A chiral bipyridine ligand, its synthesis method and application

Abstract

This invention discloses a novel chiral bipyridine ligand, its synthesis method, and its application. The novel chiral bipyridine ligand is selected from compounds with the following structures: The chiral ligand of this invention has been successfully applied in the copper-catalyzed asymmetric ring-opening / cross-coupling reaction of cyclic diaryl iodine and secondary amine, yielding the product with excellent yield and ee value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a chiral bipyridine ligand, its synthesis method, and its application. Background Technology

[0002] Currently, bipyridine compounds have a wide range of applications. However, studies have found that nitrogen-containing bidentate chiral ligands with large open spaces, especially chiral ligands containing the 5H-cyclopentane[2,1-b:3,4-b']bipyridine structure, have been almost never reported. Summary of the Invention

[0003] In response to the aforementioned research background, this invention provides a chiral bipyridine ligand, its synthetic method, and its applications. The chiral bipyridine ligand of this invention has been successfully applied in the copper-catalyzed asymmetric ring-opening / cross-coupling reaction of cyclic diaryl iodine and secondary amines, yielding the product with excellent yield and high ee value.

[0004] The chiral bipyridine ligands of this invention are selected from compounds with the following structures:

[0005]

[0006] The present invention provides a method for synthesizing chiral bipyridine ligands, using chiral 1,1'-binaphthyl-2,2'-dicarboxylic acid 1 as the starting material, and obtaining the target ligand through two synthetic routes.

[0007] Route 1:

[0008] A carboxylic acid-directed ortho-arylation reaction catalyzed by palladium acetate was used to generate a 3,3'-functionalized derivative 2 in 71% yield. Compound 2 reacted with iodomethane in the presence of potassium carbonate to form a diester. The ester group was reduced to a hydroxyl group by LiALH4 in tetrahydrofuran solvent, and then reacted with PBr3 to generate a dibromo compound 3. The 5H-cyclopentane[2,1-b:3,4-b']bipyridine derivative was dissolved in tetrahydrofuran, and then a tetrahydrofuran solution of dibromo compound 3 was added dropwise under ice bath conditions. The reaction was brought back to room temperature and stirred. After the reaction was confirmed to be complete by TLC, water was added to quench the reaction, followed by extraction with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and the organic solvent was removed by rotary evaporation to obtain the crude product. After separation and purification, the target ligand was obtained.

[0009] The reaction process of Route 1 is as follows:

[0010]

[0011] Route 2:

[0012] Chiral 1,1'-binaphthyl-2,2'-dicarboxylic acid 1 was first esterified to obtain compound 5. Compound 5 underwent transmetalation at the ortho position of the ester group with the [Mg(TMP)2] reagent, and after the addition of iodine, diiodide compound 6 was successfully obtained. At -78°C, DIBAL-H solution was added dropwise to a tetrahydrofuran solution of diiodide compound 6, followed by stirring in an oil bath at 45°C to reduce the corresponding diol. The diol was successfully reacted with PBr3 to obtain benzyl dibromo 7, which was then dialkylated with 5Hcyclopentane[2,1-b:3,4-b']bispyridine to obtain diiodide compound 8 in excellent yield. Compound 8 was cross-coupled with arylboranes or terminal alkynes through a catalyst to obtain chiral bipyridine ligands with different structures in a one-step process with good yield.

[0013] The catalyst is a transition metal palladium, or a bimetallic catalyst of transition metal palladium and copper. Specifically, the transition metal palladium catalyzes the coupling reaction of compound 8 with arylborane; the transition metal palladium and copper bimetallic catalyst catalyzes the coupling reaction of compound 8 with a terminal alkyne compound.

[0014] The terminal alkyne compound is 1-ethynyl-4-methoxybenzene, which, when coupled with compound 8, yields L3.

[0015] The arylborane is selected from compounds with the following structure, and after coupling with compound 8, L4-L9 are obtained.

[0016] , , ,

[0017] , , .

[0018] The reaction process of Route 2 is illustrated below:

[0019]

[0020] R2 is selected from the following groups:

[0021] .

[0022] The application of the chiral bipyridine ligand of the present invention is to use the chiral bipyridine ligand in the copper-catalyzed asymmetric ring-opening / cross-coupling reaction of cyclic diaryl iodine 9 and secondary amine 10 to obtain the product with excellent yield and ee value.

[0023] The cyclic diaryl iodine 9 is selected from one of the following structures:

[0024] ;

[0025] The secondary amine 10 is selected from one of the following structures:

[0026] .

