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

Abstract

This invention discloses a chiral naphthidine-nitrogen oxide ligand, including the chiral naphthidine-bis(nitrogen oxide) ligand Nap-2NO obtained via two different synthetic routes, and the chiral naphthidine-mono(nitrogen oxide) ligand Nap-NO. These ligands contain a naphthidine group and a nitrogen oxide group, and can form six-membered ring coordination with Lewis metals to generate chiral ligand-metal complexes. The inventors have also discovered the application of these ligands as chiral ligands in asymmetric catalytic reactions. Therefore, they have significant application value in the field of asymmetric catalytic synthesis, and their synthetic 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 naphthidine-nitrogen oxide ligand (Nap-2NO and Nap-NO), its preparation method, and its application in asymmetric catalytic indole-indole-involved Friedel-Crafts alkylation reactions. 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 naphthidine-bis(oxy) ligand, Nap-2NO, and tested its application in the indole asymmetric Friedel-Crafts alkylation reaction. Based on the design and synthesis of this novel type of chiral naphthidine-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 naphthidine nitrogen group 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 naphthidine-nitrogen oxide ligand (Nap-2NO and Nap-NO), its preparation method, and its applications. This is an important class of chiral naphthidine-nitrogen oxide ligands, containing a naphthidine group and a nitroxide group (the nitrogen group of naphthidine and the oxygen atom of the nitroxide group are electron-rich coordination sites). These ligands can form six-membered ring coordination with Lewis metals, thereby generating chiral ligand-metal complexes, which can be 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.

[0006] The present invention is achieved as follows: a chiral naphthidine-nitrogen oxide ligand (Nap-2NO and Nap-NO), wherein the chiral naphthidine-bis-nitrogen oxide ligand Nap-2NO has a structure as shown in general formula (I), and the chiral naphthidine-mono-nitrogen oxide ligand Nap-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 fluorine, chlorine, bromine, ethyl, methyl or hydrogen-substituted benzene ring.

[0009] The preparation method of chiral naphthidine-bis(nitroxide) ligand Nap-2NO involves the condensation reaction of the corresponding proline amide or hydroxyproline amide 1 with naphthidine-dicarboxaldehyde 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 chiral naphthidine-bis(nitroxide) ligand Nap-2NO.

[0010] The synthesis route is as follows:

[0011]

[0012] The preparation method of chiral naphthidine-monooxy ligand Nap-NO involves a condensation reaction between the corresponding proline amide or hydroxyproline amide 1 and naphthidine-monoformaldehyde 2 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 naphthidine-monooxy ligand Nap-NO.

[0013] The synthesis route is as follows:

[0014]

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

[0016] This invention also discovers the application of the chiral naphthidine-monooxy ligand Nap-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 undergoes a condensation reaction with naphthidine-diformaldehyde 2 to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperoxybenzoic acid to generate the final product, the chiral naphthidine-bis(nitroxide) ligand Nap-2NO. Alternatively, the corresponding proline amide or hydroxyproline amide 1 undergoes a condensation reaction with naphthidine-monoformaldehyde 2 to generate intermediate 3. Then, the nitrogen atom in intermediate 3 undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperoxybenzoic acid to generate the final product, the chiral naphthidine-mono(nitroxide) ligand Nap-NO. These ligands contain a naphthidine group and a nitroxide group (the nitrogen group and the oxygen atom of the nitroxide group are electron-rich coordination sites), and can form six-membered ring coordination with Lewis metals to generate chiral ligand-metal complexes, which can be used as chiral ligands in asymmetric catalytic reactions. Therefore, they have significant application value in the field of asymmetric catalytic synthesis, and their synthetic method is very economical and simple. It also has good air stability, wide applicability, and good compatibility with various substituents. Attached Figure Description

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

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

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

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

[0024] Figure 7 and Figure 8 The spectral data of the chiral naphthidine-monooxy ligand Nap-1-NO in this embodiment of the invention;

[0025] Figure 9and Figure 10 The spectral data of the chiral naphthidine-monooxy ligand Nap-2-NO in this embodiment of the 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 and Figure 13 The NMR spectrum data of compound 6a in this embodiment of the invention are shown. Detailed Implementation

[0028] (I) Preparation of chiral naphthidine-bis(nitroxide) ligand Nap-2NO

[0029]

