Chiral pyridine nitrogen oxide ligands, methods for their preparation and use in asymmetric catalysis

Abstract

The application discloses a kind of chiral pyridine nitrogen oxygen ligand, the present application is with various substituted proline amide or hydroxyproline amide 1 and pyridine formaldehyde or pyridine dimethyl formaldehyde 2 first condensation reaction, generate intermediate 3, then nitrogen atom in intermediate 3 occurs nitrogen oxygen oxidation reaction under the action of oxidizing agent m-chloroperbenzoic acid, generate final product chiral pyridine double nitrogen oxygen ligand L1 or chiral pyridine single nitrogen oxygen ligand L2.This kind of ligand includes latent pyridine group and nitrogen oxygen group, can and Lewis metal form six-membered ring coordination, to generate chiral ligand metal complex, as chiral ligand application in asymmetric catalytic reaction.The present application is simple and easy to operate, raw material synthesis is cheap and easy to obtain (chiral source is economic and easy to obtain chiral proline or proline), the ligand prepared by the present application has good air stability, wide applicability, and has good compatibility for various substituents.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chiral chemistry and asymmetric catalytic synthesis, in particular to a kind of chiral pyridine nitrogen oxygen ligand and its preparation method and application in asymmetric catalytic indole involved Friedel-Crafts alkylation reaction. BACKGROUND

[0002] The design and synthesis of superior chiral ligands play a key role in the development of asymmetric catalytic reactions, and are the most attractive and challenging goal in asymmetric catalysis. In addition, an economically viable synthetic route is also crucial for superior chiral ligands so that they can be widely used. In particular, N-oxides of amines are highly polar substances, and N-oxides of amines can be easily prepared by N-oxidation of pyridine compounds or tertiary amines. The oxygen atom generated in the N-oxide belongs to an electron-rich coordination site. Therefore, the unique properties of the electron pair of the N-oxide provide an opportunity to form complexes with a variety of metals. Some studies focus on the development of new chiral amine N-oxide ligands for metal-catalyzed reactions.

[0003] In N-oxides derived from tertiary amines, if the parent tertiary amine contains three different groups, a stable chiral center will be generated at the nitrogen center of the corresponding N-oxyl group. In this context, therefore, we designed and developed a new chiral pyridine-nitrogen oxygen ligand L derived from tertiary amines, and tested their application in asymmetric Friedel-Crafts alkylation of indole. Based on the design and synthesis of metal complexes of new types of pyridine nitrogen oxygen ligands, our design idea refers to the "eagle catches chicken" biomimetic catalytic model (as shown in Figure 1 ). The two nitrogen oxygen groups are analogous to two eagle claws, the metal is analogous to a chicken, the two phenyl groups are analogous to the wings of an eagle, and the nitrogen group of pyridine is analogous to the beak of an eagle. To our knowledge, our work is the first to design and synthesize chiral nitrogen oxygen groups with amide groups in trans configuration (as shown in Figure 1 ). SUMMARY

[0004] The purpose of the present application is to provide a kind of chiral pyridine nitrogen oxygen ligand (L1 and L2) and its preparation method and application, which is an important chiral pyridine nitrogen oxygen ligand. This kind of ligand contains a pyridine group and a nitrogen oxygen group (the nitrogen atom of pyridine and the oxygen atom of the nitrogen oxygen group belong to an electron-rich coordination site), which can form a six-membered ring coordination with a Lewis metal, thereby generating a chiral ligand metal complex, which is used as a chiral ligand in asymmetric catalytic reactions. Therefore, it has important application value in the field of asymmetric catalytic synthesis, and its synthesis method is very economical and simple. It also has good air stability, wide applicability, and good compatibility for various substituents.

[0005] The present application also discloses application of the chiral pyridine nitroxide ligand (L1 and L2) in asymmetric catalysis of Friedel-Crafts alkylation of indole.

[0006] The present application is achieved as follows: a chiral pyridine nitroxide ligand characterized in that the compound has a structure as shown in the general formula (I):

[0007]

[0008] in the formula, R 1 is hydroxyl or hydrogen; R 2 is fluorine, chlorine, bromine, methoxy, methyl, fused benzene or hydrogen; and Ar is a benzene ring substituted by fluorine, chlorine, bromine, methoxy or methyl.

[0009] Specifically, the chiral pyridine nitroxide ligand has one of the following structural formulae:

[0010]

[0011]

[0012] The preparation method of the chiral pyridine nitroxide ligand is characterized by: condensation reaction of corresponding proline amide or hydroxyproline amide 1 and pyridine formaldehyde or pyridine dimethyl formaldehyde 2 to generate an intermediate 3, then nitrogen atom in the intermediate 3 is oxidized by an oxidant m-chloroperoxybenzoic acid to generate the final product chiral pyridine bis-nitroxide ligand L1 or chiral pyridine mono-nitroxide ligand L2.

[0013] The synthesis route is as follows:

[0014]

[0015] The application of the chiral pyridine nitroxide ligand in asymmetric catalysis of Friedel-Crafts alkylation of indole.

[0016] The design idea of the present application is:

[0017] Our design: C2 symmetrical chiral pyridine nitroxide new ligand derived from tertiary amine

[0018]

[0019] Our design idea: "eagle catches chicken" biomimetic catalyst model: two nitroxide groups are analogous to two eagle claws, the metal is analogous to a chicken, two benzene groups are analogous to wings of an eagle, and the nitrogen group of pyridine is analogous to an eagle beak

[0020] By adopting the technical scheme, various substituted prolinamide or hydroxyprolinamide 1 is firstly subjected to condensation reaction with pyridine carboxaldehyde or pyridine dicarboxaldehyde 2 to generate intermediate 3, then the nitrogen atom in the intermediate 3 is subjected to nitrogen oxidation reaction under the action of oxidant meta-chloroperoxybenzoic acid to generate final product chiral pyridine bisnitrogen oxide ligand L1 or chiral pyridine mononitrogen oxide ligand L2, the ligand comprises potential pyridine groups and nitrogen oxide groups (the nitrogen atom of the pyridine and the oxygen atom of the nitrogen oxide group belong to electron-rich coordination sites), can form a six-membered ring with a Lewis metal, thereby generating a chiral ligand metal complex, which is applied as a chiral ligand in an asymmetric catalytic reaction. The present application is simple and easy to operate, and the raw materials are cheap and easy to synthesize (the chiral source is an economically available chiral proline or proline), the ligand prepared by the present application can be reacted in various organic solvents, has good air stability, wide applicability and good compatibility with various substituents. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 Design idea diagram of the chiral pyridine mononitrogen oxide ligand synthesized by the present application;

[0022] Figure 1 In the formula, M represents a metal, and Py-2NO-M represents a pyridine nitrogen oxide ligand and a metal complex;

[0023] Figure 2 Single crystal diagram of the chiral pyridine mononitrogen oxide ligand L2b and L2c of the embodiment of the present application;