[0027]

[0028] The asymmetric ring-opening reaction of cyclic diaryl iodine has not been successfully achieved before. This invention provides a method for synthesizing a chiral bipyridine ligand. The chiral ligand L6 synthesized by this method, in co-catalysis with cuprous thiocyanate, achieves an asymmetric ring-opening / cross-coupling reaction between a cyclic diaryl iodine and a secondary amine, yielding the product with excellent yield and ee value. Detailed Implementation

[0029] The technical solution of the present invention will be further analyzed and explained through specific embodiments below.

[0030] Example 1:

[0031]

[0032] Under a nitrogen atmosphere, (S)-[1,1'-biphenyldicarboxylic acid]-2,2'-dicarboxylic acid (2.32 g, 6.8 mmol, 1.0 equivalent), 4-iodo-1,1'-biphenyl (11.37 g, 40.6 mmol, 6.0 equivalent), Pd(OAc)₂ (152 mg, 10.0 mol%), Ag₂CO₃ (2.09 g, 7.5 mmol, 1.1 equivalent), and K₂CO₃ (0.94 mg, 6.8 mmol, 1.0 equivalent) were added to a Schlenk reaction tube. Then, AcOH (4.0 mL) was added. The mixture was stirred at 120 °C for 24 hours, then cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1, containing 1% AcOH) to give colorless solid 2 (3.09 g, 71%).

[0033] 1 H NMR (600 MHz, CDCl3) δ 8.03 (s, 2H), 7.92 (d, J = 7.8 Hz, 2H), 7.71– 7.59 (m, 12H), 7.52 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 4H), 7.38 (t,J = 7.5 Hz, 2H), 7.29 (t,J = 7.8 Hz, 2H), 7.11 (d,J = 9.0 Hz, 2H).

[0034] 13 C NMR (151 MHz, CDCl3) δ 171.9, 140.6, 140.5, 138.8, 135.8, 133.7,132.9, 132.0, 131.2, 130.4, 129.0, 128.8, 128.2, 128.0, 127.7, 127.5, 127.3,127.1, 126.6.

[0035] HRMS (ESI) m / z: [M + Na] + Calcd for C 46 H 30 NaO4 669.2036; Found669.2017.

[0036] Example 2:

[0037]

[0038] Under a nitrogen atmosphere, iodomethane (0.50 mL, 8.0 mmol, 8.0 equivalent) was added dropwise to a solution of compound 2 (646.7 mg, 1.0 mmol, 1.0 equivalent) and K₂CO₃ (1.11 g, 8.0 mmol, 8.0 equivalent) in 15.0 mL of THF at 0 °C. After complete addition, the cooling bath was removed, and the reaction mixture was stirred overnight at room temperature. THF was removed under reduced pressure, and the residue was dispersed in water and extracted with ethyl acetate. The combined organic layers were washed with an aqueous solution of sodium thiosulfate and brine, and dried over Na₂SO₄. After filtration, the filtrate was concentrated and used in the next step without further purification. Under a nitrogen atmosphere, the crude product was dissolved in 5.0 mL of THF, and LiAlH₄ (160.0 mg, 4.0 mmol, 4.0 equivalent) was added at 0 °C. After addition, the cooling bath was removed, and the reaction mixture was stirred at 45 °C for 4 hours. The reaction was quenched with NH4Cl solution, the mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated. The filtrate was concentrated and used in the next step without further purification. The crude product was dissolved in THF (5.0 mL), cooled to 0°C, and PBr3 (0.37 mL, 4.0 mmol, 4.0 equivalent) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid 3 (0.61 g, 82%).

[0039] 1H NMR (600 MHz, CDCl3) δ 7.98 (s, 2H), 7.94 (d, J = 8.4z Hz, 2H), 7.74 (t, J = 7.2 Hz, 7H), 7.72 – 7.69 (m, 5H), 7.54 (t, J = 7.5 Hz, 2H), 7.49(t, J = 7.6 Hz, 4H), 7.39 (t, J = 7.4 Hz, 2H), 7.35 – 7.29 (m, 2H), 7.20 (d,J = 8.4 Hz, 2H), 4.43 – 4.31 (m, 4H).

[0040] 13 C NMR (151 MHz, CDCl3) δ 140.8, 140.7, 140.5, 139.6, 136.6, 133.3,132.5, 132.0, 130.6, 130.1, 129.0, 128.1, 127.5, 127.5, 127.4, 127.3, 127.0,126.7, 32.3.

[0041] Example 3:

[0042]

[0043] Under a nitrogen atmosphere, 2-bromopropane (22.5 mL, 0.24 mol, 10.0 equivalent) was added dropwise to a mixture of compound 1 (8.21 g, 24.0 mmol, 1.0 equivalent), Bu4NHSO4 (1.63 g, 4.8 mmol, 20.0% mol), and KF (13.94 g, 0.24 mmol, 10.0% equivalent) in THF-water (180.0 mL, THF / H2O = 2:1, v / v). The reaction mixture was stirred overnight at 85 °C and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give colorless solid 5 (8.80 g, 86%).

