Chiral bipyridine-nitrogen oxide ligands, their preparation methods, and their applications in asymmetric catalytic reactions

Abstract

This invention discloses a chiral bipyridine-nitrogen oxide ligand, its preparation method, and its application in asymmetric catalytic reactions. The chiral bipyridine-bis(nitrogen oxide) ligand BPy-2NO has the structure shown in general formula (I), and the chiral bipyridine-mono(nitrogen oxide) ligand BPy-NO has the structure shown in general formula (II). These ligands contain a bipyridine group and a nitrogen oxide group, and can form six-membered and five-membered rings with Lewis metals to generate chiral ligand-metal complexes, which are then used as chiral ligands in asymmetric catalytic reactions. Therefore, they have significant application value in the field of asymmetric catalytic synthesis, and their synthesis method is very economical and simple. They also exhibit good air stability, wide applicability, and good compatibility with various substituents.

Description

Technical Field

[0001] This invention relates to the fields of chiral chemistry and asymmetric catalytic synthesis, and in particular to a chiral bipyridine-nitrogen oxide ligand (BPy-2NO and BPy-NO), its preparation method, and its application in asymmetric catalytic indole-indole-mediated Friedel-Crafts alkylation reaction. Background Technology

[0002] Chiral pharmaceuticals are a cutting-edge field in the pharmaceutical industry. The Nobel Prizes in Chemistry in 2001 and 2021 were awarded to major contributors to chiral catalysis. Currently, there are approximately 2,000 drugs in use worldwide, with chiral drugs accounting for more than 50%. Among the 250 commonly used drugs in clinical practice, as many as 200 are chiral.

[0003] Key technologies for the preparation of chiral drugs have been selected as one of the "Top Ten Chemical Inventions That Change the World" by IUPAC. Asymmetric catalysis is the most efficient and environmentally friendly approach to obtaining chiral molecules, and one of its core scientific challenges is the creation of dominant chiral ligands and catalysts. The design and synthesis of original dominant chiral ligands play a crucial role in the development of asymmetric catalytic reactions and are among the most attractive and challenging goals in asymmetric catalysis, providing core technologies for the efficient and environmentally friendly synthesis of chiral drugs and drug candidates. Furthermore, economically feasible synthetic routes are also essential for dominant chiral ligands, enabling their widespread application. In particular, N-oxides of amines are highly polar substances, and they can be readily prepared through the N-oxidation of pyridine compounds or tertiary amines. The oxygen atoms generated in N-oxides belong to electron-rich coordination sites. Therefore, the unique properties of the electron pairs in N-oxides provide opportunities for complex formation with various metals. Some research focuses on developing novel chiral amine N-oxide ligands for metal-catalyzed reactions.

[0004] In tertiary amine-derived N-oxides, if the parent tertiary amine contains three distinct groups, the nitrogen center on the corresponding N-oxy group will generate a stable chiral center. Against this backdrop, we designed and developed a novel type of chiral tertiary amine-derived bipyridine-bis(oxy) ligand BPy-2NO and tested their application in the indole asymmetric Friedel-Crafts alkylation reaction. Based on the design and synthesis of this novel type of chiral bipyridine-bis(oxy) ligand-metal complex, our design concept references the biomimetic model of "eagle catching chicks"—a multidentate ligand chelation catalytic mechanism: the bis(oxy) group is likened to two eagle claws, the metal group to a chick, the two phenyl groups to the eagle's wings, and the nitrogen group of the bipyridine to the eagle's beak (e.g., ). Figure 1 and Figure 2 (As shown). Summary of the Invention

[0005] The purpose of this invention is to provide a chiral bipyridine-nitrogen oxide ligand (BPy-2NO and BPy-NO), its preparation method, and its applications. This is an important class of chiral bipyridine-nitrogen oxide ligands, containing a bipyridine group and a nitroxide group (the nitrogen group of bipyridine and the oxygen atom of the nitroxide group are electron-rich coordination sites). It can form six-membered and five-membered rings with Lewis metals, thereby generating chiral ligand-metal complexes, which are used as chiral ligands in asymmetric catalytic reactions. Therefore, it has significant application value in the field of asymmetric catalytic synthesis, and its synthesis method is very economical and simple. It also exhibits good air stability, wide applicability, and good compatibility with various substituents.

[0006] The present invention is achieved as follows: a chiral bipyridine-nitrogen oxide ligand (BPy-2NO and BPy-NO), characterized in that: the chiral bipyridine-bisnitrogen oxide ligand BPy-2NO has a structure as shown in general formula (I), and the chiral bipyridine-mononitrogen oxide ligand BPy-NO has a structure as shown in general formula (II).

[0007]

[0008] In the formula, R is a hydroxyl group or hydrogen; Ar is a benzene ring substituted with fluorine, chlorine, bromine, ethyl, isopropyl, tert-butyl, methoxy, methyl, or hydrogen.

[0009] A method for preparing chiral bipyridine-bis(nitroxide) ligand BPy-2NO is characterized by: a condensation reaction first occurs between the corresponding proline amide or hydroxyproline amide 1 and bipyridine-dicarboxaldehyde 2 to generate intermediate 3, and then the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant metachloroperoxybenzoic acid to generate the final product chiral bipyridine-bis(nitroxide) ligand BPy-2NO.

