Chiral phenanthroline-diazoxy ligand and intermediate, preparation method thereof and application in asymmetric catalytic reaction

Abstract

The present invention discloses a chiral phenanthroline-bis-nitrogen oxide ligand and intermediate and its preparation method and application in asymmetric catalytic reaction.Chiral phenanthroline-bis-nitrogen oxide ligand Pe-2NO and intermediate Pe-2N, it is characterised in that: chiral phenanthroline-bis-nitrogen oxide ligand Pe-2NO has the structure shown in general formula (Ⅰ), intermediate Pe-2N has the structure shown in general formula (Ⅱ); Such ligands include phenanthroline groups and nitrogen oxide groups, can form two six-membered rings and one five-membered ring coordination with Lewis metal, thereby generating a chiral ligand metal complex, which is applied as a chiral ligand in asymmetric catalytic reaction. The present invention is simple and easy to operate, and raw material synthesis is cheap and easy to obtain (chiral source is economically easy to obtain chiral proline or proline), and the ligand prepared by the present invention can be reacted in various organic solvents, also has good air stability, wide applicability, and has good compatibility for various substituents.

Description

Technical Field

[0001] The present invention relates to the technical fields of chiral chemistry and asymmetric catalytic synthesis, in particular to a chiral phenanthroline-diazoxy ligand and intermediate, a preparation method thereof, and application in asymmetric catalytic reactions. Background Art

[0002] Chiral pharmaceuticals are at the forefront of the pharmaceutical industry. The 2001 and 2021 Nobel Prizes in Chemistry were awarded to key contributors to chiral catalysis. Currently, there are approximately 2,000 drugs in use worldwide, with chiral drugs accounting for over 50%. Of the 250 drugs commonly used in clinical practice, as many as 200 are chiral.

[0003] A key technology for the preparation of chiral drugs has been selected as one of the "Top Ten World-Changing Chemical Inventions" by IUPAC. Asymmetric catalysis is the most efficient and greenest approach to obtaining chiral molecules. One of its core scientific challenges is the creation of chirally dominant ligands and catalysts. Original chirally dominant catalysts are the foundation and source of independent research and development for the synthesis of chiral compounds. They enable many challenging or previously unattainable new reactions and provide core technologies for the efficient and green synthesis of chiral drugs and drug candidates. Furthermore, economically viable synthetic routes are crucial for chirally dominant ligands, ensuring their widespread application. In particular, amine N-oxides are highly polar substances and can be readily prepared through the N-oxidation of pyridines or tertiary amines. The oxygen atoms generated in N-oxides are electron-rich coordination sites. Therefore, the unique properties of the electron pairs of N-oxides offer opportunities for complex formation with a variety of metals. Several studies have focused 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 different groups, the nitrogen center on the corresponding N-oxyl group will generate a stable chiral center. In this context, we designed and developed a new type of chiral tertiary amine-derived phenanthroline-diazotyl ligand Pe-2NO and tested its application in the asymmetric Friedel-Crafts alkylation of indole. Based on the design and synthesis of a new type of chiral phenanthroline-diazotyl ligand metal complex, our design approach refers to the multidentate ligand chelation catalytic mechanism of the "eagle catching chicks" biomimetic model: the dizotyl group is likened to the two eagle claws, the metal group is likened to the chick, the two phenyl groups are likened to the eagle's wings, and the nitrogen group of the phenanthroline is likened to the eagle's beak (such as Figure 1 and Figure 2 shown). Summary of the Invention

[0005] The present invention aims to provide a chiral phenanthroline-diazolyl ligand Pe-2NO and an intermediate Pe-2N, and a preparation method and application thereof. The chiral phenanthroline-diazolyl ligand comprises a phenanthroline group and a nitroxide group (the nitrogen group of the phenanthroline and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), and can form two six-membered rings and one five-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, the chiral ligand 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.

[0006] The present invention is achieved as follows: a chiral phenanthroline-diazolyl ligand Pe-2NO and an intermediate Pe-2N, characterized in that the chiral phenanthroline-diazolyl ligand Pe-2NO has a structure as shown in general formula (I), and the intermediate Pe-2N 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, methoxy, methyl or hydrogen.

[0009] The method for preparing a chiral phenanthroline-diazoxy ligand Pe-2NO and an intermediate Pe-2N is characterized in that: a corresponding prolineamide or hydroxyprolineamide 1 and a phenanthroline-2,9-dicarboxaldehyde 2 are first subjected to a condensation reaction to generate the desired intermediate Pe-2N, and then the nitrogen atom in the intermediate Pe-2N undergoes a nitrogen oxidation reaction under the action of an oxidant, meta-chloroperbenzoic acid, to generate a chiral phenanthroline-diazoxy ligand Pe-2NO.

[0010] The synthetic route is as follows:

[0011]

[0012] The present invention also finds the application of the chiral phenanthroline-diazolyl ligand intermediate Pe-2N in synthesizing the chiral phenanthroline-diazolyl ligand Pe-2NO.