[0024] Figure 3 And Figure 4 Spectrum data of the chiral pyridine mononitrogen oxide ligand L1a of the embodiment of the present application;

[0025] Figure 5 And Figure 6 Spectrum data of the chiral pyridine mononitrogen oxide ligand L1d of the embodiment of the present application;

[0026] Figure 7 And Figure 8 Spectrum data of the chiral pyridine mononitrogen oxide ligand L2f of the embodiment of the present application;

[0027] Figure 9 Spectrum data of the racemate and chiral liquid of compound 6a of the embodiment of the present application;

[0028] Figure 10 Spectrum data of the racemate and chiral liquid of compound 6b of the embodiment of the present application;

[0029] Figure 11 And Figure 12 Spectrum data of compound 6a of the embodiment of the present application;

[0030] Figure 13 AndFigure 14 Spectroscopic data of compound 6b of the embodiments of the present application. DETAILED DESCRIPTION

[0031] (1) Synthesis of chiral pyridine nitroxide ligand L1

[0032]

[0033] Chiral pyridine nitroxide ligand L1a: The starting material hydroxyprolinamide 1a (2.5 eq) and pyridine-2,6-dicarboxaldehyde (1 eq, 0.78 mmol) 2 were dissolved in a suitable amount of absolute ethanol, refluxed for 10 h, and then purified by silica gel column to obtain the white solid intermediate 3. The intermediate 3 (100 mg, 1 eq) of the second step reaction was dissolved in a suitable amount of chloroform, reacted with meta-chloroperoxybenzoic acid (2.5 eq) at room temperature for 20 min, and then purified by silica gel column after treatment of the reaction solution to obtain the white solid L1a, melting point: 249.1-249.3℃; yield 63%, >20:1 dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (CDCI3, 400 MHz) δ: 2.53-2.60 (m, 4H), 3.80-3.84 (m, 2H), 3.96 (d, J = 10.8 Hz, 2H), 4.14-4.17 (m, 2H), 4.51-4.53 (m, 2H), 6.05 (s, 2H), 7.19-7.25 (m, 8H), 7.68 (d, J = 7.6 Hz, 2H), 7.89-7.92 (m, 1H); 13 CNMR (CDCI3, 100 MHz) δ: 35.7, 70.2, 73.5, 75.0, 86.0, 122.3, 127.5, 128.6, 131.6, 132.4, 136.7, 148.5, 167.0; HRMS (ESI-TOF) m / z: Calcd. for C 29 H 29 N5NaO6[M+Na] + : 566.2008; Found: 566.2002.

[0034] The preparation methods of pyridine nitroxide ligands L1b-L1j prepared by the examples are the same as those of pyridine nitroxide ligand L1a, and the same feeding ratio as that of ligand L1a can be used to obtain ligands L1b-L1j, and the reaction yields are shown in Table 1, but it should be emphasized that the examples are intended to illustrate rather than limit the scope of the present application. The compounds of the present application are not limited to the contents shown in Table 1.

[0035] Table 1 is the chemical structure of the chiral pyridine nitroxide ligand L1

[0036]

[0037] The present example prepared chiral pyridine nitroxide ligand L1b: white solid, melting point: 248.6-249.5°C; yield 62%, 18:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.23 (s, 6H), 2.31-2.36 (m, 2H), 2.43-2.48 (m, 2H), 3.72 (d, J = 8.4 Hz, 2H), 4.14-4.18 (m, 2H), 4.35-4.39 (m, 2H), 4.44 (s, 2H), 6.79 (s, 2H), 7.10 (d, J = 8.4 Hz, 4H), 7.36 (d, J = 8.4 Hz, 4H), 7.59 (d, J = 8.0 Hz, 2H), 7.84-7.88 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 20.9, 36.4, 70.9, 74.9, 76.7, 86.8, 124.5, 128.7, 129.9, 133.4, 136.9, 151.1, 168.8; HRMS (ESI-TOF) m / z: Calcd. for C 31 H 33 N5NaO6[M+Na] + : 594.2323; Found: 594.2325.

[0038] The present example prepared chiral pyridine nitroxide ligand L1c: white solid, melting point: 245.3-245.6°C; yield 61%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.50-2.61 (m, 4H), 3.80-3.84 (m, 2H), 3.96 (d, J = 10.8 Hz, 2H), 4.14-4.17 (m, 2H), 4.51-4.53 (m, 2H), 6.05 (s, 2H), 7.19-7.24 (m, 8H), 7.68 (d, J = 7.6 Hz, 2H), 7.89-7.92 (m, 1H); 13 C NMR (CDC13, 100 MHz) δ: 35.7, 70.2, 73.5, 75.0, 86.0, 122.3, 127.5, 128.6, 131.6, 132.4, 136.7, 148.5, 167.0; HRMS (ESI-TOF) m / z: Calcd. for C 29 H 27 Cl2N5NaO6[M+Na] +: 634.1228; Found: 634.1220.

[0039] This example prepared chiral pyridine nitroxide ligand L1d: white solid, melting point: 223.5-224.0 °C; yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 1.97-2.03 (m, 2H), 2.25-2.36 (m, 4H), 2.46-2.54 (m, 2H), 3.80-3.85 (m, 6H), 6.08 (s, 2H), 7.06-7.10 (m, 2H), 7.19-7.23 (m, 4H), 7.31-7.33 (m, 4H), 7.67 (d, J = 7.6 Hz, 2H), 7.75-7.79 (m, 1H); 13 CNMR (CDC13, 100 MHz) δ: 21.7, 23.7, 70.4, 86.8, 120.8, 125.6, 127.2, 128.4, 134.5, 136.6, 149.3, 167.5; HRMS (ESI-TOF) m / z: Calcd. for C 29 H 29 N5NaO4[M+Na] + : 534.2112; Found: 534.2107.

[0040] This example prepared chiral pyridine nitroxide ligand L1e: white solid; yield 52%, 12:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 1.98-2.00 (m, 2H), 2.12-2.20 (m, 4H), 2.25-2.30 (m, 2H), 3.62-3.66 (m, 4H), 3.93-4.01 (m, 2H), 6.89 (s, 2H), 7.00-7.04 (m, 2H), 7.30-7.37 (m, 4H), 7.59 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 7.6 Hz, 2H), 7.85-7.89 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 22.8, 24.5, 71.4, 77.3, 86.4, 109.9 (d, J CF = 26.2 Hz), 113.3 (d, J CF = 21.1 Hz), 118.5, 129.0, 131.1 (d, J CF = 9.0 Hz), 136.8, 137.9 (d, JCF = 10.1 Hz), 150.5, 162.7 (d, J = 242.3 Hz), 169.3; HRMS (ESI-TOF) m / z: Calcd. for C CF = 242.3 Hz), 169.3; HRMS (ESI-TOF) m / z: Calcd. for C 29 H 27 F2N5NaO4[M+Na] + : 570.1923; Found: 570.1918.