[0044] 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 8.5Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.50 (ddd, J = 8.1, 6.8, 1.1 Hz, 2H), 7.24(ddd, J = 8.2, 6.8, 1.2 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 4.76 (p, J = 6.2Hz, 2H), 0.76 (d, J = 5.5 Hz, 6H), 0.44 (d, J = 6.0 Hz, 6H).

[0045] 13 C NMR (126 MHz, CDCl3) δ 166.8, 139.6, 134.7, 133.2, 128.3, 127.7, 127.7, 127.5, 127.5, 126.6, 126.1, 67.7, 21.1, 20.7.

[0046] HRMS (ESI) m / z: [M + Na] + Calcd for C 28 H 26 O4Na 449.1724; Found449.1729.

[0047] Example 4:

[0048]

[0049] Under a nitrogen atmosphere, Mg(TMP)₂ (50.0 mmol, 4.0 equivalent) was added dropwise to a solution of 5 (5.78 g, 12.5 mmol, 1.0 equivalent) in 40.0 mL of THF at 0 °C, and the mixture was stirred at 45 °C for 3 hours. The reaction mixture was then cooled to -78 °C, and I₂ (22.80 g, 90 mmol, 7.2 equivalent) dissolved in 40.0 mL of THF was added. Stirring was continued at 45 °C for another 3 hours, and the mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the residue was dispersed in water and extracted with dichloromethane. The combined organic layers were washed with an aqueous solution of sodium thiosulfate and sodium chloride and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a yellow solid 6 (5.51 g, 65%).

[0050] 1H NMR (600 MHz, CDCl3) δ 8.52 (s, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.51(ddd, J = 8.1, 6.8, 1.2 Hz, 2H), 7.1 34 (ddd, 2 Hz, J. 3.8), 7.34. 7.17(d, J = 8.4 Hz, 2H), 4.76 (p, J = 6.3 Hz, 2H), 0.76 (d, J = 6.0 Hz, 6H), 0.68(d, J = 6.0 Hz, 6H)。

[0051] 13 C NMR (151 MHz, CDCl3) δ

[0052] HRMS (ESI) m / z: [M + Na] + Calcd for C 28 H 24 I2O4Na 700.96576;Found700.9677。

[0053] Chapter 5:

[0054]

[0055] Under a nitrogen atmosphere, a THF (20.0 mL) solution of compound 6 (5.53 g, 8.2 mmol, 1.0 equivalent) was cooled to -78 °C, followed by dropwise addition of DIBAL-H (1.0 M toluene solution, 82.0 mL, 82 mmol, 10.0 equivalent). After complete addition, the reaction mixture was slowly heated to 45 °C and stirred for 5 hours. The mixture was cooled to 0 °C, diluted with saturated Rochelle salt solution, and stirred overnight. The remaining white suspension was filtered off and washed with THF. It was then extracted with dichloromethane and Et₂O, and the combined organic layers were dried over Na₂SO₄ and concentrated under vacuum, followed by filtration. The concentrated filtrate was used for the next step without further purification. The crude product was dissolved in a THF (80.0 mL) solution and cooled to 0 °C, with PBr₃ (3.1 mL, 32.8 mmol, 4.0 equivalent) added dropwise. The reaction mixture was stirred at room temperature for 4 hours, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 2 / 1) to give yellow solid 7 (4.62 g, 82%).

[0056] Example 6:

[0057]

[0058] Under a nitrogen atmosphere, a 20.0 mL solution of compound 4a (336.4 mg, 2.0 mmol, 1.0 equivalent) in THF was cooled to 0 °C, followed by the addition of KHMDS (4.2 mL, 4.2 mmol, 2.1 equivalent) in 1.0 M THF solution. After stirring the reaction mixture at room temperature for 0.5 hours, a 40.0 mL solution of 7 (1.38 g, 2.0 mmol, 1.0 equivalent) in THF was added dropwise to the mixture at 0 °C, and the mixture was stirred at room temperature for 2 hours. After the starting material was completely consumed, the mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL) and extracted with dichloromethane (50 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / dichloromethane = 2 / 1) to give a yellow solid 8 (1.28 g, 92%).

[0059] 1H NMR (500 MHz, CDCl3) δ 8.81 – 8.71 (m, 2H), 8.66 (s, 2H), 7.89 (d,J = 8.0 Hz, 2H), 7.51 (ddd, J = 8.0, 6.7, 1.1 Hz, 2H), 7.29 (ddd, J = 8.3,6.8, 1.3 Hz, 2H), 7.25 – 7.18 (m, 4H), 7.14 (d, J = 9.0 Hz, 2H), 3.27 (d, J =14.0 Hz, 2H), 3.06 (d, J = 14.0 Hz, 2H).

