Method for asymmetric arylation of alpha-site C-H bond of palladium-catalyzed amine

Abstract

The method comprises the following steps: by taking aryl bromide (I) and imine (II) as raw materials and transition metal palladium as a catalyst, carrying out an intermolecular coupling reaction in an organic solvent in the presence of a chiral monophosphine ligand and alkali, so as to obtain the asymmetric arylation of the alpha-position C-H bond of the palladium-catalyzed amine, namely the asymmetric arylation of the alpha-position C-H bond of the palladium-catalyzed amine. Reducing and purifying to obtain an alpha-position asymmetric arylation compound (III) of amine; wherein Flu is # imgabs0; R1 and R2 are independently selected from halogen, hydrogen, nitro, alkyl and alkoxy; r is selected from hydrogen, alkyl, aryl and heteroaryl; x is halogen or an-OTf group; and Ar is substituted or unsubstituted aryl or heteroaryl. The invention opens up a new way for synthesizing a series of alpha-chiral arylamine with excellent enantioselectivity and high yield, and can be applied to synthesis of drug molecules. # imgabs1 #

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for asymmetric arylation of α-position CH bonds of amines catalyzed by palladium. Background Art

[0002] Chiral amines are important intermediates for the synthesis of pharmaceuticals, fine chemicals, and agrochemicals. It is worth noting that about 40% of commercially available chiral drugs use chiral amines as their structural cornerstones (Wood, A et al. Nat. Chem. 2018, 10, 383.), among which chiral α-aryl substituted amines are particularly common.

[0003] Over the past two decades, CH functionalization has emerged as a very effective and straightforward method for α-chiral amines. Yu Jinquan and co-workers elucidated the directing group for the asymmetric α-CH arylation reaction between secondary amines and arylboronic acids under oxidative conditions through a Pd(II) / Pd(0) catalytic cycle (Yu.J.-Q et al. Nat.Chem. 2017, 9, 140.). The success of the reaction depends on the coordination of sulfamide to Pd(II), promoting subsequent CH activation and forming a key palladium ring intermediate. Martin and co-workers recently combined nickel catalysts and visible light to produce α-carbon radical intermediates for α-position CH arylation of amines through photoredox catalysis (Martin, R et al. ACS Catal. 2020, 10, 4671.).

[0004] Although there are many chemical methods (e.g., El-Shazly, M et al. Adv. Synth. Catal. 2010, 352, 753, etc.) that can be used to prepare these α-aryl substituted amines, the pursuit of new strategies remains at the core of progress in organic synthesis and provides a new paradigm for molecular assembly. Summary of the invention

[0005] The invention provides a method for palladium-catalyzed asymmetric arylation of the α-position CH bond of an amine, which generates chiral α-aryl substituted amines with excellent enantioselectivity and medium-to-high yield.

[0006] The technical solution of the present invention is as follows:

[0007] A method for palladium-catalyzed asymmetric arylation of the α-position CH bond of an amine, comprising: using an aryl bromide (I) and an imine (II) as raw materials, using transition metal palladium as a catalyst, carrying out an intermolecular coupling reaction in an organic solvent in the presence of a chiral monophosphine ligand and a base, and then reducing and purifying to obtain a compound (III) with asymmetric arylation of the α-position of the amine;

[0008]

[0009] in:

[0010] Flu R1 and R2 are independently selected from halogen, hydrogen, nitro, alkyl, alkoxy;

[0011] R is selected from hydrogen, alkyl, aryl, heteroaryl;

[0012] X is a halogen or an -OTf group;

[0013] Ar is a substituted or unsubstituted aryl or heteroaryl group.

[0014] The present invention uses transition metal palladium as a catalyst and a chiral monophosphine ligand to couple aryl bromide and imine, and obtains chiral α-aryl substituted amines with excellent enantioselectivity and medium to high yields after reduction. This practical transformation shows significant tolerance to a variety of functional groups, thus opening up a new way to synthesize a series of α-chiral aryl amines with excellent enantioselectivity and medium to high yields, and can be applied to the synthesis of drug molecules.

[0015] Preferably, in the aryl bromide (I), Ar is selected from substituted or unsubstituted phenyl, benzo[d][1,3]dioxolyl, carbazolyl, benzothiophenyl, indolyl; and the substituent is halogen, alkyl, alkoxy, amine, alkylthio.

[0016] Preferably, the aryl bromide (I) is selected from:

[0017]

[0018] Preferably, the imine (II) is selected from:

[0019]

[0020] Preferably, the catalyst is allylpalladium(II) chloride dimer.

[0021] Preferably, the chiral monophosphine ligand is selected from:

[0022]

[0023] Preferably, the base is at least one of potassium tert-butoxide, lithium tert-butoxide and sodium tert-butoxide.

[0024] Preferably, the organic solvent is at least one of dichloromethane, ethyl acetate, tetrahydrofuran, cyclohexane and diethyl ether.

[0025] Preferably, the molar ratio of aryl bromide (I) to imine (II) is 1:1-3; most preferably 1:2.

[0026] Preferably, the reaction temperature is 10-50°C and the reaction time is 5-36h.

[0027] After the reaction is completed, the final product is separated by column chromatography. The eluent of the column chromatography is a mixed solvent of ethyl acetate / petroleum ether, and the percentage of ethyl acetate is 5-50%.

[0028] The present invention also provides a compound (III) in which the α-position of the amine is asymmetrically arylated and prepared by the above method.

[0029] The compound (III) in which the amine is asymmetrically arylated at the α-position is selected from:

[0030]

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) In the present invention, under the catalysis of transition metal palladium, an aryl bromide and an imine undergo an intermolecular coupling reaction to obtain a compound with asymmetric arylation of the α-position of the amine, which has good functional group compatibility and high atom economy.

[0033] (2) The present invention has mild reaction conditions, simple operation and is easy to industrialize.

[0034] (3) The raw materials used in the present invention are widely available and inexpensive, which greatly reduces the preparation cost of the final product.

[0035] (4) The present invention has a wide range of applications and high practicability, and can rapidly and diversely synthesize a series of novel amine asymmetric arylation compounds at the α-position, which will be of great significance for new drug screening. DETAILED DESCRIPTION

[0036] The present invention is described in detail below through examples. It is necessary to point out here that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by technicians in this field based on the above content of the present invention all belong to the scope of protection of the present invention.

[0037] Embodiments 1 to 5

[0038] Examples 1 to 5 use aryl bromide I-1 and fluorenyl protected imine II-1 as raw materials, potassium tert-butoxide as base, cyclohexane as solvent, allylpalladium (II) chloride dimer as catalyst, and carry out asymmetric arylation reaction of amine at the α-position under the action of 5 different chiral monophosphine ligands. The reaction formula is as follows:

[0039]

[0040] Under nitrogen atmosphere, I-1 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 50°C for 12 hours, trimethoxybenzene (0.2 mmol) was added, and the solvent was directly distilled off under reduced pressure, and the reaction was monitored. 1 H NMR yields. The results are shown in Table 1.

[0041] Table 1: Effect of chiral monophosphine ligand on the reaction

[0042]

[0043] a. NMR yield using 1,3,5-trimethoxybenzene as internal standard

[0044] Embodiments 6 to 8

[0045] In Examples 6 to 8, aryl bromide I-1 and fluorenyl-protected imine II-1 were used as raw materials, cyclohexane was used as solvent, L5 was a chiral monophosphine ligand, and allylpalladium (II) chloride dimer was used as catalyst to cause asymmetric arylation of amine at the α-position under the action of three different bases. The reaction formula is as follows:

[0046]

[0047] Under nitrogen atmosphere, I-1 (0.4 mmol), II-1 (0.2 mmol), base (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 50°C for 12 hours, trimethoxybenzene (0.2 mmol) was added, and the solvent was directly distilled off under reduced pressure, and the reaction was monitored. 1 H NMR yields. The results are shown in Table 2.

[0048] Table 2: Effect of base on reaction

[0049]

[0050] a. NMR yield using 1,3,5-trimethoxybenzene as internal standard

[0051] Embodiments 9 to 11

[0052] Examples 9 to 11: Using aryl bromide I-1 and fluorenyl-protected imine II-1 as raw materials, potassium tert-butoxide as a base, L5 as a chiral monophosphine ligand, and allylpalladium (II) chloride dimer as a catalyst, α-position asymmetric arylation of amines was carried out in three different solvents. The reaction formula is as follows:

[0053]

[0054] Under nitrogen atmosphere, I-1 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent (2 ml) was added. After stirring at 50°C for 12 hours, trimethoxybenzene (0.2 mmol) was added, and the solvent was directly distilled off under reduced pressure, and the reaction was monitored. 1 H NMR yields. The results are shown in Table 3.