[0013] The present invention also found the application of chiral phenanthroline-diazotol ligand intermediate Pe-2N as a ligand in the asymmetric catalytic indole-involved Friedel-Crafts alkylation reaction.

[0014] The present invention also finds the application of chiral phenanthroline-diazoxide ligand Pe-2NO in asymmetric catalytic indole Friedel-Crafts alkylation reaction.

[0015] The design idea of ​​the present invention is:

[0016]

[0017] By adopting the above technical scheme, the corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with phenanthroline-2,9-dicarboxaldehyde 2 to generate the desired intermediate Pe-2N, and then the nitrogen atom in the intermediate Pe-2N undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperbenzoic acid to generate a chiral phenanthroline-diazotoxy ligand Pe-2NO. This type of ligand contains a phenanthroline group and a nitroxide group (the nitrogen group of phenanthroline and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), which can form two six-membered rings and one five-membered ring coordination with the Lewis metal, thereby generating a chiral ligand metal complex, which is used as a chiral ligand in asymmetric catalytic reactions. The present invention is simple and easy to operate, the raw materials are cheap and easy to synthesize (the chiral source is economically available chiral proline or proline), and the ligand prepared by the present invention can react in various organic solvents, also has good air stability, wide applicability, and good compatibility with various substituents. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 and Figure 2 The design ideas and creative drawings of the chiral phenanthroline-diazolyl ligand complex synthesized by the present invention;

[0019] Figure 2 Among them, the dinitrogen oxide group is likened to the two eagle claws, the metal group is likened to the chick, the two phenyl groups are likened to the eagle's wings, and the nitrogen group of phenanthroline is likened to the eagle's beak;

[0020] Figure 3 and Figure 4 This is the spectrum data of the chiral phenanthroline-diazotol ligand Pe-1-2NO according to an embodiment of the present invention;

[0021] Figure 5 and Figure 6 This is the spectrum data of the chiral phenanthroline-diazotol ligand Pe-2-2NO according to an embodiment of the present invention;

[0022] Figure 7 and Figure 8 This is the Pe-1-2N spectrum data of the intermediate of the chiral phenanthroline-diazolyl ligand of the embodiment of the present invention;

[0023] Figure 9 This is a single crystal image of the intermediate Pe-3-2N according to an embodiment of the present invention;

[0024] Figure 10 The racemate and chiral liquid chromatography chromatographic data of compound 5a according to the examples of the present invention are shown. DETAILED DESCRIPTION

[0025] (I) Synthesis and preparation of the intermediate Pe-2N of chiral phenanthroline-diazoxide ligand

[0026]

[0027] Chiral phenanthroline-diazoxide ligand intermediate Pe-1-2N: Prolinamide 1a (2.5 eq) and phenanthroline-2,9-dicarboxaldehyde 2 (1 eq, 0.78 mmol) were dissolved in an appropriate amount of anhydrous ethanol and refluxed for 10 h. The reaction solution was treated and purified by column chromatography to obtain intermediate Pe-1-2N as a pale yellow solid in 73% yield with a >20:1 dr ratio. Nuclear magnetic resonance and high-resolution mass spectrometry results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.84-1.89(m,4H),2.18-2.23(m,4H),3.04-3.10(m,2H),3.47-3.52(m,2H),4.23-4.26(m,2H) ,6.15(s,2H),6.95-6.99(m,2H),7.14-7.18(m,4H),7.47(d,J=8.0Hz,2H),7.58-7.61(m,6H),8.09(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:23.7,26.9,55.3,63.8,83.6,118.3,120.0,123.9,125.3, 127.3,127.8,136.2,136.4,144.5,157.5,173.9; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 32 N6NaO2[M+Na] + :603.2479;Found:603.2467.

[0028] The chiral phenanthroline-diazoxide ligand intermediates Pe-2-2N to Pe-15-2N prepared in the examples are prepared using the same method as the chiral phenanthroline-diazoxide ligand intermediate Pe-1-2N. The feed ratios are the same as for the ligand Pe-1-2N, and the ligands Pe-2-2N to Pe-15-2N are obtained. The reaction yields are shown in Table 1. However, it should be emphasized that the examples are intended to illustrate rather than limit the scope of the present invention. The compounds of the present invention are not limited to those shown in Table 1.

[0029] Table 1 shows the chemical structure of the intermediate Pe-2N for the preparation of chiral phenanthroline-diazolyl ligands.

[0030]

[0031] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-2-2N was prepared: a pale yellow solid with a yield of 75% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.84-1.89(m,4H),2.13(s,6H),2.17-2.22(m,4H),3.06-3.12(m,2H),3.47-3.53(m,2H) ,4.20-4.24(m,2H),6.13(s,2H),6.96(d,J=8.4Hz,4H),7.45-7.49(m,6H),7.62(s,2H),8.09(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:19.7,23.8,27.0,55.4,63.9,83.8,118.5,120.3,125.4,127 .4,128.4,133.7,133.8,136.4,144.6,157.7,173.8; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 36 N6NaO2[M+Na] + :631.2792;Found:631.2783.