[0010] The synthesis route is as follows:

[0011]

[0012] A method for preparing chiral bipyridine-monooxy ligand BPy-NO is characterized by: a condensation reaction first between the corresponding proline amide or hydroxyproline amide 1 and bipyridine-monoformaldehyde 2 to generate intermediate 3, and then the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant metachloroperoxybenzoic acid to generate the final product chiral bipyridine-monooxy ligand BPy-NO.

[0013] The synthesis route is as follows:

[0014]

[0015] This invention also discovers the application of the chiral bipyridine-bis(oxo) ligand BPy-2NO as a ligand in the asymmetric catalytic Friedel-Crafts alkylation reaction involving indole.

[0016] This invention also discovers the application of the chiral bipyridine-monooxy ligand BPy-NO in asymmetric catalytic Friedel-Crafts alkylation reactions involving indole.

[0017] Our design concept is:

[0018]

[0019] By employing the above technical solutions, the corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with bipyridine-diformaldehyde 2 to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant meta-chloroperoxybenzoic acid to generate the final product, the chiral bipyridine-bis(nitroxide) ligand BPy-2NO. Alternatively, the corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with bipyridine-monoformaldehyde 2 to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant meta-chloroperoxybenzoic acid to generate the final product, the chiral bipyridine-mono(nitroxide) ligand BPy-NO. This type of ligand contains a bipyridine group and a nitroxide group (the nitrogen group of bipyridine and the oxygen atom of the nitroxide group are electron-rich coordination sites), and can form six-membered and five-membered rings with Lewis metals to generate chiral ligand-metal complexes, which can be used as chiral ligands in asymmetric catalytic reactions. Therefore, it has significant application value in the field of asymmetric catalytic synthesis, and its synthetic method is very economical and simple. It also exhibits good air stability, wide applicability, and excellent compatibility with various substituents. Attached Figure Description

[0020] Figure 1 and Figure 2 This invention presents the design concept and inventive diagram of the chiral bipyridine-bis(oxo) ligand complex synthesized in this invention.

[0021] Figure 2 In this context, the diazoxide group is likened to two eagle claws, the metal group to a chick, the two phenyl groups to an eagle's wings, and the nitrogen group of bipyridine to an eagle's beak.

[0022] Figure 3 and Figure 4 The spectral data of the chiral bipyridine-bis(oxo) ligand BPy-1-2NO are from an embodiment of the present invention.

[0023] Figure 5 and Figure 6 The spectral data of the chiral bipyridine-bis(oxo) ligand BPy-2-2NO are from an embodiment of the present invention.

[0024] Figure 7 and Figure 8 The spectral data of the chiral phenanthroline-bis(oxo) ligand Bpy-1-NO in this embodiment of the invention;

[0025] Figure 9 and Figure 10 The spectral data of the chiral phenanthroline-bis(oxo) ligand Bpy-2-NO are from an embodiment of the present invention.

[0026] Figure 11 The racemic mixture and chiral liquid phase spectral data of compound 6a from embodiments of the present invention are shown below.

[0027] Figure 12 The racemic mixture and chiral liquid phase spectral data of compound 8a from an embodiment of the present invention;

[0028] Figure 13 and Figure 14 The NMR spectrum data of compound 6a in this embodiment of the invention; Detailed Implementation

[0029] (I) Preparation of chiral bipyridine-bis(oxo) ligand BPy-2NO

[0030]

[0031] Chiral bipyridine-bis(oxo) ligand BPy-1-2NO: Proline 1a (2.5 eq) and bipyridine-dicarboxaldehyde (1 eq, 0.78 mmol)2 were dissolved in an appropriate amount of anhydrous ethanol and refluxed for 10 h. After treatment of the reaction solution, the mixture was purified by column chromatography to obtain a white solid intermediate 3. Intermediate 3 (100 mg, 1 eq) from the second step reaction was dissolved in an appropriate amount of chloroform and reacted at room temperature for 20 min. After treatment of the reaction solution, the mixture was purified by column chromatography to obtain a white solid BPy-1-2NO; the overall yield was 53%, >20:1dr. The results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.28(m,2H),2.45-2.66(m,6H),3.91-3.95(m,2H),4.16-4.24(m,2H),4.73-4.76(m,2H),6.79 (s,2H),7.12-7.16(m,2H),7.23-7.27(m,4H),7.40-7.43(m,4H),7.70-7.72(m,2H),7.97-8.01(m,2H),8.38-8.40(m,2H); 13C NMR (CD3OD, 100MHz) δ: 35.5, 70.0, 76.3, 76.7, 88.1, 122.2, 122.9, 126.8, 127.7, 128.9, 135.3, 138.2, 149.8, 155.2, 168.7; HRMS (ESI-TOF) m / z: Calcd.for C 34 H 32 N6NaO4[M+Na] + :611.2376;Found:611.2372。

[0032] The chiral bipyridine-bis(oxo) ligands BPy-2-2NO to BPy-17-2NO prepared by the examples were prepared using the same method as chiral bipyridine-bis(oxo) ligand BPy-1-2NO, with the same feed ratio. The ligands BPy-2-2NO to BPy-17-2NO were obtained, and the reaction yields are shown in Table 1. However, it should be emphasized that the examples are intended to illustrate, not limit, the scope of the invention. The compounds of the present invention are not limited to those shown in Table 1.

[0033] Table 1 shows the chemical structures for preparing the chiral bipyridine-bis(oxo) ligand BPy-2NO.