[0055] Table 3: Effect of solvent on reaction

[0056]

[0057] a. NMR yield using 1,3,5-trimethoxybenzene as internal standard

[0058] Embodiments 12 to 14

[0059] Examples 12 to 14 use aryl bromide I-1 and fluorenyl protected imine II-1 as raw materials, potassium tert-butoxide as base, cyclohexane as solvent, L5 as chiral monophosphine ligand, allylpalladium (II) chloride dimer as catalyst, and carry out asymmetric arylation reaction of amine at the α-position at different temperatures. The reaction formula is as follows:

[0060]

[0061] Under nitrogen atmosphere, I-1 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, trimethoxybenzene (0.2 mmol) was added, and the solvent was directly distilled off under reduced pressure, and the reaction was monitored. 1 H NMR yields. The results are shown in Table 4.

[0062] Table 4: Effect of temperature on reaction

[0063]

[0064] a. NMR yield using 1,3,5-trimethoxybenzene as internal standard

[0065] Embodiment 15

[0066] Under nitrogen atmosphere, I-1 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-1 with asymmetric arylation of the amine at the α-position was obtained.

[0067]

[0068] Yellow oily compound, 99% ee value, 68% yield, (0.2 mmol specification, 43 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0069] 1 H NMR (400MHz, CDCl3) δ7.58–7.52(m,2H),7.50(d,J=7.5Hz,1H),7.44(d,J=7.1Hz,1H),7.39(d,J=7.0Hz,2H),7.29–7.21(m,4H),7.21–7.1 5(m,2H),7.14–7.10(m,1H),4.55(s,1H),4.11(t,J=6.8Hz,1H),1.70(s,1H),1.63–1.48(m,2H),1.25–1.02(m,2H),0.74(t,J=7.3Hz,3H).

[0070] 13 C NMR (101MHz, CDCl3) δ147.5,146.9,144.6,140.5,140.1,128.4,128.0,127.8,127.8,127.3,1 27.1,127.0,125.3,125.2,119.9,119.6,61.2,60.9,41.4,19.6,14.1.HRMS(ESI):calculated for C 23 H 23 N[M+H] + 314.1903, found:314.1893.

[0071] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =4.2min,t minor =5.4min.

[0072] Optical rotation:

[0073] Example 16

[0074] Under nitrogen atmosphere, I-2 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-2 with asymmetric arylation of the amine at the α-position was obtained.

[0075]

[0076] Yellow oily compound, 99% ee value, 73% yield, (0.2 mmol specification, 48 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0077] 1 H NMR (400MHz, CDCl3) δ7.66(q,J=6.4Hz,3H),7.58(d,J=6.4Hz,1H),7.39(t,J=7.1Hz,2H),7.32(dt,J=14.6,7.3Hz,3H),7.23(d,J=7.5Hz,1H),7.1 9(d,J=7.5Hz,2H),4.69(s,1H),4.22(t,J=6.7Hz,1H),2.37(s,3H),1.79 (s,1H),1.68(q,J=7.6Hz,2H),1.34–1.13(m,2H),0.85(t,J=7.4Hz,3H).

[0078] 13C NMR (101MHz, CDCl3) δ147.7,147.1,141.4,140.6,140.1,136.7,129.2,128.0,127.8,127.8,127. 4,127.1,125.4,125.3,120.0,119.6,61.1,60.8,41.5,21.3,19.7,14.2.HRMS(ESI):calculated for C 24 H 25 N[M+H] + 328.2060, found:328.2052.

[0079] HPLC conditions: Daicel Chiralpak OD-H column, hexane / iPrOH (97 / 3), 1mL / min, UV=190nm:t major =4.1min,t minor =4.6min.

[0080] Optical rotation:

[0081] Embodiment 17

[0082] Under nitrogen atmosphere, I-3 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-3 with asymmetric arylation of the amine at the α-position was obtained.

[0083]

[0084] Yellow oily compound, 97% ee value, 66% yield, (0.2 mmol specification, 45 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0085] 11H NMR (400 MHz, CDCl3) δ 7.67–7.61 (m, 2H), 7.59 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.31 (dt, J = 13.5, 6.6 Hz, 3H), 7.24–7.19 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 4.65 (s, 1H), 4.16 (t, J = 6.9 Hz, 1H), 3.79 (s, 3H), 1.72 (s, 1H), 1.67–1.58 (m, 2H), 1.29–1.11 (m, 3H), 0.82 (t, J = 7.4 Hz, 3H).

[0086] 13 13C NMR (101 MHz, CDCl3) δ 147.6, 147.0, 144.7, 140.6, 140.2, 128.5, 128.1, 127.9, 127.8, 127.4, 127.2, 127.1, 125.4, 125.3, 120.0, 119.7, 77.5, 77.2, 76.8, 61.3, 61, 41.5, 19.7, 14.2.

[0087] HRMS (ESI): calculated for C 24 H 25 NO[M + H] + 344.2009, found: 344.2005.

[0088] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 202 nm: t major = 5.1 min, t minor = 6.9 min.

[0089] Optical rotation:

[0090] Example 18

[0091] Under nitrogen atmosphere, I-4 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-4 with asymmetric arylation of the amine at the α-position was obtained.

[0092]

[0093] Yellow oily compound, 97% ee value, 79% yield, (0.2 mmol specification, 59 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0094] 1 H NMR (400MHz, CDCl3) δ7.68–7.54(m,4H),7.42–7.29(m,7H),7.22(t,J=7.4Hz,1H),4.70(s,1H),4.20(t, J=6.8Hz,1H),1.80(s,1H),1.69(q,J=8.2Hz,2H),1.35(s,9H),1.31–1.14(m,2H),0.87(d,J=7.3Hz,3H).

[0095] 13 C NMR (101MHz, CDCl3) δ150.0,147.7,147.0,141.4,140.6,140.3,128.0,127.8,127.5 ,127.4,127.1,125.4,125.3,119.9,119.7,61.0,60.9,41.4,34.6,31.6,19.7,14.2.

[0096] HRMS(ESI):calculated for C 27 H 31 N[M+H] + 370.2529,found:370.2522.

[0097] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=208nm:t major =3.5min,t minor =4.4min.

[0098] Optical rotation:

[0099] Embodiment 19

[0100] Under nitrogen atmosphere, I-5 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-5 with asymmetric arylation of the amine at the α-position was obtained.

[0101]

[0102] Yellow oily compound, 93% ee value, 70% yield, (0.2 mmol specification, 50 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0103] 1 H NMR (400MHz, CDCl3) δ7.67(t,J=8.4Hz,3H),7.58(d,J=5.8Hz,1H),7.40(d,J=8.4Hz,2H),7.35(t,J=7.4Hz,2H),7.29(d,J=6.6Hz,1H),7.25(d,J=7 .5Hz,1H),6.79(d,J=8.6Hz,2H),4.70(s,1H),4.20(t,J=6.9Hz,1H),1.7 9(s,1H),1.67(q,J=7.4Hz,2H),1.35–1.15(m,2H),0.85(t,J=7.4Hz,3H).

[0104] 13C NMR (101MHz, CDCl3) δ150.0,148.0,147.3,140.6,140.1,132.2,128.6,127.9,127.8, 127.4,127.1,125.4,125.3,120.0,119.6,112.8,60.9,60.7,41.5,40.9,19.8,14.2.

[0105] HRMS(ESI):calculated for C 25 H 28 N2[M+H] + 357.2325, found:357.2320.

[0106] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=203nm:t major =4.7min,t minor =6.1min.

[0107] Optical rotation:

[0108] Embodiment 20

[0109] Under nitrogen atmosphere, I-6 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-6 with asymmetric arylation of the amine at the α-position was obtained.

[0110]

[0111] Yellow oily compound, 97% ee value, 55% yield, (0.2 mmol specification, 39 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0112] 11H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.2, 3.8 Hz, 2H), 7.50–7.44 (m, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.24 (tt, J = 10.4, 6.8 Hz, 3H), 7.19–7.10 (m, 3H), 4.56 (s, 1H), 4.07 (t, J = 6.8 Hz, 1H), 2.41 (s, 3H), 1.69 (s, 1H), 1.61–1.50 (m, 2H), 1.19–1.05 (m, 2H), 0.75 (t, J = 7.4 Hz, 3H).

[0113] 13 13C NMR (101 MHz, CDCl3) δ 147.4, 146.8, 141.7, 140.6, 140.2, 136.8, 128.4, 128.1, 127.9, 127.4, 127.1, 127.0, 125.3, 125.3, 120.0, 119.7, 61.0, 60.8, 41.4, 19.6, 16.3, 14.2.