[0032] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-3-2N was prepared: a pale yellow solid with a yield of 74% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.84-1.90(m,4H),2.17-2.22(m,10H),3.04-3.11(m,2H),3.48-3.54(m,2H),4.20-4.23(m,2H),6.16(s,2H), 6.79(d,J=7.2Hz,2H),7.01-7.05(m,2H),7.25-7.28(m,2H),7.46(d,J=8.4Hz,2H),7.52(s,2H),7.62(s,2H),8.10(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:19.5,22.9,26.1,54.5,63.0,82.8,116.4,117.5,119.9,124.1,124 .5,126.5,126.8,135.4,135.6,136.9,143.8,156.8,173.1; HRMS(ESI-TOF)m / z:Calcd.for C38 H 36 N6NaO2[M+Na] + :631.2792;Found:631.2787.

[0033] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-4-2N was prepared: a pale yellow solid with a yield of 73% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.86-1.92(m,4H),2.18-2.24(m,4H),3.03-3.09(m,2H),3.48-3.53(m,2H),4.2 2-4.26(m,2H),6.11(s,2H),7.25-7.29(m,4H),7.48-7.54(m,6H),7.66(s,2H),8.14(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:24.9,28.2,56.6,65.0,84.7,118.1,119.7,122.7,126.7, 128.6,132.0,136.6,137.7,145.7,158.3,175.2; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 Br2N6NaO2[M+Na] + :759.0689;Found:759.0694.

[0034] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-5-2N was prepared: a pale yellow solid with a yield of 71% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.83-1.91(m,4H),2.18-2.23(m,4H),3.02-3.08(m,2H),3.47-3.52(m,2H),4.22-4.25(m, 2H),6.11(s,2H),7.10-7.14(m,4H),7.48(d,J=8.4Hz,2H),7.54-7.58(m,4H),7.66(s,2H),8.13(d,J=8.4Hz,2H); 13C NMR(CDCl3,100MHz)δ:23.0,26.3,54.7,63.1,82.9,117.8,120.5,124.8,126.7, 127.2,128.4,134.2,135.9,143.8,156.5,173.3; HRMS(ESI-TOF)m / z:Calcd.forC 36 H 30 Cl2N6NaO2[M+Na] + :671.1700;Found:671.1708.

[0035] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-6-2N was prepared: a pale yellow solid with a yield of 73% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.02-1.05(m,6H),1.83-1.89(m,4H),2.16-2.22(m,4H),2.40-2.46(m,4H),3.04-3.10(m,2H),3.47 -3.52(m,2H),4.19-4.23(m,2H),6.14(s,2H),6.99(d,J=8.8Hz,4H),7.47-7.50(m,6H),7.60(s,2H),8.08(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:15.4,24.9,28.1,28.2,56.5,65.0,85.0,119.6,121.5,126.5,1 28.4,128.5,135.0,137.6,141.3,145.7,158.9,175.0; HRMS(ESI-TOF)m / z:Calcd.for C 40 H 40 N6NaO2[M+Na] + :659.3105;Found:659.3099.

[0036] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-7-2N was prepared: a pale yellow solid with a yield of 70% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1H NMR(CDCl3,400MHz)δ:1.82-1.89(m,4H),2.17-2.22(m,4H),3.02-3.08(m,2H),3.49-3.54(m,2H),4.19-4.22(m,2H),6.14(s,2H),6 .65-6.70(m,2H),7.05-7.11(m,2H),7.19-7.21(m,2H),7.47(d,J=8.0Hz,2H),7.64(s,2H),7.69-7.73(m,2H),8.13(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:22.9,26.0,54.5,62.9,82.6,106.7(d,J CF =26.3Hz),109.8(d,J CF =22.2Hz),114.2(d,J CF =3.4Hz),117.6,124.6,126.6,128.1(d,J CF =10.2Hz),135.7,137.1,137.2,143.7,156.3,161.8(d,J CF =244.1Hz),173.4; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 F2N6NaO2[M+Na] + :639.2291;Found:639.2297.

[0037] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-8-2N was prepared: a pale yellow solid with a yield of 72% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.13(s,18H),1.84-1.90(m,4H),2.17-2.23(m,4H),3.06-3.12(m,2H),3.51-3.57(m,2 H),4.18-4.21(m,2H),6.17(s,2H),7.18-7.21(m,5H),7.47-7.52(m,6H),7.61(s,2H),8.09(d,J=8.4Hz,2H); 13C NMR(CDCl3,100MHz)δ:23.9,27.1,30.2,33.3,55.5,63.9,83.8,118.5,119.8,124.9,1 25.5,127.5,133.8,136.6,144.7,147.0,157.9,174.0; HRMS(ESI-TOF)m / z:Calcd.for C 44 H 48 N6NaO2[M+Na] + :715.3731;Found:715.3722.