[0034]

[0035] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-2-2NO: a white solid was prepared with an overall yield of 51% and a concentration >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1H NMR(CD3OD,400MHz)δ:2.65-2.72(m,2H),2.84-2.91(m,2H),3.95(d,J=12.0Hz,2H),4.42-4.46(m,2H),4.65(d,J=6.0Hz,2H),4.97-5.00(m,2 H),6.80(s,2H),7.13-7.17(m,2H),7.24-7.28(m,4H),7.39-7.42(m,4 H),7.70(d,J=7.2Hz,2H),7.97-8.01(m,2H),8.37(d,J=8.0Hz,2H); 13C NMR (CD3OD, 100MHz) δ: 35.5, 70.0, 76.3, 76.7, 88.1, 122.2, 122.9, 126.8, 127.7, 128.9, 135.3, 138.2, 149.8, 155.2, 168.7; HRMS (ESI-TOF) m / z: Calcd.for C34H32N6NaO6[M+Na]+:643.2271; Found:643.2262.

[0036] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-3-2NO: a white solid was prepared with an overall yield of 50% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:1.05(s,6H),1.07(s,6H),2.23-2.28(m,2H),2.46-2.65(m,6H),2.69-2.76(m,2H),3.92-3.96(m,2H),4.15-4.22(m, 2H),4.75-4.78(m,2H),6.75(s,2H),7.07(d,J=8.4Hz,4H),7.31(d,J=8.4Hz,4H),7.70-7.72(m,2H),7.97-8.01(m,2H),8.41-8.43(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.4,22.9,23.0,24.6,33.5,71.0,76.9,87.9,122.0,123.0,1 26.9,127.5,133.1,138.2,147.8,150.4,155.2,169.3; HRMS(ESI-TOF)m / z:Calcd.for C 40 H 44 N6NaO4[M+Na] + :695.3312;Found:695.3294.

[0037] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-5-2NO: a white solid was prepared with an overall yield of 49% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.27-2.32(m,2H),2.50-2.60(m,4H),2.65-2.70(m,2H),3.98-4.02(m,2H),4.19-4.26(m,2H),4.79-4.82(m,2 H),6.83-6.88(m,2H),6.92(s,2H),7.20-7.27(m,4H),7.47-7.51(m,2H),7.81(d,J=7.6Hz,2H),8.05-8.09(m,2H),8.41-8.43(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.4,24.7,71.1,76.9,87.3,109.5(d,J CF=26.0Hz), 113.0(d,J CF =22.1Hz), 117.5(d,J CF =3.1Hz),122.1,127.7,130.4(d,J CF =9.0Hz), 137.1(d,J CF =10.0Hz),138.3,150.0,155.2,162.8(d,J CF =244.3Hz),169.4; HRMS(ESI-TOF)m / z:Calcd.for C 34 H 30 F2N6NaO4[M+Na] + :647.2186;Found:647.2173。

[0038] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-6-2NO: a white solid was prepared with an overall yield of 48% and a dr ratio >20:1. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:1.00-1.04(m,6H),2.23-2.28(m,2H),2.41-2.65(m,10H),3.92-3.96(m,2H),4.15-4.22(m,2H),4.75-4 .78(m,2H),6.74(s,2H),7.01(d,J=8.8Hz,4H),7.29(d,J=8.4Hz,4H),7.69-7.71(m,2H),7.98-8.02(m,2H),8.40-8.43(m,2H); 13 C NMR (CD3OD, 100MHz) δ: 14.5, 22.4, 24.6, 27.8, 71.0, 77.0, 87.9, 121.9, 123.0, 127. 6,128.3,133.0,138.2,143.3,150.3,155.1,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 40 N6NaO4[M+Na] + :667.3001;Found:667.2991.

[0039] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-7-2NO: a white solid was prepared with an overall yield of 50% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1H NMR(CD3OD,400MHz)δ:2.25-2.30(m,2H),2.46-2.70(m,6H),3.95-3.99(m,2H),4.17-4.24(m,2H),4.75-4.78(m,2H) ,6.83(s,2H),7.11-7.15(m,4H),7.39-7.43(m,4H),7.76(d,J=7.6Hz,2H),8.02-8.06(m,2H),8.40(d,J=8.0Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 22.5, 24.7, 71.0, 76.8, 87.4, 122.1, 123.9, 127.8, 128.9, 131.7, 134.2, 138.3, 150.0, 155.1, 169.4; HRMS (ESI-TOF) m / z: Calcd.forC 34 H 30 Cl2N6NaO4[M+Na] + :679.1593;Found:679.1582。

[0040] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-8-2NO: a white solid was prepared with an overall yield of 53% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:1.11(s,18H),2.23-2.28(m,2H),2.47-2.66(m,6H),3.95-3.99(m,2H),4.14-4.22(m,2H),4.77-4.80(m, 2H),6.77(s,2H),7.21(d,J=8.8Hz,4H),7.34(d,J=8.8Hz,4H),7.75(d,J=7.6Hz,2H),7.99-8.03(m,2H),8.44(d,J=7.6Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 22.5, 24.7, 30.3, 34.0, 71.0, 76.9, 87.8, 122.0, 122.4, 125. 9,127.6,132.9,138.3,149.8,150.4,155.2,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 42 H 48 N6NaO4[M+Na] + :723.3629;Found:723.3629.