[0041] The chiral pyridine nitroxide ligand L1f was prepared in this example: white solid, melting point: 268.2-268.9 °C; yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 HNMR (DMSO-d6, 400 MHz) δ: 1.97-1.99 (m, 2H), 2.13-2.33 (m, 12H), 3.65-3.69 (m, 2H), 3.94-4.03 (m, 4H), 6.75 (s, 2H), 7.06 (d, J = 8.8 Hz, 4H), 7.39 (d, J = 8.4 Hz, 4H), 7.57 (d, J = 7.6 Hz, 2H), 7.76-7.79 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 21.0, 22.9, 24.6, 71.6, 77.4, 87.4, 123.9, 128.4, 129.9, 133.6, 136.4, 136.9, 151.5, 169.2; HRMS (ESI-TOF) m / z: Calcd. for C 31 H 33 N5NaO4[M+Na] + : 562.2425; Found: 562.2418.

[0042] The chiral pyridine nitroxide ligand L1g was prepared in this example: white solid; yield 50%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.07-2.15 (m, 4H), 2.29 (s, 6H), 2.34-2.37 (m, 4H), 3.80 (s, 2H), 4.10-4.17 (m, 2H), 4.55 (s, 2H), 6.54 (s, 2H), 6.86-6.89 (m, 2H), 7.14-7.25 (m, 6H), 7.42 (d, J = 7.6 Hz, 2H), 7.70-7.74 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) δ: 18.5, 23.5, 25.6, 72.9, 77.7, 88.4, 127.6, 127.7, 129.2, 131.1, 133.9, 136.8, 137.6, 153.0, 170.4; HRMS (ESI-TOF) m / z: Calcd. for C 31 H 33 N5NaO4[M+Na] + : 562.2425; Found: 562.2419.

[0043] The chiral pyridine nitroxide ligand L1h was prepared in this example: white solid; yield 45%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.06-2.12 (m, 4H), 2.34-2.36 (m, 4H), 3.78-3.82 (m, 2H), 3.84 (s, 6H), 4.20-4.26 (m, 2H), 4.54-4.55 (m, 2H), 6.31 (s, 2H), 6.67-6.71 (m, 2H), 7.08-7.10 (m, 2H), 7.13 (s, 2H), 7.25-7.29 (m, 2H), 7.50 (d, J = 3.6 Hz, 2H), 7.68-7.72 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 23.0, 25.3, 56.4, 72.2, 77.4, 87.7, 112.5, 121.3, 122.8, 127.6, 130.6, 131.0, 137.4, 152.6, 155.8, 170.2; HRMS (ESI-TOF) m / z: Calcd. for C 31 H 33 N5NaO6[M+Na] + : 594.2323; Found: 594.2331.

[0044] The chiral pyridine nitroxide ligand L1i was prepared in this example: white solid; yield 45%, 14:1 dr; results of high resolution mass spectrometry tests, etc. are as follows: HRMS (ESI-TOF) m / z: Calcd. for C 29 H 27 F2N5NaO4[M+Na] + : 570.1923; Found: 634.1216.

[0045] The present example prepared chiral pyridine nitroxide ligand L1j: white solid; yield 45%, 12: 1 dr; the results of high resolution mass spectrometry test and the like are as follows: HRMS (ESI-TOF) m / z: Calcd. for C 29 H 27 Cl2N5NaO4[M+Na] + : 602.1332; Found: 602.1337.

[0046] (II), synthesis and preparation of chiral pyridine nitroxide ligand L2

[0047]

[0048] Chiral pyridine nitroxide ligand L2a: the starting proline amide 1a (1.1 eq) and pyridine-2-carboxaldehyde derivative 2 (1 eq, 0.4 mmol) were dissolved in an appropriate amount of anhydrous ethanol, refluxed for 10 h, and then purified by silica gel column to obtain white solid intermediate 3. The intermediate 3 (100 mg, 1 eq) of the second step reaction was dissolved in an appropriate amount of chloroform, and m-chloroperbenzoic acid (1.1 eq) was added at room temperature and reacted for 20 min. After the reaction solution was treated, purification by silica gel column was carried out to obtain yellowish solid L2a, melting point: 145.1-145.7℃; yield 65%, >20:1 dr. The results of nuclear magnetic resonance and high resolution mass spectrometry test are as follows: 1 H NMR (CDCI3, 400 MHz) δ: 2.06-2.13 (m, 1H), 2.38-2.46 (m, 1H), 2.53-2.63 (m, 2H), 3.93-3.99 (m, 2H), 4.63-4.66 (m, 1H), 6.20 (s, 1H), 7.05-7.09 (m, 1H), 7.17-7.21 (m, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.45-7.49 (m, 1H), 7.59-7.64 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H); 13 C NMR (CDCI3, 100 MHz) δ: 21.9, 23.8, 70.5, 87.8, 121.3, 122.2, 125.6, 126.5, 126.6, 127.5, 128.3, 128.8, 129.0, 134.8, 135.5, 146.5, 149.9, 168.5; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 19 N3NaO2[M+Na] + : 368.1369; Found: 368.1361.

[0049] The preparation method of pyridine nitrogen oxide ligand L2b~L2z-3 prepared by the example is the same as pyridine nitrogen oxide ligand L2a, the feeding ratio is the same as ligand L2a, and ligand L2b~L2z-3 can be obtained, and the reaction yield is shown in Table 2, but it should be emphasized that the examples are intended to illustrate but not limit the scope of the present application. The compounds of the present application are not limited to the contents represented in Table 2 and Table 3.

[0050] Table 2 is the chemical structure of preparing chiral pyridine nitrogen oxide ligand L2

[0051]

[0052] Table 3 is the chemical structure of preparing chiral pyridine nitrogen oxide ligand L2

[0053]

[0054] The example prepares chiral pyridine nitrogen oxide ligand L2b: light yellow solid, melting point: 143.5-143.9℃; yield 67%, >20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.04-2.07 (m, 1H), 2.17-2.23 (m, 1H), 2.35-2.44 (m, 2H), 3.66-3.70 (m, 1H), 3.96-4.03 (m, 1H), 4.31-4.34 (m, 1H), 6.83 (s, 1H), 7.16-7.20 (m, 1H), 7.32-7.36 (m, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 8.10-8.12 (m, 1H), 8.71 (d, J = 2.4 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 23.0, 24.9, 71.7, 77.5, 86.5, 121.5, 122.4, 126.5, 129.4, 129.5, 136.5, 139.4, 150.3, 151.4, 169.8; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 BrN3NaO2[M+Na] + : 396.0318; Found: 396.0322.