[0038] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-9-2N was prepared: a pale yellow solid with a yield of 75% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.85-1.91(m,4H),2.17-2.24(m,4H),3.03-3.09(m,2H),3.45-3.50(m,2H),4.2 5-4.29(m,2H),6.07(s,2H),6.82-6.86(m,4H),7.48-7.54(m,6H),7.65(s,2H),8.13(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:23.9,27.1,55.5,63.9,84.2,114.7(d,J CF =22.3Hz),118.8,122.6(d,J CF =7.3Hz),125.6,127.6,132.3(d,J CF =3.2Hz),136.6,144.6,157.5,159.8(d,J CF =244.2Hz),174.0; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 F2N6NaO2[M+Na] + :639.2291;Found:639.2287.

[0039] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-10-2N was prepared: a pale yellow solid with a yield of 70% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1H NMR(CDCl3,400MHz)δ:1.83-1.96(m,4H),2.16-2.30(m,4H),3.14-3.20(m,2H),3.41-3.46(m,2H),4.39-4.42(m,2 H),5.96(s,2H),6.82-6.86(m,2H),6.96-7.07(m,4H),7.30-7.34(m,2H),7.56-7.61(m,4H),8.09(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:25.0,28.1,56.5,64.3,85.6,116.4(d,J CF =20.3Hz),120.5,124.0(d,J CF =11.2Hz),124.5,126.5,128.5,128.8(d,J CF =8.2Hz),129.8,137.2,145.7,158.5,158.7(d,J CF =249.0Hz),175.5; HRMS(ESI-TOF)m / z:Calcd.forC 36 H 30 F2N6NaO2[M+Na] + :639.2291;Found:639.2285.

[0040] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-11-2N was prepared: a pale yellow solid with a yield of 70% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.85-1.91(m,4H),2.18-2.23(m,4H),3.02-3.08(m,2H),3.48-3.53(m,2H),4.23-4.26(m,2H),6.11(s,2H),6 .97-7.01(m,2H),7.09-7.12(m,2H),7.34-7.37(m,2H),7.48(d,J=8.4Hz,2H),7.65(s,2H),8.05-8.06(m,2H),8.13(d,J=8.4Hz,2H); 13C NMR(CDCl3,100MHz)δ:23.2,26.4,54.8,63.2,82.9,117.7,118.0,121.0,122.4,124.9, 126.3,126.9,128.5,136.0,137.2,144.1,156.5,173.7; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 Br2N6NaO2[M+Na] + :759.0689;Found:759.0695.

[0041] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-12-2N was prepared: a pale yellow solid with a yield of 74% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.84-1.90(m,4H),2.18-2.23(m,4H),3.02-3.08(m,2H),3.49-3.54(m,2H),4.21-4.25(m,2H),6.12(s,2H),6 .93-6.96(m,2H),7.03-7.07(m,2H),7.30-7.33(m,2H),7.48(d,J=8.4Hz,2H),7.65(s,2H),7.90-7.91(m,2H),8.12(d,J=8.0Hz,2H); 13 C NMR(CDCl3,100MHz)δ:23.9,27.0,55.5,63.9,83.6,117.9,118.6,120.3,124.1,125.6, 127.5,128.9,133.6,136.6,137.7,144.7,157.2,174.4; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 Cl2N6NaO2[M+Na] + :671.1700;Found:671.1709.

[0042] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-13-2N was prepared: a pale yellow solid with a yield of 75% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1H NMR(CDCl3,400MHz)δ:1.84-1.88(m,4H),2.17-2.22(m,4H),3.06-3.12(m,2H),3.46-3.51(m,2H),3.59(s,6H) ,4.22-4.25(m,2H),6.08(s,2H),6.68(d,J=9.2Hz,4H),7.42-7.49(m,6H),7.64(s,2H),8.11(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:22.9,26.2,53.3,54.5,63.0,83.4,112.2,117.8,121.6,124 .5,126.5,128.2,135.6,143.6,155.1,156.9,172.7; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 36 N6NaO4[M+Na] + :663.2690;Found:663.2681.

[0043] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-14-2N was prepared: a pale yellow solid with a yield of 73% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:1.12-1.14(m,12H),1.90-1.96(m,4H),2.24-2.30(m,4H),2.74-2.81(m,2H),3.12-3.18(m,2H),3.55 -3.60(m,2H),4.28-4.32(m,2H),6.22(s,2H),7.11(d,J=8.4Hz,4H),7.55-7.60(m,6H),7.65(s,2H),8.14(d,J=8.0Hz,2H); 13 C NMR (CDCl3, 100MHz) δ: 23.9, 24.9, 28.1, 33.5, 56.5, 65.0, 85.0, 119.6, 121.4, 126. 5,127.0,128.5,135.1,137.6,145.8,158.9,175.0; HRMS(ESI-TOF)m / z:Calcd.for C 42 H 44 N6NaO2[M+Na] + :687.3418;Found:687.3423.