[0060] 13 C NMR (126 MHz, CDCl3) δ 156.8, 150.2, 143.5, 139.7, 136.2, 135.4,134.2, 132.9, 131.6, 127.2, 127.1, 127.0, 126.7, 123.2, 99.3, 57.6, 44.5.

[0061] HRMS (ESI) m / z: [M + H] + Calcd for C 33 H 21 Br2I2N2 698.9789; Found698.9796.

[0062] Example 7:

[0063]

[0064] Under a nitrogen atmosphere, compound 4a (168.2 mg, 1.0 mmol, 1.0 equivalent) was dissolved in THF (15.0 mL) and cooled to 0°C. NaH (60% in mineral oil, 280.0 mg, 7.0 mmol, 7.0 equivalent) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h. A solution of 3 (744.6 mg, 1.0 mmol, 1.0 equivalent) in THF (15.0 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred at room temperature for 2 h. After the starting material was completely consumed, the mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a colorless solid L1 (485.2 mg, 65%).

[0065] 1 1H NMR (600 MHz, CDCl3) δ 8.54 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 9.0Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.45 (dd, J =15.9, 8.2 Hz, 3H), 7.41 (t, J = 7.6 Hz, 2H), 7.39 – 7.37 (m, 1H), 7.37 – 7.30(m, 3H), 7.16 – 7.12 (m, 1H), 7.09 (dd, J = 7.6, 4.9 Hz, 1H), 3.27 (dd, J =13.7, 2.8 Hz, 1H), 3.03 – 2.88 (m, 1H).

[0066] 13 13C NMR (151 MHz, CDCl3) δ 156.5, 149.6, 144.3, 140.3, 140.0, 139.8,139.2, 136.3, 132.62, 132.60, 132.1, 131.4, 130.5, 129.5, 128.6, 128.3,127.2, 127.0, 126.9, 126.7, 126.2, 126.0, 122.5, 56.7, 36.5。

[0067] HRMS (ESI) m / z: [M + H] + Calcd for C[[ID=​​​​​​​​​​​Compound 4b (196.2 mg, 1.0 mmol, 1.0 equivalent) was dissolved in THF (15.0 mL) under a nitrogen atmosphere and cooled to 0 °C. NaH (60% in mineral oil, 280.0 mg, 7.0 mmol, 7.0 equivalent) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 0.5 h. A solution of 3 (744.6 mg, 1.0 mmol, 1.0 equivalent) in THF (15.0 mL) was added dropwise to the mixture at 0 °C, and the mixture was stirred at room temperature for 2 h. After the starting material was completely consumed, the mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a colorless solid L2 (377.0 mg, 48%).

[0071] 1 H NMR (600 MHz, CDCl3) δ 8.08 – 8.03 (m, 4H), 7.57 (ddd, J = 8.0,6.6, 1.2 Hz, 2H), 7.51 – 7.48 (m, 4H), 7.40 (q, J = 8.2 Hz, 10H), 7.37 – 7.34(m, 2H), 7.34 – 7.29 (m, 6H), 6.98 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 7.8 Hz,2H), 3.20 (d, J = 13.8 Hz, 2H), 2.87 (d, J = 13.8 Hz, 2H), 2.57 (s, 6H).

[0072] 13 C NMR (151 MHz, CDCl3) δ 158.8, 156.4, 142.1, 140.7, 140.2, 140.0,139.5, 136.4, 133.2, 132.8, 132.3, 131.6, 130.7, 129.6, 128.8, 128.5, 127.4,127.3, 127.2, 126.9, 126.3, 126.1, 122.1, 56.4, 36.8, 24.5.

[0073] HRMS (ESI) m / z: [M + H] + Calcd for C 59 H 43N2 779.3421; Found 779.3413.

[0074] Example 9:

[0075]

[0076] Under a nitrogen atmosphere, 8 (41.9 mg, 0.060 mmol, 1.0 equivalent), 1-ethynyl-4-methoxybenzene (46.7 µL, 0.36 mmol, 6.0 equivalent), Pd2(dba)3 (5.5 mg, 10 mol%), dppf (6.7 mg, 20 mol%), CuI (2.3 mg, 20 mol%), Et3N (2.0 mL), and THF (1.0 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 45 °C for 24 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give a colorless solid product L3 (30.4 mg, 43%).

