Chiral phenol dinitrogen oxygen ligand and intermediate, preparation method of chiral phenol dinitrogen oxygen ligand and intermediate, and application of chiral phenol dinitrogen oxygen ligand and intermediate in asymmetric catalytic reaction

Abstract

The invention discloses a chiral phenol dinitrogen-oxygen ligand Bf-2NO and an intermediate Bf.The chiral phenol dinitrogen-oxygen ligand Bf-2NO is prepared by the steps that various substituted prolinamide or hydroxyprolinamide 1 and phenol-2, 5-dicarboxaldehyde 2 are subjected to a condensation reaction to generate the intermediate Bf, then nitrogen atoms in the intermediate Bf are subjected to a nitrogen oxidation reaction under the action of an oxidizing agent m-chloroperoxybenzoic acid, and the chiral phenol dinitrogen-oxygen ligand Bf-2NO is obtained. The chiral phenol dinitrogen-oxygen ligand Bf-2NO is generated by using the chiral phenol as a ligand, the ligand comprises a phenol group and a nitrogen-oxygen group (hydroxyl oxygen atoms of phenol and oxygen atoms of the nitrogen-oxygen group belong to electron-rich coordination sites), and can form seven-membered ring coordination with Lewis metal, so that a chiral ligand metal compound is generated and is applied as a chiral ligand in an asymmetric catalytic reaction. The method is simple and easy to operate, raw materials are cheap and easy to obtain in synthesis, and the ligand prepared by the method can react in various organic solvents, also has better air stability and wide applicability, and has very good compatibility with various substituent groups.

Description

Technical Field

[0001] The invention relates to the technical field of chiral chemistry and asymmetric catalytic synthesis, in particular to a chiral phenol dinitrogen oxide ligand and an intermediate, a preparation method thereof and an application thereof in an asymmetric catalytic reaction. Background Art

[0002] Chiral pharmaceuticals are at the forefront of the pharmaceutical industry, and the 2001 and 2021 Nobel Prizes in Chemistry were awarded to the major contributors to chiral catalysis.

[0003] The key preparation technology of chiral drugs was selected as one of the "Top Ten Chemical Technology Inventions that Changed the World" proposed by IUPAC. The design and synthesis of dominant chiral ligands play a key role in the development of asymmetric catalytic reactions and are the most attractive and challenging goals in asymmetric catalysis. In addition, economically feasible synthetic routes are also crucial for dominant chiral ligands so that they can be widely used. In particular, N-oxides of amines are highly polar substances, which can be easily prepared by N-oxidation reactions 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 of N-oxides provide opportunities to form complexes with a variety of metals. Some research focuses on the development of new 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 therefore designed and developed a new type of chiral tertiary amine-derived chiral phenol-diazoxy ligand Bf-2NO and tested their application in the asymmetric Friedel-Crafts alkylation of indole. Based on the design and synthesis of a new type of phenol-diazoxy ligand metal complex, our design idea refers to the tridentate ligand chelation catalytic mechanism of the "lobster" biomimetic model: the dizoxy group is likened to the two crab legs of the "lobster", and the hydroxyl group of phenol is likened to the mouth of the "lobster" (such as Figure 1 and Figure 2 shown). Summary of the invention

[0005] The purpose of the present invention is to provide a chiral phenol dinitrogen oxide ligand Bf-2NO and an intermediate Bf and a preparation method and application thereof, which is an important class of chiral phenol dinitrogen oxide ligands, and the ligands include a phenol group and a nitroxide group (the hydroxyl oxygen atom of the phenol and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), which can form a seven-membered ring coordination with a Lewis metal, thereby generating a chiral ligand metal complex, and being used as a chiral ligand in an asymmetric catalytic reaction. Therefore, the invention 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 also finds the application of chiral phenol dinitrogen oxide ligand Bf-2NO in asymmetric catalytic indole Friedel-Crafts alkylation reaction.

[0007] The present invention is achieved as follows: a chiral phenol dinitrogen oxide ligand Bf-2NO and an intermediate Bf, characterized in that: the chiral phenol dinitrogen oxide ligand Bf-2NO has a structure as shown in general formula (I), and the intermediate Bf has a structure as shown in general formula (II);

[0008]

[0009] In the formula, R 1 is hydroxyl or hydrogen; R is methyl or hydrogen; Ar is a benzene ring substituted with fluorine, isopropyl, tert-butyl, methoxy, methyl or hydrogen.