[0044] In this example, a chiral phenanthroline-diazoxide ligand intermediate Pe-15-2N was prepared: a pale yellow solid with a yield of 67% and a dr ratio of >20:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CDCl3,400MHz)δ:0.83(s,3H),0.85(s,3H),1.16-1.19(m,12H),1.48( s,3H),1.49(s,3H),1.89-1.94(m,4H),2.18-2.26(m,4H),2.28-2.36(m,2H ),3.08-3.15(m,2H),4.49-4.53(m,2H),5.58(s,2H),6.74-6.76(m,2H),7. 16-7.19(m,4H),7.38(d,J=8.4Hz,2H),7.63(s,2H),8.03(d,J=8.4Hz,2H); 13 C NMR(CDCl3,100MHz)δ:22.4,23.3,24.9,25.3,25.6,28.4,28.9,29.0,57.3,65.2,88.0,122.2,123.8,124 .2,126.5,128.5,129.3,129.8,136.5,145.5,146.4,148.1,158.6,175.1; HRMS(ESI-TOF)m / z:Calcd.for C 48 H 56 N6NaO2[M+Na] + :771.4357;Found:771.4348.

[0045] (II) Synthesis of Chiral Phenanthroline-Dinitrogen Oxygen Ligand Pe-2NO

[0046]

[0047] Chiral phenanthroline-diazoxide ligand Pe-1-2NO: The intermediate Pe-2 (100 mg, 1 eq) from the previous step was dissolved with m-chloroperoxybenzoic acid (2.5 eq) in chloroform and reacted at room temperature for 20 min. The reaction solution was then purified by column chromatography to afford Pe-1-2NO as a pale yellow solid in a 37% overall yield with a >20:1 dr ratio. Nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) results are as follows: 1H NMR(CD3OD,400MHz)δ:2.24-2.26(m,2H),2.50-2.58(m,2H),2.64-2.82(m,4H),3.97-4.01(m,2H),4.19-4.27(m,2H),5.43(d,J=7.6Hz, 2H),6.92(s,2H),7.09-7.13(m,2H),7.22-7.26(m,4H),7.44-7.46(m,4H),7.80-7.83(m,2H),7.97(d,J=8.0Hz,2H),8.38-8.40(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.0,24.8,71.0,77.4,87.4,122.6,126.0,126.4,127.3, 128.9,129.7,135.7,137.2,145.8,151.7,169.5; HRMS(ESI-TOF)m / z:Calcd.forC 36 H 32 N6NaO4[M+Na] + :635.2371;Found:635.2363.

[0048] The chiral bipyridine-diazoxy ligands Pe-2-2NO to Pe-14-2NO prepared in the examples were prepared using the same method as the chiral bipyridine-diazoxy ligand Pe-1-2NO, using the same feed ratios as for the ligand Pe-1-2NO. The ligands Pe-2-2NO to Pe-14-2NO were obtained, with the reaction yields shown in Table 2. It should be emphasized that the examples are intended to illustrate, not to limit, the scope of the present invention. The compounds of the present invention are not limited to those shown in Table 2.

[0049] Table 2 shows the chemical structure of the chiral phenanthroline-diazolyl ligand Pe-2NO.

[0050]

[0051] In this example, a chiral phenanthroline-diazoxide ligand Pe-2-2NO was prepared: a light yellow solid with a total yield of 32%, 12:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1H NMR(CD3OD,400MHz)δ:2.17(s,3H),2.23-2.24(m,2H),2.52-2.57(m,2H),2.66-2.70(m,2H),2.74-2.79(m,2H),3.97-4.01(m,2H),4.19-4.27( m,2H),5.44(d,J=11.6Hz,2H),6.88(s,2H),7.05(d,J=8.4Hz,4H),7.28 -7.34(m,4H),7.71(s,2H),7.94(d,J=8.0Hz,2H),8.31(d,J=8.0Hz,2H); 13 C NMR(CD3OD,100MHz)δ:23.5,25.9,28.7,75.0,81.3,91.6,126.7,129.9,131.2,133 .3,133.6,137.0,140.6,141.1,149.8,155.7,173.4; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 36 N6NaO4[M+Na] + :663.2682;Found:663.2675.

[0052] In this example, chiral phenanthroline-diazoxide ligand Pe-3-2NO was prepared as a light yellow solid with a total yield of 31% and a dr ratio of 11:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.22-2.26(m,8H),2.50-2.57(m,2H),2.65-2.80(m,4H),3.96-4.00(m,2H),4.18-4.25(m,2H),5.44(s,2H),6. 90-6.94(m,4H),7.07-7.12(m,2H),7.18-7.22(m,2H),7.31-7.33(m,2H),7.71-7.78(m,2H),7.98(d,J=8.0Hz,2H),8.32-8.38(m,2H); 13 C NMR(CD3OD,100MHz)δ:20.0,22.0,24.8,71.0,77.4,87.4,119.5,122.6,125.9,127.1,127 .2,128.7,129.7,135.7,137.2,139.1,145.8,151.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 38 H36 N6NaO4[M+Na] + :663.2682;Found:663.2679.