[0030] Chiral naphthidine-bis(oxo) ligand Nap-1-2NO: Proline 1a (2.5 eq) and naphthidine-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 dichloromethane 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 Nap-1-2NO; melting point: 247.1-247.9 °C; overall yield 51%, >20:1dr. The results of NMR and high-resolution mass spectrometry are as follows: 1 HNMR(CD3OD,400MHz)δ:2.20-2.27(m,2H),2.44-2.58(m,6H),3.92-3.96(m,2H),4.13-4.20(m,2H),4.80-4.82(m,2H ),7.02(s,2H),7.14-7.18(m,2H),7.26-7.30(m,4H),7.47-7.50(m,4H),7.95(d,J=8.4Hz,2H),8.54(d,J=8.4Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 22.3, 24.1, 70.8, 76.8, 87.3, 122.4, 124.1, 125.6, 126.6, 129.0, 135.6, 138.5, 154.4, 156.0, 168.8; HRMS (ESI-TOF) m / z: Calcd.for C 32 H 30 N6NaO4[M+Na] + :585.2221;Found:585.2228。

[0031] The chiral naphthidine-diazooxygen ligands Nap-2-2NO to Nap-13-2NO prepared by the examples were prepared by the same method as those for chiral naphthidine-diazooxygen ligand Nap-1-2NO, with the same feed ratio. The reaction yields of Nap-2-2NO to Nap-13-2NO 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.

[0032] Table 1 shows the chemical structures for preparing the chiral naphthidine-bis(nitroxide) ligand Nap-2NO.

[0033]

[0034] In this embodiment, chiral naphthidine-bis(nitroxide) ligand Nap-2-2NO: was prepared as a white solid with a melting point of 247.1-247.9 °C; the overall yield was 45%, >20:1dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.57-2.63 (m, 2H), 2.83-2.90 (m, 2H), 3.95 (d, J = 12.4Hz, 2H), 4.41-4.45 (m, 2H), 4.66 (s, 2H), 5.02-5. 05(m,2H),7.02(s,2H),7.14-7.17(m,2H),7.26-7.30(m,4H),7.46-7.48(m,4H),7.94(d,J=8.4Hz,2H),8.52(d,J=8.4Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 35.1, 69.8, 76.5, 76.8, 87.9, 122.6, 124.2, 125.7, 126.7, 129.0, 135.4, 138.5, 154.3, 155.6, 168.0; HRMS (ESI-TOF) m / z: Calcd.for C 32 H 30 N6NaO6[M+Na] + :617.2119;Found:617.2118。

[0035] In this embodiment, chiral naphthidine-bis(nitroxide) ligand Nap-3-2NO was prepared as a white solid with a melting point of 231.3-232.2 °C; the overall yield was 46%, 19:1 dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1H NMR(CD3OD,400MHz)δ:1.08-1.12(m,6H),2.22-2.27(m,2H),2.45-2.59(m,10H),3.93-3.97(m,2H),4.13-4.20(m,2H),4 .80-4.83(m,2H),6.99(s,2H),7.11(d,J=8.8Hz,4H),7.39(d,J=8.4Hz,4H),7.94(d,J=8.4Hz,2H),8.53(d,J=8.0Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 14.6, 22.3, 24.1, 27.9, 70.8, 76.9, 87.6, 122.7, 124.1, 125. 6,128.3,133.1,138.4,143.2,154.4,156.0,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 38 N6NaO4[M+Na] + :641.2834;Found:641.2826。

[0036] In this embodiment, chiral naphthidine-bis(nitroxide) ligand Nap-4-2NO was prepared as a white solid with a melting point of 246.7-247.1℃; the overall yield was 41%, >20:1dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.30-2.34(m,2H),2.46-2.64(m,6H),4.01-4.05(m,2H),4.25-4.34(m,2H),4.82-4.84(m,2H) ,6.85(s,2H),7.06-7.10(m,2H),7.22-7.27(m,2H),7.32-7.40(m,4H),7.90(d,J=8.4Hz,2H),8.52(d,J=8.4Hz,2H); 13 C NMR(CD3OD,100MHz)δ:22.4,24.1,71.1,76.2,87.7,116.3(d,J CF =19.4Hz), 121.9(d,J CF =12.1Hz), 124.2, 124.8 (d, J) CF =3.3Hz),125.8,129.5,130.5(d,J CF =8.2Hz),138.3,154.2,155.7,157.8(d,J CF=248.4Hz),169.4; HRMS(ESI-TOF)m / z:Calcd.for C 32 H 28 F2N6NaO4[M+Na] + :621.2032;Found:621.2037。

