A method for the asymmetric aryl alkylation of non-activated olefins catalyzed by nickel

Abstract

The present invention discloses a method for asymmetric aryl alkylation reaction of three-component non-activated olefins catalyzed by nickel. Non-activated olefins using 8-aminoquinoline as a directing group are coordinated with a nickel catalyst, and the target product is obtained with a high yield under the regulation of a specific chiral ligand and the enantioselectivity is as high as 96.5:3.5. The whole method is simple, easy and safe, and a multi-component asymmetric coupling reaction of non-activated olefins with halogenated aromatics and halogenated alkanes is achieved in one step. Under optimized reaction conditions, the yield of the target product after separation can be as high as 85%, which is a general, efficient, economical and environmentally friendly method for constructing carbon-carbon bonds.

Description

Technical Field

[0001] The invention belongs to the field of catalytic synthesis technology and fine chemical synthesis, and relates to a method for a nickel-catalyzed asymmetric aryl alkylation reaction of three-component non-activated olefins. Background Art

[0002] Constructing chiral carbon-carbon bonds is one of the important reactions in organic synthesis. So far, chemists have developed many strategies for constructing chiral carbon-carbon bonds. Among them, the asymmetric 1,2-aryl alkylation strategy of olefins is to introduce aryl and alkyl groups into the molecule at the same time, that is, to form C(sp3)-C(sp2) and C(sp3)-C(sp3) bonds in one step, which is an effective means to efficiently construct chiral carbon-carbon bonds. However, the current 1,2-aryl alkylation of olefins is mainly limited to the use of active alkyl zinc reagents as nucleophilic "carbon sources" to construct CC bonds. Although the 1,2-aryl alkylation of olefins using alkyl halides as electrophilic "carbon sources" has been achieved in recent years, the research on the asymmetric 1,2-aryl alkylation of three-component non-activated olefins is still in its infancy, and there is still a lack of systematic asymmetric catalytic research. Therefore, 1) developing new asymmetric catalytic methods; 2) achieving regioselective control of the reaction; 3) enriching the scope of application of olefins (non-activated internal olefins and multi-substituted olefins) are scientific issues that need to be addressed in this field. There are many scientific problems currently existing in the three-component asymmetric 1,2-dicarbonization: lack of effective asymmetric catalytic systems, difficult to control selectivity, β-hydrogen elimination side reactions, and limited scope of application of olefin substrates. Summary of the invention

[0003] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a method for nickel-catalyzed asymmetric aryl alkylation of three-component non-activated olefins. The method revolves around the pattern of asymmetric electrophilic reductive coupling reaction of olefins catalyzed by inexpensive metals, and regioselectively realizes the asymmetric 1,2-aryl alkylation reaction of three-component non-activated olefins. It provides a simple, convenient, fast and efficient strategy for the asymmetric synthesis of complex natural products and biologically active molecules. The present invention achieves enantioselectivity and develops a new asymmetric cross-reduction coupling catalytic system by regulating the selective migration and insertion process of aromatic metals to olefins through chiral ligands and olefin substrates. It solves the problem of regioselectivity in the current asymmetric 1,2-aryl alkylation reaction of three-component non-activated olefins and realizes the efficient construction of multiple carbon chiral centers.

[0004] Technical solution: In order to achieve the above-mentioned purpose, the method for nickel-catalyzed asymmetric aromatic alkylation of non-activated olefins described in the present invention comprises the following steps: in a solvent, aryl halides and alkanes are used as electrophilic reagents, nickel is used as a catalyst, and a cheap metal element is used as a reducing agent, and reacts with non-activated olefins under the regulation of chiral ligands to obtain 1,2-aromatic alkylation products, and simultaneously constructs C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds to achieve efficient construction of continuous carbon chiral centers, and control the enantioselectivity of the reaction, so as to achieve asymmetric 1,2-aromatic alkylation of non-activated olefins under the regulation of chiral ligands.

[0005] The general reaction formula is as follows:

[0006]

[0007] In the formula: AQ in 1a is 8-aminoquinoline; Ar1X represents halogenated aromatic hydrocarbon, R1X represents halogenated aromatic hydrocarbon, and Chiralligands represents chiral ligands.

[0008] Wherein, the X is bromine or iodine, and the Ar1 represents a substituent on the halogenated aromatic hydrocarbon, which is selected from any substituted aromatic group.

[0009] Wherein, X is bromine or iodine, and R1 represents a substituent group on a halogenated alkane, and the substituent groups on the halogenated alkane are independently and arbitrarily selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, amine or cyano.

[0010] Wherein, the nickel is selected from nickel chloride, anhydrous nickel bromide, hydrated nickel bromide, nickel iodide, nickel carbonate, bis-(1,5-cyclooctadiene) nickel, nickel chloride ethylene glycol dimethyl ether complex, nickel bromide ethylene glycol dimethyl ether complex, (2,2'-bipyridine) nickel dibromide, dibromo(1,10-phenanthroline) nickel, chlorobistrihexyl phosphate nickel salt, bis(triphenylphosphine) nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, (1,1'-bis(triphenylphosphine) ethane) nickel chloride, Any one of (diphenylphosphino)ferrocene) nickel dichloride, nickel bromide diethylene glycol dimethyl ether complex, nickel acetylacetonate, nickel trifluoromethanesulfonate, bis(2,2,6,6,-tetramethyl-3,5-heptanedione) nickel, bis(hexafluoroacetylacetonate) nickel, nickel perchlorate, nickel p-toluenesulfonate, 1,3-bis(diphenylphosphinopropane) nickel dichloride, nickel tetrafluoroborate hexahydrate, bis(triphenylphosphine) nickel dibromide, and dibromobis(tributylphosphine) nickel.

[0011] Among them, the chiral ligands represent chiral ligands, mainly including bidentate chiral N ligands, bidentate chiral P ligands, bidentate chiral N, P ligands, monodentate chiral N ligands, etc.

[0012] Preferably, the chiral ligand includes chiral oxazoline ligand, chiral diamine ligand, chiral bidentate phosphine ligand, biphenyl diphosphine ligand, spirocyclic phosphine ligand, chiral phosphate ligand and the like.

[0013] More preferably, the chiral ligand is a chiral oxazoline ligand, such as (S)-iBuPHOX.

[0014] Wherein, the cheap metal element is selected from any one of zinc, manganese and magnesium metal reducing agents.