[0010] The preparation method of chiral phenol dinitrogen oxide ligand Bf-2NO and intermediate Bf is characterized in that: the corresponding proline amide or hydroxyproline amide 1 and phenol-2,5-dicarboxaldehyde 2 are first subjected to a condensation reaction to generate the desired intermediate Bf, and then the nitrogen atom in the intermediate Bf is subjected to a nitrogen oxidation reaction under the action of an oxidant, meta-chloroperbenzoic acid, to generate chiral phenol dinitrogen oxide ligand Bf-2NO;

[0011] The synthetic route is as follows:

[0012]

[0013] In the formula, R 1 is hydroxyl or hydrogen; R is methyl or hydrogen; Ar is a benzene ring substituted with fluorine, isopropyl, tert-butyl, methoxy, methyl or hydrogen.

[0014] Application of intermediate Bf in the synthesis of chiral phenol dinitrogen oxide ligand Bf-2NO.

[0015] Application of chiral phenol dinitrogen oxide ligand Bf-2NO in asymmetric catalytic Friedel-Crafts alkylation of indole.

[0016] The design idea of ​​the present invention is:

[0017] Our design: Tertiary amine-derived C2-symmetric chiral phenol dinitrogen oxide ligand

[0018]

[0019] By adopting the above technical scheme, various substituted proline amides or hydroxyproline amides 1 and phenol-2,5-diformaldehyde 2 first undergo condensation reaction to generate an intermediate Bf, and then the nitrogen atom in the intermediate Bf undergoes nitrogen oxidation reaction under the action of the oxidant meta-chloroperbenzoic acid to generate a chiral phenol dinitrogen oxide ligand Bf-2NO, which contains a phenol group and a nitrogen oxide group (the hydroxyl oxygen atom of phenol and the oxygen atom of the nitrogen oxide group belong to electron-rich coordination sites), and can form a seven-membered ring coordination with a Lewis metal to generate a chiral ligand metal complex, which is used as a chiral ligand in an asymmetric catalytic reaction. The present invention is simple and easy to operate, the raw material synthesis is cheap and easy to obtain (the chiral source is economically available chiral proline or proline), and the ligand prepared by the present invention can react in various organic solvents, and also has good air stability, wide applicability, and good compatibility for various substituents. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 and Figure 2 The design idea and creative diagram of the chiral phenol dinitrogen oxide ligand Bf-2NO synthesized by the present invention;

[0021] Figure 2 In the figure, the dinitrogen oxide groups are likened to the two legs of a lobster, and the hydroxyl groups of phenol are likened to the mouth of a lobster.

[0022] Figure 3 and Figure 4 The spectrum data of the chiral phenol dinitrogen oxide ligand Bf-01-2NO of the embodiment of the present invention;

[0023] Figure 5 and Figure 6 The spectrum data of the chiral phenol dinitrogen oxide ligand Bf-05-2NO of the embodiment of the present invention;

[0024] Figure 7 and Figure 8 The spectral data of the chiral phenol dinitrogen oxide ligand intermediate Bf-1 of the embodiment of the present invention;

[0025] Fig. 9 Single crystal images of chiral phenol dinitrogen oxide ligand intermediates Bf-23 and Bf-26 according to embodiments of the present invention. DETAILED DESCRIPTION

[0026] (I) Synthesis and preparation of chiral phenol dinitrogen oxide ligand intermediate Bf

[0027]

[0028] Chiral phenol dinitrogen oxide ligand intermediate Bf-1: The raw material hydroxyproline amide 1a (2.5eq) and phenol-2,5-dicarboxaldehyde (1eq, 0.78mmol) 2 were dissolved in an appropriate amount of anhydrous ethanol and refluxed for 10h. After the reaction solution was treated, it was purified by column chromatography to obtain the intermediate Bf-1 as a white solid with a yield of 79% and a dr of 15:1. The results of the nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 HNMR(CD3OD,400MHz)δ:1.81-1.86(m,5H),1.89-1.95(m,2H),2.05-2.08(m,2H),2.13-2.18(m,2H),2.89-2.95 (m,2H),3.21-3.26(m,2H),4.01-4.05(m,2H),5.89(s,2H),6.55(s,2H),7.06-7.10(m,2H),7.17-7.19(m,8H); 13 C NMR (CD3OD, 100MHz) δ: 19.0, 24.3, 27.6, 54.4, 64.8, 81.3, 123.7, 123.8, 126.2, 127.9, 128.6, 129.2, 136.4, 153.1, 174.2; HRMS (ESI-TOF) m / z: Calcd.for C 31 H 32 N4NaO3[M+Na] + :531.2367;Found:531.2371.