[0053] In this example, chiral phenanthroline-diazoxide ligand Pe-4-2NO was prepared as a light yellow solid with a total yield of 35% and a 15:1 dr ratio. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.27(m,2H),2.53-2.57(m,2H),2.66-2.68(m,2H),2.74-2.79(m,2H),3.97-4.01(m,2H),4.20-4. 27(m,2H),5.38(d,J=8.4Hz,2H),6.95(s,2H),7.37-7.44(m,8H),7.87-7.89(m,2H),8.00(d,J=8.4Hz,2H),8.44-8.47(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.0,24.8,71.1,77.2,87.1,119.4,124.2,126.1,127.4, 129.8,131.9,134.8,137.4,145.8,151.4,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 Br2N6NaO4[M+Na] + :791.0579;Found:791.0550.

[0054] In this example, chiral phenanthroline-diazoxide ligand Pe-5-2NO was prepared as a light yellow solid with a total yield of 36% and a 13:1 dr ratio. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.27(m,2H),2.55-2.58(m,2H),2.68-2.71(m,2H),2.77-2.83(m,2H),4.00-4.02(m,2H),4.22-4.27(m, 2H),5.43(s,2H),6.95-6.99(m,2H),7.23-7.28(m,4H),7.47-7.54(m,4H),7.76-7.85(m,2H),7.99-8.03(m,2H),8.39-8.44(m,2H); 13C NMR(CD3OD,100MHz)δ:22.1,24.8,71.1,77.3,87.2,124.1,126.1,127.3,129.0, 129.8,131.7,134.4,137.4,145.8,151.5,169.5; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 Cl2N6NaO4[M+Na] + :703.1588;Found:703.1566.

[0055] In this example, chiral phenanthroline-diazoxide ligand Pe-6-2NO was prepared as a light yellow solid with a total yield of 38% and a dr ratio of 18:1. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:1.03-1.06(m,6H),2.23-2.25(m,2H),2.44-2.50(m,4H),2.53-2.59(m,2H),2.64-2.81(m,4H),3.98-4.02(m,2H) ,4.20-4.27(m,2H),6.90(s,2H),7.08(d,J=8.4Hz,4H),7.37(d,J=8.4Hz,4H),7.63(s,2H),7.95(d,J=8.0Hz,2H),8.26(d,J=8.0Hz,2H); 13 C NMR(CD3OD,100MHz)δ:14.7,22.0,24.7,27.9,71.1,77.4,87.6,122.8,126.0,127.2,1 28.3,129.6,133.3,137.1,143.0,145.8,151.7,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 40 H 40 N6NaO4[M+Na] + :691.2993;Found:691.2975.

[0056] In this example, a chiral phenanthroline-diazoxide ligand Pe-7-2NO was prepared: a light yellow solid with a total yield of 35%, 15:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1H NMR(CD3OD,400MHz)δ:2.25-2.27(m,2H),2.51-2.61(m,2H),2.66-2.75(m,2H),2.76-2.85(m,2H),3.95-4.00(m,2H),4.17-4.25(m,2H),5.39(d ,J=6.4Hz,2H),6.83-6.88(m,2H),6.99(s,2H),7.17-7.26(m,4H),7.49 -7.53(m,2H),7.87(s,2H),8.04(d,J=8.0Hz,2H),8.46(d,J=8.0Hz,2H); 13 C NMR(CD3OD,100MHz)δ:22.0,24.9,71.1,77.3,86.8,108.9(d,J CF =26.3Hz),112.7(d,J CF =21.4Hz),117.0,126.0,127.3,129.8,130.4(d,J CF =10.1Hz),137.3(d,J CF =8.4Hz),145.8,151.4,162.6(d,J CF =243.4Hz),169.4; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 F2N6NaO4[M+Na] + :671.2189;Found:671.2186.

[0057] In this example, chiral phenanthroline-diazoxide ligand Pe-9-2NO was prepared as a light yellow solid with a total yield of 38% and a 20:1 dr ratio. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.27(m,2H),2.54-2.56(m,2H),2.62-2.67(m,2H),2.76-2.78(m,2H),4.02(s,2H),4.27(d,J=9.6Hz,2 H),5.44(s,2H),6.90-6.93(m,2H),6.97-7.03(m,4H),7.46-7.51(m,4H),7.81-7.87(m,2H),7.95-7.99(m,2H),8.41-8.45(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.1,24.7,71.1,77.2,87.7,115.6(d,JCF =23.0Hz),125.5(d,J CF =9.3Hz),126.1,127.3,129.8,131.6(d,J CF =3.3Hz),137.3,145.9,151.6,161.5(d,J CF =244.1Hz),169.6; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 F2N6NaO4[M+Na] + :671.2189;Found:671.2177.

[0058] In this example, chiral phenanthroline-diazoxide ligand Pe-10-2NO was prepared: light yellow solid, total yield 32%, 13:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.31(m,2H),2.50-2.62(m,4H),2.67-2.73(m,2H),4.03-4.07(m,2H),4.32-4.39(m,2H),5.43 -5.45(m,2H),6.73(s,2H),6.91-6.95(m,2H),7.00-7.10(m,2H),7.19-7.29(m,4H),7.89-7.94(m,4H),8.43-8.46(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.1,24.7,71.3,76.7,87.6,116.1(d,J CF =20.3Hz),121.9(d,J CF =12.1Hz),124.8(d,J CF =4.4Hz),126.1,127.4,129.5,129.9,130.2(d,J CF =8.5Hz),137.2,146.0,151.5,158.4(d,J CF =248.2Hz),170.1; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 F2N6NaO4[M+Na] + :671.2189;Found:671.2170.