[0037] In this embodiment, chiral naphthidine-bis(oxo) ligand Nap-5-2NO: was prepared as a white solid with a melting point of 247.3-248.3 °C; the overall yield was 51%, 18:1 dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.22-2.27(m,2H),2.46-2.58(m,6H),3.93-3.97(m,2H),4.14-4.21(m,2H) ,4.75-4.78(m,2H),7.05(s,2H),7.41-7.47(m,8H),7.97(d,J=8.0Hz,2H),8.56(d,J=8.4Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 26.2, 28.1, 74.8, 80.6, 90.9, 123.4, 127.9, 128.1, 129.7, 135.9, 138.7, 142.5, 158.3, 159.6, 172.6; HRMS (ESI-TOF) m / z: Calcd.for C 32 H 28 Br2N6NaO4[M+Na] + :741.0417;Found:741.0405。

[0038] In this embodiment, chiral naphthidine-bis(oxo) ligand Nap-6-2NO was prepared as a white solid with a melting point of 260.4-260.9 °C; the overall yield was 52%, and the ratio was 17:1 dr. The results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.28(m,2H),2.45-2.59(m,6H),3.93-3.97(m,2H),4.14-4.21(m,2H),4.75-4. 78(m,2H),7.05(s,2H),7.27-7.30(m,4H),7.49-7.53(m,4H),7.97(d,J=8.4Hz,2H),8.57(d,J=8.4Hz,2H); 13C NMR (CD3OD, 100MHz) δ: 22.3, 24.1, 70.8, 76.7, 87.0, 123.8, 124.2, 125.7, 128.9, 131.8, 134.3, 138.6, 154.4, 155.7, 168.7; HRMS (ESI-TOF) m / z: Calcd.forC 32 H 28 Cl2N6NaO4[M+Na] + :653.1434;Found:653.1428。

[0039] In this embodiment, chiral naphthidine-bis(nitroxide) ligand Nap-7-2NO was prepared as a white solid with a melting point of 241.6-242.3 °C; the overall yield was 45%, and the ratio was 17:1 dr. The results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:1.07-1.10(m,6H),2.47-2.53(m,4H),2.57-2.63(m,2H),2.83-2.89(m,2H),3.96(d,J=12.4Hz,2H),4.41-4.45(m,2 H),4.66(s,2H),5.03-5.06(m,2H),6.99(s,2H),7.10(d,J=8.8Hz,4H),7.37(d,J=8.4Hz,4H),7.93(d,J=8.4Hz,2H),8.50(d,J=8.4Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 14.6, 27.9, 35.1, 69.9, 76.4, 76.8, 88.1, 122.8, 124.2, 125. 7,128.3,132.9,138.5,143.3,154.3,155.6,168.0; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 38 N6NaO6[M+Na] + :673.2745;Found:673.2745.

[0040] In this embodiment, chiral naphthidine-bis(oxo) ligand Nap-8-2NO was prepared as a white solid with a melting point of 223.2-224.0 °C; the overall yield was 41% (15:1 dr); the results of NMR and high-resolution mass spectrometry tests are as follows: 1H NMR(CD3OD,400MHz)δ:2.30-2.36(m,4H),2.51(s,6H),2.56-2.62(m,4H),3.99-4.04(m,2H),4.28-4.35(m,2H),4 .82-4.86(m,2H),6.92(s,2H),7.08-7.12(m,2H),7.17-7.26(m,6H),7.84(d,J=8.4Hz,2H),8.46(d,J=8.4Hz,2H); 13 C NMR(CD3OD,100MHz)δ:17.8,22.5,23.8,70.9,76.7,88.7,124.2,125.8,126.5,126.8, 128.7,131.4,133.0,136.6,138.1,153.9,155.7,168.6; HRMS(ESI-TOF)m / z:Calcd.for C 34 H 34 N6NaO4[M+Na] + :613.2517;Found:613.2509.