[0041] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-9-2NO: a white solid was prepared with an overall yield of 52% and a dr ratio >20:1. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.10(s,6H),2.22-2.26(m,2H),2.43-2.66(m,6H),3.92-3.96(m,2H),4.14-4.22(m,2H),4.75-4.78(m, 2H),6.74(s,2H),6.98(d,J=8.8Hz,4H),7.26(d,J=8.8Hz,4H),7.71(d,J=7.2Hz,2H),7.97-8.01(m,2H),8.41(d,J=7.6Hz,2H); 13 C NMR(CD3OD,100MHz)δ:19.6,22.5,24.6,71.0,76.9,87.9,121.9,122.9,127.6, 129.4,132.8,136.9,138.2,150.3,155.1,169.3; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 36 N6NaO4[M+Na] + :639.2687;Found:639.2676.

[0042] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-10-2NO: a white solid was prepared with an overall yield of 51% and a dr ratio >20:1. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.28(m,2H),2.44-2.68(m,6H),3.92-3.96(m,2H),4.15-4.22(m,2H),4.72-4.75(m,2H) ,6.81(s,2H),7.25-7.28(m,4H),7.32-7.35(m,4H),7.74(d,J=8.1Hz,2H),8.01-8.04(m,2H),8.37(d,J=8.2Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 22.4, 24.7, 71.0, 76.8, 87.3, 119.5, 122.1, 124.0, 127.7, 131.9, 134.7, 138.3, 150.1, 155.1, 169.2; HRMS (ESI-TOF) m / z: Calcd.forC 34 H30 Br2N6NaO4[M+Na] + :767.0579;Found:767.0561.

[0043] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-13-2NO: a white solid was prepared with an overall yield of 53% and a 15:1 dr ratio. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.24-2.27 (m, 2H), 2.46-2.63 (m, 6H), 3.66 (s, 6H), 3.91-3.95 (m, 2H), 4.18-4.25 (m, 2H), 4.74 (d, J = 9. 2Hz,2H),6.68(s,2H),6.77-6.79(m,4H),7.26-7.28(m,4H),7.66(d,J=7.6Hz,2H),7.98-8.02(m,2H),8.42(d,J=7.6Hz,2H); 13 C NMR(CD3OD,100MHz)δ:22.4,24.5,54.5,71.0,76.9,88.4,114.1,121.8,125.2, 127.6,127.8,138.1,150.3,155.1,158.7,169.5; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 36 N6NaO6[M+Na] + :671.2581;Found:671.2565.

[0044] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-14-2NO: a white solid was prepared with an overall yield of 49% and a ratio of 18:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.30(m,2H),2.46-2.69(m,6H),3.93-3.97(m,2H),4.17-4.24(m,2H),4.75-4.78(m,2H),6.88(d,J=2H),7.0 6-7.09(m,2H),7.15-7.19(m,2H),7.28-7.30(m,2H),7.66-7.67(m,2H),7.77(d,J=7.6Hz,2H),8.02-8.06(m,2H),8.38(d,J=7.6Hz,2H); 13C NMR(CD3OD,100MHz)δ:22.4,24.7,71.0,76.8,87.2,120.4,122.1,122.5,126.4,127 .7,130.2,134.4,136.8,138.3,150.0,155.2,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 34 H 30 Cl2N6NaO4[M+Na] + :679.1598;Found:679.1595。

[0045] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-15-2NO: a white solid was prepared with an overall yield of 48% and a dr ratio >20:1. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.30(m,2H),2.44-2.67(m,6H),3.92-3.96(m,2H),4.19-4.26(m,2H),4.73-4.76(m, 2H),6.78(s,2H),7.00-7.04(m,4H),7.42-7.46(m,4H),7.70-7.72(m,2H),8.00-8.04(m,2H),8.39-8.41(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.4,24.6,71.0,76.8,87.9,115.6(d,J CF =23.1Hz), 122.0, 125.3 (d, J) CF =8.3Hz), 127.7, 131.5 (d, J) CF =3.4Hz),138.2,150.1,155.1,161.6(d,J CF =245.3Hz),169.4; HRMS(ESI-TOF)m / z:Calcd.for C 34 H 30 F2N6NaO4[M+Na] + :647.2189;Found:647.2189.

[0046] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-16-2NO: a white solid was prepared with an overall yield of 46% and a 20:1 dr ratio. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1H NMR(CD3OD,400MHz)δ:2.23-2.30(m,2H),2.43-2.68(m,6H),3.98-4.02(m,2H),4.26-4.33(m,2H),4.80-4.83(m,2H),6.63 (s,2H),7.03-7.07(m,2H),7.17-7.25(m,4H),7.29-7.35(m,2H),7.67-7.69(m,2H),7.99-8.03(m,2H),8.50-8.52(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.5,24.6,71.2,76.4,88.0,116.4(d,J CF =20.2Hz), 121.8(d,J CF =11.1Hz), 122.1, 124.7 (d, J) CF =4.3Hz),127.7,128.6,130.4(d,J CF =8.2Hz),138.3,150.1,155.2,158.7(d,J CF =249.1Hz),169.7; HRMS(ESI-TOF)m / z:Calcd.for C 34 H 30 F2N6NaO4[M+Na] + :647.2189;Found:647.2187.

[0047] In this embodiment, chiral bipyridine-bis(oxo) ligand BPy-17-2NO: a white solid was prepared with an overall yield of 50% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.16(s,6H),2.22-2.26(m,2H),2.45-2.65(m,6H),3.91-3.95(m,2H),4.16-4.23(m,2H),4.73-4.76(m,2 H),6.78(s,2H),6.95(d,J=7.6Hz,2H),7.09-7.17(m,4H),7.28(s,2H),7.70-7.72(m,2H),7.98-8.02(m,2H),8.39-8.41(m,2H); 13C NMR(CD3OD,100MHz)δ:20.0,22.4,24.6,70.9,77.0,87.9,119.9,121.9,123.5,127 .5,128.7,135.3,138.1,139.2,150.3,155.1,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 36 N6NaO4[M+Na] + :639.2690; Found:639.2689.