[0055] The example prepares chiral pyridine nitrogen oxide ligand L2c: light yellow solid, melting point: 150.2-151.1℃; yield 66%, >20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test are as follows: 1H NMR (DMSO-d6, 400 MHz) δ: 2.02-2.09 (m, 1H), 2.15-2.23 (m, 1H), 2.33-2.47 (m, 2H), 3.64-3.68 (m, 1H), 3.95-4.02 (m, 1H), 4.33-4.36 (m, 1H), 6.80 (s, 1H), 7.17-7.22 (m, 1H), 7.34-7.38 (m, 2H), 7.48-7.50 (m, 2H), 7.64-7.66 (m, 1H), 7.69-7.71 (m, 1H), 7.77-7.81 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 23.0, 24.9, 71.9, 77.5, 86.6, 122.7, 126.7, 127.0, 129.3, 129.5, 136.3, 140.2, 141.0, 154.0, 169.7; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 Br N3NaO2 [M+Na] + : 396.0318; Found: 396.0315.

[0056] The present example prepared chiral pyridine nitrogen oxide ligand L2d: yellowish solid, melting point: 145.8-146.9 °C; yield 68%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.02-2.08 (m, 1H), 2.16-2.23 (m, 1H), 2.33-2.47 (m, 2H), 3.65-3.69 (m, 1H), 3.95-4.02 (m, 1H), 4.35-4.38 (m, 1H), 6.83 (s, 1H), 7.17-7.21 (m, 1H), 7.34-7.38 (m, 2H), 7.49-7.53 (m, 3H), 7.68 (d, J = 7.2 Hz, 1H), 7.88-7.92 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 23.0, 24.9, 71.9, 77.5, 86.6, 122.6, 125.6, 126.6, 126.8, 129.5, 136.3, 140.5, 150.0, 153.5, 169.7; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 Cl N3NaO2 [M+Na] +: 352.0823; Found: 352.0825.

[0057] This example prepared chiral pyridine nitroxide ligand L2e: pale yellow solid, melting point: 120.1-120.1 °C; yield 64%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.03-2.07 (m, 1H), 2.17-2.24 (m, 1H), 2.36-2.45 (m, 2H), 3.71-3.76 (m, 1H), 4.05-4.12 (m, 1H), 4.31-4.34 (m, 1H), 7.03 (s, 1H), 7.16-7.20 (m, 1H), 7.33-7.37 (m, 2H), 7.49-7.53 (m, 3H), 7.76-7.81 (m, 1H), 8.46 (d, J = 4.8 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 23.0, 24.9, 71.9, 77.5, 81.6, 122.5, 124.4 (d, J CF = 21.2 Hz), 126.6, 127.1, 127.2, 129.5, 136.3, 140.3, 140.4, 145.7 (d, J CF = 5.5 Hz), 160.5 (d, J CF = 258.0 Hz), 170.0; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 FN3NaO2[M + Na] + : 336.1119; Found: 336.1121.

[0058] This example prepared chiral pyridine nitroxide ligand L2f: pale yellow solid, melting point: 145.7-146.6 °C; yield 65%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1H NMR (DMSO-d6, 400 MHz) δ: 2.50-2.54 (m, 2H), 3.74 (d, J = 9.2 Hz, 1H), 4.13-4.17 (m, 1H), 4.46 (d, J = 3.2 Hz, 1H), 4.76-4.80 (m, 1H), 6.75 (br s, 1H), 6.86 (s, 1H), 7.15-7.19 (m, 1H), 7.31-7.35 (m, 2H), 7.38-7.42 (m, 1H), 7.47-7.49 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.83-7.87 (m, 1H), 8.60-8.61 (m, 1H); 13 CNMR (DMSO-d6, 100 MHz) δ: 36.9, 71.1, 75.0, 76.8, 86.6, 122.5, 125.1, 126.5, 127.8, 129.4, 136.3, 137.0, 149.7, 151.6, 169.2; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 17 N3NaO3[M+Na] + : 334.1162; Found: 334.1166.

[0059] The present example prepared chiral pyridine nitrogen oxide ligand L2g: yellowish solid, melting point: 160.2-161.1 °C; yield 62%, 18: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry test, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.50-2.54 (m, 2H), 3.74 (d, J = 9.2 Hz, 1H), 4.13-4.17 (m, 1H), 4.46 (d, J = 3.2 Hz, 1H), 4.76-4.80 (m, 1H), 6.75 (br s, 1H), 6.86 (s, 1H), 7.15-7.19 (m, 1H), 7.31-7.35 (m, 2H), 7.38-7.42 (m, 1H), 7.47-7.49 (m, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.83-7.87 (m, 1H), 8.60-8.61 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 36.7, 71.0, 75.3, 76.8, 81.1, 122.7, 124.5 (d, J CF = 18.2 Hz), 126.8, 127.4 (d, J CF = 5.2 Hz), 129.6, 136.0, 139.5, 139.6, 145.8 (d, J CF = 5.3 Hz), 160.8 (d, J CF= 258.1 Hz), 169.3; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 FN3NaO3[M+Na] + : 352.1068; Found: 352.1071.

[0060] The chiral pyridine nitroxide ligand L2h was prepared in this example: pale yellow solid, melting point: 170.2-171.3 °C; yield 61%, 17:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.50-2.53 (m, 2H), 3.73 (d, J = 9.2 Hz, 1H), 4.14-4.18 (m, 1H), 4.46 (d, J = 3.2 Hz, 1H), 4.71-4.74 (m, 1H), 6.91 (s, 1H), 7.17-7.20 (m, 1H), 7.32-7.36 (m, 2H), 7.45-7.46 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 8.12-8.14 (m, 1H), 8.74 (d, J = 2.4 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 36.7, 70.9, 75.2, 76.8, 86.2, 121.8, 122.6, 126.7, 129.3, 129.4, 129.5, 136.1, 139.6, 150.5, 167.0; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 BrN3NaO3[M+Na] + : 412.0267; Found: 412.0263.

[0061] The chiral pyridine nitroxide ligand L2i was prepared in this example: pale yellow solid, melting point: 153.6-154.4 °C; yield 65%, 12:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1H NMR (DMSO-d6, 400 MHz) δ: 2.50-2.55 (m, 2H), 3.73 (d, J = 9.2 Hz, 1H), 4.14-4.18 (m, 1H), 4.46 (s, 1H), 4.73-4.77 (m, 1H), 6.90 (s, 1H), 7.18-7.22 (m, 1H), 7.34-7.38 (m, 2H), 7.46 (d, J = 7.6 Hz, 2H),.67 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.79-7.83 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 36.8, 71.0, 75.2, 76.8, 86.1, 122.9, 126.9, 127.1, 129.6, 129.7, 136.0, 140.3, 141.2, 153.2, 168.9; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 BrN3NaO3[M+Na] + : 412.0267; Found: 412.0264.