[0041] In this embodiment, chiral naphthidine-bis(oxo) ligand Nap-9-2NO₂ was prepared as a white solid with a melting point of 236.0-237.1℃; the overall yield was 40%, >20:1dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.33(s,6H),2.36-2.42(m,2H),2.48(s,6H),2.52-2.59(m,4H),2.63-2.70(m,2H),3.91-3.96(m,2H),4.30 -4.37(m,2H),4.96-5.00(m,2H),6.80(s,2H),6.94-6.97(m,2H),7.04-7.10(m,4H),7.88(d,J=8.4Hz,2H),8.36(d,J=8.4Hz,2H); 13 C NMR (CD3OD, 100MHz) δ: 18.4, 18.7, 22.8, 24.0, 70.6, 77.2, 88.2, 123.9, 125.7, 128.8, 129. 0,129.5,131.0,135.4,137.6,138.0,153.0,155.0,168.1; HRMS(ESI-TOF)m / z:Calcd.for C 36 H 38 N6NaO4[M+Na] +:641.2845;Found:641.2836。

[0042] In this embodiment, chiral naphthidine-bis(oxo) ligand Nap-10-2NO: was prepared as a white solid with a melting point of 239.0-239.9 °C; the overall yield was 51%, 18:1 dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.21(s,6H),2.24-2.28(m,2H),2.45-2.58(m,6H),3.92-3.96(m,2H),4.13-4.20(m,2H),4.79 -4.82(m,2H),6.97(s,2H),7.08(d,J=8.4Hz,4H),7.35(d,J=8.8Hz,4H),7.93(d,J=8.4Hz,2H),8.53(d,J=8.4Hz,2H); 13 C NMR(CD3OD,100MHz)δ:19.6,22.3,24.1,70.8,76.9,87.6,122.6,124.0,125.6, 129.4,132.9,136.8,138.4,154.4,156.0,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 34 H 34 N6NaO4[M+Na] + :613.2534;Found:613.2529。

[0043] In this embodiment, chiral naphthidine-bis(oxo) ligand Nap-11-2NO was prepared as a white solid with a melting point of 245.7-246.6 °C; the overall yield was 48%, and the ratio was 17:1 dr. The results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.26-2.29(m,2H),2.46-2.60(m,6H),3.95-3.99(m,2H),4.18-4.25(m,2H),4 .78-4.81(m,2H),7.01-7.07(m,6H),7.50-7.53(m,4H),7.95(d,J=8.4Hz,2H),8.55(d,J=8.4Hz,2H); 13 C NMR(CD3OD,100MHz)δ:22.3,24.1,70.8,76.7,87.6,115.6(d,J CF =23.1Hz), 124.2, 125.3 (d, J) CF=8.3Hz),125.8,131.5,138.5,154.4,155.8,160.8(d,J CF =241.1Hz),168.9; HRMS(ESI-TOF)m / z:Calcd.for C 32 H 28 F2N6NaO4[M+Na] + :621.2032;Found:621.2036。

[0044] In this embodiment, chiral naphthidine-bis(nitroxide) ligand Nap-13-2NO was prepared as a white solid with a melting point of 232.9-233.2 °C; the overall yield was 44%, 12:1 dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.56-2.62(m,2H),2.83-2.89(m,2H),3.96(d,J=12.4Hz,2H),4.41-4.45(m,2H),4.65(s,2H),4.95-4.98(m,2H) ,7.09(s,2H),7.14-7.18(m,2H),7.28-7.30(m,2H),7.36-7.39(m,2H),7.87-7.88(m,2H),7.98(d,J=8.4Hz,2H),8.55(d,J=8.0Hz,2H); 13 C NMR(CD3OD,100MHz)δ:35.2,69.9,76.4,76.6,87.3,120.7,122.1,124.3,125.5,125 .9,129.4,130.4,136.8,138.6,154.2,155.1,168.1; HRMS(ESI-TOF)m / z:Calcd.for C 32 H 28 Br2N6NaO6[M+Na] + :773.0308;Found:773.0299。

[0045] (II) Preparation of chiral naphthidine-mononitroxide ligand Nap-NO

[0046]

[0047] Chiral naphthidine-monooxy ligand Nap-1-NO: Proline amide 1a (1.5 eq) and naphthidine-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 dichloromethane 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 white solid Nap-1-NO with a melting point of 215.5-216.9 °C and a total yield of 51% (12:1 dr). The results of NMR and high-resolution mass spectrometry are as follows: 1 H NMR(CD3OD,400MHz)δ:2.25-2.32(m,1H),2.48-2.62(m,3H),3.96-4.01( m,1H),4.20-4.27(m,1H),4.85-4.88(m,1H),7.06(s,1H),7.13-7.17(m, 1H),7.26-7.30(m,2H),7.53-7.55(m,2H),7.63-7.66(m,1H),7.93(d,J= 8.4Hz,1H),8.44-8.47(m,1H),8.49(d,J=8.0Hz,1H),9.05-9.07(m,1H); 13 C NMR(CD3OD,100MHz)δ:22.3,24.1,70.8,76.9,87.5,122.9,123.3,123.7,125.1,126.7, 128.9,135.5,138.3,138.5,153.9,154.5,155.1,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 20 H 18 N4NaO2[M+Na] + :369.1322;Found:369.1316.