[0029] The preparation method of the chiral phenol dinitrogen oxide ligands Bf-02-2NO to Bf-10-2NO prepared in the examples is the same as that of the ligand Bf-01-2NO, and the feed ratio is the same as that of the ligand Bf-01-2NO, and the ligands Bf-02-2NO to Bf-10-2NO can be obtained. The reaction yields are shown in Table 2, but 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 the contents shown in Table 1.

[0030] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-2: white solid; yield 77%, 17:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(CD3OD,400MHz)δ:1.89(s,3H),2.17-2.23(m,2H),2.32-2.38(m,2H),3.08-3.12(m,2H),3.30-3.33(m, 2H),4.25-4.29(m,2H),4.52-4.54(m,2H),6.00(s,2H),6.63(s,2H),7.13-7.17(m,2H),7.24-7.32(m,8H); 13 C NMR (CD3OD, 100MHz) δ: 19.1, 36.4, 61.7, 63.8, 71.1, 81.4, 123.5, 123.9, 126.1, 128.0, 128.7, 129.0, 136.5, 153.0, 174.1; HRMS (ESI-TOF) m / z: Calcd.for C 31 H 32 N4NaO5[M+Na] + :563.2265;Found:563.2265.

[0031] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-3: white solid; yield 81%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.85-1.92(m,5H),1.95-2.01(m,2H),2.08-2.15(m,2H),2.19-2.26(m,8H),2.95-3.01(m, 2H),3.26-3.31(m,2H),4.08-4.12(m,2H),5.93(s,2H),6.64(s,2H),7.05(d,J=8.4Hz,4H),7.13(d,J=8.4Hz,4H); 13 CNMR(CD3OD,100MHz)δ:19.1,19.7,24.3,27.6,54.4,64.8,81.4,123.7,123.8, 127.9,129.2,129.3,133.8,136.2,153.3,174.1; HRMS(ESI-TOF)m / z:Calcd.for C 33 H 36 N4NaO3[M+Na] + :559.2680;Found:559.2675.

[0032] Table 1 shows the chemical structure of the intermediate Bf for preparing chiral phenol dinitrogen oxide ligand

[0033]

[0034] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-5: white solid; yield 80%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.12-1.16(m,6H),1.86-1.91(m,5H),1.94-1.99(m,2H),2.10-2.16(m,2H),2.19-2.24(m,2H),2.52-2.58(m, 4H),2.95-3.01(m,2H),3.26-3.32(m,2H),4.07-4.12(m,2H),5.95(s,2H),6.63(s,2H),7.07(d,J=8.8Hz,4H),7.17(d,J=8.4Hz,4H); 13 C NMR(CD3OD,100MHz)δ:14.7,19.1,24.3,27.6,28.0,54.4,64.7,81.3,123.8,1 27.9,128.0,129.2,134.0,142.6,153.2,174.1; HRMS(ESI-TOF)m / z:Calcd.for C 35 H 40 N4NaO3[M+Na] + :587.2993;Found:587.2994.

[0035] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-7: white solid; yield 71%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.12-1.16(m,6H),1.16(s,6H),1.18(s,6H),1.86(s,3H),2.17-2.22(m,2H),2.31-2.38(m,2H),2.79-2.86(m,2H),3.08 -3.12(m,2H),3.30-3.34(m,2H),4.24-4.28(m,2H),4.52-4.54(m,2H), 5.96(s,2H),6.60(s,2H),7.11(d,J=8.4Hz,4H),7.19(d,J=8.4Hz,4H); 13C NMR (CD3OD, 100MHz) δ: 19.1, 23.0, 33.5, 36.4, 61.7, 63.8, 71.1, 81.5, 123.7, 123. 8,126.6,127.9,129.0,134.1,147.1,153.1,174.0; HRMS(ESI-TOF)m / z:Calcd.for C 37 H 44 N4NaO5[M+Na] + :647.3204;Found:647.3203.