[0077] 1 H NMR (500 MHz, CDCl3) δ 8.67 (dd, J = 4.5, 1.5 Hz, 2H), 8.31 (s,2H), 7.99 (d, J = 8.0 Hz, 2H), 7.52 (dt, J = 8.1, 3.9 Hz, 2H), 7.39 (dd, J =7.8, 1.5 Hz, 2H), 7.33 – 7.27 (m, 4H), 7.15 (dd, J = 7.7, 4.8 Hz, 2H), 6.87 –6.79 (m, 4H), 6.76 – 6.69 (m, 4H), 3.76 (s, 6H), 3.39 (d, J = 13.5 Hz, 2H),3.22 (d, J = 13.5 Hz, 2H).

[0078] 13C NMR (126 MHz, CDCl3) δ 159.7, 156.9, 150.0, 144.9, 135.7, 135.0,132.8, 132.6, 132.2, 131.4, 128.1, 127.2, 126.8, 126.2, 122.9, 122.0, 114.5,113.9, 93.9, 87.0, 57.7, 55.2, 38.6.

[0079] HRMS (ESI) m / z: [M + H] + Calcd for C 51 H 35 N2O2 707.2693; Found 707.2695.

[0080] Example 10:

[0081]

[0082] Under a nitrogen atmosphere, 8 (41.9 mg, 0.060 mmol, 1.0 equivalent), (4-(phenylethynyl)phenyl)boronic acid (111.1 mg, 0.50 mmol, 8.3 equivalent), Pd(PPh3)4 (6.9 mg, 10.0 mol%), Na2CO3 (42.2 mg, 0.40 mmol, 6.7 equivalent), toluene (1.0 mL), MeOH (0.10 mL), and H2O (0.10 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give product L4 (35.9 mg, 75%) as a colorless solid.

[0083] 11H NMR (600 MHz, CDCl3) δ 8.46 (d, J = 4.8 Hz, 2H), 8.14 – 8.04 (m, 4H), 7.59 (t, J = 7.5 Hz, 2H), 7.50 – 7.43 (m, 8H), 7.43 – 7.36 (m, 8H), 7.35 – 7.30 (m, 2H), 7.26 – 7.18 (m, 4H), 7.13 (d, J = 7.8 Hz, 2H), 7.00 (t, J = 6.3 Hz, 2H), 3.25 (d, J = 13.8 Hz, 2H), 2.87 (d, J = 13.8 Hz, 2H).

[0084] 13 13C NMR (151 MHz, CDCl3) δ 156.5, 149.6, 144.3, 140.9, 140.70, 140.66, 140.3, 136.2, 132.7, 132.6, 132.1, 131.4, 129.5, 129.1, 128.9, 128.6, 128.3, 127.3, 127.1, 127.0, 126.2, 126.1, 125.9, 122.4, 56.8, 36.6.

[0085] HRMS (ESI) m / z: [M + H] + Calcd for C 61 H 39 N2 799.3108; Found 799.3105.

[0086] Example 11:

[0087]

[0088] Under a nitrogen atmosphere, 8 (41.9 mg, 0.060 mmol, 1.0 equivalent), (3,5-dimethylphenyl)boronic acid (75.1 mg, 0.50 mmol, 8.3 equivalent), Pd(PPh3)4 (6.9 mg, 10.0 mol%), Na2CO3 (42.2 mg, 0.40 mmol, 6.7 equivalent), toluene (1.0 mL), MeOH (0.10 mL), and H2O (0.10 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give product L5 (32.2 mg, 82%) as a colorless solid.

[0089] 1 H NMR (600 MHz, CDCl3) δ 8.53 (dd, J = 4.2, 1.8 Hz, 2H), 8.03 (d, J =8.4 Hz, 2H), 7.98 (s, 2H), 7.59 – 7.50 (m, 2H), 7.39 (d, J = 9.0 Hz, 2H),7.37 – 7.30 (m, 2H), 7.15 – 7.06 (m, 4H), 6.83 (s, 4H), 6.75 (s, 2H), 3.15(d, J = 13.8 Hz, 2H), 2.77 (d, J = 13.8 Hz, 2H), 2.16 (s, 12H).

[0090] 13 C NMR (151 MHz, CDCl3) δ 156.6, 149.4, 144.5, 140.7, 140.1, 137.2,136.1, 132.8, 132.6, 132.5, 131.3, 129.1, 128.6, 128.2, 128.1, 127.0, 126.0,125.9, 122.2, 56.8, 36.6, 21.1.

[0091] HRMS (ESI) m / z: [M + H] + Calcd for C 49 H 39 N2 655.3108; Found 655.3114.

[0092] Example 12:

[0093]

[0094] Under a nitrogen atmosphere, 8 (2.03 g, 2.9 mmol, 1.0 equivalent), (9,9-dimethyl-9H-fluorene-2-yl)boronic acid (4.14 g, 17.4 mmol, 6.0 equivalent), Pd(PPh3)4 (335.0 mg, 10.0 mol%), Na2CO3 (1.54 g, 14.5 mmol, 5.0 equivalent), toluene (60.0 mL), MeOH (6.0 mL), and H2O (6.0 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give the product as a colorless solid. (2.27g, 94%).