[0015] The organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propylene glycol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-diethylacetamide, N,N-dimethylpropylene urea, N-methylpyrrolidone, ethyl acetate, 1,4-dioxane or tetrahydrofuran.

[0016] The molar ratio of olefin, halide, nickel and manganese is: 1:(1-2):(1-2):(0.1-0.2):(2-3)

[0017] Wherein, the reaction temperature is 30-60°C and the reaction time is 48-96 hours.

[0018] The nickel catalyst in the method of the present invention has the characteristics of wide sources, rich types and low price. During the reaction process, metal nickel is complexed with a chiral ligand to form a chiral metal intermediate, and then the regional selectivity and enantioselectivity of the reaction are controlled by the coordination effect of olefins to obtain the target product with an enantioselectivity greater than 96:4.

[0019] The present invention takes the asymmetric 1,2-aryl alkylation reaction as a breakthrough point, breaking the current situation where research is limited by terminal olefin substrates. The present invention solves the following problems by studying the key scientific issues of the regioselectivity and stereoselectivity of metal-catalyzed non-activated olefin 1,2-aryl alkylation reactions promoted by chiral ligands: (1) Breaking through the existing limitations of asymmetric 1,2-aryl alkylation reactions and realizing a completely new regioselective asymmetric 1,2-aryl alkylation reaction. (2) Developing a new asymmetric cross-reduction coupling catalytic system by regulating the selective migration and insertion process of aromatic metals to olefins through specific chiral ligands and olefin substrates. (3) Solving the problem of regioselectivity in the current three-component non-activated olefin asymmetric 1,2-aryl alkylation reaction.

[0020] The present invention adopts a brand-new reaction system and strategy to utilize the coordination of olefins and nickel catalysts to control the regioselectivity and stereoselectivity in the reaction process, so that the reaction can be coupled with halides under very mild conditions to obtain the target product with high regioselectivity and stereoselectivity, especially for complex substrates, and an ideal catalytic effect can be achieved.

[0021] The present invention establishes a new method for the asymmetric 1,2-aryl alkylation of three-component non-activated olefins catalyzed by cheap metals: by developing chiral ligands to control the chemical selectivity of the metal-catalyzed reaction, combined with the synergistic regulation of the substrate, the metal active intermediates are regulated to migrate and insert the olefins regioselectively and stereoselectively, thereby achieving a highly stereoselective asymmetric 1,2-aryl alkylation reaction. The core content of the present invention revolves around the asymmetric cross-reduction coupling reaction of non-activated olefins relay catalyzed by cheap metals (Ni, Co, etc.), based on the asymmetric 1,2-aryl alkylation reaction of non-activated olefins (internal olefins), and explores the asymmetric carbon heterofunctionalization reaction of multi-component non-activated olefins. The successful implementation of the present invention will open up a new breakthrough in the three-component asymmetric 1,2-dicarbonization reaction of non-activated olefins, enrich its reaction types, expand the application scope of substrates, especially the expansion of olefin substrate types (non-activated internal olefins and multi-substituted olefins); solve scientific problems such as the difficulty in controlling the selectivity of such reactions; at the same time, provide a simple, efficient and novel method for constructing complex chiral molecules, and have certain guiding significance for other types of difunctionalization reactions; it has very important scientific significance and application value in the development and synthesis of natural products, drugs and chiral materials.

[0022] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0023] (1) By using the coordinated regulation strategy of catalysts, chiral ligands and directing groups, the present invention has established a breakthrough asymmetric catalytic mode for the 1,2-aryl alkylation reaction of three-component non-activated olefins, realizing asymmetric reactions with new domain selectivity control, and enriching the types of olefin double carbonization reactions. It solves the current situation that the reaction is limited to terminal olefins, and has expanded the olefins to challenging internal olefins and multi-substituted olefins, realizing the efficient construction of multiple carbon chiral centers.

[0024] (2) Develop new strategies for the reductive coupling reaction of asymmetric 1,2-aryl alkylation of olefins, make full use of the control mode involving chiral ligands and directing groups, realize the regioselective and stereoselective migration and insertion of aryl metals into olefins, and pioneer the exploration of asymmetric 1,2-aryl alkylation of three-component non-activated olefins. The new asymmetric method developed by the present invention is a supplement to the traditional regioselectivity of asymmetric 1,2-dicarbonization reaction of olefins, and at the same time establishes a new method for constructing the diversity of chiral molecules. The chiral ligand used in the present invention is the decisive factor for realizing the present invention. The chiral ligand has the characteristics of improving the activity of the catalyst, controlling the regioselectivity of the migration and insertion of aryl metals into olefins, inhibiting β-hydrogen elimination and promoting reductive elimination. The present invention examines the influence of the type of chiral ligand on the reaction, screens out the dominant skeleton, and then studies the influence of the steric hindrance and electronic effects of the ligand on the stereoselectivity of the reaction, and screens out the dominant ligand to achieve high enantioselectivity of the reaction. The directing group plays a vital role in controlling the regioselectivity of the reaction, and at the same time, it also plays a certain role in inhibiting factors such as β-hydrogen elimination.

[0025] (3) The key to the method of the present invention is that it can use ideal nickel as a catalyst to carry out a three-component catalytic reaction. The key is to use a specific reaction system. Through the coordination of the nickel catalyst with the olefin with a strong 8-aminoquinoline (AQ) directing group and combined with specific raw materials and reaction conditions, the selectivity of the reaction can be well controlled, while avoiding the occurrence of other side reactions, and achieving an ideal catalytic effect on complex substrates. Through the regulation of specific chiral ligands, the activity of the catalyst is improved, the regioselectivity of the migration and insertion of aryl metals to olefins is controlled, the side reaction of β-hydrogen elimination is suppressed, and the reduction elimination is promoted to obtain an asymmetric 1,2-aryl alkylation product.

[0026] (4) The method of the present invention can quickly construct carbon-carbon double bonds that can be used as organic intermediates for drugs or bioactive molecules and is widely used in the synthesis of pharmaceutical intermediates and high value-added fine chemicals.