[0048] (II) Preparation of chiral bipyridine-monoxoxoligand BPy-NO

[0049]

[0050] Chiral bipyridine-monooxy ligand Bpy-1-NO: Proline amide 1a (1.5 eq) and bipyridine-monoformaldehyde (1 eq, 0.78 mmol) 2 were dissolved in an appropriate amount of anhydrous ethanol and refluxed for 10 h. After treatment of the reaction solution, the mixture was purified by column chromatography to obtain a white solid intermediate 3. Intermediate 3 (100 mg, 1 eq) from the second step reaction was dissolved in an appropriate amount of chloroform with m-chloroperoxybenzoic acid (1.5 eq) and reacted at room temperature for 20 min. After treatment of the reaction solution, the mixture was purified by column chromatography to obtain a pale yellow solid Bpy-1-NO, with a total yield of 52% and a dr ratio >20:1. The results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.29(m,

[0051] 1H),2.45-2.65(m,3H),3.93-3.97(m,1H),4.18-4.25(m,1H),4.77-4.80(m,1H),6.81(s,1H),7.15-7.20(m,1H),7.27-7.3 2(m,2H),7.39-7.42(m,1H),7.44-7.47(m,2H),7.68-7.70(m,1H),7.88-7.93(m,1H),7.97-8.00(m,1H),8.34(d,J=8.0Hz,

[0052] 1H),8.43-8.45(m,1H),8.61-8.63(m,1H); 13C NMR(CD3OD,100MHz)δ:22.4,24.5,70.9,76.8,87.8,120.9,121.8,122.9,124.3,126.8,127.2, 129.0,135.5,137.4,137.9,148.9,150.0,155.0,155.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for

[0053] C 22 H 20 N4NaO2[M+Na] + :395.1478;Found:395.1478.

[0054] The chiral bipyridine-monooxy ligands Bpy-2-NO to Bpy-12-NO prepared by the examples were prepared by the same method as those for chiral bipyridine-monooxy ligand Bpy-1-NO, with the same feed ratio as ligand Bpy-1-NO, yielding ligands Bpy-2-NO to Bpy-12-NO. The reaction yields are shown in Table 2. However, it should be emphasized that the examples are intended to illustrate, not limit, the scope of the invention. The compounds of the present invention are not limited to those shown in Table 2.

[0055] Table 2 shows the chemical structures for preparing the chiral bipyridine-monoxazone ligand BPy-NO.

[0056]

[0057] In this embodiment, chiral bipyridine-monooxy ligand Bpy-2-NO: a pale yellow solid was prepared with an overall yield of 50% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR (CD3OD, 400MHz)δ:

[0058] 2.64-2.71(m,1H),2.85-2.92(m,1H),3.98-4.01(m,1H),4.44-4.48(m,1H),

[0059] 4.66-4.69(m,1H),5.00-5.03(m,1H),6.81(s,1H),7.16-7.20(m,1H),7.27-7.32(m,

[0060] 2H),7.40-7.45(m,3H),7.68-7.70(m,1H),7.89-7.94(m,1H),7.97-8.01(m,1H),

[0061] 8.33-8.36(m,1H),8.44-8.46(m,1H),8.62-8.64(m,1H); 13 C NMR(CD3OD,100MHz)δ:35.5,70.0,76.4,76.6,88.2,120.9,122.0,123.0,124.3,126.8,127. 4,128.9,135.3,137.4,138.0,148.9,149.5,155.0,155.9,168.7; HRMS(ESI-TOF)m / z:Calcd.

[0062] for C 22 H 20 N4NaO3[M+Na] + :411.1428;Found:411.1427。

[0063] In this embodiment, chiral bipyridine-monooxy ligand Bpy-3-NO: a pale yellow solid was prepared with an overall yield of 51% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.20(s,3H),2.23-2.28(m,1H),2.45-2.62(m,3H),3.93-3. 97(m,1H),4.17-4.24(m,1H),4.76-4.79(m,1H),6.75(s,1H),7.08(d,J=8.4Hz,2H ),7.31(d,J=8.4Hz,2H),7.38-7.41(m,1H),7.67(d,J=7.6Hz,1H),7.88-7.92(m,1 H),7.95-7.99(m,1H),8.34-8.36(m,1H),8.43(d,J=8.0Hz,1H),8.61-8.63(m,1H); 13 C NMR(CD3OD,100MHz)δ:19.6,22.4,24.5,70.9,76.8,88.0,120.9,121.8,123.1,124.3,127.2,129 .4,132.8,137.1,137.4,137.9,148.9,150.1,155.0,155.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 23 H 22 N4NaO2[M+Na] + :409.1635; Found:409.1627.