[0059] In this example, chiral phenanthroline-diazoxide ligand Pe-12-2NO was prepared: light yellow solid, total yield 32%, 12:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.27(m,2H),2.51-2.59(m,2H),2.67-2.74(m,2H ),2.76-2.82(m,2H),3.95-3.99(m,2H),4.17-4.25(m,2H),5.38(d,J=6.8Hz, 2H),6.99(s,2H),7.11-7.13(m,2H),7.17-7.21(m,2H),7.31-7.33(m,2H),7. 68(d,J=2.0Hz,2H),7.85(s,2H),8.04(d,J=8.4Hz,2H),8.45(d,J=8.4Hz,2H); 13 C NMR(CD3OD,100MHz)δ:22.0,24.9,71.1,77.3,86.8,120.0,121.6,126.0,126.1,127.4, 129.8,130.2,134.3,137.1,137.4,145.8,151.4,169.5; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 30 Cl2N6NaO4[M+Na] + :703.1591;Found:703.1577.

[0060] In this example, chiral phenanthroline-diazoxide ligand Pe-13-2NO was prepared: light yellow solid, total yield 35%, 13:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.28(m,2H),2.50-2.57(m,2H),2.62-2.65(m,2H),2.70-2.75(m,2H),3.64(s,6H),3.97-4.01(m,2H),4. 23-4.30(m,2H),5.41-5.44(m,2H),6.76-6.81(m,6H),7.28-7.32(m,4H),7.81-7.87(m,2H),7.91(d,J=8.0Hz,2H),8.37-8.43(m,2H); 13C NMR(CD3OD,100MHz)δ:22.0,24.6,54.5,71.0,77.3,88.1,114.1,125.3,126.0,127 .3,128.0,129.7,137.1,145.9,151.8,158.6,169.6; HRMS(ESI-TOF)m / z:Calcd.for C 38 H 36 N6NaO6[M+Na] + :695.2589;Found:695.2589.

[0061] In this example, chiral phenanthroline-diazoxide ligand Pe-14-2NO was prepared: light yellow solid, total yield 33%, 12:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.08-1.10(m,12H),2.24-2.26(m,2H),2.52-2.55(m,2H),2.67-2.79(m,6H),3.99(s,2H),4.20-4.27(m,2H),5. 42(s,2H),6.88(d,J=4.0Hz,2H),7.11(d,J=6.8Hz,4H),7.35-7.37(m,4H),7.71-7.81(m,2H),7.95(d,J=8.0Hz,2H),8.32-8.39(m,2H); 13 C NMR(CD3OD,100MHz)δ:22.0,22.8,24.7,33.5,71.0,77.3,87.6,122.8,126.0,126.8,1 27.2,129.7,133.3,137.2,145.8,147.6,151.8,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 42 H 44 N6NaO4[M+Na] + :719.3309;Found:719.3290.

[0062] (III) Application of chiral phenanthroline-diazoxide ligand Pe-2NO and intermediate Pe-2N in asymmetric catalytic Friedel-Crafts alkylation of indole

[0063] The chiral phenanthroline-diazoxy ligand of formula (1) of the present invention, Pe-2NO, and the intermediate Pe-2N, which contain a phenanthroline group and a nitroxide group (the nitrogen group of the phenanthroline and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), can form six-membered rings and five-membered rings with Lewis metals to form chiral ligand-metal complexes, which are used as the dominant chiral ligand in the asymmetric catalytic Friedel-Crafts alkylation reaction of indole. However, it should be emphasized that the chiral pyridine nitroxide ligand of the present invention is not limited to use as a chiral ligand in the asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0064] Example 1: Application of Chiral Ligands Pe-2NO with Various Substitutions in Catalyzing the Asymmetric Friedel-Crafts Alkylation of Indole 3a and Enone Ester 4a

[0065] To demonstrate the application value of the developed chiral ligand Pe-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of indole 3a and enone ester 4a as the template reaction, and selected compounds Pe-1-2NO to Pe-14-2NO as phenanthroline-diazolyl ligands to in situ generate chiral complexes with the Lewis acid Ni(OTf)2 to verify the asymmetric catalytic effect of the chiral ligand Pe-2NO (Table 3).

[0066] Table 3 shows the application of chiral ligand Pe-2NO with various substituents in asymmetric catalytic reactions

[0067]

[0068] Experimental Conclusion: The asymmetric catalytic Friedel-Crafts alkylation template reaction of indole 3a and enone ester 4a was selected as the evaluation indicator. The experimental results show that the chiral ligands Pe-1-2NO to Pe-14-2NO with various substituents represented by formula (1) all exhibit asymmetric catalytic effects in the Friedel-Crafts alkylation reaction of indole 3a and enone ester 4a, and can be developed into new advantageous chiral phenanthroline-diazotol ligands Pe-2NO, which are worthy of further in-depth study.