[0095] Example 13:

[0096]

[0097] Under a nitrogen atmosphere, 8 (69.8 mg, 0.10 mmol, 1.0 equivalent), (9,9-dimethyl-9H-fluorene-3-yl)boronic acid (142.8 mg, 0.60 mmol, 6.0 equivalent), Pd(PPh3)4 (11.6 mg, 10.0 mol%), Na2CO3 (52.8 mg, 0.50 mmol, 5.0 equivalent), toluene (2.0 mL), MeOH (0.20 mL), and H2O (0.20 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give product L7 (52.4 mg, 85%) as a colorless solid.

[0098] 11H NMR (600 MHz, CDCl3) δ 8.41 (s, 2H), 8.10 – 8.06 (m, 4H), 7.63 –7.50 (m, 6H), 7.46 – 7.34 (m, 7H), 7.30 – 7.27 (m, 3H), 7.24 – 7.12 (m, 6H),7.07 – 7.03 (m, 2H), 3.25 (d, J = 13.8 Hz, 2H), 2.94 (d, J = 13.8 Hz, 2H),1.38 (s, 12H).

[0099] 13 13C NMR (151 MHz, CDCl3) δ 156.6, 153.8, 152.3, 149.6, 144.4, 140.8,139.2, 139.0, 138.7, 136.3, 133.0, 132.7, 132.3, 131.4, 129.7, 129.2, 128.3,127.3, 127.1, 126.8, 126.2, 126.0, 122.6, 122.4, 122.1, 121.8, 119.7, 56.9,46.6, 36.6, 27.1, 26.9.

[0100] HRMS (ESI) m / z: [M + H] + Calcd for C 63 H 47 N2 831.3734; Found 831.3727.

[0101] Example 14:

[0102]

[0103] Under a nitrogen atmosphere, 8 (69.8 mg, 0.10 mmol, 1.0 equivalent), dibenzo[b,d]furan-3-ylboronic acid (127.2 mg, 0.60 mmol, 6.0 equivalent), Pd(PPh3)4 (11.6 mg, 10.0 mol%), Na2CO3 (52.8 mg, 0.50 mmol, 5.0 equivalent), toluene (2.0 mL), MeOH (0.20 mL), and H2O (0.20 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give product L8 (68.5 mg, 88%) as a colorless solid.

[0104] 1 H NMR (600 MHz, CDCl3) δ 8.41 (s, 2H), 8.10 – 8.06 (m, 4H), 7.63 – 7.50 (m, 6H), 7.46 – 7.34 (m, 7H), 7.30 – 7.27 (m, 3H), 7.24 – 7.12 (m, 6H),7.07 – 7.03 (m, 2H), 3.25 (d, J = 13.8 Hz, 2H), 2.94 (d, J = 13.8 Hz, 2H), 1.38 (s, 12H).

[0105] 13 C NMR (151 MHz, CDCl3) δ 156.6, 153.8, 152.3, 149.6, 144.4, 140.8,139.2, 139.0, 138.7, 136.3, 133.0, 132.7, 132.3, 131.4, 129.7, 129.2, 128.3,127.3, 127.1, 126.8, 126.2, 126.0, 122.6, 122.4, 122.1, 121.8, 119.7, 56.9,46.6, 36.6, 27.1, 26.9.

[0106] HRMS (ESI) m / z: [M + H] + Calcd for C 63 H 47N2 831.3734; Found 831.3727.

[0107] Example 15:

[0108]

[0109] Under a nitrogen atmosphere, 8 (69.8 mg, 0.10 mmol, 1.0 equivalent), 9-phenyl-9H-carbazole-2-yl)boronic acid (127.2 mg, 0.60 mmol, 6.0 equivalent), Pd(PPh3)4 (11.6 mg, 10.0 mol%), Na2CO3 (52.8 mg, 0.50 mmol, 5.0 equivalent), toluene (2.0 mL), MeOH (0.20 mL), and H2O (0.20 mL) were added sequentially to a Schlenk tube. The resulting mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with brine and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give product L9 (68.5 mg, 88%) as a colorless solid.

[0110] 1 H NMR (600 MHz, CDCl3) δ 8.30 (bs, 2H), 8.11 – 8.04 (m, 4H), 8.02 (d,J = 7.8 Hz, 2H), 7.89 (d, J = 7.8 Hz, 2H), 7.65 (s, 4H), 7.59 – 7.41 (m,10H), 7.39 – 7.34 (m, 4H), 7.32 (d, J = 8.4 Hz, 2H), 7.30 – 7.26 (m, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.14 – 7.04 (m, 2H), 7.01 (d, J = 7.2 Hz, 2H), 6.62(bs, 2H), 3.15 (d, J = 13.8 Hz, 2H), 2.76 (d, J = 13.8 Hz, 2H).