[0064] In this embodiment, chiral bipyridine-monooxy ligand Bpy-4-NO: a pale yellow solid was prepared with an overall yield of 50% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23(s,3H),2.24-2.29(m,1H),2.45-2.63(m,3H),3.92-3.96( m,1H),4.17-4.24(m,1H),4.76-4.79(m,1H),6.79(s,1H),7.01(d,J=7.2Hz,1H),7.14 -7.22(m,2H),7.33(s,1H),7.39-7.42(m,1H),7.69(d,J=7.6Hz,1H),7.89-7.94(m,1H ),7.96-8.00(m,1H),8.35(d,J=8.0Hz,1H),8.43(d,J=8.0Hz,1H),8.62-8.63(m,1H); 13 C NMR(CD3OD,100MHz)δ:20.0,22.4,24.5,70.9,76.8,87.9,120.0,120.9,121.8,123.5,124.3,127.2,127 .5,128.8,135.3,137.4,137.9,139.2,148.9,150.1,155.0,155.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 23 H 22 N4NaO2[M+Na] + :409.1635; Found:409.1628.

[0065] In this embodiment, chiral bipyridine-monooxy ligand Bpy-5-NO: a pale yellow solid was prepared with an overall yield of 49% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:1.19(s,9H),2.23-2.29(m,1H),2.47-2.65(m,3H),3.94-3.98(m,1H),4.17-4.24(m,1H),4.77-4.80(m,1H),6.78(s ,1H),7.31-7.39(m,5H),7.69-7.71(m,1H),7.84-7.88(m,1H),7.96- 8.00(m,1H),8.33-8.36(m,1H),8.42-8.45(m,1H),8.59-8.61(m,1H); 13C NMR(CD3OD,100MHz)δ:22.4,24.5,30.2,34.0,70.9,76.8,87.9,120.9,121.8,122.6,124.3,125.9,1 27.2,132.8,137.4,137.9,148.9,150.1,150.2,155.0,155.8,169.4; HRMS(ESI-TOF)m / z:Calcd.forC 26 H 28 N4NaO2[M+Na] + :451.2104;Found:451.2108。

[0066] In this embodiment, chiral bipyridine-monooxy ligand Bpy-6-NO: a pale yellow solid was prepared with an overall yield of 48% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.24-2.29(m,1H),2.46-2.65(m,3H),3.93-3.97(m,1H),4.17-4.24(m,1H),4.76-4.79(m,1H),6.84(s,1H),7.36-7 .40(m,1H),7.43(s,4H),7.72-7.74(m,1H),7.86-7.90(m,1H),7.99- 8.03(m,1H),8.30-8.32(m,1H),8.44-8.46(m,1H),8.60-8.62(m,1H); 13 C NMR(CD3OD,100MHz)δ:22.4,24.6,71.0,76.7,87.4,119.7,120.9,122.0,124.2,124.3,127.3, 132.0,134.8,137.4,138.0,149.0,149.8,154.9,155.9,169.3; HRMS(ESI-TOF)m / z:Calcd.for C 22 H 19 BrN4NaO2[M+Na] + :473.0584;Found:473.0579。

[0067] In this embodiment, chiral bipyridine-monooxy ligand Bpy-7-NO: a pale yellow solid was prepared with an overall yield of 47% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1H NMR(CD3OD,400MHz)δ:1.07-1.11(m,3H),2.24-2.28(m,1H),2.46-2.63(m,5H),3. 93-3.97(m,1H),4.17-4.25(m,1H),4.77-4.80(m,1H),6.76(s,1H),7.11(d,J=8.8 Hz,2H),7.33-7.36(m,2H),7.37-7.40(m,1H),7.67-7.68(m,1H),7.86-7.91(m,1H ),7.95-7.99(m,1H),8.35(d,J=7.6Hz,1H),8.43-8.45(m,1H),8.61-8.63(m,1H); 13 C NMR(CD3OD,100MHz)δ:14.5,22.4,24.5,27.9,70.9,76.8,88.0,120.9,121.8,123.2,124.3,127.2,1 28.3,133.0,137.4,137.9,143.4,148.9,150.1,155.0,155.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 24 H 24 N4NaO2[M+Na] + :423.1791;Found:423.1796.

[0068] In this embodiment, chiral bipyridine-monooxy ligand Bpy-8-NO was prepared as a pale yellow solid with an overall yield of 45% and a ratio of 14:1 dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.67-2.73(m,1H),2.86-2.92(m,1H),4.00-4.03(m,1H), 4.46-4.51(m,1H),4.67-4.70(m,1H),5.03-5.06(m,1H),6.79(s,1H),7.03-7.07 (m,2H),7.38-7.42(m,1H),7.45-7.48(m,2H),7.69-7.71(m,1H),7.88-7.92(m, 1H),7.98-8.02(m,1H),8.34-8.37(m,1H),8.46-8.48(m,1H),8.62-8.64(m,1H); 13 C NMR(CD3OD,100MHz)δ:35.5,70.1,76.4,76.5,88.3,115.7(d,J CF=23.3Hz),120.9,122.1,124.4,125.5(d,J CF =8.1Hz), 127.5, 131.3 (d, J) CF =3.5Hz),137.4,138.1,149.0,149.4,154.9,156.0,161.7(d,J CF =245.4Hz),168.8; HRMS(ESI-TOF)m / z:Calcd.forC 22 H 19 FN4NaO3[M+Na] + :429.1339;Found:429.1350。

[0069] In this embodiment, the chiral bipyridine-monooxy ligand Bpy-9-NO: a pale yellow solid was prepared with an overall yield of 46% and a 20:1 dr ratio. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:1.12(s,3H),1.14(s,3H),2.64-2.71(m,1H),2.76-2.81(m,1H),2.85-2. 91(m,1H),3.99(d,J=11.6Hz,1H),4.43-4.48(m,1H),4.66-4.69(m,1H),5.00-5.03(m,1H),6.7 6(s,1H),7.15(d,J=8.4Hz,2H),7.32(d,J=8.8Hz,2H),7.40-7.43(m,1H),7.66-7.69(m,1H),7. 89-7.93(m,1H),7.96-8.00(m,1H),8.35(d,J=8.0Hz,1H),8.44-8.46(m,1H),8.62-8.64(m,1H); 13 C NMR(CD3OD,100MHz)δ:22.8,33.5,35.4,70.0,76.4,76.6,88.3,121.0,122.0,123.2,124.3,126.9,1 27.4,132.8,137.4,138.0,148.1,148.9,149.6,155.0,155.9,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 25 H 26 N4NaO3[M+Na] + :453.1897;Found:453.1901.