[0062] The present example prepared chiral pyridine nitrogen oxide ligand L2j: light yellow solid, melting point: 151.2-153.2 °C; yield 63%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry test, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.48-2.51 (m, 2H), 3.77 (d, J = 9.2 Hz, 1H), 4.10-4.14 (m, 1H), 4.46 (d, J = 2.8 Hz, 1H), 4.64-4.68 (m, 1H), 6.80 (br s, 1H), 7.01 (s, 1H), 7.13-7.17 (m, 1H), 7.28-7.34 (m, 3H), 7.41-7.43 (m, 2H), 7.65-7.67 (m, 1H), 8.40-8.41 (m, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 18.7, 36.9, 71.3, 74.9, 76.7, 83.1, 122.2, 124.8, 126.3, 129.4, 136.5, 136.6, 138.8, 146.8, 149.7, 169.5; HRMS (ESI-TOF) m / z: Calcd. for C 18 H 19 N3NaO3[M+Na] + : 348.1319; Found: 348.1322.

[0063] The present example prepared chiral pyridine nitroxide ligand L2k: light yellow solid, melting point: 152.3-153.0 °C; yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.18 (s, 3H), 2.59-2.70 (m, 2H), 3.85-3.89 (m, 1H), 4.02-4.07 (m, 1H), 4.50 (s, 1H), 4.92-4.96 (m, 1H), 6.20 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.38-7.40 (m, 1H), 7.46 (d, J = 4.4 Hz, 2H); 13 C NMR (CDC13, 100 MHz) δ: 21.0, 36.4, 71.0, 74.5, 76.2, 87.5, 123.2, 125.8, 130.0, 130.1, 132.2, 137.5, 139.1, 142.3, 150.9, 168.0; HRMS (ESI-TOF) m / z: Calcd. for C 18 H 18 BrN3NaO3[M+Na] + : 426.0424; Found: 426.0425.

[0064] The present example prepared chiral pyridine nitroxide ligand L2k: light yellow solid, melting point: 152.3-153.0 °C; yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.18 (s, 3H), 2.59-2.70 (m, 2H), 3.85-3.89 (m, 1H), 4.02-4.07 (m, 1H), 4.50 (s, 1H), 4.92-4.96 (m, 1H), 6.20 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.38-7.40 (m, 1H), 7.46 (d, J = 4.4 Hz, 2H); 13C NMR (CDC13, 100 MHz) δ: 19.3, 35.1, 69.9, 72.5, 74.7, 86.5, 121.0, 121.2, 126.0, 126.2, 126.9, 128.3, 128.4, 128.5, 131.0, 135.3, 135.5, 146.0, 148.5, 167.0; HRMS (ESI-TOF) m / z: Calcd. for C 18 H 19 N3NaO3[M + Na] + : 348.1319; Found: 348.1317.

[0065] The chiral pyridine nitroxide ligand L2m was prepared in this example: pale yellow solid, melting point: 146.2-147.7 °C; yield 60%, >20: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.15 (s, 3H), 2.70 (d, J = 6.0 Hz, 2H), 3.90-3.94 (m, 1H), 4.08 (d, J = 6.0 Hz, 1H), 4.55 (s, 1H), 5.03-5.06 (m, 1H), 6.23 (d, J = 1.6 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.47-7.51 (m, 1H), 7.58-7.66 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H); 13 C NMR (CDC13, 100 MHz) δ: 19.3, 35.1, 69.9, 72.5, 74.7, 86.5, 121.0, 121.2, 126.0, 126.2, 126.9, 128.3, 128.4, 128.5, 131.0, 135.3, 135.5, 146.0, 148.5, 167.0; HRMS (ESI-TOF) m / z: Calcd. for C 22 H 21 N3NaO3[M + Na] + : 398.1475; Found: 398.1477.

[0066] The chiral pyridine nitroxide ligand L2n was prepared in this example: pale yellow solid, melting point: 153.6-154.4 °C; yield 64%, >20: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1H NMR (CDC13, 400 MHz) δ: 2.69-2.73 (m, 2H), 3.85-3.89 (m, 1H), 4.02 (d, J = 10.4 Hz, 1H), 4.55-4.58 (m, 1H), 4.96-5.00 (m, 1H), 6.01 (s, 1H), 7.18-7.24 (m, 5H), 7.30-7.33 (m, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.70-7.75 (m, 1H), 8.62 (d, J = 8.4 Hz, 1H); 13 C NMR (CDC13, 100 MHz) δ: 35.8, 70.4, 73.4, 75.3, 86.9, 122.5, 124.4, 125.5, 128.5, 131.5, 132.8, 135.9, 148.5, 149.2, 167.7; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 ClN3NaO3 [M + Na] + : 368.0772; Found: 368.0775.

[0067] The present example prepared chiral pyridine nitrogen oxide ligand L2o: yellowish solid, melting point: 152.4-153.6 °C; yield 60%, 15: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.03-2.06 (m, 1H), 2.17-2.23 (m, 1H), 2.33-2.45 (m, 2H), 3.65-3.69 (m, 1H), 3.97-4.04 (m, 1H), 4.35-4.37 (m, 1H), 6.79 (s, 1H), 7.37-7.41 (m, 3H), 7.55 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.82-7.86 (m, 1H), 8.56 (d, J = 4.8 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 22.9, 24.9, 71.7, 77.3, 86.9, 123.9, 125.0, 127.9, 129.4, 130.3, 135.5, 136.8, 149.5, 152.0, 170.1; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 ClN3NaO2 [M + Na] + : 352.0823; Found: 352.0824.

[0068] The present example prepared chiral pyridine nitroxide ligand L2p: light yellow solid, melting point: 146.1-147.0 °C; yield 57%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.07-2.11 (m, 1H), 2.16 (s, 3H), 2.22-2.29 (m, 1H), 2.38-2.51 (m, 2H), 3.75-3.79 (m, 1H), 4.02-4.09 (m, 1H), 4.51-4.54 (m, 1H), 6.97 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.58-7.63 (m, 1H), 7.73-7.77 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.96-8.00 (m, 2H), 8.35 (d, J = 8.0 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 20.9, 23.1, 24.9, 71.7, 77.7, 87.6, 122.8, 124.6, 127.7, 128.3, 128.4, 129.5, 129.8, 130.3, 134.1, 135.9, 136.3, 147.1, 153.4, 169.7; HRMS (ESI-TOF) m / z: Calcd. for C 22 H 21 N3NaO2[M + Na] + : 382.1526; Found: 382.1526.