[0111] 13C NMR (151 MHz, CDCl3) δ 156.3, 149.4, 144.3, 141.22, 141.15, 140.4,138.3, 137.5, 136.1, 133.0, 132.5, 132.1, 131.3, 129.8, 129.5, 128.2, 127.5,127.4, 127.0, 126.1, 126.0, 125.9, 122.8, 122.5, 122.2, 122.1, 120.2, 120.0,119.6, 110.9, 109.6, 56.6, 36.7.

[0112] HRMS (ESI) m / z: [M + H] + Calcd for C 69 H 45 N4 929.3639; Found 929.3641.

[0113] Example 16:

[0114]

[0115] Under a nitrogen atmosphere, cyclic diaryliodomonium salt 9a (68.4 mg, 0.15 mmol), CuSCN (1.2 mg, 10.0 mol%), L6 (12.5 mg, 15.0 mol%), CaO (11.2 mg, 0.2 mmol), and dichloromethane (1.0 mL) were added sequentially to a Schlenk tube. Then, 1,2,3,4-tetrahydroquinoline (13.3 mg, 0.10 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give the corresponding product 11a (42.6 mg, 97%, 96% ee).

[0116] 11H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1Hz, 1H), 7.28 – 7.25 (m, 1H), 7.17 (t, J = 8.1 Hz, 2H), 6.93 (dd, J = 7.4,1.6 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 6.87 – 6.82 (m, 1H), 6.63 (bs, 1H),6.59 (td, J = 7.3, 1.2 Hz, 1H), 3.25 (bs, 1H), 3.05 (m, 1H), 2.74 (dt, J =14.4, 6.5 Hz, 1H), 2.59 (dt, J = 14.9, 6.4 Hz, 1H), 2.04 (s, 6H), 1.70 (bs,1H), 1.49 (bs, x000C1H)。

[0117] 13 13C NMR (151 MHz, CDCl3) δ 146.1, 145.1, 142.9, 141.7, 139.0, 138.4,136.7, x000C130.0, 129.5, 128.6, 128.5, 127.3, 126.1, 125.8, 123.2, 117.0, 115.3,102.9, 50.2, 27.8, 22.0, 21.6, 20.3。

[0118] HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 23 NI 440.0870; Found 440.0873。[[ID=1x000C4]] [[ID=xx000C5]]

[0119] HPLCconditions: Chiralcel OD-H, isopropanol / hexane = 0:100, flow: 0.8mL / min, λ= 320 nm; t r = 13.6 min (major), 17.3 min (minor), 96% ee。 [[ID=xx000C0]]

[0120] Example 17:

[0121]

[0122] Under a nitrogen atmosphere, cyclic diaryliodomonium salt 9a (68.4 mg, 0.15 mmol), CuSCN (1.2 mg, 10.0 mol%), L6 (12.5 mg, 15.0 mol%), CaO (11.2 mg, 0.2 mmol), and dichloromethane (1.0 mL) were added sequentially to a Schlenk tube. Then, benzylmorpholine (13.5 mg, 0.10 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give the corresponding product 11b (43.7 mg, 99%, 97% ee).

[0123] 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.31 (dt, J =15.2, 7.4 Hz, 2H), 7.21 (t, J = 8.3 Hz, 2H), 6.93 (t, J = 7.8 Hz, 1H), 6.86 –6.71 (m, 2H), 6.71 – 6.63 (m, 2H), 4.11 – 3.94 (m, 1H), 3.93 – 3.80 (m, 1H), 3.38 (bs, 1H), 3.18 – 3.04 (m, 1H), 2.08 (s, 3H), 2.06 (s, 3H).

[0124] 13 C NMR (126 MHz, CDCl3) δ 144.9, 144.7, 142.7, 141.1, 138.4, 136.9,133.7, 130.2, 128.8, 128.7, 127.4, 125.0, 120.6, 118.9, 116.9, 102.7, 64.1, 48.4, 21.9, 20.2.

[0125] HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 21 INO 442.0663; Found 442.0667.

[0126] HPLCconditions: Chiralcel AD-H, isopropanol / hexane = 0.3:99.7, flow:1.0 mL / min, λ= 320 nm; t r = 7.2 min (minor), 9.3 min (major), 97% ee.