[0069] Example 2: Application of the chiral ligand Pe-1-2NO in the asymmetric catalytic Friedel-Crafts alkylation of variously substituted indoles 3 with variously substituted enone esters 4

[0070] To demonstrate the application value of the developed chiral ligand Pe-1-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of various substituted indoles 3 and various substituted enone esters 4 as template reactions to verify the catalytic effect of the chiral ligand Pe-1-2NO (Table 4).

[0071] Table 4 shows the application of chiral ligand Pe-1-2NO in the asymmetric catalytic Friedel-Crafts alkylation of various substituted indoles 3 and various substituted enone esters 4

[0072]

[0073] Experimental Conclusion: The asymmetric catalytic Friedel-Crafts alkylation template reaction of indole 3 and various substituted enone esters 4 was selected as the evaluation indicator. The experimental results show that the chiral ligand Pe-1-2NO represented by formula (1) in situ generates a chiral complex with Ni(OTf)2, which exhibits asymmetric catalytic effect in the Friedel-Crafts alkylation reaction of various substituted indoles 3 and various substituted enone esters 4. It can be developed into a new advantageous chiral nitrogen oxide ligand and is worthy of further in-depth study.

[0074] Example 3: Application of the intermediate Pe-2N of various chiral phenanthroline-diazoxide ligands in catalyzing the asymmetric Friedel-Crafts alkylation of indole 3a and enone ester 4a

[0075] In order to demonstrate the application value of the developed compound Pe-2N in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of indole 3a and enone ester 4a as the template reaction, and selected compounds Pe-1-2N to Pe-15-2N as chiral ligands to in situ generate chiral complexes with Lewis acid Ni(OTf)2 to verify the asymmetric catalytic effect of the chiral ligand Pe-2N (Table 5).

[0076] Table 5 shows the application of compounds Pe-2N with various substituents in asymmetric catalytic reactions

[0077]

[0078] Experimental Conclusion: The asymmetric catalytic Friedel-Crafts alkylation of indole 3a and enone ester 4a was selected as the evaluation indicator. The experimental results show that the compounds Pe-1-2N to Pe-15-2N with various substituents represented by formula (1) all exhibit asymmetric catalytic effects in the Friedel-Crafts alkylation of indole 3a and enone ester 4a, and can be developed into new chiral ligands Pe-2N, which are worthy of further research.

Claims

1. A chiral phenanthroline-diazotol ligand Pe-2NO, characterized in that: The chiral phenanthroline-diazoxide ligand Pe-2NO has a structure as shown in the general formula (Ⅰ); In the formula, R is a hydroxyl group or hydrogen; Ar is a benzene ring substituted with fluorine, chlorine, bromine, ethyl, isopropyl, methoxy, methyl or hydrogen.

2. The chiral phenanthroline-diazoxide ligand Pe-2NO according to claim 1, characterized in that: The chiral phenanthroline-diazolyl ligand Pe-2NO is specifically one of the following structural formulas:

3. A synthetic intermediate Pe-2N of the chiral phenanthroline-diazoxide ligand Pe-2NO as claimed in claim 1, characterized in that: The intermediate Pe-2N has a structure as shown in general formula (II); In the formula, R is a hydroxyl group or hydrogen; Ar is a benzene ring substituted with fluorine, chlorine, bromine, ethyl, isopropyl, methoxy, methyl or hydrogen.

4. The chiral phenanthroline-diazoxide ligand intermediate Pe-2N according to claim 3, characterized in that: The chiral phenanthroline-diazolyl ligand intermediate Pe-2N is specifically one of the following structural formulas:

5. A method for preparing the chiral phenanthroline-diazoxide ligand Pe-2NO as claimed in claim 1 or 2, characterized in that: The corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with phenanthroline-2,9-dicarboxaldehyde 2 to generate the desired intermediate Pe-2N. Then, the nitrogen atom in the intermediate Pe-2N undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperbenzoic acid (m-CPBA) to generate the chiral phenanthroline-diazotol ligand Pe-2NO. The synthetic route is as follows:

6. A method for preparing the intermediate Pe-2N according to claim 3 or 4, characterized in that: The corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with phenanthroline-2,9-dicarboxaldehyde 2 to generate the desired intermediate Pe-2N; The synthetic route is as follows:

7. Use of the intermediate Pe-2N according to claim 3 or 4 in the synthesis of the chiral phenanthroline-diazoxide ligand Pe-2NO according to claim 1.

8. Use of the chiral phenanthroline-diazoxide ligand intermediate Pe-2N as claimed in claim 3 or 4 as a ligand in asymmetric catalytic indole-involved Friedel-Crafts alkylation reaction, characterized in that: The alkylation reaction synthesis route is as follows:

9. Use of the chiral phenanthroline-diazoxide ligand Pe-2NO as claimed in claim 1 in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole, characterized in that: The alkylation reaction synthesis route is as follows:

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