[0036] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-11: white solid; yield 77%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.16(s,6H),1.18(s,6H),1.86-1.93(m,5H),1.95-2.02(m,2H),2.10-2.18(m,2H),2.20-2.24(m,2H),2.79-2 .86(m,2H),2.96-3.02(m,2H),3.28-3.34(m,2H),4.09-4.12(m,2H),5.95(s,2H),6.62(s,2H),7.11-7.13(m,4H),7.17-7.20(m,4H); 13 C NMR (CD3OD, 100MHz) δ: 19.1, 23.0, 24.3, 27.6, 33.6, 54.4, 64.7, 81.3, 123.7, 123. 8,126.5,127.9,129.1,134.1,147.2,153.2,174.1; HRMS(ESI-TOF)m / z:Calcd.for C 37 H 44 N4NaO3[M+Na] + :615.3306;Found:615.3309.

[0037] This example prepares chiral phenol dinitrogen oxide ligand intermediate Bf-16: white solid; yield 78%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(CD3OD,400MHz)δ:1.87-1.96(m,5H),1.97-2.04(m,2H),2.09-2.17(m,2H),2.19-2.26(m,2H),2.99-3.05(m,2H) ,3.23-3.28(m,2H),3.71(s,6H),4.12-4.15(m,2H),5.84(s,2H),6.63(s,2H),6.76-6.80(m,4H),7.06-7.10(m,4H); 13 C NMR(CD3OD,100MHz)δ:19.0,24.3,27.8,54.4,54.5,64.8,82.1,113.8,123.3,1 26.1,127.8,128.6,129.8,153.6,158.4,173.9; HRMS(ESI-TOF)m / z:Calcd.forC 33 H 36 N4NaO5[M+Na] + :591.2578;Found:591.2581.

[0038] This example prepares chiral phenol dinitrogen oxide ligand intermediate Bf-17: white solid; yield 75%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.76-1.81(m,5H),1.87-1.90(m,2H),2.01-2.06(m,2H),2.08-2.16(m,8H),2.86-2.92(m,2H),3.18 -3.23(m,2H),4.00-4.03(m,2H),5.86(s,2H),6.54(s,2H),6.86(d,J=7.6Hz,2H),6.94(d,J=8.0Hz,2H),7.00-7.04(m,4H); 13 C NMR(CD3OD,100MHz)δ:19.1,20.1,24.3,27.6,54.4,64.7,81.3,120.7,123.7,124.3,1 26.9,127.8,128.5,129.3,136.3,138.7,153.3,174.1; HRMS(ESI-TOF)m / z:Calcd.for C 33 H 36 N4NaO3[M+Na] + :559.2680;Found:559.2681.

[0039] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-20: white solid; yield 72%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.88-1.95(m,5H),1.98-2.04(m,2H),2.10-2.16(m,2H),2.20-2.27(m,2H),2.98-3.05 (m,2H),3.26-3.32(m,2H),4.13-4.16(m,2H),5.91(s,2H),6.67(s,2H),6.97-7.03(m,4H),7.25-7.28(m,4H); 13 C NMR(CD3OD,100MHz)δ:19.0,24.3,27.7,54.4,64.8,81.8,115.2(d,J CF =23.1Hz),123.4,126.2(d,J CF =9.2Hz),128.0,129.7,132.3,132.4(d,J CF =3.1Hz),161.8(d,J CF =244.2Hz),174.1; HRMS(ESI-TOF)m / z:Calcd.for C 31 H 30 F2N4NaO3[M+Na] + :567.2178;Found:567.2172.

[0040] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-23: white solid; yield 71%, 19:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(DMSO-d6,400MHz)δ:1.70-1.77(m,2H),1.81-1.87(m,2H),1.94-2.02(m,5H),2.07-2.11(m,2H),2.84-2.9 0(m,2H),3.24-3.29(m,2H),3.96-4.01(m,2H),6.21(s,2H),6.67(s,2H),7.23-7.37(m,6H),7.88-7.89(m,2H); 13C NMR(DMSO-d6,100MHz)δ:20.8,24.8,27.8,55.2,64.4,78.8,120.7,122.1,124.4,126 .6,127.8,128.2,128.5,131.2,139.3,151.9,174.8; HRMS(ESI-TOF)m / z:Calcd.forC 31 H 30 Br2N4NaO3[M+Na] + :687.0577;Found:687.0584.

