 1;

[0076] Figure 2 is the C spectrum of the product of Example 1;

[0077] Figure 3 is the H spectrum of the product of Example 4;

[0078] Figure 4 is the C spectrum of the product of Example 4;

[0079] Figure 5 is the H spectrum of the product of Example 7;

[0080] Figure 6 is the C spectrum of the product of Example 7;

[0081] Figure 7 is the H spectrum of the product of Example 15;

[0082] Figure 8 is the C spectrum of the product of Example 15;

[0083] Figure 9 is the H spectrum of the product of Example 16;

[0084] Figure 10 is the C spectrum of the product of Example 16;

[0085] Figure 11 is the H spectrum of the product of Example 22;

[0086] Figure 12 is the C spectrum of the product of Example 22;

[0087] Figure 13 is the H spectrum of the product of Example 24;

[0088] Figure 14 is the C spectrum of the product of Example 24;

[0089] Figure 15 is the H spectrum of the product of Example 29;

[0090] Figure 16 is the C spectrum of the product of Example 29;

[0091] Figure 17 is the H spectrum of the product of Example 30;

[0092] Figure 18 This is the C spectrum of the product of Example 30. DETAILED DESCRIPTION

[0093] The features and advantages of the present invention can be further understood through the following detailed description. The examples provided are merely illustrative of the method of the present invention and are not intended to limit the remainder of the present invention in any way.

[0094] In the following examples, Ni(NO3)2·6H2O refers to nickel (II) nitrate hexahydrate, (MeO)2MeSiH refers to dimethoxymethylsilane (DMMS), (EtO)2MeSiH refers to diethoxymethylsilane (DEMS), Tol refers to toluene, NMP refers to N-methylpyrrolidone, DMA refers to N,N-dimethylacetamide, DMF refers to N,N-dimethylformamide, DME refers to ethylene glycol dimethyl ether, Et2O refers to diethyl ether, equiv refers to equivalents, and the migration ligand L refers to Chiral ligand L * for One of them.

[0095] Example 1

[0096]

[0097] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (44.1 mg, white solid, yield 72%) was obtained by column chromatography separation and purification. The rr value (97:3) and ee value (92%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ8.01(d,J=8.3Hz,2H),7.81–7.70(m,2H),7.58–7.46(m,1H),7.48–7.37(m,4H),6.39(d, J=7.6Hz,1H),5.21(q,J=7.6Hz,1H),3.90(s,3H),2.03–1.73(m,2H),1.55–1.31(m,2H),0.96(t,J=7.3Hz,3H); 13C NMR (126MHz, CDCl3) δ167.0,147.9,134.5,131.8,130.2,129.4,128.8,127.0,126.7,53.7,52.2,38.5,19.6,14.0; HRMS(ESI)calcd.for C 19 H 21 NO3Na[M+Na] + m / z 334.1413,found 334.1414;IR(neat,cm -1 )3356,2920,1632,1282,709; mp131.1–132.4℃; [α] D 17 =+2.0(c=0.51,CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,254nmUV detector,t R (major)=11.2min,t R (minor)=16.9min.

[0098] Example 2

[0099]

[0100] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (67.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (42.8 mg, white solid, yield 67%) was obtained by column chromatography separation and purification. The rr value (95:5) and ee value (90%) of the target product were measured. 1H NMR (500MHz, CDCl3) δ7.77(d,J=7.5Hz,2H),7.63–7.54(m,2H),7.52–7.38(m,5H),6.56(d,J=7 .6Hz,1H),5.19(q,J=7.5Hz,1H),1.93–1.73(m,2H),1.51–1.25(m,2H),0.95(t,J=7.4Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.1,146.8,134.4,131.8,129.6(q,J=32.7Hz),128.7,1 27.1,127.0,125.7(q,J=3.7Hz),124.2(q,J=272.2Hz),53.6,38.5,19.6,13.9; 19 F NMR(471MHz, CDCl3)δ–62.5;; HRMS(ESI)calcd.forC 18 H 18 F3NONa[M+Na] + m / z 344.1232,found 344.1236;IR(neat,cm -1 )3322,1633,1330,1121,760; mp148.9–150.1℃; [α] D 17 =–3.5(c=1.44,CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,220nm UV detector,t R (major)=6.0min,t R (minor)=7.6min.

[0101] Example 3

[0102]

[0103] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (87.9 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (41.2 mg, white solid, yield 53%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (94%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.82–7.70(m,5H),7.61–7.48(m,1H),7.46–7.38(m,2H),6.63(d,J=7. 5Hz,1H),5.23(q,J=7.5Hz,1H),1.97–1.76(m,2H),1.57–1.29(m,2H),0.97(t,J=7.4Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.2, 145.7, 134.0, 132.1, 132.0 (q, J = 34.0Hz), 128.9, 127.1, 126.9 (d, J = 2.5Hz), 123.4 (q, J = 273.4Hz), 121.5 (p, J = 3.8Hz), 53.5, 38.5, 19.7, 13.9; 19 F NMR(471MHz, CDCl3)δ–62.8; HRMS(ESI)calcd.forC 19 H 17 F6NONa[M+Na] + m / z 412.1106,found 412.1108;IR(neat,cm -1 )3323,1264,904,724; mp135.9–136.0℃; [α] D 17 =–19.0(c=1.16,CHCl3); HPLC analysis AD-Hcolumn, 5% iPrOH in hexane,0.8mL / min,220nm UV detector,t R (major)=7.8min,t R (minor)=8.7min.

[0104] Example 4

[0105]

[0106] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution of the migrating ligand L (prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (54.3 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (29.1 mg, white solid, yield 52%) was obtained by column chromatography separation and purification. The rr value (95:5) and ee value (95%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.79–7.74(m,2H),7.63–7.63(m,2H),7.55–7.48(m,1H),7.48–7.39(m,4H),6.4 5(d,J=7.6Hz,1H),5.16(q,J=7.5Hz,1H),1.93–1.78(m,2H),1.50–1.31(m,2H),0.96(t,J=7.3Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.1,148.3,134.2,132.6,131.9,128.8,127.4,127.1,118.9,111.3,53.7,38.3,19.6,13.9; HRMS(ESI)calcd.for C 18 H 18 N2ONa[M+Na] + m / z 301.1311,found 301.1309;IR(neat,cm-1 )3019,2229,1214,744; mp148.0–149.2℃; [α] D 17 =–16.2 (c=0.58, CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,220nm UVdetector,t R (major)=10.7min,t R (minor)=14.9min.