[0114] HRMS (ESI): calculated for C 24 H 25 NS [M+H] + 360.1780, found: 360.1776.

[0115] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 204 nm: t major =4.9 min, t minor =6.2 min.

[0116] Optical rotation:

[0117] Example 21

[0118] Under nitrogen atmosphere, I-7 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-7 with asymmetric arylation of the amine at the α-position was obtained.

[0119]

[0120] Yellow oily compound, 95% ee value, 69% yield, (0.2 mmol specification, 53 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0121] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=7.4Hz,2H),7.59(d,J=6.9Hz,2H),7.51(d,J=8.0Hz,2H),7.46(d,J=7.6Hz,2H),7.38–7.29(m,3H),7.21(t,J=7.5Hz ,1H),4.70(s,1H),4.20(t,J=6.8Hz,1H),1.85(s,1H),1.68(m,J=7.3Hz,2 H), 1.24 (m, J = 30.6, 14.8, 7.3Hz, 2H), 0.85 (t, J = 7.4Hz, 3H), 0.29 (s, 9H).

[0122] 13 C NMR (101MHz, CDCl3) δ147.5,147.0,145.2,140.6,140.3,139.0,133.5,128.1,12 7.8,127.4,127.3,127.1,125.4,120.0,119.7,61.3,61.0,41.4,19.7,14.2,0.0.

[0123] HRMS(ESI):calculated for C 26 H 31 NSi[M+H] +386.2299, found:386.2291.

[0124] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=190nm:t major =3.4min,t minor =4.2min.

[0125] Optical rotation:

[0126] Embodiment 22

[0127] Under nitrogen atmosphere, I-8 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-8 with asymmetric arylation of the amine at the α-position was obtained.

[0128]

[0129] Yellow oily compound, 99% ee value, 64% yield, (0.2 mmol specification, 44 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0130] 1 H NMR(400MHz, CDCl3)δ7.66(d,J=7.4Hz,2H),7.53(t,J=8.1Hz,2H),7.41–7.28(m,7H),7.20(t,J=7.5Hz,1H), 4.64(s,1H),4.12(t,J=6.8Hz,1H),1.81(s,1H),1.69–1.53(m,2H),1.36–1.08(m,2H),0.83(t,J=7.3Hz,3H).

[0131] 13C NMR (101MHz, CDCl3) δ147.1,146.6,143.3,140.6,140.3,132.6,129.2,128.6,128 .2,127.9,127.5,127.1,125.3,125.3,120.0,119.7,61.1,60.4,41.4,19.6,14.1.

[0132] HRMS(ESI):calculated for C 23 H 22 NCl[M+H] + 348.1514, found:348.1508.

[0133] HPLC conditions: Daicel Chiralpak OD-H column, hexane / iPrOH (97 / 3), 1mL / min, UV=190nm:t major =6.3min,t minor =11.5min.

[0134] Optical rotation:

[0135] Embodiment 23

[0136] Under nitrogen atmosphere, I-9 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-9 with asymmetric arylation of the amine at the α-position was obtained.

[0137]

[0138] Yellow oily compound, 97% ee value, 62% yield, (0.2 mmol specification, 50 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0139] 11H NMR (400 MHz, CDCl3) δ 7.66 (t, J = 6.8 Hz, 2H), 7.60 (s, 2H), 7.38–7.29 (m, 7H), 7.22 (t, J = 7.7 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 7.8 Hz, 2H), 6.94 (s, 2H), 4.75 (s, 1H), 4.12 (t, 1H), 1.73–1.54 (m, 2H), 1.30–1.09 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H).

[0140] 13 13C NMR (101 MHz, CDCl3) δ 157.6, 156.1, 147.3, 146.7, 140.5, 140.2, 139.6, 129.7, 129.0, 128.0, 127.8, 127.3, 127.0, 125.3, 125.3, 123.1, 119.9, 119.6, 118.9, 118.7, 61.1, 60.4, 41.4, 19.6, 14.1.

[0141] HRMS (ESI): calculated for C 29 H 27 NO[M + H] + 406.2165, found: 406.2160.

[0142] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 209 nm: t major = 4.9 min, t minor = 6.7 min.

[0143] Optical rotation:

[0144] Example 24

[0145] Under nitrogen atmosphere, I-10 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-10 with asymmetric arylation of the amine at the α-position was obtained.

[0146]

[0147] Yellow oily compound, 95% ee value, 63% yield, (0.2 mmol specification, 45 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0148] 1 H NMR (400MHz, CDCl3) δ7.65(t,J=6.8Hz,2H),7.58(s,1H),7.54–7.44(m,1H),7.37(t,J=7.8Hz,1H),7.32(d,J=11.0Hz,3H),7.26(s,3H), 7.20(t,J=7.4Hz,1H),4.70(s,1H),4.17(t,1H),2.02(s,1H),1.79–1.60(m,2H),1.35(s,9H),1.30–1.15(m,3H),0.84(t,J=7.3Hz,3H).

[0149] 13 C NMR (101MHz, CDCl3) δ151.7,151.1,143.9,143.0,141.6,140.6,128.1,127.7,127.3,12 7.1,126.0,125.2,124.9,124.6,119.8,119.7,61.2,60.8,38.2,34.7,31.5,19.5,13.9.

[0150] HRMS(ESI):calculated for C 27 H 31 N[M+H] +370.2529,found:370.2523.

[0151] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=205nm:t major =3.5min,t minor =3.9min.

[0152] Optical rotation:

[0153] Embodiment 25

[0154] Under nitrogen atmosphere, I-11 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-11 with asymmetric arylation of the amine at the α-position was obtained.

[0155]

[0156] Yellow oily compound, 95% ee value, 60% yield, (0.2 mmol specification, 41 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0157] 11H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 7.1, 4.4 Hz, 2H), 7.60 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.39–7.27 (m, 4H), 7.22 (t, J = 7.4 Hz, 1H), 7.07 (s, 2H), 6.81 (d, J = 8.9 Hz, 1H), 4.67 (s, 1H), 4.19 (t, J = 6.8 Hz, 1H), 3.85 (s, 3H), 1.75 (s, 1H), 1.65 (q, J = 7.6 Hz, 2H), 1.23 (dp, J = 32.8, 7.2 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H).

[0158] 13 13C NMR (101 MHz, CDCl3) δ 159.9, 147.5, 146.9, 146.4, 140.6, 140.2, 129.4, 128.1, 127.9, 127.5, 127.1, 125.4, 120.4, 120.0, 119.7, 113.3, 112.5, 61.3, 61.0, 55.3, 41.5, 19.7, 14.2.

[0159] HRMS (ESI): calculated for C 24 H 25 NO[M + H] + 344.2009, found: 344.2006.

[0160] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 190 nm: t major = 4.7 min, t minor = 6.6 min.

[0161] Optical rotation:

[0162] Example 26

[0163] Under nitrogen atmosphere, I-12 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-12 with asymmetric arylation of the amine at the α-position was obtained.

[0164]

[0165] Yellow oily compound, 95% ee value, 52% yield, (0.2 mmol specification, 36 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0166] 1 H NMR (400MHz, CDCl3) δ7.68(dd,J=7.3,3.1Hz,2H),7.59(d,J=6.8Hz,1H),7.54(d,J=7.4Hz,1H),7.45(s,1H),7.40(t,J=6.6Hz,1H),7.34(t,J=7.4Hz,2 H),7.32–7.27(m,2H),7.25–7.20(m,2H),4.70(s,1H),4.11(t,J=6.9Hz,1H ),1.82(s,1H),1.71–1.60(m,2H),1.29–1.12(m,2H),0.86(t,J=7.4Hz,3H).

[0167] 13 C NMR (101MHz, CDCl3) δ147.2,147.0,146.5,140.6,140.4,134.3,129.7,128.2,128.0,127 .5,127.3,127.1,126.0,125.4,125.3,124.6,120.0,119.7,61.3,60.5,41.3,19.6,14.1.

[0168] HRMS(ESI):calculated for C 23 H 22 NCl[M+H]+ 348.1514, found:348.1506.

[0169] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=207nm:t major =4.1min,t minor =5.3min.

[0170] Optical rotation:

[0171] Embodiment 27

[0172] Under nitrogen atmosphere, I-13 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-13 with asymmetric arylation of the amine at the α-position was obtained.