[0070] In this embodiment, the chiral bipyridine-monooxy ligand Bpy-10-NO: a pale yellow solid was prepared with an overall yield of 47% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:1.11(s,3H),1.13(s,3H),2.25-2.29(m,1H),2.46-2.64(m,3H),2 .75-2.82(m,1H),3.93-3.97(m,1H),4.18-4.25(m,1H),4.76-4.79(m,1H),6.76(s,1H),7 .15(d,J=8.8Hz,2H),7.35(d,J=8.4Hz,2H),7.38-7.41(m,1H),7.67-7.69(m,1H),7.87- 7.91(m,1H),7.96-8.00(m,1H),8.34-8.36(m,1H),8.43-8.45(m,1H),8.61-8.63(m,1H); 13 C NMR(CD3OD,100MHz)δ:22.4,22.8,24.5,33.5,70.9,76.8,88.0,120.9,121.8,123.2,124.3,126.9,1 27.2,133.0,137.4,137.9,148.0,148.9,150.1,155.0,155.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 25 H 26 N4NaO2[M+Na] + :437.1948; Found:437.1950.

[0071] In this embodiment, the chiral bipyridine-monooxy ligand Bpy-11-NO: a pale yellow solid was prepared with an overall yield of 52% and a dr ratio >20:1. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1H NMR(CD3OD,400MHz)δ:2.25-2.30(m,1H),2.46-2.65(m,3H),3.93-3.97(m, 1H),4.18-4.25(m,1H),4.76-4.79(m,1H),6.83(s,1H),7.28-7.31(m,2H),7 .38-7.42(m,1H),7.47-7.51(m,2H),7.71-7.74(m,1H),7.88-7.92(m,1H), 7.99-8.03(m,1H),8.30-8.33(m,1H),8.44-8.46(m,1H),8.61-8.63(m,1H); 13 C NMR(CD3OD,100MHz)δ:22.4,24.6,70.9,76.7,87.5,120.9,122.0,124.1,124.3,127.3,129.0, 132.0,134.3,137.4,138.0,149.0,149.8,154.9,155.9,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 22 H 19 ClN4NaO2[M+Na] + :429.1089;Found:429.1095.

[0072] In this embodiment, the chiral bipyridine-monooxy ligand Bpy-12-NO: a pale yellow solid was prepared with an overall yield of 51% and a ratio >20:1dr. The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR(CD3OD,400MHz)δ:2.66-2.73(m,1H),2.86-2.92(m,1H),3.98-4.01(m,1H), 4.43-4.48(m,1H),4.66-4.70(m,1H),5.00-5.03(m,1H),6.83(s,1H),7.27-7.31 (m,2H),7.39-7.42(m,1H),7.44-7.48(m,2H),7.71-7.73(m,1H),7.88-7.92(m, 1H),7.99-8.03(m,1H),8.30-8.33(m,1H),8.45-8.47(m,1H),8.62-8.63(m,1H); 13C NMR(CD3OD,100MHz)δ:35.5,70.0,76.4,76.5,87.9,120.9,122.1,124.2,124.4,127.5,129.0, 132.0,134.1,137.4,138.1,149.0,149.3,154.9,156.0,168.6; HRMS(ESI-TOF)m / z:Calcd.for C 22 H 19 ClN4NaO3[M+Na] + :445.1038;Found:445.1039。

[0073] (III) Application of chiral bipyridine-nitrogen oxide ligands (BPy-2NO and BPy-NO) in asymmetric catalytic Friedel-Crafts alkylation of indole

[0074] The chiral bipyridine-oxygen ligands of formula (1) of the present invention (BPy-2NO and BPy-NO) contain a bipyridine group and an oxy group (the nitrogen atom of the bipyridine and the oxygen atom of the oxy group are electron-rich coordination sites), thereby enabling them to form six-membered and five-membered ring coordination with Lewis metals to generate chiral ligand-metal complexes. These complexes are used as dominant chiral ligands in asymmetric catalytic Friedel-Crafts alkylation reactions involving indole. However, it should be emphasized that the chiral pyridine-oxygen ligands of the present invention are not limited to use as chiral ligands only in asymmetric catalytic Friedel-Crafts alkylation reactions of indole.

[0075] Example 1: Application of chiral ligands BPy-2NO with various substituents in the asymmetric Friedel-Crafts alkylation reaction of indole 4a and enone ester 5a

[0076] Table 3 shows the applications of chiral ligands Bpy-2NO with various substituents in asymmetric catalytic reactions.