[0048] The chiral naphthidine-monooxy ligands Nap-2-NO to Nap-12-NO prepared by the examples were prepared by the same method as those for chiral naphthidine-monooxy ligands Bpy-1-NO, with the same feed ratio as ligand Nap-1-NO, to obtain ligands Nap-2-NO to Nap-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.

[0049] Table 2 shows the chemical structures for preparing the chiral naphthidine-monooxy ligand Nap-NO.

[0050]

[0051] In this embodiment, chiral naphthidine-mononitroxide ligand Nap-2-NO: was prepared as a white solid with a melting point of 203.4-204.7 °C and an overall yield of 47% (13:1 dr). The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.62-2.69 (m, 1H), 2.87-2.93 (m, 1H), 3.99 (d, J = 8.4Hz, 1H), 4.48-4.53 (m, 1H), 4.69-4.72 (m, 1H), 5.08-5.11 (m, 1H), 7.07 (s,1H),7.13-7.17(m,1H),7.26-7.30(m,2H),7.50-7.53(m,2H),7.64-7 .67(m,1H),7.91(d,J=8.0Hz,1H),8.44-8.49(m,2H),9.06-9.08(m,1H); 13 CNMR(CD3OD,100MHz)δ:35.1,69.9,76.4,76.8,88.0,123.0,123.3,123.7,125.1,126.8, 128.9,135.3,138.3,138.5,154.0,154.4,154.7,168.1; HRMS(ESI-TOF)m / z:Calcd.forC 20 H 18 N4NaO3[M+Na] + :385.1271;Found:385.1267.

[0052] In this embodiment, chiral naphthidine-mononitroxide ligand Nap-3-NO was prepared as a white solid with a melting point of 206.3-207.2 °C; the overall yield was 46%, and the dr ratio was 14:1. The results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:1.05-1.09(m,3H),2.27-2.30(m,1H),2.46-2.59(m ,5H),3.96-4.01(m,1H),4.20-4.27(m,1H),4.85-4.88(m,1H),7.03(s,1H) ,7.11(d,J=8.8Hz,2H),7.43(d,J=8.8Hz,2H),7.62-7.65(m,1H),7.91(d, J=8.4Hz,1H),8.43-8.45(m,1H),8.47(d,J=8.4Hz,1H),9.04-9.06(m,1H); 13C NMR(CD3OD,100MHz)δ:14.5,22.3,24.1,27.8,70.8,76.9,87.7,123.2,123.3,123.7,125.1,1 28.3,133.0,138.3,138.4,143.4,153.9,154.4,155.2,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 22 H 22 N4NaO2[M+Na] + :397.1635; Found:397.1632.

[0053] In this embodiment, chiral naphthidine-mononitroxide ligand Nap-4-NO: was prepared as a white solid with a melting point of 207.3-208.3 °C; the overall yield was 49%, 19:1 dr; the results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.15(s,3H),2.34-2.37(m,1H),2.50(s,3H),2.54- 2.69(m,3H),3.94-4.00(m,1H),4.36-4.41(m,1H),5.30-5.33(m,1H),6.78 (s,1H),6.88-6.90(m,1H),7.05-7.07(m,2H),7.66-7.69(m,1H),7.79(d, J=8.0Hz,1H),8.40(d,J=8.4Hz,1H),8.44-8.46(m,1H),9.11-9.12(m,1H); 13 C NMR(CD3OD,100MHz)δ:18.4,18.5,22.7,24.0,70.8,77.1,87.9,123.3,123.6,124.8,128.9,129.0,1 29.4,131.0,135.7,137.9,138.2,138.3,154.1,154.2,154.8,168.4; HRMS(ESI-TOF)m / z:Calcd.for C 20 H 17 ClN4NaO2[M+Na] + :403.0932;Found:403.0927。

[0054] In this embodiment, the chiral naphthidine-mononitroxide ligand Nap-6-NO₂ was prepared as a white solid with a melting point of 208.0-208.7 °C; the overall yield was 42% (20:1 dr); the results of NMR and high-resolution mass spectrometry tests are as follows: 1H NMR(CD3OD,400MHz)δ:2.31-2.36(m,1H),2.38(s,3H),2.48-2.64(m,3H),4.01-4.05(m,1H),4.30-4.37(m,1H),5.02-5.05(m,1H), 6.86(s,1H),7.03-7.07(m,1H),7.15-7.23(m,3H),7.68-7.71(m,1H),7.80(d,J=8.4Hz,1H),8.46-8.50(m,2H),9.12-9.14(m,1H); 13 C NMR(CD3OD,100MHz)δ:17.4,22.5,24.0,71.0,76.8,88.5,123.3,123.7,125.1,126.6,128.8,1 31.3,133.0,136.5,138.4,138.5,154.1,154.4,155.3,169.0; HRMS(ESI-TOF)m / z:Calcd.forC 21 H 20 N4NaO2[M+Na] + :383.1478;Found:383.1481.