[0041] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-25: white solid; yield 71%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.86-1.95(m,2H),1.96-2.02(m,5H),2.09-2.16(m,2H),2.20-2.28(m,2H),2.95-3.01 (m,2H),3.27-3.33(m,2H),4.08-4.13(m,2H),5.99(s,2H),6.69(s,2H),7.23-7.27(m,4H),7.39-7.41(m,4H); 13 C NMR (CD3OD, 100MHz) δ: 19.1, 24.3, 27.5, 54.4, 64.7, 80.7, 119.0, 123.8, 125.1, 128.4, 129.3, 131.7, 135.7, 153.0, 174.2; HRMS (ESI-TOF) m / z: Calcd.for C 31 H 30 Br2N4NaO3[M+Na] + :687.0577;Found:687.0583.

[0042] This example prepares chiral phenol dinitrogen oxide ligand intermediate Bf-26: white solid, yield 73%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(DMSO-d6,400MHz)δ:1.72-1.80(m,2H),1.82-1.89(m,2H),1.95-2.01(m,2H),2.06-2.13(m,2H),2.84-2.91(m,2H),3.26-3.31(m,2H),3. 92-3.95(m,2H),6.21(s,2H),6.54-6.58(m,1H),6.79(d,J=7.6Hz,2H) ,7.09-7.13(m,2H),7.27-7.31(m,4H),7.43(d,J=8.0Hz,4H),10.98(br s,1H); 13 C NMR (DMSO-d6, 100MHz) δ: 24.9, 27.7, 55.0, 64.3, 79.0, 119.4, 122.4, 125.6, 126.4, 127.3, 129.3, 137.7, 154.7, 174.3; HRMS (ESI-TOF) m / z: Calcd.for C 30 H 30 N4NaO3[M+Na] + :517.2210;Found:517.2212.

[0043] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-27: white solid, yield 70%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.17-2.22(m,2H),2.32-2.38(m,2H),3.08-3.12(m,2H),3.30-3.34(m,2H),4.24-4.28(m,2 H),4.52-4.54(m,2H),6.04(s,2H),6.45-6.49(m,1H),6.80(d,J=8.0Hz,2H),7.12-7.16(m,2H),7.23-7.32(m,8H); 13 C NMR (CD3OD, 100MHz) δ: 36.4, 61.6, 63.8, 71.1, 81.3, 118.5, 123.5, 124.0, 126.1, 128.6, 128.7, 136.5, 155.5, 174.1; HRMS (ESI-TOF) m / z: Calcd.for C 30 H 30 N4NaO5[M+Na] + :549.2108;Found:549.2108.

[0044] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-28: white solid, yield 75%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.85-1.91(m,2H),1.93-2.01(m,2H),2.09-2.22(m,4H),2.23(s,6H),2.95-3.02(m,2H),3.26-3.32(m ,2H),4.07-4.11(m,2H),5.97(s,2H),6.46-6.50(m,1H),6.80(d,J=7.6Hz,2H),7.03(d,J=8.4Hz,4H),7.14(d,J=8.8Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 19.7, 24.3, 27.6, 54.4, 64.7, 81.3, 118.5, 123.8, 128.9, 129.2, 133.7, 136.2, 155.8, 174.0; HRMS (ESI-TOF) m / z: Calcd.forC 32 H 34 N4NaO3[M+Na] + :545.2523;Found:545.2523.

[0045] This example prepares the chiral phenol dinitrogen oxide ligand intermediate Bf-29: white solid, yield 70%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.98(s,3H),2.00(s,3H),2.23-2.27(m,4H),3.20-3.27(m,4H),4.37-4.41(m,2H),4. 59-4.63(m,2H),5.78(s,2H),6.44-6.48(m,1H),6.80(d,J=7.6Hz,4H),7.04-7.08(m,2H),7.15-7.20(m,4H); 13 C NMR(CD3OD,100MHz)δ:16.6,36.7,62.1,63.8,71.5,83.5,117.9,122.7,126.3,128 .0,128.3,130.4,130.6,133.7,136.7,156.2,173.1; HRMS(ESI-TOF)m / z:Calcd.for C 32 H 34 N4NaO5[M+Na]+ :577.2421;Found:577.2425.