[0077]

[0078] To demonstrate the application value of the developed chiral ligand Bpy-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction involving indole 4a and enone ester 5a as the template reaction. We selected compounds Bpy-1-2NO to Bpy-17-2NO as chiral bipyridine-bis(oxo) ligands to generate chiral complexes in situ with Lewis acid Ni(OTf)2, and verified the asymmetric catalytic effect of chiral ligand Bpy-2NO (Table 3).

[0079] Experimental conclusion: The Friedel-Crafts alkylation template reaction of indole 4a and enone ester 5a was selected as the evaluation index for asymmetric catalysis. The experimental results show that the chiral ligands Bpy-1-2NO to Bpy-17-2NO with various substituents shown in formula (1) all exhibited asymmetric catalytic effects in the Friedel-Crafts alkylation reaction involving indole 4a and enone ester 5a, and can be developed into a new dominant chiral bipyridine-bis(nitroxide) ligand Bpy-2NO, which is worthy of further in-depth research.

[0080] Example 2: Application of chiral ligand Bpy-1-2NO in the asymmetric catalytic Friedel-Crafts alkylation reaction of various substituent indoles 4 with various substituent enone esters 5

[0081] To demonstrate the application value of the developed chiral ligand Bpy-1-2NO in asymmetric catalytic systems, we selected Friedel-Crafts alkylation reactions of various substituents of indole 4 and various substituents of enone ester 5 as template reactions to verify the catalytic effect of chiral ligand Bpy-1-2NO (Table 4).

[0082] Table 4 shows the application of the chiral ligand Bpy-1-2NO in the asymmetric catalytic Friedel-Crafts alkylation of various substituents of indole 4 and various substituents of ketene ester 5.

[0083]

[0084] Experimental conclusion: The Friedel-Crafts alkylation template reaction of indole 4 and various substituent ketene esters 5 was selected as the evaluation index for asymmetric catalysis. The experimental results show that the chiral ligand Bpy-1-2NO shown in formula (1) and Ni(OTf)2 in situ generated a chiral complex that exhibits asymmetric catalytic effect in the Friedel-Crafts alkylation reaction of various substituent indole 4 and various substituent ketene esters 5. It can be developed into a new dominant chiral pyridine nitrogen-oxygen ligand, which is worthy of further in-depth research.

[0085] Example 3: Application of chiral ligands BPy-NO with various substituents in the catalytic asymmetric Friedel-Crafts alkylation reaction of indole 4a and 2,3-dioxopyrrolidine olefin 7a

[0086] To demonstrate the application value of the developed chiral ligand Bpy-NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction involving indole 4a and 2,3-dioxopyrrolidine olefin 7a as the template reaction. We selected compounds Bpy-1-NO to Bpy-12-NO as chiral bipyridine-nitrogen oxide ligands to generate chiral complexes in situ with Lewis acid Ni(OTf)2, thus verifying the asymmetric catalytic effect of the chiral ligand Bpy-NO (Table 5).

[0087] Table 5 shows the applications of chiral ligands Bpy-NO with various substituents in asymmetric catalytic reactions.

[0088]

[0089] Experimental Conclusion: The Friedel-Crafts alkylation template reaction of indole 4a and 2,3-dioxopyrrolidine olefin 7a was selected as the evaluation index. The experimental results show that the chiral ligands Bpy-1-NO to Bpy-12-NO with various substituents shown in formula (1) all exhibited asymmetric catalytic effects in the Friedel-Crafts alkylation reaction involving indole 4a and 2,3-dioxopyrrolidine olefin 7a, and can be developed into a new dominant chiral bipyridine-nitrogen oxide ligand Bpy-NO, which is worthy of further in-depth research.

Claims

1. A chiral bipyridine-nitrogen oxide ligand (BPy-2NO and BPy-NO), characterized in that: The chiral bipyridine-bis(nitroxide) ligand BPy-2NO has the structure shown in general formula (I), and the chiral bipyridine-mono(nitroxide) ligand BPy-NO has the structure shown in general formula (II). （I） （Ⅱ）； In the formula, R is a hydroxyl group or hydrogen; Ar is a fluorine, chlorine, bromine, ethyl, isopropyl, tert-butyl, methoxy, methyl, or hydrogen-substituted phenyl group.

2. A chiral bipyridine-nitrogen oxide ligand (BPy-2NO and BPy-NO), characterized in that: The chiral bipyridine-bis(oxo) ligand BPy-2NO has one of the following structural formulas: ； The chiral bipyridine-monooxy ligand BPy-NO has one of the following structural formulas: 。 3. A method for preparing the chiral bipyridine-bis(oxo) ligand BPy-2NO as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 and bipyridine-dicarboxaldehyde 2 first undergo a condensation reaction to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant metachloroperoxybenzoic acid to generate the final product chiral bipyridine-dinitrogen oxide ligand BPy-2NO. The synthesis route is as follows: 。 4. A method for preparing the chiral bipyridine-monooxy ligand BPy-NO as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 and bipyridine-monoformaldehyde 2 first undergo a condensation reaction to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant metachloroperoxybenzoic acid to generate the final product chiral bipyridine-monooxy ligand BPy-NO. The synthesis route is as follows: 。 5. The application of the chiral bipyridine-bis(oxo) ligand BPy-2NO as described in claim 2 as a ligand in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole, characterized in that, The alkylation reaction synthesis route is as follows: 。 6. The application of the chiral bipyridine-monooxy ligand BPy-NO as described in claim 2 in asymmetric catalytic Friedel-Crafts alkylation reactions involving indole, characterized in that, The alkylation reaction synthetic route is as follows: 。

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