[0055] In this embodiment, chiral naphthidine-mononitroxide ligand Nap-7-NO: was prepared as a white solid with a melting point of 209.3-209.9 °C; the overall yield was 40%, and the ratio was 19:1 dr. The results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:1.05-1.10(m,3H),2.48-2.51(m,2H),2.62-2.68(m,1 H),2.86-2.93(m,1H),4.01(d,J=12.4Hz,1H),4.48-4.53(m,1H),4.71(s,1H) ,5.09(d,J=8.8Hz,1H),7.02(s,1H),7.09-7.12(m,2H),7.39-7.41(m,2H),7. 63-7.68(m,1H),7.89(d,J=8.0Hz,1H),8.45-8.47(m,2H),9.06-9.08(m,1H); 13C NMR(CD3OD,100MHz)δ:14.5,27.8,35.1,69.9,76.4,76.8,88.2,123.3,123.4,123.7,125.1,1 28.3,132.8,138.3,138.4,143.4,154.0,154.4,154.7,168.1; HRMS(ESI-TOF)m / z:Calcd.for C 22 H 22 N4NaO3[M+Na] + :413.1584;Found:413.1586。

[0056] In this embodiment, chiral naphthidine-mononitroxide ligand Nap-8-NO was prepared as a white solid with a melting point of 205.3-205.7 °C and an overall yield of 50% (>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),2.25-2.30(m,1H),2.48-2.61(m,3H),3 .96-4.00(m,1H),4.19-4.26(m,1H),4.84-4.86(m,1H),6.98(d,J=7.6Hz,1 H),7.04(s,1H),7.13-7.17(m,1H),7.28(d,J=8.0Hz,1H),7.41(s,1H),7.6 5-7.68(m,1H),7.91(d,J=8.4Hz,1H),8.47-8.51(m,2H),9.06-9.08(m,1H); 13 C NMR(CD3OD,100MHz)δ:19.9,22.3,24.1,70.8,76.9,87.6,120.0,123.3,123.6,123.7,125.1,127 .4,128.7,135.3,138.3,138.4,139.2,153.9,154.4,155.2,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 21 H 20 N4NaO2[M+Na] + :383.1478;Found:383.1477。

[0057] In this embodiment, the chiral naphthidine-mononitroxide ligand Nap-9-NO₂ was prepared as a white solid with a melting point of 204.4-205.2 °C and an overall yield of 52% (15:1 dr). The results of NMR and high-resolution mass spectrometry measurements are as follows: 1H NMR(CD3OD,400MHz)δ:2.19(s,3H),2.25-2.30(m,1H),2.47-2.62(m,3H) ,3.96-4.00(m,1H),4.20-4.27(m,1H),4.84-4.88(m,1H),7.01(s,1H),7 .08(d,J=8.4Hz,2H),7.39(d,J=8.8Hz,2H),7.64-7.67(m,1H),7.90(d,J =8.4Hz,1H),8.45-8.48(m,1H),8.49(d,J=8.4Hz,1H),9.06-9.07(m,1H); 13 C NMR(CD3OD,100MHz)δ:19.5,22.3,24.1,70.8,76.9,87.7,123.1,123.3,123.7,125.1,129 .4,132.8,137.0,138.3,138.4,153.9,154.4,155.2,168.7; HRMS(ESI-TOF)m / z:Calcd.for C 21 H 20 N4NaO2[M+Na] + :383.1478;Found:383.1475。