[0173]

[0174] Yellow oily compound, 94% ee value, 52% yield, (0.2 mmol specification, 40 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0175] 1 H NMR (400MHz, CDCl3) δ7.55(q,J=7.5Hz,3H),7.44(dd,J=15.1,7.5Hz,2H),7.36(dd,J=8.1,4.4Hz,2H),7.31–7.22(m,3H),7.17(d,J=8.3Hz ,1H),7.04(t,J=7.4Hz,1H),4.59(s,1H),3.99(t,J=6.9Hz,1H),1.74(s,1H),1.63–1.47(m,2H),1.19–1.01(m,2H),0.74(t,J=7.3Hz,3H).

[0176] 13 C NMR (101MHz, CDCl3) δ146.7,146.2,140.5,131.2,130.8,130.5,128.7,128.3,127.9,127.5,127.1,125.8,125.4, 125.2(m,J=271.4Hz),124.6(q,J=3.8Hz),123.9(q,J=4.0Hz),123.1,120.0,119.8,61.4,60.3,41.3,19.6,14.1.

[0177] 19 F NMR (376MHz,CDCl3)δ-62.41.

[0178] HRMS(ESI):calculated for C 24 H 22 NF3[M+H] + 382.1777, found:382.1771.

[0179] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =3.9min,t minor =4.7min.

[0180] Optical rotation:

[0181] Embodiment 28

[0182] Under nitrogen atmosphere, I-14 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-14 with asymmetric arylation of the amine at the α-position was obtained.

[0183]

[0184] Yellow oily compound, 94% ee value, 52% yield, (0.2 mmol specification, 40 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0185] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.5Hz,2H),7.49–7.42(m,2H),7.28(t,J=6.7Hz,1H),7.14–7.07(m,3H),6.88–6.81(m,1H ),4.58(s,1H),4.06(t,J=6.8Hz,1H),1.74(s,1H),1.54(td,J=11.3,5.7Hz,2H),1.22–1.04(m,2H),0.75(t,J=7.4Hz,3H).

[0186] 13 C NMR (101MHz, CDCl3) δ163.3 (d, J = 245.3Hz), 147.8, 147.7, 147.1, 146.6, 140.6, 140.3, 129.8, 129.8, 128.2, 127.9, 127 .5,127.1,125.4,123.6,120.0,119.7,114.6,114.3(dd,J=44.7,21.3Hz),114.1,113.9,61.1,60.6,41.4,19.6,14.1.

[0187] 19 F NMR (376MHz,CDCl3)δ-113.57.

[0188] HRMS(ESI):calculated for C 23 H 22 NF[M+H] + 332.1809, found:332.1802.

[0189] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=203nm:t major =4.1min,t minor =5.5min.

[0190] Optical rotation:

[0191] Embodiment 29

[0192] Under nitrogen atmosphere, I-15 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-15 with asymmetric arylation of the amine at the α-position was obtained.

[0193]

[0194] Yellow oily compound, 95% ee value, 63% yield, (0.2 mmol specification, 47 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0195] 1 H NMR (400MHz, CDCl3) δ7.63(dd,J=14.8,7.1Hz,4H),7.40–7.28(m,3H),7.22(t,J=6.8Hz,1H),6.63(s,2H),6.34(s, 1H),4.73(s,1H),4.11(t,J=6.9Hz,1H),3.82(s,6H),1.73–1.61(m,2H),1.33–1.13(m,3H),0.83(t,J=7.3Hz,3H).

[0196] 13 C NMR (101MHz, CDCl3) δ160.9,147.3,146.8,140.6,140.3,128.1,127.9,127.4 ,127.1,125.4,120.0,119.7,105.8,99.0,61.4,61.0,55.5,41.3,19.7,14.2.

[0197] HRMS(ESI):calculated for C 25 H 27 NO2[M+H] +374.2115, found:374.2110.

[0198] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=202nm:t major =5.2min,t minor =8.5min.

[0199] Optical rotation:

[0200] Embodiment 30

[0201] Under nitrogen atmosphere, I-16 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-16 with asymmetric arylation of the amine at the α-position was obtained.

[0202]

[0203] Yellow oily compound, 98% ee value, 53% yield, (0.2 mmol specification, 38 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0204] 1 H NMR (400MHz, CDCl3) δ7.65(dd,J=7.4,3.6Hz,4H),7.37(t,J=7.1Hz,1H),7.32(t,J=7.4Hz,2H),7.22(t,J=7.3Hz,1H),7.01(s,1H),6.81(s ,1H),6.72(d,J=8.1Hz,1H),5.93(s,2H),4.76(s,1H),4.08(t,J=7.6Hz,1H),1.75–1.59(m,2H),1.25–1.05(m,3H),0.83(t,J=7.3Hz,3H).

[0205] 13 C NMR (101MHz, CDCl3) δ147.9,146.7,140.6,128.3,127.9,127.5,127.1,125 .6,121.4,120.0,119.7,108.0,107.9,101.0,60.9,60.8,41.1,19.6,14.1.

[0206] HRMS(ESI):calculated for C 24 H 23 NO2[M+H] + 358.1802, found:358.1797.

[0207] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=202nm:t major =5.2min,t minor =7.3min.

[0208] Optical rotation:

[0209] Embodiment 31

[0210] Under nitrogen atmosphere, I-17 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-17 with asymmetric arylation of the amine at the α-position was obtained.

[0211]

[0212] Yellow oily compound, 91% ee value, 65% yield, (0.2 mmol specification, 49 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0213] 1 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.0, 2.7 Hz, 2H), 7.54 (t, J = 7.3 Hz, 2H), 7.44 (s, 1H), 7.36 (t, J = 6.6 Hz, 1H), 7.31 (t, J = 7.3 Hz, 2H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.66 (s, 1H), 4.06 (t, J = 6.8 Hz, 1H), 1.83 (s, 1H), 1.60 (q, J = 8.2 Hz, 2H), 1.29–1.11 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H).

[0214] 13 13C NMR (101 MHz, CDCl3) δ 154.0, 147.3, 146.6, 140.5, 140.3, 138.0, 129.5, 128.1, 127.9, 127.5, 127.1, 127.1, 125.3, 122.4, 120.0, 119.7, 112.0, 61.1, 60.1, 56.3, 41.4, 19.6, 14.1.

[0215] HRMS (ESI): calculated for C 24 H 24 NOCl [M + H] + 378.1619, found: 378.1603.

[0216] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 209 nm: t major = 5.6 min, t minor = 9.1 min.

[0217] Optical rotation:

[0218] Example 32

[0219] Under nitrogen atmosphere, I-18 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-18 with asymmetric arylation of the amine at the α-position was obtained.

[0220]

[0221] Yellow oily compound, 99% ee value, 58% yield, (0.2 mmol specification, 48 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0222] 1 H NMR (400MHz, CDCl3) δ8.21(s,1H),8.15(d,J=7.1Hz,1H),7.71(d,J=7.3Hz,1H),7.65(t,J=8.5Hz,3H),7.58(s,1H),7.49(t,J=8.3Hz,1H),7.45–7. 38(m,3H),7.36–7.27(m,4H),7.24(s,1H),4.73(s,1H),4.43(s,1H),3.8 6(s,3H),1.79(d,J=7.8Hz,2H),1.34–1.18(m,2H),0.85(t,J=7.3Hz,3H).

[0223] 13 C NMR (101MHz, CDCl3) δ147.9,147.2,141.4,140.6,140.2,135,128,127.8,127.5,127.1,125.7,125.4 ,125.3,122.9,122.8,120.4,120,119.7,119.6,118.9,108.5,108.5,61.8,61,42,29.3,19.9,14.2.

[0224] HRMS(ESI):calculated for C 30 H 28N2[M+H] + 417.2325, found:417.2319.

[0225] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=205nm:t major =9.1min,t minor =15.8min.

[0226] Optical rotation:

[0227] Embodiment 33

[0228] Under nitrogen atmosphere, I-19 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-19 with asymmetric arylation of the amine at the α-position was obtained.

[0229]

[0230] Yellow oily compound, 94% ee value, 47% yield, (0.2 mmol specification, 35 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0231] 1 H NMR (400MHz, CDCl3) δ7.93–7.87(m,2H),7.64(dd,J=11.1,7.3Hz,3H),7.60–7.53(m,2H),7.45(d,J=5.5Hz,1H),7.37–7.28(m,4H),7. 21(t,J=7.0Hz,1H),4.69(s,1H),4.35(t,J=6.9Hz,1H),1.86(s,1H),1.73(m,J=7.3Hz,2H),1.35–1.15(m,2H),0.85(t,J=7.3Hz,3H).