[0107] Example 5

[0108]

[0109] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution of the migrating ligand L (prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (54.3 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (31.9 mg, white solid, yield 57%) was obtained by column chromatography separation and purification. The rr value (96:4) and ee value (90%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.79–7.75(m,2H),7.64(s,1H),7.60(d,J=8.1Hz,1H),7.56–7.49(m,2H),7.48–7.41(m, 3H),6.46(d,J=7.7Hz,1H),5.15(q,J=7.5Hz,1H),1.95–1.80(m,2H),1.51–1.30(m,2H),0.97(t,J=7.3Hz,3H); 13C NMR (126MHz, CDCl3) δ167.1,144.5,134.1,132.0,131.6,131.1,130.1,129.6,128.8,127.1,119.0,112.9,53.4,38.4,19.6,13.9; HRMS(ESI)calcd.for C 18 H 18 N2ONa[M+Na] + m / z 301.1311,found 301.1310;IR(neat,cm -1 )3019,1634,1214,745; mp120.6–121.7℃; [α] D 17 =–10.0 (c=0.34, CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,220nm UV detector,t R (major)=7.2min,t R (minor)=9.8min.

[0110] Example 6

[0111]

[0112] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (70.2 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (32.5 mg, white solid, yield 50%) was obtained by column chromatography separation and purification. The rr value (97:3) and ee value (93%) of the target product were measured. 1H NMR (500MHz, CDCl3) δ7.97–7.91(m,1H),7.87–7.75(m,3H),7.70–7.63(m,1H),7.57–7.46(m,2H),7.45–7.38(m,2H),6 .65(d,J=7.7Hz,1H),5.22(q,J=7.6Hz,1H),3.03(s,3H),1.96–1.78(m,2H),1.59–1.29(m,2H),0.94(t,J=7.3Hz,3H); 13 CNMR(126MHz, CDCl3)δ167.1,145.1,141.0,134.2,132.6,131.9,129.8,128.8,127.1,126.3,125.0,53.6,44.6,38.6,19.7,13.9; HRMS(ESI)calcd.for C 18 H 21 NO3SNa[M+Na] + m / z354.1134,found 354.1132;IR(neat,cm -1 )3329,1650,1214,743; mp179.1–180.6℃; [α] D 17 =–7.6 (c=0.55, CHCl3); HPLC analysis AD-H column, 20% i PrOH inhexane,0.8mL / min,220nm UV detector,t R (major)=9.4min,t R (minor)=13.0min.

[0113] Example 7

[0114]

[0115] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (59.4 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (34.4 mg, white solid, yield 58%) was obtained by column chromatography separation and purification. The rr value (94:6) and ee value (92%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.98–7.89(m,2H),7.82–7.73(m,2H),7.52–7.45(m,1H),7.45–7.36(m,4H),6.55(d,J= 7.6Hz,1H),5.19(q,J=7.6Hz,1H),2.57(s,3H),1.96–1.80(m,2H),1.52–1.29(m,2H),0.95(t,J=7.4Hz,3H); 13 C NMR (126MHz, CDCl3) δ197.8,167.0,148.2,136.4,134.5,131.8,129.0,128.8,127.1,126.9,53.7,38.5,26.8,19.6,13.9; HRMS(ESI)calcd.for C 19 H 21 NO2Na[M+Na] + m / z 318.1464,found318.1466;IR(neat,cm -1 )3019,1633,1214,745; mp157.2–158.6℃; [α] D 17 =+5.5(c=0.62,CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,220nm UV detector,t R (major)=10.5min,t R(minor)=18.2min.

[0116] Example 8

[0117]

[0118] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (67.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (32.2 mg, white solid, yield 50%) was obtained by column chromatography separation and purification. The rr value (95:5) and ee value (92%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ8.00(d,J=8.4Hz,2H),7.84–7.70(m,2H),7.52–7.38(m,5H),6.35(d,J=7.8Hz,1H),5.22(q,J=7.5Hz, 1H),2.74–2.61(m,1H),2.02–1.81(m,2H),1.53–1.32(m,2H),1.25–1.13(m,2H),1.09–1.00(m,2H),0.97(t,J=7.4Hz,3H); 13 C NMR (126MHz, CDCl3) δ200.3,166.9,147.6,137.3,131.8,128.8,128.7,127.0,126.8,53.7,38.5,19.7,17.3,14.0,11.7; HRMS(ESI)calcd.for C 21 H 23 NO2Na[M+Na] + m / z 344.1621,found 344.1626;IR(neat,cm -1)3018,1633,1215,747; mp183.3–184.7℃; [α] D 17 =+4.9 (c=0.57, CHCl3); HPLC analysis AD-H column, 20% i PrOH inhexane,0.8mL / min,254nm UV detector,t R (major)=13.9min,t R (minor)=24.2min.

[0119] Example 9

[0120]

[0121] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (55.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (37.4 mg, white solid, yield 66%) was obtained by column chromatography separation and purification. The rr value (97:3) and ee value (89%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ9.99 (s, 1H), 7.86 (d, J = 8.3Hz, 2H), 7.81–7.74 (m, 2H), 7.55–7.48 (m, 3H), 7.48–7.40 (m, 2H),6.39(d,J=7.7Hz,1H),5.22(q,J=7.6Hz,1H),2.00–1.80(m,2H),1.51–1.33(m,2H),0.97(t,J=7.3Hz,3H); 13C NMR (126MHz, CDCl3) δ192.0,167.0,149.8,135.7,134.4,131.9,130.4,128.8,127.3,127.1,53.8,38.5,19.7,14.0; HRMS(ESI)calcd.for C 18 H 19 NO2Na[M+Na] + m / z 304.1308,found304.1305;IR(neat,cm -1 )3355,2921,1635,1264,729;[α] D 17 =–1.6 (c=0.37, CHCl3); 89%ee;

[0122] mp125.3–126.1℃; HPLC analysis AD-H column, 20% i PrOH inhexane,0.8mL / min,220nm UV detector,t R (major)=10.6min,t R (minor)=16.3min.