[0058] In this embodiment, the chiral naphthidine-mononitroxide ligand Nap-10-NO was prepared as a white solid with a melting point of 203.4-204.2 °C and an overall yield of 47% (17:1 dr). The results of NMR and high-resolution mass spectrometry measurements are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.63-2.69 (m, 1H), 2.88-2.94 (m, 1H), 4.01 (d, J = 12.4Hz ,1H),4.46-4.51(m,1H),4.69-4.72(m,1H),5.06-5.10(m,1H),6.87-6.92(m,1 H),7.13(s,1H),7.23-7.31(m,2H),7.53-7.56(m,1H),7.67-7.70(m,1H),7.97 (d,J=8.4Hz,1H),8.49-8.51(m,1H),8.53(d,J=8.4Hz,1H),9.07-9.09(m,1H); 13 CNMR(CD3OD,100MHz)δ:35.1,69.9,76.5,76.7,87.4,109.7(d,J CF =26.1Hz), 113.1(d,J CF=21.2Hz), 117.6(d,J CF =3.3Hz),123.4,123.8,125.2,130.3(d,J CF =9.1Hz), 136.9(d,J) CF =10.0Hz), 138.5(d,J) CF =26.1Hz), 154.1, 154.4 (d, J) CF =4.4Hz), 162.4(d,J CF =244.2Hz),168.0; HRMS(ESI-TOF)m / z:Calcd.for C 20 H 17 FN4NaO3[M+Na] + :403.1177;Found:403.1181.

[0059] In this embodiment, the chiral naphthidine-mononitroxide ligand Nap-12-NO was prepared as a white solid with a melting point of 188.0-188.9 °C; the overall yield was 50%, and the ratio was 19:1 dr. The results of NMR and high-resolution mass spectrometry tests are as follows: 1 H NMR(CD3OD,400MHz)δ:2.28-2.32(m,1H),2.47-2.63(m,3H),3.97-4.01(m,1H),4.23-4.30(m,1H),4.82-4.89(m,1H), 7.02-7.07(m,3H),7.55-7.58(m,2H),7.68-7.71(m,1H),7.91(d,J=8.0Hz,1H),8.49-8.54(m,2H),9.08-9.10(m,1H); 13 C NMR(CD3OD,100MHz)δ:22.3,24.0,70.8,76.7,87.7,115.6(d,J CF =21.3Hz),123.3,123.7,125.2,125.7(d,J CF =8.3Hz), 138.4(d,J) CF =17.4Hz),154.0,154.4,154.9,161.3(d,J CF =244.3Hz),168.8; HRMS(ESI-TOF)m / z:Calcd.for C 20 H 17 FN4NaO2[M+Na] + :387.1228;Found:387.1233。

[0060] (III) Application of chiral naphthidine-nitrogen oxide ligands (Nap-2NO and Nap-NO) in asymmetric catalytic Friedel-Crafts alkylation of indole

[0061] The chiral naphthidine-nitrogen oxide ligands of formula (1) of the present invention (Nap-2NO and Nap-NO) contain a naphthidine group and a nitrogen oxide group (the nitrogen atom of naphthidine and the oxygen atom of the nitrogen oxide group are electron-rich coordination sites), thereby forming a six-membered ring coordination with Lewis metals to generate chiral ligand-metal complexes, which are used as dominant chiral ligands in asymmetric catalytic indole-indole Friedel-Crafts alkylation reactions. However, it should be emphasized that the chiral naphthidine-nitrogen oxide ligands of the present invention are not limited to use as chiral ligands only in asymmetric catalytic indole Friedel-Crafts alkylation reactions.

[0062] Example 1: Application of Nap-2NO, a chiral ligand with various substituents, in the asymmetric catalytic Friedel-Crafts alkylation reaction of indole 4a and nitrostyrene 5a.

[0063] To demonstrate the application value of the developed chiral ligand Nap-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction involving indole 4a and nitrostyrene 5a as the template reaction, and chose compounds Nap-1-2NO to Nap-13-2NO as chiral naphthidine-bis(nitrosyl)oxine ligands to generate chiral complexes in situ with Lewis acid Ni(OTf)2, thus verifying the asymmetric catalytic effect of the chiral ligand Nap-2NO (Table 3).

[0064] Table 3 shows the applications of chiral ligands Nap-2NO with various substituents in asymmetric catalytic reactions.

[0065]

[0066] Experimental conclusions: The Friedel-Crafts alkylation template reaction of indole 4a and nitrostyrene 5a was selected as the evaluation index for asymmetric catalysis. Experimental results show that the chiral ligands Nap-1-2NO to Nap-13-2NO with various substituents shown in formula (1) exhibit asymmetric catalytic effects in the Friedel-Crafts alkylation reaction involving indole 4a and nitrostyrene 5a, and can be developed into a new dominant chiral naphthidine-bis(nitrosyl) ligand Nap-2NO, which warrants further in-depth research.