[0232] 13 C NMR (101MHz, CDCl3) δ147.6,146.9,140.9,140.6,140.2,139.9,138.6,128.1,127.8,127.4,127 .1,126.6,125.4,125.3,124.3,123.9,123.1,122.6,120.0,119.7,61.3,61.0,41.7,19.7,14.2.

[0233] HRMS(ESI):calculated for C 25 H 23 NS[M+H] + 370.1624, found:370.1620.

[0234] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=203nm:t major =5.2min,t minor =7.0min.

[0235] Optical rotation:

[0236] Embodiment 34

[0237] Under nitrogen atmosphere, I-20 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-20 with asymmetric arylation of the amine at the α-position was obtained.

[0238]

[0239] Yellow oily compound, 99% ee value, 66% yield, (0.2 mmol specification, 48 mg product), eluent: petroleum ether containing 10% ethyl acetate. The product is characterized as follows:

[0240] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=7.8Hz,2H),7.67(d,J=8.1Hz,2H),7.49(s,1H),7.43–7.27(m,5H),7.06(s,1H), 6.51(s,1H),4.76(s,1H),4.40(t,1H),3.80(s,3H),1.90–1.66(m,2H),1.33–1.16(m,2H),0.86(t,J=7.4Hz,4H).

[0241] 13 C NMR (101MHz, CDCl3) δ147.6,140.6,140.3,136.4,129.0,128.5,128.1,127.8,127.5,127 .1,125.6,121.5,120.6,119.9,119.6,109.4,100.9,61.9,60.6,41.5,33.0,19.8,14.1.

[0242] HRMS(ESI):calculated for C 26 H 26 N2[M+H] + 367.2169, found:367.2162.

[0243] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=205nm:t major =5.9min,t minor =9.9min.

[0244] Optical rotation:

[0245] Embodiment 35

[0246] Under nitrogen atmosphere, I-21 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-21 with asymmetric arylation of the amine at the α-position was obtained.

[0247]

[0248] Yellow oily compound, 88% ee value, 78% yield, (0.2 mmol specification, 67 mg product), eluent: petroleum ether containing 10% ethyl acetate. The product is characterized as follows:

[0249] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=7.0Hz,2H),7.80–7.76(m,1H),7.66(d,J=6.8Hz,2H),7.61–7.50(m,5H),7.39–7.33(m,4H),7.32–7. 28(m,1H),7.16(t,J=7.6Hz,1H),4.72(s,1H),4.15(t,1H),1.88(s,1H),1.78–1.57(m,2H),1.30–1.14(m,2H),0.84(t,J=7.3Hz,3H).

[0250] 13 C NMR (101MHz, CDCl3) δ163.3,150.9,142.3,140.6,140.4,128.4,128.3,128.0,127.8,127.5,127 .1,125.9,125.4,125.3,125.1,124.7,120.1,120.0,119.8,110.7,61.4,60.7,41.2,19.6,14.1.

[0251] HRMS(ESI):calculated for C 30 H 26 N2O[M+H] +431.2118, found:431.2111.

[0252] HPLC conditions: Daicel Chiralpak OD-H column, hexane / iPrOH (95 / 5), 0.5mL / min, UV=202nm:t major =17.2min,t minor =19.2min.

[0253] Optical rotation:

[0254] Embodiment 36

[0255] Under nitrogen atmosphere, I-22 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-22 with asymmetric arylation of the amine at the α-position was obtained.

[0256]

[0257] Yellow oily compound, dr>20:1, 58% yield, (0.2 mmol specification, 62 mg product), eluent: petroleum ether containing 10% ethyl acetate. The product is characterized as follows:

[0258] 11H NMR (400 MHz, CDCl3) δ 7.66 (dd, J = 7.2, 3.4 Hz, 2H), 7.60 (d, J = 7.3 Hz, 1H), 7.57–7.52 (m, 1H), 7.38–7.28 (m, 5H), 7.23 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 4.69 (s, 1H), 4.15 (t, J = 6.7 Hz, 1H), 4.02 (td, J = 10.5, 4.2 Hz, 1H), 2.26 (t, J = 7.8 Hz, 1H), 2.19 (d, J = 11.6 Hz, 1H), 1.79 (s, 1H), 1.73 (d, J = 11.1 Hz, 2H), 1.65 (q, J = 8.6 Hz, 2H), 1.52 (t, J = 9.8 Hz, 2H), 1.36–1.17 (m, 2H), 1.13–0.91 (m, 10H), 0.85 (t, J = 7.3 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H).

[0259] 13 13C NMR (101 MHz, CDCl3) δ 157.5, 147.7, 147.1, 140.5, 140.2, 136.3, 128.8, 128.0, 127.7, 127.4, 127.1, 125.4, 119.9, 119.6, 115.8, 60.9, 60.7, 48.2, 41.5, 40.5, 34.7, 31.6, 26.1, 23.8, 22.3, 21.2, 20.9, 19.7, 16.7, 14.2.

[0260] HRMS (ESI): calculated for C 33 H 41 NO[M + H] + 468.3261, found: 468.3260.

[0261] Optical rotation:

[0262] Example 37

[0263] Under nitrogen atmosphere, I-23 (0.4 mmol), II-1 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-23 with asymmetric arylation of the amine at the α-position was obtained.

[0264]

[0265] Yellow oily compound, dr>20:1, 61% yield, (0.2 mmol specification, 83 mg product), eluent: petroleum ether containing 10% ethyl acetate. The product is characterized as follows:

[0266] 1H NMR(400MHz,CDCl3)δ7.65(dd,J=7.0,4.1Hz,2H),7.60(d,J=7.5Hz,1H),7.53(d,J=7.9Hz,1H),7.34(t,J=8.6Hz,4H),7.31–7.28(m,1H),7.22(td,J=7.5,1.3Hz,1H),6.89(d,J=8.6Hz,2H),4.68(s,1H),4.52(t,J=2.8Hz,1H),4.15(t,J=6.8Hz,1H),1.98(dt,J=12.3,3.3Hz,1H),1.95–1.87(m,1H),1.87–1.76(m,2H),1.69–1.65(m,3H),1.64(t,J=3.1Hz,3H),1.58–1.52(m,2H),1.49(ddd,J=18.3,4.9,2.9Hz,3H),1.40(dd,J=13.6,3.7Hz,2H),1.37–1.33(m,3H),1.29–1.27(m,1H),1.27–1.24(m,1H),1.24–1.19(m,3H),1.17–1.12(m,4H),1.10(s,1H),1.02(dd,J=11.4,5.9Hz,3H),0.92(d,J=6.5Hz,4H),0.89(d,J=1.9Hz,3H),0.87(d,J=1.9Hz,3H),0.83(t,J=3.7Hz,6H),0.67(s,3H).

[0267] 13 C NMR(101MHz,CDCl3)δ157.0,147.7,147.1,140.6,140.2,136.2,128.8,128.0,127.8,127.4,127.1,125.4,125.3,120.0,119.7,116.0,72.3,60.9,60.8,56.7,56.4,54.3,42.7,41.5,40.2,39.7,39.7,36.3,35.9,35.9,35.7,32.9,32.9,32.1,28.6,28.4,28.2,25.8,24.3,24.0,23.0,22.7,20.9,19.7,18.8,14.2,12.2,11.6.

[0268] HRMS(ESI):calculated for C 49 H 67 NO[M+H] +686.5295,found:686.5295.

[0269] Optical rotation:

[0270] Embodiment 38

[0271] Under nitrogen atmosphere, I-4 (0.4 mmol), II-2 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-24 with asymmetric arylation of the amine at the α-position was obtained.

[0272]

[0273] Yellow oily compound, 90% ee value, 88% yield, (0.2 mmol specification, 60 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0274] 1 H NMR (400MHz, CDCl3) δ7.63 (dd, J=7.4, 3.4Hz, 2H), 7.57 (d, J=7.4Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.37–7. 25(m,5H),7.23–7.18(m,1H),4.68(s,1H),4.34(q,J=6.6Hz,1H),1.70(s,1H),1.33(s,3H),1.30(s,9H).

[0275] 13 C NMR (101MHz, CDCl3) δ150.0,147.3,147.0,142.6,140.6,140.3,128.0,127.9,127 .4,127.1,126.8,125.5,125.4,125.4,120.0,119.7,61.2,55.8,34.6,31.6,25.4.

[0276] HRMS(ESI):calculated for C 25 H 27 N[M+H] + 342.2216, found:342.2211.

[0277] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =4.2min,t minor =4.6min.

[0278] Optical rotation:

[0279] Embodiment 39

[0280] Under nitrogen atmosphere, I-4 (0.4 mmol), II-3 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-25 with asymmetric arylation of the amine at the α-position was obtained.