[0123] Example 10

[0124]

[0125] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (57.0 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (41.1 mg, white solid, yield 72%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (89%) of the target product were measured.1 H NMR (500MHz, CDCl3) δ7.80–7.72(m,2H),7.56–7.46(m,1H),7.46–7.39(m,2H),7.34–7.26(m,4H),6.2 9(d,J=7.7Hz,1H),5.14(q,J=7.6Hz,1H),2.01–1.77(m,2H),1.50–1.29(m,2H),0.96(t,J=7.3Hz,3H); 13 C NMR(126MHz, CDCl3)δ166.9,141.2,134.6,133.2,131.7,129.0,128.8,128.1,127.0,53.3,38.5,19.7,14.0; HRMS(ESI)calcd.for C 17 H 18 ClNONa[M+Na] + m / z 310.0969,found 310.0967;IR(neat,cm -1 )3326,2926,1632,1214,744; mp141.5–142.6℃; [α] D 17 =+1.6 (c=0.37, CHCl3); 89%ee; HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,220nm UVdetector,t R (major)=7.1min,t R (minor)=9.5min.

[0126] Example 11

[0127]

[0128] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (91.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (54.4 mg, white solid, yield 68%) was obtained by column chromatography separation and purification. The rr value (96:4) and ee value (88%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.76 (d, J = 7.1Hz, 2H), 7.57–7.48 (m, 1H), 7.46–7.38 (m, 4H), 7.24–7.20 (m, 2H), 6. 49(d,J=7.6Hz,1H),5.18(q,J=7.6Hz,1H),1.93–1.77(m,2H),1.52–1.29(m,2H),0.95(t,J=7.3Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.0, 148.7, 143.4, 134.3, 131.8, 128.8, 128.6, 127.1, 121.6, 118.8 (q, J = 321.3Hz), 53.1, 38.4, 19.7, 13.9; 19 F NMR(471MHz, CDCl3)δ-72.9; HRMS(ESI)calcd.forC 18 H 18 F3NO4SNa[M+Na] + m / z 424.0801,found 424.0801;IR(neat,cm -1 )3294,1634,1422,1209,1139,888; mp110.0–111.4℃; [α] D 17 =+1.6(c=1.01,CHCl3); HPLC analysis OD-H column, 20% iPrOH in hexane,0.8mL / min,254nm UV detector,t R (minor)=6.6min,t R (major)=7.7min.

[0129] Example 12

[0130]

[0131] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (98.2 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (46.2 mg, white solid, yield 55%) was obtained by column chromatography separation and purification. The rr value (97:3) and ee value (91%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.77–7.68(m,4H),7.54–7.40(m,3H),7.33–7.25(m,4H),6.99–6.93(m,2H),6.25(d,J= 7.8Hz,1H),5.15(q,J=7.7Hz,1H),2.44(s,3H),1.92–1.76(m,2H),1.45–1.30(m,2H),0.95(t,J=7.3Hz,3H); 13 C NMR (126MHz, CDCl3) δ166.9,148.8,145.5,141.6,134.5,131.8,129.9,128.8, 128.6,127.9,127.0,122.7,53.1,38.5,21.9,19.6,13.9; HRMS(ESI)calcd.for C 24 H 25 NO4SNa[M+Na] +m / z446.1396,found 446.1393;IR(neat,cm -1 )3327,2928,1638,1306,1149,769;[α] D 17 =–11.2(c=0.34,CHCl3); HPLC analysis AD-H column, 30% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (minor)=11.6min,t R (major)=14.5min.

[0132] Example 13

[0133]

[0134] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (70.2 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (72.3 mg, white solid, yield 62%) was obtained by column chromatography separation and purification. The rr value (97:3) and ee value (86%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ7.76(d,J=7.3Hz,2H),7.54–7.46(m,1H),7.45–7.33(m,4H),7.18(d,J=8.2Hz,2H), 6.40(d,J=8.0Hz,1H),5.17(q,J=7.6Hz,1H),2.34–1.64(m,2H),1.67–1.16(m,2H),0.96(t,J=7.3Hz,3H); 13C NMR (126MHz, CDCl3) δ166.9, 148.5, 141.4, 134.5, 131.8, 128.7, 128.1, 127.1, 121.3, 120.6 (q, J = 258.3Hz), 53.2, 38.5, 19.7, 13.9; 19 F NMR(471MHz, CDCl3)δ–57.9; HRMS(ESI)calcd.for C 18 H 18 F3NO2Na[M+Na] + m / z 360.1182,found 360.1179;IR(neat,cm -1 )3314,2924,1638,1215,745; mp127.7–128.7℃; [α] D 17 =+2.8(c=0.50,CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,220nm UV detector,t R (major)=5.7min,t R (minor)=6.9min.

[0135] Example 14

[0136]

[0137] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (60.9 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product (27.6 mg, white solid, yield 46%) was obtained by column chromatography separation and purification. The rr value (98:2) and ee value (92%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ7.83–7.71(m,2H),7.55–7.40(m,1H),7.44–7.37(m,2H),7.33–7.24(m,2H),7.26–7.20(m,2H),6 .37(d,J=8.1Hz,1H),5.13(q,J=7.6Hz,1H),2.46(s,3H),1.95–1.78(m,2H),1.53–1.29(m,2H),0.94(t,J=7.4Hz,3H); 13 CNMR(126MHz, CDCl3)δ166.8,139.5,137.5,134.7,131.6,128.7,127.3,127.1,127.0,53.4,38.4,19.7,16.1,14.0; HRMS(ESI)calcd.for C 18 H 21 NOSNa[M+Na] + m / z 322.1236,found322.1233;IR(neat,cm -1 )3321,1631,1214,744; mp177.3–179.3℃; [α] D 17 =+21.4(c=0.72,CHCl3); HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=8.8min,tR (minor)=12.4min.