[0127] Example 18:

[0128]

[0129] Under a nitrogen atmosphere, cyclic diaryliodomonium salt 9a (68.4 mg, 0.15 mmol), CuSCN (1.2 mg, 10.0 mol%), L6 (12.5 mg, 15.0 mol%), CaO (11.2 mg, 0.2 mmol), and dichloromethane (1.0 mL) were added sequentially to a Schlenk tube. Then, N-methylaniline (10.7 mg, 0.10 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to give the corresponding product 11c (28.9 mg, 70%, 94% ee).

[0130] 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8Hz, 1H), 7.19 (ddd, J = 7.5, 5.0, 1.1 Hz, 2H), 7.14 – 7.07 (m, 3H), 6.87 (t,J = 7.8 Hz, 1H), 6.74 – 6.67 (m, 3H), 2.88 (s, 3H), 2.02 (s, 3H), 1.98 (s,3H).

[0131] 13 C NMR (151 MHz, CDCl3) δ 149.3, 146.5, 142.7, 141.5, 138.8, 138.3,136.8, 130.0, 128.62, 128.58, 128.4, 127.3, 125.7, 117.7, 115.0, 102.8, 39.3, 21.8, 20.2.

[0132] HRMS (ESI) m / z: [M + H] + Calcd for C 21 H 21 IN 414.0714; Found 414.0728.

[0133] HPLC conditions: Chiralcel OD-H, isopropanol / hexane = 0:100, flow:0.8 mL / min, λ= 320 nm; t r = 15.6 min (major), 22.6 min (minor), 94% ee.

[0134] Example 19:

[0135]

[0136] Under a nitrogen atmosphere, cyclic diaryliodomonium salt 9b (79.2 mg, 0.15 mmol), CuSCN (1.2 mg, 10.0 mol%), L6 (12.5 mg, 15.0 mol%), CaO (11.2 mg, 0.2 mmol), and dichloromethane (1.0 mL) were added sequentially to a Schlenk tube. Then, benzylmorpholine (13.5 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to give the corresponding product 11d (35.8 mg, 70%, 88% ee).

[0137] 1 H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4Hz, 1H), 7.94 (dd, J = 8.4, 1.2 Hz, 1H), 7.90 – 7.82 (m, 1H), 7.70 – 7.60 (m,2H), 7.48 (ddd, J = 8.0, 6.7, 1.1 Hz, 1H), 7.44 (bs, 1H), 7.32 (t, J = 7.3Hz, 1H), 7.21 (bs, 2H), 6.83 – 6.58 (m, 3H), 4.31 – 3.34 (m, 2H), 3.05 (bs, 1H).

[0138] 13 C NMR (151 MHz, CDCl3) δ 144.8, 140.4, 136.1, 135.6, 134.0, 133.5,133.0, 131.7, 129.9, 129.4, 128.2, 127.1, 127.0, 126.9, 126.6, 126.1, 125.80,125.77, 120.7, 119.7, 116.8, 64.3, 48.3。

[0139] HRMS (ESI) m / z: [M + H] + Calcd for C 28 H 21 INO 514.0662; Found 514.0653。

[0140] HPLC conditions: Chiralcel AD-H, isopropanol / hexane = 3:97, flow: 1.0mL / min, λ= 320 nm; t r = 6.7 min (major), 10.0 min (minor), 88% ee。

Claims

1. A chiral bipyridine ligand, characterized in that... Its structure is as follows: 。 2. The method for synthesizing the chiral bipyridine ligand according to claim 1, characterized in that: Chiral 1,1'-binaphthyl-2,2'-dicarboxylic acid 1 was first esterified to obtain compound 5. Compound 5 underwent transmetalation at the ortho position of the ester group with the [Mg(TMP)2] reagent, and after the addition of iodine, diiodide compound 6 was successfully obtained. At -78°C, DIBAL-H solution was added dropwise to tetrahydrofuran solution of diiodide compound 6, and then the mixture was stirred in an oil bath at 45°C to reduce it to the corresponding diol. The diol was successfully reacted with PBr3 to obtain benzyl dibromo 7, which was then dialkylated with 5Hcyclopentane[2,1-b:3,4-b']bispyridine to obtain diiodide compound 8. Compound 8 was cross-coupled with arylborane through a catalyst to obtain chiral bipyridine ligand L6. The reaction route is shown below: ； The structure of the arylborane is shown below: 。 3. The synthesis method according to claim 2, characterized in that: When compound 8 undergoes a cross-coupling reaction with arylborane via a catalyst, the catalyst is a transition metal palladium.

4. The application of the chiral bipyridine ligand according to claim 1, characterized in that: The chiral bipyridine ligand was applied to a copper-catalyzed asymmetric ring-opening / cross-coupling reaction of cyclic diaryl iodine 9 and secondary amine 10 to obtain the product; The cyclic diaryl iodine 9 is selected from one of the following structures: ； The secondary amine 10 is selected from one of the following structures: 。

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