[0281]

[0282] Yellow oily compound, 90% ee value, 88% yield, (0.2 mmol specification, 60 mg product), eluent: petroleum ether containing 5%-10% ethyl acetate. The product is characterized as follows:

[0283] 1 H NMR (400MHz, CDCl3) δ7.63 (dd, J=7.4, 3.4Hz, 2H), 7.57 (d, J=7.4Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.37–7. 25(m,5H),7.23–7.18(m,1H),4.68(s,1H),4.34(q,J=6.6Hz,1H),1.70(s,1H),1.33(s,3H),1.30(s,9H).

[0284] 13 C NMR (101MHz, CDCl3) δ150.0,147.3,147.0,142.6,140.6,140.3,128.0,127.9,127 .4,127.1,126.8,125.5,125.4,125.4,120.0,119.7,61.2,55.8,34.6,31.6,25.4.

[0285] HRMS(ESI):calculated for C 25 H 27 N[M+H] + 342.2216, found:342.2211.

[0286] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =4.2min,t minor =4.6min.

[0287] Optical rotation:

[0288] Embodiment 40

[0289] Under nitrogen atmosphere, I-4 (0.4 mmol), II-5 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-26 with asymmetric arylation of the amine at the α-position was obtained.

[0290]

[0291] Yellow solid compound, 99% ee value, 76% yield, (0.2 mmol specification, 58 mg product), eluent: petroleum ether containing 5%-20% ethyl acetate. The product is characterized as follows:

[0292] 1 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, 1H), 7.33 (dq, J = 14.5, 6.9 Hz, 7H), 7.20 (t, J = 8.1 Hz, 1H), 4.65 (s, 1H), 4.08 (d, J = 9.0 Hz, 1H), 2.65–2.44 (m, 1H), 2.04 (s, 1H), 1.92–1.57 (m, 6H), 1.32 (s, 9H).

[0293] 13 13C NMR (101 MHz, CDCl3) δ 149.9, 147.6, 146.9, 140.5, 140.3, 139.3, 128.1, 127.7, 127.7, 127.4, 127.1, 125.5, 125.5, 125.2, 119.9, 119.6, 67.2, 60.9, 42.8, 34.6, 31.6, 26.8, 25.5, 17.7.

[0294] HRMS (ESI): calculated for C 28 H 31 N [M+H] + 382.2529, found: 382.2522.

[0295] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 205 nm: t major = 3.4 min, t minor = 3.6 min.

[0296] Optical rotation:

[0297] Example 41

[0298] Under nitrogen atmosphere, I-4 (0.4 mmol), II-6 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-27 with asymmetric arylation of the amine at the α-position was obtained.

[0299]

[0300] Yellow oily compound, 98% ee value, 49% yield, (0.2 mmol specification, 38 mg product), eluent: petroleum ether containing 5%-20% ethyl acetate. The product is characterized as follows:

[0301] 1 H NMR (400MHz, CDCl3) δ7.63(t,J=8.0Hz,3H),7.51(d,J=5.6Hz,1H),7.40(d,J=8 .1Hz,2H),7.36–7.27(m,5H),7.20(t,J=7.4Hz,1H),4.66(s,1H),3.95(d,J=9. 0Hz,1H),2.14(q,J=7.8Hz,1H),1.89(s,2H),1.68–1.60(m,1H),1.58–1.49(m, 2H),1.47–1.39(m,1H),1.34(s,9H),1.29(d,J=5.8Hz,1H),1.20–1.08(m,1H).

[0302] 13 C NMR (101MHz, CDCl3) δ149.8,147.9,147.1,140.9,140.5,140.2,128.0,127.7,127.4,127. 1,125.6,125.4,125.1,119.9,119.6,67.1,61.0,48.1,34.6,31.6,30.8,30.7,25.5,25.1.

[0303] HRMS(ESI):calculated for C 29 H 33N[M+H] + 396.2686, found:396.2682.

[0304] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=205nm:t major =3.8min,t minor =4.2min.

[0305] Optical rotation:

[0306] Embodiment 42

[0307] Under nitrogen atmosphere, I-4 (0.4 mmol), II-4 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-28 with asymmetric arylation of the amine at the α-position was obtained.

[0308]

[0309] Yellow oily compound, 98% ee value, 74% yield, (0.2 mmol specification, 57 mg product), eluent: petroleum ether containing 5%-20% ethyl acetate. The product is characterized as follows:

[0310] 1 H NMR (400MHz, CDCl3) δ7.64(dd,J=13.2,7.4Hz,3H),7.51(dd,J=11.3,7.2Hz,1H),7.34(dt,J=14.5,7.1Hz,7H),7.22(t,J=7.6Hz,1H ),4.68(s,1H),4.27(t,1H),1.81(s,1H),1.60(s,2H),1.51–1.41(m,1H),1.33(s,9H),0.88(d,J=6.4Hz,3H),0.84(d,J=6.5Hz,3H).

[0311] 13 C NMR (101MHz, CDCl3) δ149.9,147.7,147.0,141.6,140.5,140.2,129.2,128.0,127.8 ,127.4,127.1,124.5,120.4,119.9,119.6,60.9,58.8,48.6,34.6,31.6,24.9,22.9.

[0312] HRMS(ESI):calculated for C 28 H 33 N[M+H] + 384.2686, found:384.2080.

[0313] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=205nm:t major =3.5min,t minor =4.6min.

[0314] Optical rotation:

[0315] Embodiment 43

[0316] Under nitrogen atmosphere, I-4 (0.4 mmol), II-7 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-29 with asymmetric arylation of the amine at the α-position was obtained.

[0317]

[0318] Yellow oily compound, 93% ee value, 68% yield, (0.2 mmol specification, 57 mg product), eluent: petroleum ether containing 5%-20% ethyl acetate. The product is characterized as follows:

[0319] 1 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.5 Hz, 2H), 7.56 (dd, J = 18.4, 7.6 Hz, 2H), 7.40–7.28 (m, 7H), 7.21 (t, J = 7.3 Hz, 1H), 4.68 (s, 1H), 4.29 (t, J = 6.9 Hz, 1H), 1.85–1.70 (m, 2H), 1.69–1.53 (m, 6H), 1.35 (s, 9H), 1.24–1.08 (m, 4H), 0.88 (q, J = 11.3 Hz, 2H).

[0320] 13 13C NMR (101 MHz, CDCl3) δ 149.8, 147.7, 147.0, 142.0, 140.5, 140.3, 128.0, 127.7, 127.3, 127.1, 125.4, 125.3, 120.0, 119.6, 61.1, 57.9, 47.3, 34.6, 34.3, 33.8, 33.4, 31.6, 26.7, 26.3, 26.2.

[0321] HRMS (ESI): calculated for C 31 H 37 N [M+H] + 424.2999, found: 424.2996.

[0322] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 203 nm: t major = 3.7 min, t minor = 5.3 min.

[0323] Optical rotation:

[0324] Example 44

[0325] Under nitrogen atmosphere, I-4 (0.4 mmol), II-8 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-30 with asymmetric arylation of the amine at the α-position was obtained.

[0326]

[0327] Yellow oily compound, 96% ee value, 43% yield, (0.2 mmol specification, 37 mg product), eluent: petroleum ether containing 5%-20% ethyl acetate. The product is characterized as follows:

[0328] 1 H NMR(400MHz, CDCl3) δ7.59(dd,J=13.9,7.5Hz,2H),7.38–7.27(m,7H),7.23(t,J=7.3Hz,2H),7.07(t,1H),7.02 (q,J=8.2Hz,4H),4.70(s,1H),4.30(t,J=5.4Hz,1H),3.08–2.77(m,2H),2.30(s,3H),1.92(s,1H),1.32(s,9H).

[0329] 13 C NMR (101MHz, CDCl3) δ150.1,146.9,146.5,140.4,135.9,135.8,129.3,129.2,127.9,127 .6,127.6,127.3,126.9,125.4,125.3,119.7,119.5,62.3,61.5,45.4,34.6,31.6,21.2.

[0330] HRMS(ESI):calculated for C 32 H 33 N[M+H] + 432.2686, found:432.2675.

[0331] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=190nm:t major =3.8min,t minor =4.2min.

[0332] Optical rotation:

[0333] Embodiment 45

[0334] Under nitrogen atmosphere, I-4 (0.4 mmol), II-9 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-31 with asymmetric arylation of the amine at the α-position was obtained.