[0138] Example 15

[0139]

[0140] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (56.7 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (36.2 mg, white solid, yield 64%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (94%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ8.50(s,2H),7.75–7.70(m,2H),7.51–7.44(m,1H),7.42–7.35(m,2H),6.67–6.62( m,1H),5.09(q,J=7.6Hz,1H),3.97(s,3H),1.97–1.78(m,2H),1.50–1.29(m,2H),0.95(t,J=7.3Hz,3H); 13 C NMR(126MHz, CDCl3)δ167.2,165.1,158.1,134.1,131.9,129.2,128.7,127.1,55.1,49.4,37.6,19.6,13.8; HRMS(ESI)calcd.for C 16 H 20 N3O2[M+H] + m / z 286.1550,found 286.1541;IR(neat,cm -1 )3309,2957,1479,1311,1032,802,694; mp132.9–133.1℃; [α] D25 =-4.7 (c=0.80, CHCl3); HPLC analysis OD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UVdetector,t R (major)=8.1min,t R (minor)=10.4min.

[0141] Example 16

[0142]

[0143] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (45.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (43.0 mg, white solid, yield 60%) was obtained by column chromatography separation and purification. The target product had a rr value (>99:1) and an ee value (93%). 1 H NMR (500MHz, CDCl3) δ8.27 (s, 1H), 8.04–8.00 (m, 2H), 7.93–7.79 (m, 4H), 7.64–7.49 (m, 2H), 7.46 (d, J = 8.4Hz, 2H), 6. 61(d,J=7.9Hz,1H),5.27(q,J=7.6Hz,1H),3.90(s,3H),2.01–1.81(m,2H),1.51–1.34(m,2H),0.97(t,J=7.3Hz,3H); 13CNMR (126MHz, CDCl3) δ167.1,167.0,147.9,134.9,132.7,131.7,130.2,129.4,129.0,128.7, 127.9,127.8,127.5,127.0,126.8,123.7,53.8,52.2,38.5,19.7,14.0; HRMS(ESI)calcd.for C 23 H 23 NO3Na[M+Na] + m / z 384.1570,found 384.1563;IR(neat,cm -1 )3302,2956,1721,1279,906,731; mp148.5–150.2℃; [α] D 17 =–47.8 (c=1.0, CHCl3); HPLC analysis AD-H column, 30% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=8.8min,t R (minor)=11.6min.

[0144] Example 17

[0145]

[0146] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (41.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (39.9 mg, white solid, yield 59%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (93%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.98(d,J=8.4Hz,2H),7.73(d,J=8.8Hz,2H),7.40(d,J=8.4Hz,2H),6.88(d,J=8.9Hz,2H),6.52(d,J =8.0Hz,1H),5.17(q,J=7.6Hz,1H),3.89(s,3H),3.82(s,3H),1.95–1.75(m,2H),1.47–1.27(m,2H),0.93(t,J=7.3Hz,3H); 13 C NMR (126MHz, CDCl3) δ167.0,166.5,162.4,148.2,130.1,129.2,128.9,126.7,126.6,113.9,55.5,53.6,52.2,38.5,19.6,13.9; HRMS(ESI)calcd.for C 20 H 23 NO4Na[M+Na] + m / z 364.1519,found 364.1517;IR(neat,cm -1 )3310,3019,1214,744; mp193.0–194.3℃; [α] D 17 =–25.8(c=1.07,CHCl3); HPLC analysis AD-H column, 30% i PrOH in hexane,0.8mL / min,254nm UV detector,t R(major)=10.8min,t R (minor)=17.6min.

[0147] Example 18

[0148]

[0149] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (46.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (41.6 mg, white solid, yield 56%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (87%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ8.04–8.01(m,2H),8.00–7.96(m,2H),7.81–7.78(m,2H),7.42–7.38(m,2H),6.73(d,J=7.9Hz ,1H),5.18(q,J=7.6Hz,1H),3.92(s,3H),3.89(s,3H),2.05–1.77(m,2H),1.44–1.30(m,2H),0.94(t,J=7.3Hz,3H); 13 C NMR (126MHz, CDCl3) δ166.9,166.4,166.1,147.5,138.4,133.0,130.2,130.0, 129.5,127.1,126.7,53.9,52.6,52.3,38.4,19.7,13.9; HRMS(ESI)calcd.for C 21 H 23 NO5Na[M+Na] + m / z392.1468,found 392.1466;IR(neat,cm -1)3019,1720,1214,744; mp178.3–179.9℃; [α] D 17 =–19.7(c=1.22,CHCl3); HPLC analysis OD-H column, 20% i PrOH inhexane,0.8mL / min,254nm UV detector,t R (minor)=12.1min,t R (major)=15.6min.

[0150] Example 19

[0151]

[0152] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (25.4 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (26.5 mg, white solid, yield 50%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (92%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ8.02–7.97(m,2H),7.36–7.31(m,2H),5.76(d,J=8.2Hz,1H),4.98(q,J=7.6Hz,1H), 3.90(s,3H),2.00(s,3H),1.80–1.71(m,2H),1.38–1.24(m,2H),1.24–1.09(m,2H),0.86(t,J=7.1Hz,3H); 13C NMR(126MHz, CDCl3)δ169.4,167.0,147.9,130.1,129.3,126.7,53.5,52.2,36.0,28.4,23.6,22.6,14.0; HRMS(ESI)calcd.for C 15 H 21 NO3Na[M+Na] + m / z 286.1413,found 286.1409;IR(neat,cm -1 )3020,1722,1214,748; mp121.1–122.0℃; [α] D 25 =+96.6(c=0.21,CHCl3); HPLC analysis AD-H column, 10% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=10.0min,t R (minor)=12.1min.