[0027] (5) The present invention uses an olefin with a directing group in the reaction process to coordinate with a nickel catalyst to obtain the target product with a high yield and an enantioselectivity of up to 96.5:3.5. The entire method is simple, easy and safe, and a one-step method is used to achieve a multi-component asymmetric coupling reaction of non-activated olefins with halogenated aromatics and halogenated alkanes. Under optimized reaction conditions, the yield of the target product after separation can be as high as 85%. It is a general, efficient, economical and environmentally friendly method for constructing carbon-carbon bonds. DETAILED DESCRIPTION

[0028] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0029] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described can be obtained from commercial sources or simply prepared by the following methods unless otherwise specified.

[0030] Some of the initial substrates were synthesized by the following method or purchased commercially, and the remaining substrates were reported or commercially available or synthesized with reference to the following method.

[0031]

[0032] Under nitrogen, enyl acid (1.5 equiv 630 mg) and 8-aminoquinoline (1.0 equiv 720 mg) and anhydrous dichloromethane (15 ml) were added to a dried round-bottom flask in sequence, and pyridine (2.0 equiv 790 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.0 equiv 1.91 g) were added under stirring. After reacting at room temperature for 2 hours, the mixture was quenched with water, extracted with ethyl acetate, and separated by vacuum spin drying chromatography to obtain the target product (substrate 1a). The raw materials enyl acid, 8-aminoquinoline, pyridine and EDCI are all commercially available raw materials.

[0033] The starting materials 2 and 3 in the examples are commercially available or reported compounds.

[0034] The chiral ligand L used in each example is (S)-iBuPHOX, CAS No. 2757082-85-0, which is commercially available.

[0035] The specific structural formula is:

[0036]

[0037] The specific structures of all substrates and products in the examples are shown in Table 1. The products of each reaction simultaneously construct C(sp3)-C(sp3)-C(sp2) bonds. The upper group on the right side of the product is a C(sp3)-C(sp3) bond, and the lower group on the right side of the product is a C(sp3)-C(sp2) bond. For example, in product 1 is a C(sp3)-C(sp3) bond, It is a C(sp3)-C(sp2) bond.

[0038] Example 1

[0039] Synthesis of compound 1

[0040] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045mmol), chiral ligand L (0.06mmol), N,N-dimethylformamide (0.72mL) and 1,3-dimethyl-2-imidazolidinone (0.18mL), manganese powder (0.9mmol) were added to a 10mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30min. The catalyst was started, and substrate 1a (0.3mmol), aromatic substrate 1b (0.45mmol), alkyl substrate 1c (0.6mmol) were added in sequence, and N,N-dimethylformamide (0.4mL) was added. The reaction mixture was placed at 30℃ for 48h. After the reaction was completed, the product 1 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 85% (95.5:4.5er).

[0041] 1 H NMR(400MHz, CDCl3)δ9.78(s,1H),9.26–8.69(m,2H),8.14(dt,J=8.4,1.8Hz,1H),7.70–7.36(m,3H),7.31–7.12(m,2H),7.09(d,J=7.7 Hz,2H),2.70(qd,J=13.6,7.0Hz,2H),2.49(d,J=6.9Hz,2H),2.45–2.32(m,1H),2.29(s,3H),1.57–1.37(m,2H),1.01(t,J=7.4Hz,3H). 13 C NMR (100MHz, CDCl3) δ171.46,148.15,138.36,137.33,136.41,135.42,134.61,129 .34,129.03,127.99,127.49,121.63,121.40,116.44,42.08,39.49,38.92,26.22, 21.07,11.24.IR(neat):3355,3046,2960,2922,2874,1683,1596,1578,1520,1483 ,1460,1423,1364,1384,1258,1151,1063,825,790,755,676.HRMS(ESI):Calcd.for C 22 H 25 N2O[M+H] + :333.1982; Found:333.1954.HPLC analysis:Theenantiomeric excess was determined on a Lux μm Cellulose-1 (5% iPrOH inhexane, 1.0mL / min, 35℃, λ = 250nm), t R (major)=30.87min,t R (minor) = 26.25min.[α] D 15 =-0.41°(c=0.11,CHCl3).

[0042] Example 2

[0043] Synthesis of compound 2

[0044] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 1b (0.45 mmol), alkyl substrate 2c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 2 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1), and the yield was 65% (95.5:4.5er). 1H NMR (400MHz, CDCl3) δ9.75 (s, 1H), 8.79 (ddd, J = 8.9, 5.8, 1.6Hz, 2H), 8.16 (d d,J=8.3,1.6Hz,1H),7.55–7.41(m,3H),7.13(d,J=8.0Hz,2H),7.07(d,J=7. 9Hz,2H),2.68(dd,J=21.3,6.9Hz,2H),2.47(d,J=6.7Hz,2H),2.43–2.32(m, 1H),2.28(s,3H),1.41(s,4H),1.28–1.20(m,8H),0.84(t,J=6.9Hz,3H).13C NMR (100MHz, CDCl3) δ171.52,148.18,138.45,137.40,136.47,135.46,134.67,129.40,12 9.07,128.06,127.58,121.68,121.41,116.51,42.55,39.98,37.54,33.76,32.01,29.96,2 9.71,29.41,26.91,22.79,21.13,14.26.IR(neat):3356,2924,2853,1684,1596,1578,152 1,1484,1460,1423,1385,1323,1257,1150,1063,825,791,755,679.HRMS(ESI):Calcd.for C 26 H 33 N2O[M+H]+:389.2588; Found:407.389.2582.HPLC analysis:The enantiomeric excess was determined on a Lux μm Cellulose-1 (10% iPrOH in hexane, 1.0 mL / min, 35 ℃, λ = 250 nm), t R (major) = 23.11min, t R (minor) = 13.59min.[α] D 15 =2.44°(c=0.11,CHCl3).