[0067] Example 2: Application of chiral ligand Nap-1-2NO in the asymmetric catalytic Friedel-Crafts alkylation reaction of various substituents of indole 4 and various substituents of nitrostyrene 5.

[0068] To demonstrate the application value of the developed chiral ligand Nap-1-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of various substituents of indole 4 and various substituents of nitrostyrene 5 as the template reaction to verify the catalytic effect of the chiral ligand Nap-1-2NO (Table 4).

[0069] Table 4 shows the application of the chiral ligand Nap-1-2NO in the Friedel-Crafts alkylation reaction of various substituents of indole 4 with various substituents of nitrostyrene 5 via asymmetric catalysis.

[0070]

[0071] Experimental Conclusion: The Friedel-Crafts alkylation template reaction of various substituents of indole 4 and various substituents of nitrostyrene 5 was selected as the evaluation index for asymmetric catalysis. The experimental results show that the chiral ligand Nap-1-2NO and Ni(OTf)2 generated in situ as chiral complexes in the Friedel-Crafts alkylation reaction of various substituents of indole 4 and various substituents of nitrostyrene 5, as shown in formula (1), all exhibit asymmetric catalytic effects and can be developed into new dominant chiral naphthidine-bis(nitrosyl) ligands, which are worthy of further in-depth research.

[0072] Example 3: Application of Nap-NO, a chiral ligand with various substituents, in the asymmetric Friedel-Crafts alkylation reaction of indole 4a and nitrostyrene 5a.

[0073] To demonstrate the application value of the developed chiral ligand Nap-NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction involving indole 4a and nitrostyrene 5a as the template reaction, and selected compounds Nap-1-NO to Nap-12-NO as chiral naphthidine-monooxy ligands to generate chiral complexes in situ with Lewis acid Ni(OTf)2, thus verifying the asymmetric catalytic effect of the chiral ligand Nap-NO (Table 5).

[0074] Table 5 shows the applications of chiral ligands Nap-NO with various substituents in asymmetric catalytic reactions.

[0075]

[0076] Experimental conclusions: The Friedel-Crafts alkylation template reaction of indole 4a and enone ester 6a was selected as the evaluation index for asymmetric catalysis. Experimental results show that the chiral ligands Nap-1-NO to Nap-12-NO with various substituents shown in formula (1) exhibit asymmetric catalytic effects in the Friedel-Crafts alkylation reaction involving indole 4a and enone ester 6a, and can be developed into new chiral naphthidine-monooxy ligands Nap-NO, which warrants further in-depth research.

Claims

1. A chiral naphthidine-nitrogen oxide ligand, characterized in that: Chiral naphthidine-nitrogen oxide ligands are naphthidine-bis(nitrogen oxide) ligand Nap-2NO and naphthidine-mono(nitrogen oxide) ligand Nap-NO. Chiral naphthidine-bis(nitrogen oxide) ligand Nap-2NO has the structure shown in general formula (Ⅰ), and chiral naphthidine-mono(nitrogen oxide) ligand Nap-NO has the structure shown in general formula (Ⅱ). （I） （Ⅱ）； In the formula, R is a hydroxyl group or hydrogen, and Ar is a phenyl group substituted with fluorine, chlorine, bromine, methoxy, or methyl.

2. A chiral naphthidine-nitrogen oxide ligand, characterized in that: The chiral naphthidine-bis(nitroxide) ligand Nap-2NO specifically has one of the following structural formulas: 。 3. A chiral naphthidine-nitrogen oxide ligand, characterized in that: The chiral naphthidine-mononitroxide ligand Nap-NO specifically has one of the following structural formulas: 。 4. A method for preparing the chiral naphthidine-bis(nitroxide) ligand Nap-2NO as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 and naphthidine-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 naphthidine-dinitrogen oxide ligand Nap-2NO. The synthesis route is as follows: 。 5. A method for preparing the chiral naphthidine-mononitroxide ligand Nap-NO as described in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 and naphthidine-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-mononitroxide ligand Nap-NO. The synthesis route is as follows: 。 6. The application of the chiral naphthidine-bis(nitroxide) ligand Nap-2NO as described in claim 2 as a ligand in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole, characterized in that, The alkylation reaction is as follows: 。 7. The application of the chiral naphthidine-mononitroxide ligand Nap-NO as described in claim 3 in asymmetric catalytic Friedel-Crafts alkylation reactions involving indole, characterized in that, The alkylation reaction is as follows: 。

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