[0069] The present example prepared chiral pyridine nitroxide ligand L2q: light yellow solid, melting point: 160.2-161.3 °C; yield 56%, 16:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1H NMR (CDC13, 400 MHz) δ: 2.09-2.15 (m, 1H), 2.36-2.41 (m, 1H), 2.55-2.62 (m, 2H), 3.99-4.04 (m, 1H), 4.15-4.22 (m, 1H), 4.59-4.61 (m, 1H), 6.19 (s, 1H), 6.93-6.97 (m, 1H), 7.01-7.06 (m, 1H), 7.12-7.17 (m, 1H), 7.39-7.43 (m, 1H), 7.46-7.50 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.63-7.67 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 8.03-8.09 (m, 2H); 13 C NMR (CDC13, 100 MHz) δ: 21.9, 23.5, 70.7, 87.3, 115.4 (d, J CF = 19.2 Hz), 121.1 (d, J CF = 12.4 Hz), 122.8, 123.9 (d, J CF = 4.4 Hz), 126.6, 127.5, 128.8, 128.9, 129.0, 135.3, 146.4, 149.6, 156.8 (d, J CF = 247.3 Hz), 169.2; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 18 FN3NaO2[M+Na] + : 386.1275; Found: 386.1274.

[0070] The present example prepared chiral pyridine nitrogen oxide ligand L2r: light yellow solid, melting point: 160.5-161.1 °C; yield 53%, 10: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.06-2.12 (m, 1H), 2.34-2.38 (m, 1H), 2.55-2.62 (m, 2H), 3.94-3.98 (m, 1H), 4.07-4.14 (m, 1H), 4.61-4.63 (m, 1H), 5.99 (s, 1H), 6.97-7.01 (m, 1H), 7.03-7.08 (m, 1H), 7.16-7.25 (m, 3H), 7.41 (d, J = 7.6 Hz, 1H), 7.59-7.64 (m, 1H), 8.60-9.61 (m, 1H); 13C NMR(CDCl3,100MHz)δ:21.8,23.6,70.7,75.4,87.4,87.5,115.4(d,J CF =20.1Hz), 121.0(d,J CF =12.1Hz),123.9,124.0,126.2,128.6,129.0(d,J CF =8.4Hz),135.4,148.6,149.2,156.8(d,J CF =248.0Hz),160.9; HRMS(ESI-TOF)m / z:Calcd.for C 17 H 16 FN3NaO2[M+Na] + :336.1119;Found:336.1122。

[0071] In this embodiment, chiral pyridine nitrogen-oxygen ligand L2s was prepared as a pale yellow solid with a melting point of 158.4-159.2℃; yield 60%, 12:1 dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:2.00-2.07(m,1H),2.28(s,3H),2.32-2.37(m,1H),2.49-2.54(m,2H),3.97-4.02(m,2H),4.77-4.80(m,1H),6.18(s,1H ),6.89-6.92(m,1H),6.98-7.08(m,3H),7.40-7.44(m,1H),7.48(d,J=8 .4Hz,1H),7.58-7.62(m,1H),7.65(d,J=8.0Hz,1H),7.97-8.02(m,2H); 13 C NMR(CDCl3,100MHz)δ:18.7,23.0,24.5,71.3,77.0,89.6,123.7,126.9,127.1,127.5,127.7,128.5, 128.8,129.7,130.0,131.6,133.3,136.0,136.3,147.3,151.2,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 22 H 21 N3NaO2[M+Na] + :382.1526;Found:382.1525。

[0072] This example prepared chiral pyridine nitroxide ligand L2t: light yellow solid, melting point: 156.7-157.2 °C; yield 63%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 1.97-2.03 (m, 1H), 2.19 (s, 3H), 2.27-2.31 (m, 1H), 2.44-2.50 (m, 2H), 3.96-4.02 (m, 2H), 4.75-4.77 (m, 1H), 5.98 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.94-6.98 (m, 1H), 7.05-7.16 (m, 3H), 7.30 (d, J = 7.6 Hz, 1H), 7.49-7.53 (m, 1H), 8.54 (d, J = 4.8 Hz, 1H); 13 C NMR (CDC13, 100 MHz) δ: 17.5, 21.8, 23.5, 70.4, 75.9, 88.5, 123.9, 125.9, 126.1, 126.2, 127.8, 130.5, 132.1, 135.0, 135.5, 148.6, 149.7, 168.4; HRMS (ESI-TOF) m / z: Calcd. for C 18 H 19 N3NaO2[M+Na] + : 332.1369; Found: 332.1368.

[0073] This example prepared chiral pyridine nitroxide ligand L2u: light yellow solid, melting point: 150.9-151.2 °C; yield 65%, 20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.09-2.13 (m, 1H), 2.24-2.30 (m, 1H), 2.39-2.53 (m, 2H), 3.76-3.80 (m, 1H), 4.06-4.13 (m, 1H), 4.51-4.55 (m, 1H), 7.07 (s, 1H), 7.39-7.42 (m, 2H), 7.61-7.65 (m, 3H), 7.75-7.79 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.97-8.01 (m, 2H), 8.39 (d, J = 8.4 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ: 23.1, 24.9, 71.7, 77.6, 87.1, 124.2, 124.7, 127.8, 128.3, 128.4, 129.4, 129.5, 130.4, 130.5, 135.5, 136.4, 147.1, 153.0, 170.0; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 18 ClN3NaO2[M+Na] + : 402.0980; Found: 402.0981.

[0074] The chiral pyridine nitroxide ligand L2v was prepared in this example: pale yellow solid, melting point: 156.2-156.9 °C; yield 59%, 19:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 1.97-2.04 (m, 1H), 2.29-2.34 (m, 1H), 2.46-2.53 (m, 2H), 3.74 (s, 3H), 3.92-3.97 (m, 1H), 4.26-4.33 (m, 1H), 4.58-4.60 (m, 1H), 6.24 (s, 1H), 6.66-6.70 (m, 1H), 6.76-6.78 (m, 1H), 7.05-7.10 (m, 1H), 7.27-7.30 (m, 1H), 7.36-7.40 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.54-7.62 (m, 2H), 7.95-8.02 (m, 2H); 13 C NMR (CDC13, 100 MHz) δ: 22.8, 24.5, 55.8, 71.1, 76.4, 87.7, 111.6, 121.1, 122.3, 123.8, 127.4, 127.6, 128.4, 129.8, 129.9, 130.2, 136.2, 147.3, 151.1, 154.7, 170.1; HRMS (ESI-TOF) m / z: Calcd. for C 22 H 21 N3NaO3[M+Na] + : 398.1475; Found: 398.1475.

[0075] The chiral pyridine nitroxide ligand L2w was prepared in this example: pale yellow solid, melting point: 154.3-154.7 °C; yield 57%, 20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1H NMR (DMSO-d6, 400 MHz) δ: 2.09-2.13 (m, 1H), 2.24-2.31 (m, 1H), 2.40-2.53 (m, 2H), 3.77-3.81 (m, 1H), 4.06-4.13 (m, 1H), 4.52-4.55 (m, 1H), 7.07 (s, 1H), 7.52-7.65 (m, 5H), 7.74-7.79 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.97-8.00 (m, 2H), 8.39 (d, J = 8.4 Hz, 1H); 13 CNMR (DMSO-d6, 100 MHz) δ: 23.1, 25.0, 71.7, 77.6, 87.0, 118.7, 124.4, 124.7, 127.8, 128.3, 128.5, 129.5, 130.4, 132.3, 136.0, 136.4, 147.1, 153.0, 169.9; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 18 BrN3NaO2[M+Na] + : 446.0475; Found: 446.0476.