[0045] Example 3

[0046] Synthesis of compound 3

[0047] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 1b (0.45 mmol), alkyl substrate 3c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 3 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1), and the yield was 61% (96.5:3.5er). 1 H NMR(400MHz, CDCl3)δ9.76(s,1H),8.79(ddd,J=8.6,5.8,1.4Hz,2H),8.16(dd,J=8.3,1.5Hz,1H),7.67–7.38(m,3H),7.22(d,J=7.3Hz,2H),7.17–7.10 (m,5H),7.07(d,J=7.9Hz,2H),2.78–2.73(m,J=11.6,8.0Hz,4H),2.54(d,J =6.3Hz,2H),2.48(dt,J=13.7,6.8Hz,1H),2.28(s,3H),1.86–1.71(m,2H). 13C NMR (100MHz, CDCl3) δ171.17,148.18,142.43,138.39,137.01,136.47,135.60,134.58,129.38,129.13,128. 48,128.42,128.03,127.54,125.82,121.69,121.49,116.53,42.40,39.90,37.31,35.67,33.39,21.12.HPLC analysis:The enantiomeric excess was determined on a Lux μmCellulose-1 (20% iPrOH in hexane, 1.0mL / min, 35℃, λ = 250nm), t R (major)=24.26min,t R (minor) = 18.03min.[α] D 15 =2.12°(c=0.17,CHCl3)

[0048] Example 4

[0049] Synthesis of compound 4

[0050] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 1b (0.45 mmol), alkyl substrate 4c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 4 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 60% (94:6er). 1H NMR (400MHz, CDCl3) δ9.75(s,1H),8.81(dd,J=4.2,1.7Hz,1H),8.75(dd,J=7.1,1.8Hz,1H),8.16(dd,J=8.3,1.6Hz,1H),7.57–7.44(m,3H),7.10( q,J=8.1Hz,4H),2.75–2.61(m,2H),2.49(dd,J=13.6,6.5Hz,2H),2.43–2 .37(m,1H),2.29(d,J=7.3Hz,5H),1.69–1.56(m,4H),1.50–1.41(m,2H). 13 C NMR (100MHz, CDCl3) δ171.07,148.23,138.34,136.92,136.55,135.72,134.49,129.3 0,129.20,128.06,127.55,121.75,121.59,119.88,116.55,42.23,39.90,37.06,32.7 2,25.97,25.55,21.13,17.16.IR(neat):3354,2923,1683,1597,1578,1521,1506,14 84,1462,1424,1386,1324,1251,1133,1034,985,826,792,751.HRMS(ESI):Calcd.for C 25 H 27 N3O[M+H] + :386.2227; Found:386.2218.HPLC analysis:The enantiomeric excess was determined on a Lux μmCellulose-1 (15% iPrOH in hexane, 0.8mL / min, 35℃, λ = 250nm), t R (major) = 22.61min, t R (minor) = 21.33min.[α] D 15 =2.18°(c=0.12,CHCl3).

[0051] Example 5

[0052] Synthesis of compound 5

[0053] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 1b (0.45 mmol), alkyl substrate 5c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 5 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 72% (95.5:4.5er). 1 H NMR(400MHz,Chloroform-d)δ9.74(s,1H),8.80(dd,J=4.3,1.7Hz,1H),8.76(dd,J=7.3,1.8Hz,1H),8.16(dd, J=8.2,1.7Hz,1H),7.57–7.49(m,2H),7.46(dd,J=8.3,4.2Hz,1H),7.12(d,J=8.1Hz,2H),7.07(d,J=7.9Hz,2H ),3.60(t,J=6.6Hz,2H),2.72(dd,J=13.7,6.6Hz,1H),2.65(t,J=6.8Hz,1H),2.47(dd,J=6.7,3.4Hz,2H),2.4 4–2.35(m,1H),2.27(s,3H),1.61(brs,1H),1.54(dd,J=7.7,6.5Hz,2H),1.48–1.41(m,4H),1.39–1.29(m,2H). 13 C NMR (101MHz, CDCl3) δ171.48,148.19,137.26,136.50,135.51,134.57,129.35,129.08, 128.04,127.55,121.69,121.49,116.54,62.99,42.47,40.04,37.34,33.69,32.77,26. 62,25.94,21.10.IR(neat):3352,3048,2929,2854,1682,1596,1578,1522,1485,1462, 1424,1386,1325,1264,1197,1150,1049,826,792,757,733,701.HRMS(ESI):Calcd.for C 25 H 31N2O3[M+H] + :407.2329; Found:407.2333.HPLC analysis:The enantiomeric excess was determined on a Lux μm Cellulose-1 (15% iPrOH inhexane, 1.0mL / min, 35℃, λ = 250nm), t R (major) = 25.12min, t R (minor) = 22.26min.[α] D 15 =4.11°(c=0.12,CHCl3).

[0054] Example 6

[0055] Synthesis of compound 6

[0056] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045mmol), chiral ligand L (0.06mmol), N,N-dimethylformamide (0.72mL) and 1,3-dimethyl-2-imidazolidinone (0.18mL), manganese powder (0.9mmol) were added to a 10mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30min. The catalyst was started, and substrate 1a (0.3mmol), aromatic substrate 1b (0.45mmol), alkyl substrate 6c (0.6mmol) were added in sequence, and N,N-dimethylformamide (0.4mL) was added. The reaction mixture was placed at 30℃ for 48h. After the reaction was completed, the product 6 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1), and the yield was 41% (96.5:3.5er). 1 H NMR(400MHz, CDCl3) δ9.75(brs,1H),8.80(dd,J=4.2,1.5Hz,1H),8.76(dd,J=7.2,1.4Hz,1H),8. 16(dd,J=8.3,1.4Hz,3H),7.60–7.41(m,2H),7.12(d,J=7.9Hz,2H),7.07(d,J=7.9Hz,2H),4.09( q,J=7.1Hz,2H),2.70(qd,J=13.7,6.9Hz,2H),2.49(d,J=6.7Hz,2H),2.40(dt,J=13.3,6.5Hz,1H ),2.28(d,J=6.6Hz,5H),1.77(dt,J=15.0,7.3Hz,2H),1.59–1.36(m,2H),1.21(t,J=7.1Hz,3H).13 C NMR (100MHz, CDCl3) δ173.73,171.16,148.20,138.39,137.04,136.46,135.57,134.5 7,129.35,129.11,128.03,127.52,121.69,121.48,116.50,60.34,42.19,39.77,37.2 3,34.57,33.14,22.37,21.10,14.33.IR(neat):3355,2924,2855,1729,1683,1596,15 78,1520,1484,1461,1424,1385,1324,1240,1180,1154,1031,952,826,792,757.HPLC analysis:The enantiomericexcess was determined on a Lux μm Cellulose-1 (10% iPrOH in hexane, 1.0mL / min, 35℃, λ = 250nm), t R (major)=50.52min,t R (minor) = 25.20min.[α] D 15 =4.61°(c=0.14,CHCl3).