[0153] Example 20

[0154]

[0155] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (34.8 mg, white solid, yield 51%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (91%) of the target product were measured. 1H NMR(500MHz, CDCl3)δ8.00–7.96(m,2H),7.85–7.71(m,2H),7.55–7.43(m,1H),7.43–7.34(m,4H),6.64(d, J=8.0Hz,1H),5.17(q,J=7.6Hz,1H),3.89(s,3H),1.97–1.78(m,2H),1.39–1.22(m,6H),0.87–0.81(m,3H); 13 C NMR(126MHz, CDCl3)δ167.0,166.9,147.9,134.5,131.8,130.2,129.3,128.8,127.1,126.7,53.9,52.2,36.3,31.6,26.0,22.6,14.1; HRMS(ESI)calcd.for C 21 H 25 NO3Na[M+Na] + m / z 362.1726,found362.1723;IR(neat,cm -1 )3287,2929,1636,1214,748; mp131.1–132.1℃; [α] D 17 =+0.7(c=0.81,CHCl3); 91%ee; HPLC analysis AD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=10.9min,t R (minor)=16.1min.

[0156] Example 21

[0157]

[0158] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (7.2 mg, 6.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv), followed by 0.1 mL of dry N,N-dimethylacetamide and 0.9 mL of a solution of the transfer ligand L in ethylene glycol dimethyl ether (prepared by dissolving 3.2 mg of the transfer ligand L in 10 mL of ethylene glycol dimethyl ether). After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (45.5 mg, yellow oily liquid, yield 67%) was obtained by column chromatography separation and purification. The target product had a rr value (>99:1) and an ee value (90%). 1 H NMR (500MHz, CDCl3) δ8.01–7.93(m,2H),7.44–7.10(m,6H),6.88(d,J=7.3Hz,1H),5.20– 4.87(m,3H),3.96–3.85(m,3H),3.77–3.59(m,2H),2.43–2.27(m,1H),1.97–1.77(m,3H); 13 C NMR (126MHz, CDCl3) δ167.0,155.0,149.8&149.0,137.0&136.5,129.9,128.8,128.5&128.3,128.1&128.0,127 .7&127.5,125.6,67.0&66.8,61.3&61.1,52.2&52.1,47.8&47.3,35.9&34.8,23.8&23.1;HRMS(ESI)calcd.for C 20 H 21 NO4Na[M+Na] + m / z 362.1363,found 362.1366;IR(neat,cm -1 )2951,1699,1408,1276,1105,770,699;[α] D 25 =–81.9 (c=1.04, CHCl3); HPLC analysis OD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UV detector,tR (major)=10.2min,t R (minor)=12.2min.

[0159] Example 22

[0160]

[0161] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (7.2 mg, 6.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv), followed by 0.1 mL of dry N,N-dimethylacetamide and 0.9 mL of a solution of the transfer ligand L in ethylene glycol dimethyl ether (prepared by dissolving 3.2 mg of the transfer ligand L in 10 mL of ethylene glycol dimethyl ether). After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (57.0 mg, 0.30 mmol, 1.5 equiv), and diethoxymethylsilane (96 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (49.7 mg, yellow oily liquid, yield 79%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (88%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.52–7.01(m,8H),6.91(d,J=5.8Hz,1H),5.21–4.82(m,3H),3.74–3.56(m,2H),2.39–2.24(m,1H),1.99–1.76(m,3H); 13 C NMR (126MHz, CDCl3) δ155.0,143.0&142.2,137.0&136.7,132.5,128.6,128.3&128.1,127.8,1 27.5,127.1,67.0&66.8,61.0&60.7,47.8&47.3,36.0&34.9,23.8&23.1; HRMS(ESI)calcd.for C 20 H 21 NO4Na[M+H] + m / z 316.1099,found 316.1092;IR(neat,cm -1)2952,1697,1406,1089,820,696;[α] D 25 =–46.5(c=1.44,CHCl3); HPLC analysis OD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=7.6min,t R (minor)=9.1min.

[0162] Example 23

[0163]

[0164] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (5.8 mg, 10.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. * To the reaction mixture was added 14.4 mg (12.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv), followed by 0.1 mL of dry N,N-dimethylformamide and 0.9 mL of an ether solution containing the transfer ligand L (the ether solution of the transfer ligand L was prepared by dissolving 6.5 mg of the transfer ligand L in 10 mL of ether). After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (67.8 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (55.4 mg, yellow oily liquid, yield 79%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (88%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ8.64–8.49(m,1H),7.71–7.49(m,2H),7.41–7.14(m,4H),6.91(d,J =7.2Hz,1H),5.22–4.84(m,3H),3.76–3.66(m,2H),2.46–2.38(m,1H),2.01–1.81(m,3H); 13C NMR (126MHz, CDCl3) δ155.1&154.7,148.1,146.9(q,J=34.8Hz),143.2&142.4,136.7&136.2,134.7&134.4,128.7&128. 5,128.3&128.2,128.1&127.9,121.7(q,J=273.9Hz),120.3,67.3&67.2,59.3&58.9,47.9&47.4,35.9&34.6,23.9&23.3; 19 F NMR(471MHz, CDCl3)δ–67.7,–67.8; HRMS(ESI)calcd.forC 18 H 18 F3N2O2[M+H] + m / z 351.1315,found 351.1310;IR(neat,cm -1 )2955,1698,1337,1131,1086,698;[α] D 25 =–44.6(c=1.93,CHCl3); HPLC analysis OD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=9.5min,t R (minor)=12.6min.