[0335]

[0336] Yellow oily compound, 96% ee value, 80% yield, (0.2 mmol specification, 69 mg product), eluent: petroleum ether containing 50% ethyl acetate. The product is characterized as follows:

[0337] 1 H NMR (400MHz, CDCl3) δ7.65(t,J=6.8Hz,2H),7.52(d,J=7.1Hz,2H),7.36(q,J=3.3Hz,5H),7.30(t,3H),7.21(q,J=7.5Hz,2H ),7.15(d,J=7.4Hz,1H),7.07(d,J=8.6Hz,2H),4.75(s,1H),4.16(t,1H),2.53(q,J=7.7Hz,2H),2.06(s,3H),1.34(s,9H).

[0338] 13C NMR (101MHz, CDCl3) δ150.2,142.0,140.6,128.5,128.4,128.1,127.9,127.6,127 .4,127.2,125.8,125.7,125.5,119.9,119.7,61.1,60.5,40.2,34.6,32.6,31.6.

[0339] HRMS(ESI):calculated for C 32 H 33 N[M+H] + 432.2686,found:432.2681.

[0340] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=213nm:t major =4.0min,t minor =5.0min.

[0341] Optical rotation:

[0342] Embodiment 46

[0343] Under nitrogen atmosphere, I-4 (0.4 mmol), II-10 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, and sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added to cool to 0°C in an ice-water bath, and the reaction was continued for 2 hours after returning to room temperature. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was continued for 30 minutes after returning to room temperature. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-32 with asymmetric arylation of the amine at the α-position was obtained.

[0344]

[0345] Yellow oily compound, 99% ee value, 72% yield, (0.2 mmol specification, 63 mg product), eluent: ethyl acetate containing 50% dichloromethane. The product is characterized as follows:

[0346] 11H NMR (400 MHz, CDCl3) δ 8.45–8.28 (m, 2H), 7.65 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.40–7.27 (m, 8H), 7.19 (td, J = 7.4, 1.1 Hz, 1H), 7.12 (dd, J = 7.8, 4.8 Hz, 1H), 4.71 (s, 1H), 4.12 (t, J = 6.8 Hz, 1H), 2.51 (q, J = 7.8 Hz, 2H), 1.99 (q, J = 8.0 Hz, 3H), 1.32 (s, 9H).

[0347] 13 13C NMR (101 MHz, CDCl3) δ 150.4, 150.0, 147.4, 147.1, 146.7, 140.6, 140.4, 137.3, 135.8, 128.2, 127.9, 127.4, 127.4, 127.1, 125.6, 125.3, 123.3, 120.0, 119.8, 61.1, 60.2, 39.9, 34.6, 31.6, 29.7.

[0348] HRMS (ESI): calculated for C 31 H 32 N2[M + H] + 433.2638, found: 433.2634.

[0349] HPLC conditions: Daicel Chiralpak AD-H column, hexane / iPrOH (97 / 3), 0.5 mL / min, UV = 213 nm: t major = 38.8 min, t minor = 47.3 min.

[0350] Optical rotation:

[0351] Example 47

[0352] Under nitrogen atmosphere, I-4 (0.4 mmol), II-11 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-33 with asymmetric arylation of the amine at the α-position was obtained.

[0353]

[0354] Yellow oily compound, 99% ee value, 70% yield, (0.2 mmol specification, 60 mg product), eluent: petroleum ether containing 5%-20% ethyl acetate. The product is characterized as follows:

[0355] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=7.1Hz,2H),7.52(d,J=7.0Hz,2H),7.37–7.29(m,7H),7.19(t,J=7.5Hz,1H),4.69(s,1H),4.21(t,J=7.1H z,1H),3.86(dt,J=13.3,6.6Hz,2H),3.34–3.20(m,2H),1.83(s,1H),1.59(d,J=15.1Hz,3H),1.43(s,2H),1.33(s,9H),1.28–1.20(m,2H).

[0356] 13 C NMR (101MHz, CDCl3) δ150.1,147.4,146.7,141.4,140.5,140.4,128.1,127.8,127.4,127. 2,127.1,125.5,125.3,120.0,119.7,67.9,61.1,57.4,46.6,34.6,33.4,33.2,31.7,31.6.

[0357] HRMS(ESI):calculated for C 30 H 35 NO[M+H] +426.2791,found:426.2783.

[0358] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=205nm:t major =5.5min,t minor =8.7min.

[0359] Optical rotation:

[0360] Embodiment 48

[0361] Under nitrogen atmosphere, I-4 (0.4 mmol), II-13 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-34 with asymmetric arylation of the amine at the α-position was obtained.

[0362]

[0363] Yellow oily compound, 90% ee value, 61% yield, (0.2 mmol specification, 65 mg product), eluent: petroleum ether containing 50% ethyl acetate. The product is characterized as follows:

[0364] 11H NMR (400 MHz, CDCl3) δ 7.68 (dd, J = 8.2, 2.2 Hz, 2H), 7.58 (t, J = 6.5 Hz, 2H), 7.38 (s, 5H), 7.33 (d, J = 7.5 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 4.70 (s, 1H), 4.12 (t, J = 6.6 Hz, 1H), 4.03 (s, 2H), 2.60 (s, 2H), 1.81 (s, 1H), 1.70 (q, J = 7.9 Hz, 2H), 1.54 (t, J = 12.1 Hz, 2H), 1.46 (s, 9H), 1.35 (s, 9H), 1.31–1.18 (m, 3H), 1.11 (t, J = 6.9 Hz, 1H), 0.99 (t, 2H).

[0365] 13 13C NMR (101 MHz, CDCl3) δ 155.0, 150.0, 147.4, 146.9, 141.1, 140.6, 140.2, 128.1, 127.8, 127.4, 127.1, 125.4, 125.4, 120.0, 119.7, 79.3, 61.2, 61.0, 44.4, 36.2, 36.2, 34.6, 33.2, 32.2, 31.6, 28.6.

[0366] HRMS (ESI): calculated for C 36 H 46 N2O2 [M+H] + 539.3632, found: 539.3628.

[0367] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1 mL / min, UV = 224 nm: t major = 7.4 min, t minor = 11.3 min.

[0368] Optical rotation:

[0369] Example 49

[0370] Under nitrogen atmosphere, I-4 (0.4 mmol), II-12 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allylpalladium chloride (II) dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-35 with asymmetric arylation of the amine at the α-position was obtained.

[0371]

[0372] Yellow oily compound, 53% ee value, 50% yield, (0.2 mmol specification, 48 mg product), eluent: petroleum ether containing 50% ethyl acetate. The product is characterized as follows:

[0373] 1 H NMR (400MHz, CDCl3) δ7.76–7.44(m,4H),7.44–7.08(m,9H),4.73(s,1H),4. 10(t,1H),3.38–2.85(m,2H),2.70(s,3H),2.16–1.64(m,2H),1.29(s,18H).

[0374] 13 C NMR (101MHz, CDCl3) δ155.7,150.2,147.3,146.7,140.5,140.3,128.1,128.1,127.9,127. 4,127.1,125.5,125.4,120.0,119.7,79.3,60.9,58.5,46.3,36.9,34.6,34.1,31.5,28.5.

[0375] HRMS(ESI):calculated for C 32 H 40 N2O2[M+H] + 485.3163, found:485.3159.

[0376] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =5.6min,t minor =6.2min.

[0377] Optical rotation:

[0378] Embodiment 50

[0379] Under nitrogen atmosphere, I-4 (0.4 mmol), II-14 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-36 with asymmetric arylation of the amine at the α-position was obtained.

[0380]

[0381] Yellow oily compound, 97% ee value, 63% yield, (0.2 mmol specification, 53 mg product), eluent: petroleum ether containing 5% ethyl acetate. The product is characterized as follows:

[0382] 1 H NMR (400MHz, CDCl3) δ7.66(dd,J=7.6,2.6Hz,2H),7.54(d,J=6.9Hz,1H),7.48(d,J=7.4Hz,1H),7.40–7.27( m,7H),7.19(t,J=7.4Hz,1H),4.73(s,1H),4.17–4.09(m,1H),2.11–1.88(m,4H),1.75(s,1H),1.32(s,9H).

[0383] 13C NMR (101MHz, CDCl3) δ150.6,146.9,146.4,140.5,140.4,139.6,128.8,128.3,128.0,127.5(q,J=276 .2Hz),127.2,127.1,126.0,125.7,125.3,120.0,119.8,61.0,59.4,34.7,31.5,30.7(q,J=28.7Hz).

[0384] 19 F NMR (376MHz,CDCl3)δ-66.08.

[0385] HRMS(ESI):calculated for C 27 H 28 NF3[M+H] + 424.2247,found:424.2243.

[0386] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =3.8min,t minor =4.8min.