[0057] Example 7

[0058] Synthesis of compound 7

[0059] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 2b (0.45 mmol), alkyl substrate 7c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 7 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 52% (92:8er). 1H NMR(400MHz, CDCl3)δ9.77(brs,1H),8.80(dd,J=4.2,1.7Hz,1H),8.77(dd,J=7.2,1.8Hz,1H),8 .16(dd,J=8.2,1.7Hz,1H),7.70–7.49(m,2H),7.45(dd,J=8.3,4.2Hz,1H),7.32–7.20(m,4H),7. 22–7.13(m,1H),3.59(t,J=6.5Hz,2H),2.72(qd,J=13.6,6.7Hz,2H),2.48(dd,J=6.6,2.3Hz,2H) ,2.47–2.29(m,1H),1.74(brs,1H),1.54(q,J=7.2Hz,2H),1.47–1.39(m,3H),1.38–1.21(m,2H). 13 C NMR (100MHz, CDCl3) δ171.41,148.23,140.45,138.39,136.52,134.54,129.49 ,128.41,128.04,127.55,126.09,121.72,121.54,116.54,62.98,42.42,40.4 6,37.29,33.62,32.74,26.61,25.92.IR(neat):3350,3026,2928,2855,1681, 1596,1577,1520,1484,1462,1424,1051,826,792,758,679.HPLCanalysis:The enantiomeric excess was determined on a Lux μm Cellulose-1 (20% iPrOH in hexane, 1.0mL / min, 35℃, λ = 250nm), t R (major) = 19.81min,t R (minor) = 17.26min.[α] D 15 =0.99°(c=0.21,CHCl3).

[0060] Example 8

[0061] Synthesis of compound 8

[0062] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 2b (0.45 mmol), alkyl substrate 8c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 8 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 78% (96:4er). 1 H NMR (400MHz, CDCl3) δ9.75 (brs, 1H), 8.81 (dd, J = 4.3, 1.7Hz, 1H), 8.76 (dd, J = 7.3, 1.8Hz, 1H), 8.16 (dd, J = 8. 3,1.7Hz,1H),7.64–7.39(m,3H),7.15(d,J=7.8Hz,2H),7.09(d,J=7.8Hz,2H),3.60(t,J=6.6Hz,2H),2.73(dd ,J=13.6,6.4Hz,1H),2.64(t,J=6.9Hz,1H),2.58(q,J=7.6Hz,2H),2.48(dd,J=6.6,5.1Hz,2H),2.43–2.36(m ,1H),1.83(brs,1H),1.53(h,J=6.5,6.0Hz,2H),1.46–1.42(m,4H),1.40–1.32(m,2H),1.19(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ171.52,148.15,141.93,138.30,137.54,136.66,134.53,129.41,128.08,127.88,12 7.61,121.69,121.52,116.72,62.99,42.47,40.09,37.33,33.76,32.76,28.52,26.62,25.94,15.69.HPLC analysis:Theenantiomeric excess was determined on a Lux μm Cellulose-1 (20% iPrOH inhexane, 0.8mL / min, 25℃, λ = 250nm), t R(major)=21.61min,t R (minor) = 18.62min.

[0063] Example 9

[0064] Synthesis of compound 9

[0065] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045mmol), chiral ligand L (0.06mmol), N,N-dimethylformamide (0.72mL) and 1,3-dimethyl-2-imidazolidinone (0.18mL), manganese powder (0.9mmol) were added to a 10mL reaction bottle in sequence. The mixture was stirred evenly at room temperature for 30min, the catalyst was started, and substrate 1a (0.3mmol), aromatic substrate 4b (0.45mmol), alkyl substrate 9c (0.6mmol) were added in sequence, and N,N-dimethylformamide (0.4mL) was added. The reaction mixture was placed at 30℃ for 48h. After the reaction was completed, the product 9 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1), and the yield was 61% (95.5:4.5er). 1 H NMR (400MHz, CDCl3) δ9.75(brs,1H),8.80(dd,J=4.3,1.7Hz,1H),8.76(dd,J=7.3,1.8Hz,1H),8.15(dd,J=8.3,1.7H z,1H),7.62–7.49(m,2H),7.45(dd,J=8.3,4.2Hz,1H),7.15(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),3.60(t,J=6.5Hz ,2H),2.84(p,J=6.9Hz,1H),2.74(dd,J=13.7,6.2Hz,1H),2.62(dd,J=13.7,7.1Hz,1H),2.57–2.45(m,2H),2.43–2. 33(m,1H),1.59(brs,1H),1.54(p,J=6.9Hz,2H),1.45(d,J=4.9Hz,4H),1.40–1.33(m,2H),1.21(s,3H),1.19(s,3H). 13C NMR (100MHz, CDCl3) δ171.50,148.19,146.55,138.39,137.65,136.52,134.58,129.38,128.06,127.57,126.42,121. 69,121.48,116.55,62.98,42.50,40.10,37.29,33.82,33.76,32.77,26.64,25.94,24.14,24.12.HPLCanalysis:The enantiomeric excess was determined on a Lux μm Cellulose-1 (20% iPrOH in hexane, 0.8mL / min, 25℃, λ = 250nm), t R (major)=20.52min,t R (minor) = 17.50min.

[0066] Example 10

[0067] Synthesis of compound 10

[0068] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 5b (0.45 mmol), alkyl substrate 10c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 10 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 71% (95:5er). 1H NMR(400MHz,CD2Cl2)δ9.73(brs,1H),8.82(dd,J=4.3,1.7Hz,1H),8.71(d,J=4.5Hz,1H),8.19(dd,J=8.3,1.7Hz,1H),7.55–7.51(m,2H),7.48(dd,J=8.3,4.2Hz,1H),7.14(d,J=8.5Hz,2H),6.79(d,J=5.9Hz,2H),3.72(s,3H),3.55(t,J=6.6Hz,2H),2.68(dd,J=13.7,6.7Hz,1H),2.59(dd,J=13.7,7.3Hz,1H),2.43(d,J=6.8Hz,2H),2.32(q,J=6.4Hz,1H),1.65(s,1H),1.51(p,J=6.9Hz,2H),1.42(q,J=3.9,3.2Hz,4H),1.32(ddd,J=11.6,7.5,3.2Hz,2H). 13 CNMR(100MHz,CD2Cl2)δ171.53,158.28,148.61,138.61,136.71,135.04,132.84,130.58,128.34,127.60,122.07,121.60,116.35,113.90,63.00,55.45,42.58,39.71,37.86,33.92,33.09,26.82,26.23.HRMS(ESI):Calcd.for C 25 H 31 N2O3[M+H] + :407.2329;Found:407.2333.IR(neat):3351,2929,2855,1682,1611,1597,1580,1522,1511,1485,1463,1424,1384,1366,1325,1300,1244,1177,1035,826,792,757.HPLC analysis:The enantiomeric excess was determined on aLux μmCellulose-1(30%iPrOH in hexane,0.7mL / min,35℃,λ=250nm),t R (major)=20.99min,t R (minor)=19.47min.[α] D 15=-0.32°(c=0.14,CHCl3).