[0165] Example 24

[0166]

[0167] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (5.8 mg, 10.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. *To the reaction mixture was added 14.4 mg (12.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv), followed by 0.1 mL of dry N,N-dimethylformamide and 0.9 mL of an ether solution containing the transfer ligand L (the ether solution of the transfer ligand L was prepared by dissolving 6.5 mg of the transfer ligand L in 10 mL of ether). After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (57.7 mg, 0.30 mmol, 1.5 equiv), and diethoxymethylsilane (96 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (47.3 mg, yellow oily liquid, yield 75%) was obtained by column chromatography separation and purification. The target product had a rr value (>99:1) and an ee value (92%). 1 H NMR(500MHz, CDCl3)δ8.31–8.17(m,1H),7.52–7.11(m,6H),6.96(s,1H),5 .20–4.82(m,3H),3.75–3.57(m,2H),2.43–2.29(m,1H),1.98–1.77(m,3H); 13 C NMR (126MHz, CDCl3) δ155.0&154.8,149.9,147.6,138.8&138.0,136.7&136.4,136.2&136.1,128.6&128. 4,128.1&128.0,127.8,124.1,67.1,58.8&58.5,47.7&47.2,35.8&34.6,23.9&23.2; HRMS(ESI)calcd.for C 17 H 17 ClN2O2Na[M+Na] + m / z 339.0871,found 339.0864;IR(neat,cm -1 )2954,2879,1700,1409,1104,698;[α] D 25 =–69.5(c=1.09,CHCl3); HPLC analysis OD-H column, 20% i PrOH in hexane,0.8mL / min,254nmUV detector,t R (major)=11.9min,t R(minor)=13.8min.

[0168] Example 25

[0169]

[0170] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (5.8 mg, 10.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. * To the reaction mixture was added 14.4 mg (12.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv). Then, 0.1 mL of dry N,N-dimethylformamide and 0.9 mL of an ether solution containing the migrating ligand L (the ether solution of the migrating ligand L was prepared by dissolving 6.5 mg of the migrating ligand L in 10 mL of ether) were added. After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (58.2 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (56.7 mg, yellow oily liquid, yield 89%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (91%) of the target product were measured. 1 H NMR (500MHz, CDCl3) δ7.90–7.74(m,1H),7.45–7.19(m,5H),7.01(d,J=6.8Hz,1 H),5.20–4.80(m,3H),3.75–3.57(m,2H),2.47–2.28(m,1H),2.05–1.79(m,3H); 13 C NMR (126MHz, CDCl3) δ155.1&154.7,151.1(d,J=236.9Hz),145.4(d,J=260.8Hz),139.8,138.9,136.6&136.2, 128.6&128.5,128.2,128.1&128.0,124.2(d,J=41.6Hz),67.3,58.5&58.1,47.7&47.3,35.8&34.6,23.9&23.3; 19 F NMR(471MHz, CDCl3)δ–90.0,–90.1,–90.2,–90.3,–139.6,–139.7,–140.0,–140.1; HRMS(ESI)calcd.for C 17 H 17F2N2O2[M+H] + m / z 313.1547,found 313.1548;IR(neat,cm -1 )2948,1698,1395,1103,1042,697;[α] D 25 =–66.1(c=1.08,CHCl3); HPLC analysis OD-H column, 20% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=9.5min,t R (minor)=11.1min.

[0171] Example 26

[0172]

[0173] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (5.8 mg, 10.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. * To the reaction mixture was added 14.4 mg (12.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv). Then, 0.1 mL of dry N,N-dimethylformamide and 0.9 mL of an ether solution containing the migrating ligand L (the ether solution of the migrating ligand L was prepared by dissolving 6.5 mg of the migrating ligand L in 10 mL of ether) were added. After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (52.8 mg, 0.30 mmol, 1.5 equiv), and diethoxymethylsilane (96 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (53.7 mg, yellow oily liquid, yield 89%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (88%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ8.14–8.06(m,1H),7.47–7.14(m,4H),7.07–6.90(m,2H),6.70(d,J= 27.8Hz,1H),5.23–4.81(m,3H),3.87–3.50(m,2H),2.48–2.27(m,1H),2.02–1.73(m,3H); 13C NMR(126MHz, CDCl3)δ164.2(d,J=239.3Hz),159.2(d,J=98.5Hz),155.0&154.7,147.8&147.7,136.6&136.2,128.6&128 .4,128.2&128.1,127.7,118.6(d,J=21.5Hz),106.6&106.3,67.2&67.1,60.4&60.1,47.7&47.3,35.3&34.2,23.8&23.1; 19 F NMR(471MHz, CDCl3)δ–68.1,–68.3; HRMS(ESI)calcd.forC 17 H 17 FN2O2Na[M+Na] + m / z 323.1166,found 323.1166;IR(neat,cm -1 )2953,1700,1409,1107,772,735;[α] D 25 =–55.8(c=1.06,CHCl3); HPLC analysis OD-H column, 30% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=8.5min,t R (minor)=12.2min.

[0174] Example 27

[0175]

[0176] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (5.8 mg, 10.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. *To the reaction mixture was added 14.4 mg (12.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv). Then, 0.1 mL of dry N,N-dimethylformamide and 0.9 mL of an ether solution containing the migrating ligand L (the ether solution of the migrating ligand L was prepared by dissolving 6.5 mg of the migrating ligand L in 10 mL of ether) were added. After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (56.4 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (50.1 mg, yellow oily liquid, yield 80%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (90%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ8.07(dd,J=11.5,5.3Hz,1H),7.43–7.15(m,4H),7.01–6.94(m,1H),6.68(dd,J=23.4,5.4Hz,1 H),6.53(d,J=21.9Hz,1H),5.23–4.78(m,3H),3.91(s,3H),3.71–3.54(m,2H),2.38–2.24(m,1H),1.94–1.78(m,3H); 13 C NMR (126MHz, CDCl3) δ164.6,156.2&155.5,155.0&154.9,147.0,136.9&136.6,128.6&128.3,128.1&128.0,127.8& 127.6,114.5&114.3,107.5,67.1&66.9,60.5&60.2,53.5,47.7&47.2,35.2&34.1,23.7&23.0; HRMS(ESI)calcd.for C 18 H 21 N2O3[M+H] + m / z311.1754,found 311.1752;IR(neat,cm -1 )2952,1700,1409,1355,1110,698;[α] D 25 =–71.7(c=1.72,CHCl3); HPLC analysis OD-H column, 20% iPrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=8.7min,t R (minor)=10.9min.