[0387] Optical rotation:

[0388] Embodiment 51

[0389] Under nitrogen atmosphere, I-4 (0.4 mmol), II-15 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-37 with asymmetric arylation of the amine at the α-position was obtained.

[0390]

[0391] Yellow oily compound, 97% ee value, 41% yield, (0.2 mmol specification, 37 mg product), eluent: petroleum ether containing 5% ethyl acetate. The product is characterized as follows:

[0392] 1 H NMR (400MHz, CDCl3) δ7.64(dd,J=7.3,2.8Hz,2H),7.53(dd,J=12.9,7.1Hz,2H),7.42–7.35(m,1H),7.32(d,J=17.6Hz,6H),7.18(t, J=7.4Hz,1H),4.70(s,1H),4.15(t,J=6.7Hz,1H),2.17(t,J=7.7Hz,2H),2.07–1.90(m,2H),1.81(s,1H),1.39(s,9H),1.32(s,9H).

[0393] 13 C NMR (101MHz, CDCl3) δ172.9,150.2,147.3,146.7,140.4,140.3,129.2,128.1,128.0,127.8,127.5,127.4,127.1,125.5,125.4,120.0 119.9,119.7,80.2,61.0,60.2,34.6,33.9,32.5,31.5,28.2.

[0394] HRMS(ESI):calculated for C 31 H 37 NO2[M+H] + 456.2897,found:456.2893.

[0395] HPLC conditions: Daicel Chiralpak IA column, hexane / iPrOH (97 / 3), 1mL / min, UV=204nm:t major =4.9min,t minor =5.9min.

[0396] Optical rotation:

[0397] Embodiment 52

[0398] Under nitrogen atmosphere, I-4 (0.4 mmol), II-16 (0.2 mmol), potassium tert-butoxide (0.4 mmol), monophosphine ligand L5 (0.01 mmol) and allyl palladium (II) chloride dimer (0.005 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (2 ml) was added. After stirring at 30°C for 24 hours, 2 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.6 mmol) and acetic acid (0.2 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 4 ml of 10% mass fraction of sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-38 with asymmetric arylation of the amine at the α-position was obtained.

[0399]

[0400] Yellow oily compound, 97% ee value, 65% yield, (0.2 mmol specification, 59 mg product), eluent: petroleum ether containing 5% ethyl acetate. The product is characterized as follows:

[0401] 1 H NMR (400MHz, CDCl3) δ7.65 (d, J=7.5Hz, 2H), 7.57 (dd, J=7.7, 3.7Hz, 2H), 7.40–7. 33(m,5H),7.31(d,J=7.4Hz,2H),7.21(t,J=7.4Hz,1H),4.69(s,1H),4.37(t,J=5. 7Hz,1H),4.17(t,J=6.7Hz,1H),3.52(dq,J=14.3,7.1Hz,3H),3.44–3.31(m,2H),1 .75(q,J=7.8Hz,2H),1.62–1.45(m,2H),1.33(s,9H),1.14(td,J=7.1,2.8Hz,6H).

[0402] 13 C NMR (101MHz, CDCl3) δ150.0,147.4,146.9,140.8,140.5,140.2,128.0,127.8,127.5,127.3,1 27.1,125.4,125.4,119.9,119.6,102.9,61.2,61.0,60.8,60.8,34.6,34.0,31.5,30.5,15.4.

[0403] HRMS(ESI):calculated for C 31H 39 NO2[M+H] + 458.3054,found:458.3051.

[0404] HPLC conditions: Daicel Chiralpak AD-H column, hexane / iPrOH (97 / 3), 0.5mL / min, UV=190nm:t major =12.9min,t minor =17.4min.

[0405] Optical rotation:

[0406] Embodiment 53

[0407] Under nitrogen atmosphere, I-4 (0.2 mmol), II-17 (0.1 mmol), potassium tert-butoxide (0.2 mmol), monophosphine ligand L5 (0.006 mmol) and allyl palladium (II) chloride dimer (0.003 mmol) were added to a 4 ml reaction bottle, and solvent cyclohexane (1 ml) was added. After stirring at 30°C for 24 hours, 1 ml of dichloromethane was added to dilute, cooled to 0°C in an ice-water bath, sodium borohydride (0.3 mmol) and acetic acid (0.1 ml) were added, and the reaction was allowed to return to room temperature for 2 hours. After cooling to 0°C in an ice-water bath, 2 ml of 10% mass fraction sodium hydroxide solution was added, and the reaction was allowed to return to room temperature for 30 minutes. The aqueous phase was extracted three times with dichloromethane and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. After separation and purification by silica gel column chromatography, the chiral amine compound III-39 with asymmetric arylation of the amine at the α-position was obtained.

[0408]

[0409] Yellow oily compound, dr>20:1, 32% yield, (0.1 mmol specification, 26 mg product), eluent: petroleum ether containing 5% ethyl acetate. The product is characterized as follows:

[0410] 1H NMR(400MHz,CDCl3)δ7.65(d,J=7.1Hz,2H),7.56(dd,J=16.0,7.4Hz,2H),7.35(d,J=4.4Hz,4H),7.33–7.27(m,3H),7.20(t,J=7.3Hz,1H),4.69(s,1H),4.08(t,J=5.3Hz,1H),3.90(s,1H),3.55(dt,J=10.9,5.8Hz,1H),1.86–1.65(m,8H),1.63–1.47(m,5H),1.41(d,J=28.4Hz,6H),1.32(s,9H),1.27–1.05(m,5H),1.02–0.92(m,3H),0.87(s,3H),0.83(d,J=6.5Hz,3H),0.53(s,3H),0.11(s,9H),0.09(s,9H).

[0411] 13 C NMR(101MHz,CDCl3)δ149.8,147.7,147.1,141.8,140.6,140.3,128.0,127.8,127.5,127.4,127.1,125.5,125.4,125.3,119.9,119.6,74.5,72.8,61.5,61.2,47.7,47.0,46.8,42.8,37.3,36.4,35.9,35.9,35.5,34.6,34.4,33.9,32.6,31.6,31.5,29.5,27.8,27.6,26.1,24.0,23.8,18.5,12.7,1.3,0.5.

[0412] HRMS(ESI):calculated for C 53 H 79 NO2Si2[M+H] + 818.5722,found:818.5699.

[0413] Optical rotation:

[0414] In summary, the present invention provides a simple method for converting simple and readily available imines into complex chiral amines and their derivatives. We propose an enantioselective palladium-catalyzed CH arylation reaction of amines and aryl bromides to produce chiral α-aryl substituted amines with excellent enantioselectivity and medium to high yields. This practical transformation shows remarkable tolerance to a variety of functional groups, thus opening up a new route for the synthesis of a series of α-chiral aryl amines with excellent enantioselectivity and medium to high yields, and can be applied to the synthesis of drug molecules.

Claims

1. A method for palladium-catalyzed asymmetric arylation of the α-CH bond of an amine, characterized in that: include: Using aryl bromide (I) and imine (II) as raw materials, using transition metal palladium as a catalyst, in the presence of a chiral monophosphine ligand and a base, an intermolecular coupling reaction occurs in an organic solvent, and then the α-position asymmetric arylation of the amine compound (III) is obtained through reduction and purification; in: Flu R1 and R2 are independently selected from halogen, hydrogen, nitro, alkyl, alkoxy; R is selected from hydrogen, alkyl, aryl, heteroaryl; X is a halogen or an -OTf group; Ar is a substituted or unsubstituted aryl or heteroaryl group.

2. The method according to claim 1, characterized in that In the aryl bromide (I), Ar is selected from substituted or unsubstituted phenyl, benzo[d][1,3]dioxolyl, carbazolyl, benzothiophenyl, indolyl; and the substituent is halogen, alkyl, alkoxy, amine, or alkylthio.

3. The method according to claim 2, characterized in that The aryl bromide (I) is selected from:

4. The method according to claim 1, characterized in that The imine (II) is selected from:

5. The method according to claim 1, characterized in that The catalyst is allylpalladium (II) chloride dimer.

6. The method according to claim 1, characterized in that The chiral monophosphine ligand is selected from:

7. The method according to claim 1, characterized in that The base is at least one of potassium tert-butoxide, lithium tert-butoxide and sodium tert-butoxide.

8. The method according to claim 1, characterized in that The molar ratio of aryl bromide (I) to imine (II) is 1:1-3; most preferably 1:

2.

9. The method according to claim 1, characterized in that: The reaction temperature is 10-50°C, and the reaction time is 5-36h.

10. A compound (III) obtained by asymmetric arylation of an amine at the α-position prepared by the method according to any one of claims 1 to 9.

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