[0069] Embodiment 11

[0070] Synthesis of compound 11

[0071] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 6b (0.45 mmol), alkyl substrate 11c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 11 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1), and the yield was 52% (93.5:6.5er). 1 H NMR(400MHz, CDCl3)δ9.76(brs,1H),8.80(dd,J=4.3,1.6Hz,1H),8.76(dd,J=7.3,1.7Hz,1H),8.16(dd,J=8.2,1.7Hz,1H),7 .59–7.48(m,2H),7.45(dd,J=8.2,4.2Hz,1H),7.18(t,J=7.8Hz,1H),6.83(d,J=7.5Hz,1H),6.78(t,J=2.1Hz,1H),6.71(dd, J=8.2,2.6Hz,1H),3.76(s,3H),3.60(t,J=6.5Hz,2H),2.73(dd,J=13.6,6.6Hz,1H),2.66(dd,J=13.6,7.0Hz,1H),2.49(dd, J=6.6,3.3Hz,2H),2.45–2.37(m,1H),1.68(brs,1H),1.54(p,J=6.9Hz,2H),1.48–1.41(m,4H),1.35(dd,J=8.5,5.1Hz,2H). 13CNMR (100MHz, CDCl3) δ171.37,159.68,148.24,142.11,138.42,136.51,134.58,129.36,128.06,127.56,121.93,121.72 ,121.52,116.53,115.14,111.42,63.01,55.24,42.47,40.57,37.22,33.72,32.76,26.61,25.93.HRMS(ESI):Calcd.for C 25 H 31 N2O3[M+H] + :407.2329; Found:407.2333.IR(neat):3350,2928,2855,1681,1596,1583,15 22,1485,1463,1424,1386,1325,1258,1152,1046,875,827,791,759,693.HPLC analysis:Theenantiomeric excess was determined on a Lux μm Cellulose-1 (20% iPrOH inhexane, 1.0mL / min, 25℃, λ = 250nm), t R (major)=18.52min,t R (minor) = 17.41min.[α] D 15 =-1.43°(c=0.16,CHCl3).

[0072] Example 12

[0073] Synthesis of compound 12

[0074] Under nitrogen conditions, nickel tetrafluoroborate hexahydrate (0.045mmol), chiral ligand L (0.06mmol), N,N-dimethylformamide (0.72mL) and 1,3-dimethyl-2-imidazolidinone (0.18mL), manganese powder (0.9mmol) were added to a 10mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30min. The catalyst was started, and substrate 1a (0.3mmol), aromatic substrate 7b (0.45mmol), alkyl substrate 12c (0.6mmol) were added in sequence, and N,N-dimethylformamide (0.4mL) was added. The reaction mixture was placed at 30℃ for 48h. After the reaction was completed, the product 12 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 75% (95:5er). 1H NMR(400MHz,CD2Cl2)δ9.20(brs,1H),8.29(dd,J=4.2,1.7Hz,1H),8.23–8.10(m,1H),7.67(dd,J=8.3,1.7Hz,1H),7.06–6.96(m,2H),6.95(dd,J=8.3,4.2Hz,1H),6.21(d,J=1.4Hz,1H),6.19–6.07(m,2H),4.91–4.66(m,2H),3.02(t,J=6.6Hz,2H),2.14(dd,J=13.7,6.7Hz,1H),2.03(dd,J=13.7,7.4Hz,1H),1.91(d,J=6.8Hz,2H),1.78(q,J=6.7Hz,1H),0.98(p,J=6.9Hz,2H),0.93–0.85(m,4H),0.82–0.76(m,J=7.9,4.7Hz,3H). 13 C NMR(100MHz,CD2Cl2)δ171.42,148.63,147.91,146.10,138.60,136.71,135.02,134.74,128.33,127.59,122.53,122.07,121.60,116.32,109.88,108.21,101.28,63.01,42.51,40.43,37.92,34.00,33.08,26.83,26.22.HRMS(ESI):Calcd.forC 25 H 29 N2O4[M+H] + :421.2122;Found:421.2117.IR(neat):3349,2927,2855,1681,1596,1522,1502,1485,1463,1440,1424,1386,1325,1243,1189,1038,928,826,792,759,735.HPLC analysis:The enantiomeric excess was determined on a Lux μmCellulose-1(20%iPrOH in hexane,0.8mL / min,25℃,λ=250nm),t R (major)=36.95min,t R (minor)=34.42min.[α] D 15=3.87°(c=0.17,CHCl3).

[0075] Embodiment 13

[0076] Synthesis of compound 13

[0077] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 8b (0.45 mmol), alkyl substrate 13c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 13 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 55% (95:5er). 1 H NMR(400MHz, CDCl3) δ9.73(brs,1H),8.80(dd,J=4.3,1.7Hz,1H),8.76(dd,J=7.3,1.7Hz,1H),8.16(dd,J =8.2,1.7Hz,1H),7.65–7.47(m,2H),7.45(dd,J=8.3,4.2Hz,1H),7.12–6.79(m,3H),3.60(t,J=6.6Hz,2H ),2.71(dd,J=13.6,6.3Hz,1H),2.59(dd,J=13.6,7.1Hz,1H),2.47(dd,J=6.6,4.7Hz,2H),2.43–2.34(m, 1H),2.18(brs,3H),2.16(s,3H),1.68(brs,1H),1.60–1.50(m,2H),1.49–1.40(m,4H),1.40–1.31(m,2H). 13 C NMR (100MHz, CDCl3)171.56,148.20,138.38,137.74,136.51,136.45,134.59,134.17,130.78,129.61,128.04,127.56,126 .87,121.69,121.47,116.50,63.01,42.52,40.04,37.32,33.81,32.78,26.63,25.94,19.86,19.40.HRMS(ESI):Calcd.for C 26 H33 N2O2[M+H] + :405.2537; Found:405.2533.IR(neat):3352,2928,2856,1682,1596,1578,1522,1485,1461,1424,1385,1325,1154,1052,1021,826,792,757.HPLC analysis:The enantiomeric excess was determined on a AD-H (15% iPrOH in hexane, 0.8mL / min, 25℃, λ = 250nm), t R (major)=18.89min,t R (minor) = 17.14min.[α] D 15 =2.16°(c=0.12,CHCl3).