[0177] Example 28

[0178]

[0179] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (5.8 mg, 10.0 mol%) and chiral ligand ent-L2 were added to the reaction tube. * To the reaction mixture was added 14.4 mg (12.0 mol%), potassium carbonate (55.4 mg, 2.0 equiv), and sodium iodide (60.0 mg, 2.0 equiv). Then, 0.1 mL of dry N,N-dimethylformamide and 0.9 mL of an ether solution containing the migrating ligand L (the ether solution of the migrating ligand L was prepared by dissolving 6.5 mg of the migrating ligand L in 10 mL of ether) were added. After stirring at 25°C for 5 minutes, the above-mentioned olefin (40.6 mg, 0.20 mmol, 1.0 equiv), aryl bromide (55.8 mg, 0.30 mmol, 1.5 equiv), and diethoxymethylsilane (96 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product (50.0 mg, yellow oily liquid, yield 81%) was obtained by column chromatography separation and purification. The rr value (>99:1) and ee value (89%) of the target product were measured. 1 H NMR(500MHz, CDCl3)δ:7.31–7.25(m,4H),7.24–7.19(m,2H),7.15–7.08(m,3H),6.93–6.88(m,2H) ,6.59–6.53(m,2H),4.22(t,J=6.8Hz,1H),3.82(s,3H),1.94–1.77(m,2H),0.97(t,J=7.4Hz,3H); 13 C NMR(126MHz,CH2Cl2)δ:159.1,148.6,140.5,136.4,135.8,129.1,127.9,127.4,125.5,118.5,114.3,114.2,59.3,55.6,32.0,11.0; HRMS(ESI)calcd.for C 22 H 23 NNaOS[M+Na] +m / z 372.1393,found372.1390;IR(neat,cm -1 )2961,2923,1258,1082,1010,789;[α] D 26 =–45.4 (c=1.0, CHCl3); HPLC analysis CHIRALCEL AD-H column, 10% i PrOH in n-hexane,0.8mL / min,254nm UVdetector,t R (minor)=11.0min,t R (major)=13.3min.

[0180] Example 29

[0181]

[0182] Under a nitrogen atmosphere, lithium aluminum hydride (200 mg, 5.0 equiv) was dissolved in tetrahydrofuran, and the pyrrolidine derivative (6d) was added to the solution at 0°C. The reaction was refluxed for six hours, then quenched with water at 0°C. The mixture was filtered through celite, washed with dichloromethane, and evaporated under vacuum to obtain the starting material. To the flask containing the starting material was added 5 mL of methanol, followed by Pd / C [palladium 10% wt on carbon (soaked with approximately 55% water), 10.6 mg, 10 mol%] and sodium hydroxide (160.0 mg, 4.0 equiv). After purging the air, hydrogen was introduced into the flask via a balloon. The reaction was stirred at room temperature for 4 hours. The mixture was then filtered through celite and concentrated. The crude product was purified by column chromatography (dimethylmethane / methanol = 10:1) to obtain the product (110.2 mg, yellow oil, 68% yield). The desired product was measured to have an ee of 92%. 1 H NMR (500MHz, CDCl3) δ8.57–8.43(m,2H),7.76–7.62(m,1H),7.29–7.22(m,1H),3.29–3.21(m,1H),3.09(t,J=8.3Hz,1 H),2.32(q,J=9.0Hz,1H),2.24–2.18(m,1H),2.17(s,3H),2.02–1.91(m,1H),1.88–1.79(m,1H),1.77–1.68(m,1H).; 13 C NMR(126MHz, CDCl3)δ149.8,148.8,135.0,123.7,69.1,57.2,40.5,35.3,22.8; HRMS(ESI)calcd.for C10 H 15 N2[M+H] + m / z 163.1230,found163.1237;IR(neat,cm -1 )2927,1706,1414,1264,731;[α] D 25 =–12.0 (c=1.00, CHCl3); HPLC analysis OD-H column, 3% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=10.4min,t R (minor)=12.8min.

[0183] Example 30

[0184]

[0185] Under a nitrogen atmosphere, pyrrolidine derivative 6b (315.0 mg, 1.0 mmol) was added to 40 mL of dry dichloromethane. The mixture was placed in an ice-water bath, and BBr (6 mL, a 1 M solution in CH2Cl2, 6.0 mmol, 6 equiv) was carefully added at 0°C. The reaction was stirred at room temperature for 5 h. Excess BBr was quenched with methanol. The reaction mixture was then concentrated to afford the crude product. The crude product was purified by column chromatography (EtOAc / MeOH / triethylamine = 9:1:0.1) to afford the title compound. The resulting product was then dissolved in 5 mL of N,N-dimethylformamide, followed by the addition of 3-methyl-1H-pyrazolo[3,4-B]pyridine-5-carboxylic acid (212.4 mg, 1.2 mmol, 1.2 equiv), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (383.4 mg, 2.0 mmol, 2.0 equiv), and 1-hydroxybenzotriazole (135.1 mg, 1.0 mmol, 1.0 equiv). After stirring for several minutes, N-methylmorpholine (303.3 mg, 3.0 mmol, 3.0 equiv) was added at room temperature, and the reaction mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield the crude product. The crude product was purified by column chromatography (EtOAc / MeOH / triethylamine = 9:1:1.0.1) to give the desired product (221.1 mg, white solid, 65% yield). 1H NMR(500MHz,DMSO-d6)δ13.50–13.22(m,1H),8.90–6.88(m,6H),5.27–4.92(m,1 H),4.00–3.52(m,2H),2.57–2.53(m,2H),2.44–2.28(m,2H),1.94–1.69(m,3H); 13 C NMR(126MHz,DMSO-d6)δ167.3,152.4,148.2,147.0,143.1,142.2,130.9,129.2,12 8.2,127.7,124.9,112.9,60.41,50.71,34.82,24.94,12.25; HRMS(ESI)calcd.for C 10 H 15 N2[M+H] + m / z341.1164, found 341.1158; mp104.0–105.7℃; [α] D 25 =–102.4 (c=0.92, CHCl3); HPLC analysis OJ-H column, 30% i PrOH in hexane,0.8mL / min,254nm UV detector,t R (major)=8.4min,t R (minor)=12.4min.