[0076] The present example prepared chiral pyridine nitrogen oxide ligand L2x: yellowish solid, melting point: 148.1-148.9 °C; yield 61%, 19:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry testing, etc. are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.03-2.05 (m, 1H), 2.17-2.23 (m, 1H), 2.33-2.43 (m, 2H), 3.67-3.72 (m, 1H), 3.97-4.04 (m, 1H), 4.36-4.38 (m, 1H), 6.81 (s, 1H), 7.37-7.40 (m, 1H), 7.47-7.54 (m, 4H), 7.66 (d, J = 7.6 Hz, 1H), 7.81-7.85 (m, 1H), 7.98-8.04 (m, 1H), 8.55 (d, J = 4.4 Hz, 1H); 13 CNMR (DMSO-d6, 100 MHz) δ: 22.9, 24.9, 71.6, 77.3, 86.8, 118.6, 124.2, 125.0, 127.9, 132.3, 135.9, 136.9, 149.6, 151.8, 169.9; HRMS (ESI-TOF) m / z: Calcd. for C 17 H 16 BrN3NaO2[M+Na]+ :396.0318; Found: 396.0322.

[0077] This example prepared chiral pyridine N-oxide ligand L2y: pale yellow solid, melting point: 157.3-157.9 °C; yield 60%, 18:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.07-2.14 (m, 1H), 2.37-2.46 (m, 1H), 2.54-2.64 (m, 2H), 3.96-3.99 (m, 2H), 4.62-4.65 (m, 1H), 6.18 (s, 1H), 6.86-6.91 (m, 2H), 7.26-7.29 (m, 2H), 7.47-7.51 (m, 1H), 7.61-7.66 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H); 13 C NMR (CDC13, 100 MHz) δ: 21.9, 23.7, 70.5, 88.0, 115.1 (d, J CF = 22.4 Hz), 122.3, 123.8 (d, J CF = 9.1 Hz), 126.6 (d, J CF = 11.4 Hz), 128.9 (d, J CF = 9.1 Hz), 135.6, 146.5, 149.6, 159.7 (d, J CF = 246.3 Hz), 168.5; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 18 FN3NaO2[M + Na] + : 386.1275; Found: 386.1277.

[0078] This example prepared chiral pyridine N-oxide ligand L2z: pale yellow solid, melting point: 156.8-156.8 °C; yield 62%, >20:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1H NMR (CDC13, 400 MHz) δ: 2.10-2.15 (m, 1H), 2.44-2.50 (m, 1H), 2.58-2.65 (m, 2H), 3.93-3.99 (m, 1H), 4.03-4.05 (m, 1H), 4.70-4.73 (m, 1H), 6.33 (s, 1H), 6.79-6.83 (m, 1H), 7.03-7.05 (m, 1H), 7.15-7.19 (m, 1H), 7.32-7.35 (m, 1H), 7.51-7.54 (m, 1H), 7.65-7.68 (m, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.78 (d, J = 6.4 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H); 13 C NMR (CDC13, 100 MHz) δ: 23.0, 24.7, 55.5, 71.5, 77.4, 89.4, 114.6, 123.4, 125.0, 127.7, 128.3, 130.0, 130.1, 136.6, 147.6, 151.0, 158.3, 169.6; HRMS (ESI-TOF) m / z: Calcd. for C 22 H 21 N3NaO3[M+Na] + : 398.1475; Found: 398.1473.

[0079] The present example prepared chiral pyridine nitrogen oxide ligand L2z-1: yellowish solid, melting point: 152.3-153.6 °C; yield 63%, 15:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.10-2.15 (m, 1H), 2.44-2.50 (m, 1H), 2.58-2.65 (m, 2H), 3.93-3.99 (m, 1H), 4.03-4.05 (m, 1H), 4.70-4.73 (m, 1H), 6.33 (s, 1H), 6.79-6.83 (m, 1H), 7.03-7.05 (m, 1H), 7.15-7.19 (m, 1H), 7.32-7.35 (m, 1H), 7.51-7.54 (m, 1H), 7.65-7.68 (m, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.78 (d, J = 6.4 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 8.16 (d, J = 6.8 Hz, 1H); 13 C NMR (CDC13, 100 MHz) δ: 22.9, 24.8, 71.5, 88.2, 109.6 (d, J CF = 20.1 Hz), 113.4 (d, JCF = 17.4 Hz), 116.9, 127.7, 127.8, 130.0 (d, J = 7.3 Hz), 130.6 (d, J = 7.3 Hz), 131.0 (d, J = 7.3 Hz), 133.7, 136.4, 138.0, 147.0, 153.1, 162.7 (d, J = 196.6 Hz), 169.5; HRMS (ESI-TOF) m / z: Calcd. for C CF H CF = 8.1 Hz), 136.8, 137.3 (d, J = 8.1 Hz), 147.6, 150.6, 162.7 (d, J = 196.6 Hz), 169.5; HRMS (ESI-TOF) m / z: Calcd. for C CF = 8.3 Hz), 147.6, 150.6, 162.7 (d, J = 196.6 Hz), 169.5; HRMS (ESI-TOF) m / z: Calcd. for C CF = 196.6 Hz), 169.5; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 18 FN3NaO2[M+Na] + : 386.1275; Found: 386.1279.

[0080] The present example prepared chiral pyridine nitrogen oxide ligand L2z-2: light yellow solid, melting point: 158.4-159.5 °C; yield 62%, 10:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.04-2.12 (m, 1H), 2.20-2.27 (m, 1H), 2.34-2.49 (m, 2H), 3.70-3.74 (m, 1H), 4.05-4.12 (m, 1H), 4.46-4.49 (m, 1H), 7.07 (s, 1H), 7.19-7.22 (m, 1H), 7.31-7.35 (m, 1H), 7.42-7.45 (m, 1H), 7.61-7.65 (m, 1H), 7.74-7.84 (m, 3H), 7.95-8.00 (m, 2H), 8.39 (d, J = 8.4 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 23.1, 25.0, 71.8, 77.6, 86.8, 120.6, 122.1, 124.7, 126.1, 127.8, 128.3, 128.4, 129.5, 130.4, 131.1, 133.7, 136.4, 138.0, 147.0, 153.1, 170.2; HRMS (ESI-TOF) m / z: Calcd. for C 21 H 18 ClN3NaO2[M+Na] + : 402.0980; Found: 402.0983.