[0078] Embodiment 14

[0079] Synthesis of compound 14

[0080] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 9b (0.45 mmol), alkyl substrate 14c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 14 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1), and the yield was 59% (95.5:4.5er). 1H NMR(400MHz,CDCl3)δ9.74(s,1H),8.78(ddd,J=9.0,5.8,1.7Hz,2H),8.15(dd,J=8.3,1.7Hz,1H),7.58–7.40(m,4H),7.22(d,J=8.4Hz,1H),7.11(dd,J=8.4,1.6Hz,1H),6.99(d,J=3.1Hz,1H),6.39(d,J=3.0Hz,1H),3.74(s,3H),3.59(t,J=6.6Hz,2H),2.87(dd,J=13.6,6.0Hz,1H),2.76(dd,J=13.6,6.5Hz,1H),2.60–2.37(m,3H),1.63–1.50(m,4fH),1.48–1.46(m,3H),1.31–1.31(m,2H). 13 C NMR(100MHz,CDCl3)δ171.75,148.17,138.38,136.47,135.54,134.63,131.08,128.95,128.62,128.02,127.56,123.42,121.66,121.39,121.30,116.49,109.09,100.56,63.05,42.58,40.56,37.87,33.71,32.96,32.79,26.68,25.94.HRMS(ESI):Calcd.for C 27 H 31 N3O2[M+H] + :430.2489;Found:430.2489.IR(neat):3350,2927,2855,1680,1596,1522,1485,1463,1424,1386,1326,1244,1155,1078,826,792,722,687.HPLC analysis:The enantiomeric excess wasdetermined on a Lux μm Cellulose-1(35%iPrOH in hexane,0.8mL / min,25℃,λ=250nm),t R (major)=17.35min,t R (minor)=15.36min.[α] D 15 =2.71°(c=0.12,CHCl3).

[0081] Embodiment 15

[0082] Synthesis of compound 15

[0083] Under nitrogen, nickel tetrafluoroborate hexahydrate (0.045 mmol), chiral ligand L (0.06 mmol), N,N-dimethylformamide (0.72 mL) and 1,3-dimethyl-2-imidazolidinone (0.18 mL), manganese powder (0.9 mmol) were added to a 10 mL reaction bottle in sequence, and the mixture was stirred evenly at room temperature for 30 min. The catalyst was started, and substrate 1a (0.3 mmol), aromatic substrate 10b (0.45 mmol), alkyl substrate 15c (0.6 mmol) were added in sequence, and N,N-dimethylformamide (0.4 mL) was added. The reaction mixture was placed at 30 ° C for 48 h. After the reaction was completed, the product 15 was directly separated by chromatography (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 61% (90:10er). 1 H NMR(400MHz, CDCl3) δ9.66(brs,1H),8.73(dd,J=7.3,1.9Hz,1H),8.66(dd,J=4.3,1.7Hz, 1H),8.10(dd,J=8.3,1.7Hz,1H),8.00(d,J=7.8Hz,1H),7.92(s,1H),7.59–7.28(m,6H),7. 17(t,J=7.4Hz,1H),3.73(s,3H),3.60(t,J=6.5Hz,2H),3.00–2.91(m,1H),2.88–2.77(m, 1H),2.52(s,3H),1.64(brs,1H),1.59–1.54(m,2H),1.51–1.48(m,4H),1.41–1.34(m,2H). 13 C NMR (100MHz, CDCl3) δ171.56,148.01,141.10,139.61,138.14,136.22,1 34.47,130.63,127.83,127.35,127.25,125.45,122.73,122.55,121.52 ,121.23,120.82,120.28,118.58,116.25,108.30,108.22,62.95,42.60 ,40.65,37.90,33.94,32.70,29.01,26.62,25.86.HRMS(ESI):Calcd.for C 31 H 33 N3O2[M+H] +:480.2646; Found:480.2647.IR(neat):3350,3049,2929,2855,1679,1597,1522,1484,1472,1 424,1386,1359,1324,1264,1247,1151,1122,1059,1022,826,792,730,701.HPLCanalysis:The enantiomeric excess was determined on a AD-H(30%iPrOH inhexane,0.7mL / min,25℃,λ=250nm),t R (major)=18.89min,t R (minor) = 17.14min.[α] D 15 =3.23°(c=0.12,CHCl3).

[0084] The raw materials and product structural formulas of Examples 1 to 15 and the corresponding experimental results are shown in Table 1 below:

[0085] Raw materials 1 (substrate 1a) are:

[0086] Table 1

[0087]

[0088]

[0089]

[0090] Example 16

[0091] The preparation method of Example 16 is the same as that of Example 1, except that: the nickel is nickel chloride, and the cheap metal element is zinc; the organic solvent is methanol; the molar ratio of the olefin, halogenated aromatic hydrocarbon, halogenated alkane, nickel, and cheap metal element is 1:1:10.1:2; the reaction temperature is 30°C, and the reaction time is 96 hours.

[0092] Embodiment 17

[0093] The preparation method of Example 17 is the same as that of Example 1, except that: the nickel is anhydrous nickel bromide; the cheap metal element is magnesium gold; the organic solvent is isopropanol; the molar ratio of the olefin, halogenated aromatic hydrocarbon, halogenated alkane, nickel, and cheap metal element is 1:2:2:0.2:3, the reaction temperature is 60°C, and the reaction time is 48 hours.

[0094] Embodiment 18

[0095] The preparation method of Example 18 is the same as that of Example 1, except that the organic solvent is selected from N-methylpyrrolidone.

[0096] Embodiment 19

[0097] The preparation method of Example 19 is the same as that of Example 1, except that the organic solvent is selected from a mixed solvent of N,N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone.

[0098] Comparative Example 1

[0099] The method of Comparative Example 1 is the same as that of Example 1, except that no nickel catalyst is added and the yield of the target product is 0.

[0100] Comparative Example 2

[0101] The method of Comparative Example 2 is the same as that of Example 1, except that no manganese reducing agent is added and the yield of the target product is 0.