[0186] Comparative Example 1

[0187]

[0188] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. *To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv). This was followed by the addition of 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution of the migrating ligand L1 (prepared by dissolving 7.4 mg of the migrating ligand L1 in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product was separated and purified by column chromatography (white solid, yield 12%). The rr value (>99:1) and ee value (89%) of the target product were measured.

[0189] Conclusion: Migration ligand replace The results showed that the regioselectivity was improved, but the yield and enantioselectivity were significantly reduced.

[0190] Comparative Example 2:

[0191]

[0192] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), 0.25 mL of dry N-methylpyrrolidone, and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of migrating ligand L was prepared by dissolving 11.8 mg of migrating ligand L in 30 mL of toluene) were added. After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the target product was purified by column chromatography to obtain a white solid (14% yield). The target product had an RR value of 60:40 and an EE value of 95%.

[0193] Conclusion: The results without the addition of NaI showed that the enantioselectivity was improved, but the regioselectivity and yield were significantly reduced.

[0194] Comparative Example 3:

[0195]

[0196] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), sodium carbonate (42.4 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl iodide (78.6 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and reacted at 25°C for 24 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the target product was separated and purified by column chromatography (white solid, yield 59%). The rr value (94:6) and ee value (92%) of the target product were measured.

[0197] Conclusion: The results of replacing aryl bromide with aryl iodide showed that the enantioselectivity remained basically unchanged, but the regioselectivity decreased and the yield was significantly reduced.

[0198] Comparative Example 4:

[0199]

[0200] Under nitrogen atmosphere, nickel nitrate (II) hexahydrate (2.9 mg, 5.0 mol%) and chiral ligand L1 were added to the reaction tube. * To the reaction mixture was added 1% hydroxybenzoic acid (5.8 mg, 6.0 mol%), potassium carbonate (55.3 mg, 2.0 equiv), and sodium iodide (15.0 mg, 0.5 equiv), followed by 0.25 mL of dry N-methylpyrrolidone and 0.75 mL of a toluene solution containing the migrating ligand L (the toluene solution of the migrating ligand L was prepared by dissolving 11.8 mg of the migrating ligand L in 30 mL of toluene). After stirring at 25°C for 5 minutes, the above-mentioned olefin (35.0 mg, 0.20 mmol, 1.0 equiv), aryl bromide (64.5 mg, 0.30 mmol, 1.5 equiv), and dimethoxymethylsilane (74 μL, 0.60 mmol, 3.0 equiv) were added. The reaction tube was capped and allowed to react at 25°C for 24 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure, and the target product was separated and purified by column chromatography (white solid, yield 70%). The rr value (>99:1) and ee value (60%) of the target product were measured.

[0201] Conclusion: The results of replacing sodium carbonate with potassium carbonate showed that the regioselectivity and yield remained basically unchanged, but the enantioselectivity was significantly reduced.

Claims

1. An application of a nickel-catalyzed asymmetric migration arylation method for olefins, characterized in that: The application in the preparation of nicotine (S)-Nicotine, the specific preparation method reaction formula is as follows: In the first step, nickel nitrate (II) hexahydrate, chiral ligand ent-L2*, and potassium carbonate were added to a reaction tube under a nitrogen atmosphere, followed by the addition of dry N,N-dimethylformamide and an ether solution containing the migration ligand L; after stirring at 25°C for 5 minutes, the above-mentioned olefin, heteroaryl bromide, and diethoxymethylsilane were added, the lid of the reaction tube was covered, and the reaction was carried out at 25°C for 24 hours; after the reaction was completed, the reaction solvent was removed by concentration under reduced pressure, and the pyrrolidine derivative was obtained by column chromatography separation and purification; the migration ligand L was ent-L2* In the second step, lithium aluminum hydride is dissolved in tetrahydrofuran under a nitrogen atmosphere, and then a pyrrolidine derivative is added to the solution at 0°C; the reaction is refluxed for six hours, and then quenched with water at 0°C; the mixture is filtered through diatomaceous earth, washed with dichloromethane, and rotary evaporated to obtain a crude material; then, the crude material is dissolved in methanol, and palladium carbon and sodium hydroxide are added; after the air is expelled, hydrogen is filled into the flask through a balloon; the reaction is stirred at room temperature for 4 hours; after the reaction is completed, the mixture is filtered through diatomaceous earth and concentrated; the crude product is purified by column chromatography to obtain the target product nicotine (S)-Nicotine.

2. Application of a nickel-catalyzed asymmetric migration arylation method for olefins, characterized in that: The application in the preparation of inhibitor MSC2530818, the specific preparation method reaction formula is as follows: In the first step, nickel nitrate (II) hexahydrate and chiral ligand ent-L2 were added to the reaction tube under nitrogen atmosphere. * , potassium carbonate, sodium iodide, followed by the addition of dry N,N-dimethylacetamide and a solution of ethylene glycol dimethyl ether containing the migration ligand L; stirring at 25°C for 5 minutes, then adding the above-mentioned olefin, aryl bromide and diethoxymethylsilane, covering the reaction tube, and reacting at 25°C for 24 hours; after the reaction is completed, concentrating under reduced pressure to remove the reaction solvent, and separating and purifying by column chromatography to obtain a pyrrolidine derivative; the migration ligand L is ent-L2* In the second step, under a nitrogen atmosphere, a pyrrolidine derivative is added to dry dichloromethane, placed in an ice-water bath, and BBr3 is carefully added at 0°C; the reaction is stirred at room temperature for 5 hours; the excess BBr3 is quenched with methanol; the reaction mixture is then concentrated to obtain a crude product; the crude product is purified by column chromatography to obtain the target compound; then, the obtained product is dissolved in N,N-dimethylformamide, followed by the addition of 3-methyl-1H-pyrazolo[3,4-B]pyridine-5-carboxylic acid, N-(3-dimethylaminopropyl)-N'ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole; after stirring for a few minutes, N-methylmorpholine is added at room temperature, and the reaction mixture is stirred overnight at room temperature; after the reaction is completed, the reaction solution is diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate; the solvent is removed under reduced pressure to obtain a crude product; the crude product is purified by column chromatography to obtain the target product.

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