[0081] The present example prepared chiral pyridine nitrogen oxygen ligand L2z-3: light yellow solid, melting point: 154.9-155.2℃; yield 61%, 20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test etc. are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 1.99-2.06 (m, 1H), 2.15 (s, 3H), 2.35-2.41 (m, 1H), 2.49-2.56 (m, 2H), 3.89-3.95 (m, 2H), 4.64-4.67 (m, 1H), 6.25 (s, 1H), 6.85 (d, J = 6.8 Hz, 1H), 6.98-7.05 (m, 2H), 7.21 (s, 1H), 7.41-7.45 (m, 1H), 7.56-7.63 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H); 13 C NMR (DMSO-d6, 100 MHz) δ: 20.4, 21.8, 23.7, 70.3, 76.4, 87.6, 118.3, 122.1, 122.2, 126.5, 126.6, 127.5, 128.0, 128.9, 129.0, 134.6, 135.5, 138.3, 146.5, 150.0, 168.3; HRMS (ESI-TOF) m / z: Calcd. for C 22 H 21 N3NaO2[M+Na] + : 382.1526; Found: 382.1525.

[0082] (Three), application of chiral pyridine nitrogen oxygen ligand in asymmetric catalytic indole Friedel-Crafts alkylation reaction

[0083] The chiral pyridine nitrogen oxygen ligand L of formula (1) of the present application, which contains a latent pyridine group and a nitrogen oxygen group (the nitrogen atom of the pyridine and the oxygen atom of the nitrogen oxygen group belong to electron-rich coordination sites), can form a six-membered ring coordination with Lewis metal to generate a chiral ligand metal complex, which is used as a dominant chiral ligand in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole. However, it should be emphasized that the chiral pyridine nitrogen oxygen ligand of the present application is not limited to only being used as a chiral ligand in asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0084] Example 1: application of chiral ligand L with various substituents in asymmetric catalytic Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxopyrrolidene olefin 5

[0085] To demonstrate the application value of the developed chiral pyridine nitrogen oxygen ligand L in asymmetric catalytic system, we choose Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidene olefin 5 as a template reaction, and select compounds L1a-L1d, L1f, L2a as chiral pyridine nitrogen oxygen ligand to generate chiral complex in situ with Lewis acid Ni(OTf)2, to verify the asymmetric catalytic effect of chiral pyridine nitrogen oxygen ligand L (Table 4).

[0086] Table 4 is the application of chiral ligand L with various substituents in asymmetric catalytic reaction

[0087]

[0088] Experimental conclusion: Friedel-Crafts alkylation template reaction of asymmetric catalytic indole 4 and 2,3-dioxypyrrolidene olefin 5 is selected as an evaluation index. The experimental results show that the chiral ligand L with various substituents of formula (1) shows asymmetric catalytic effect in Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidene olefin 5, which can develop into a new advantage chiral pyridine nitrogen oxygen ligand, and is worth further research.

[0089] Example 2: Application of chiral ligand L1a in situ generating chiral complex with various Lewis acids in Friedel-Crafts alkylation reaction of asymmetric catalytic indole 4 and 2,3-dioxypyrrolidene olefin 5

[0090] To demonstrate the application value of the developed chiral ligand L1a in asymmetric catalytic system, we choose Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidene olefin 5 as a template reaction, and select chiral ligand L1a to generate chiral complex in situ with various Lewis acids, to verify the asymmetric catalytic effect of chiral ligand L1a (Table 5).

[0091] Table 5 is the application of chiral ligand L1a in situ generating chiral complex with various Lewis acids in asymmetric catalytic reaction

[0092]

[0093] Experimental conclusion: Friedel-Crafts alkylation template reaction of asymmetric catalysis of indole 4 and 2,3-dioxypyrrolidene olefin 5 was selected as evaluation index. The experimental results showed that the chiral ligand L1a represented by formula (1) and various Lewis acids in situ generated chiral complex in Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidene olefin 5 showed asymmetric catalysis effect, which could develop into a new advantage chiral pyridine nitrogen oxygen ligand, and was worth further in-depth study.

[0094] Example 3: Application of chiral ligand L1a in asymmetric catalytic Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted 2,3-dioxypyrrolidene olefins 5

[0095] In order to prove the application value of the developed chiral ligand L1a in asymmetric catalytic system, Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted 2,3-dioxypyrrolidene olefins 5 was selected as template reaction to verify the catalytic effect of chiral ligand L1a (Table 6).

[0096] Table 6 is the application of chiral ligand L1a in asymmetric catalytic Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted 2,3-dioxypyrrolidene olefins 5

[0097]

[0098] Experimental conclusion: Friedel-Crafts alkylation template reaction of asymmetric catalysis of indole 4 and 2,3-dioxypyrrolidene olefin 5 was selected as evaluation index. The experimental results showed that the chiral ligand L1a represented by formula (1) and Ni(OTf)2 in situ generated chiral complex in Friedel-Crafts alkylation reaction of various substituted indoles 4 and various substituted 2,3-dioxypyrrolidene olefins 5 showed asymmetric catalysis effect, which could develop into a new advantage chiral pyridine nitrogen oxygen ligand, and was worth further in-depth study.

Claims

1. A chiral pyridine nitrogen-oxygen ligand, characterized in that: The compound has the structure shown in general formula (I): （I） In the formula, R 1 Ar is a hydroxyl or hydrogen; Ar is a phenyl substituted with fluorine, chlorine, bromine, methoxy or methyl.

2. A chiral pyridine nitrogen-oxygen ligand, characterized in that: Specifically, it is one of the following structures: 。 3. A chiral pyridine nitrogen-oxygen ligand, characterized in that: The compound has the structure shown in general formula (II): (I I) In the formula, R 1 For hydroxyl or hydrogen; R 2 Ar is a fluorine, chlorine, methoxy, methyl, cyclophenyl, or fluorine-, chlorine-, bromine-, methoxy-, or methyl-substituted phenyl group.

4. A chiral pyridine nitrogen-oxygen ligand, characterized in that: Specifically, it is one of the following structures: 。 5. A method for preparing the chiral pyridine nitrogen-oxygen ligand as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 undergoes a condensation reaction with compound 2 to generate intermediate 3. Then, the ammonia atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidizing agent meta-chloroperoxybenzoic acid to generate the final product, chiral pyridine dinitroxide ligand L1. The synthesis route is as follows: 。 6. A method for preparing the chiral pyridine nitrogen-oxygen ligand as described in claim 3, characterized in that: The corresponding proline amide or hydroxyproline amide 1 undergoes a condensation reaction with compound 2 to generate intermediate 3. Then, the ammonia atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidizing agent meta-chloroperoxybenzoic acid to generate the final product or chiral pyridine mononitrile ligand L2. The synthesis route is as follows: 。 7. The application of compound L in asymmetric catalytic indole-involved Friedel-Crafts alkylation reactions, characterized by: The structure of compound L is as follows: ； The asymmetric Friedel-Crafts alkylation reaction synthetic route is as follows: 。

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