[0102] Comparative Example 3

[0103] The method of Comparative Example 3 is the same as that of Example 1, except that the chiral oxazoline ligand L(S)-iBuPHOX is not added, and the ee value of the target product is 0.

[0104] Comparative Example 4

[0105] The method of Comparative Example 4 is the same as that of Example 1, except that no mixed solvent is added, and the yield and ee value of the target product are both reduced.

[0106] Comparative Example 5

[0107] The method of Comparative Example 5 is the same as that of Example 1, except that: the 8-aminoquinoline directing group is removed (the enyl acid is used directly), no reaction occurs, the yield of the target product is 0, and the actual substrate 1a is the condensation product of AQ and the enyl acid.

[0108] Comparative Example 6

[0109] The method of Comparative Example 6 is the same as that of Example 1, except that the chiral oxazoline ligand L(S)-iBuPHOX is replaced with other chiral bidentate phosphine ligands, such as (R,R)-DACH-phenyl Trost ligand, (R,R)-ANDEN-phenyl Trost ligand, (S,S)-DACH-phenyl Trost ligand, and the ee value of the target product is 0.

[0110] Comparative Example 7

[0111] The method of Comparative Example 7 is the same as that of Example 1, except that the chiral oxazoline ligand L(S)-iBuPHOX is replaced with other chiral diamine ligands, such as (R,R)-DACH-pyridyl Trost ligand, [2,2'-bipyridine]-4-amine, 6-chloro-3,4-bipyridine-2-amine, and the ee value of the target product is 0.

[0112] Comparative Example 8

[0113] Comparative Example 8 is the same as the method of Example 1, except that the chiral oxazoline ligand L is replaced with other chiral biphenyl bisphosphine ligands such as (S)-(6,6-dimethoxybiphenyl-2,2-diyl)bis(diisopropylphosphine), and the ee value of the target product is 0. In addition, the chiral oxazoline ligand L is replaced with other chiral spirocyclic phosphine ligands such as (R)-(+)-7,7'-bis(diphenylphosphine)-2,2',3,3'-tetrahydro-1,1'-spirocyclic indane or chiral phosphate ligands such as (S)-3-(1-hydroxy-3-phenylpropane-2-yl)-1-methyltriacyl-4,5-dihydro-1H-imidazole-3-ammonium hexafluorophosphate (V), and the ee value of the target product is 0.

[0114] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. The various nickel catalysts in the present invention can theoretically coordinate with olefins with a guiding function to form active nickel catalyst species, which is conducive to the smooth progress of the reaction; the modification of the substituent only affects the reaction to a certain extent, and does not play a decisive role in the occurrence of the reaction. It is not difficult for any technician familiar with this profession to understand that without departing from the scope of the technical solution of the present invention, changes or modifications can be made to obtain corresponding embodiments. For example, the substituents can be replaced, changed or modified within the scope of the present invention, and the method of the present invention can be realized. However, any modification, modification or equivalent and equivalent changes made to the above embodiments according to the present invention without departing from the purpose of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for the asymmetric aryl alkylation of three-component non-activated olefins catalyzed by nickel, characterized in that: The method comprises the following steps: in a solvent, using halogenated alkanes and halogenated aromatics as electrophilic reagents, transition metal nickel as a catalyst, and a cheap metal element as a reducing agent, reacting with non-activated olefins under the action of a chiral ligand to obtain a 1,2-aryl alkylation product, and simultaneously constructing C(sp3)-C(sp3) and C(sp3)-C(sp2) bonds; the general reaction formula is as follows: ； In the formula: AQ in 1a is 8-aminoquinoline; Ar1X represents halogenated aromatic hydrocarbon, R1X represents halogenated alkane, and Chiral ligands represent chiral ligands; The X is bromine or iodine; the Ar1 is a substituent on the halogenated aromatic hydrocarbon, Ar1 is an aryl group containing any substituent; the R1 is a substituent on the halogenated alkane, and the substituents are independently selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, amine or cyano; The chiral ligand is (S)- i BuPHOX; The nickel is selected from nickel chloride, anhydrous nickel bromide, hydrated nickel bromide, nickel iodide, nickel carbonate, bis-(1,5-cyclooctadiene) nickel, nickel chloride ethylene glycol dimethyl ether complex, nickel bromide ethylene glycol dimethyl ether complex, (2,2'-bipyridine) nickel dibromide, dibromo(1,10-phenanthroline) nickel, chlorobistrihexyl phosphate nickel salt, bis(triphenylphosphine) nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, (1,1'-bis( Any one of bis(diphenylphosphino)ferrocene)nickel dichloride, nickel bromide diethylene glycol dimethyl ether complex, nickel acetylacetonate, nickel trifluoromethanesulfonate, nickel bis(2,2,6,6,-tetramethyl-3,5-heptanedione), nickel bis(hexafluoroacetylacetonate), nickel perchlorate, nickel p-toluenesulfonate, 1,3-bis(diphenylphosphinopropane)nickel dichloride, nickel tetrafluoroborate hexahydrate, bis(triphenylphosphine)nickel dibromide, and nickel dibromide bis(tributylphosphine); The cheap metal element is selected from manganese.

2. The method for the asymmetric aryl alkylation of three-component non-activated olefins catalyzed by nickel according to claim 1, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, 1,3-propylene glycol, glycerol, n-butanol, isobutanol, tert-butanol, trifluoroethanol, 2-methyl-2-butanol, 3-methoxybutanol, sec-butanol, tert-amyl alcohol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, 3-pentanol, cyclopentanol, n-pentanol, polyethylene glycol 200-10000, acetonitrile, benzonitrile, toluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropylene urea, N-methylpyrrolidone, ethyl acetate, 1,4-dioxane, tetrahydrofuran or 1,3-dimethyl-2-imidazolidinone.

3. The method for the asymmetric aryl alkylation of three-component non-activated olefins catalyzed by nickel according to claim 1, characterized in that: The molar ratio of the olefin, halogenated aromatic hydrocarbon, halogenated alkane, nickel and cheap metal element is: 1:(1-2):(1-2):(0.1-0.2):(2-3).

4. The method for the nickel-catalyzed asymmetric aryl alkylation of non-activated olefins according to claim 1, characterized in that: The reaction temperature is 30-60°C and the reaction time is 48-96 hours.

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