[0046] (II) Synthesis and preparation of chiral phenol dinitrogen oxide ligand Bf-2NO

[0047]

[0048] Chiral phenol dinitrogen oxide ligand Bf-2NO: The intermediate Bf (100 mg, 1 eq) prepared above and m-chloroperbenzoic acid (2.5 eq) were dissolved in an appropriate amount of chloroform and reacted at room temperature for 20 min. After the reaction solution was treated, it was purified by column chromatography to obtain a white solid Bf-01-2NO, melting point: 2.37.1-237.8°C; total yield 51%, 10:1dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(DMSO-d6,400MHz)δ:2.03(s,3H),2.41-2.49(m,2H),2.56-2.63(m,2H),3.49(d,J=11.6Hz,2H),4.20-4 .24(m,2H),4.55(s,2H),4.75-4.79(m,2H),6.78(s,2H),7.06(s,2H),7.16-7.18(m,3H),7.19-7.23(m,7H); 13 C NMR(DMSO-d6,100MHz)δ:19.1,20.4,30.5,36.1,36.5,69.3,70.2,70.9,75.0,77.7,85.7,120.1,124.7,125.7 ,127.0,129.1,129.2,129.4,132.0,135.7,136.3,159.7,168.0,168.7,169.1; HRMS(ESI-TOF)m / z:Calcd.for C 31 H 32 N4NaO7[M+Na] + :595.2163;Found:595.2165.

[0049] The preparation method of the chiral phenol dinitrogen oxide ligands Bf-02-2NO to Bf-26-2NO prepared in the examples is the same as that of the ligand Bf-01-2NO, and the feed ratio is the same as that of the ligand Bf-01-2NO, and the ligands Bf-02-2NO to Bf-26-2NO can be obtained. The reaction yields are shown in Table 2, but 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 the contents shown in Table 2.

[0050] This example prepares chiral phenol dinitrogen oxide ligand Bf-02-2NO: white solid, melting point: 226.6-227.1°C; total yield 50%, 11:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.13-1.15(m,12H),2.06(s,3H),2.41-2.50(m,2H),2.54-2.59(m,2H),2.80-2.86(m,2H),3.58(d,J=12.0Hz, 2H),4.18-4.22(m,2H),4.53(s,2H),4.74-4.78(m,2H),6.71(s,2H),7.07(s,2H),7.13-7.15(m,4H),7.23(s,1H),7.27-7.30(m,3H); 13 C NMR(CD3OD,100MHz)δ:20.3,20.4,24.0,24.1,24.2,24.3,33.5,36.2,36.6,69.4,70.2,70.8,75.2,77.8,85.9,120.1,12 4.8,125.7,126.7,127.1,127.2,131.5,133.6,134.0,147.3,159.7,168.0,168.6,169.1; HRMS(ESI-TOF)m / z:Calcd.for C 37 H 44 N4NaO7[M+Na] + :679.3102;Found:679.3105.

[0051] Table 2 shows the chemical structure of the chiral phenol dinitrogen oxide ligand Bf-2NO

[0052]

[0053] This example prepares chiral phenol dinitrogen oxide ligand Bf-03-2NO: white solid, melting point: 235.5-236.2°C; total yield 49%, 13:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR (CD3OD, 400MHz) δ: 2.09 (s, 3H), 2.24 (s, 6H), 2.52-2.58 (m, 2H), 2.70-2.75 (m, 2H), 3.77 (d, J = 12.4Hz, 2H), 4.30-4.34 (m ,2H),4.65(s,2H),4.73-4.77(m,2H),6.84(s,2H),6.99-7.01(m,4H),7.09(d,J=8.0Hz,2H),7.12-7.14(m,2H),7.32(s,2H); 13 C NMR(CD3OD,100MHz)δ:19.0,19.2,19.6,20.2,35.3,35.7,36.2,69.6,70.0,70.5,75.2,77.5,85.7,120.9,124.2,127.4,127.5,1 28.0,128.4,128.6,128.8,131.6,135.0,135.2,135.5,138.9,139.0,139.2,167.5,168.2,168.9; HRMS(ESI-TOF)m / z:Calcd.for C 33 H 36 N4NaO7[M+Na] + :623.2476;Found:623.2476.

[0054] This example prepares chiral phenol dinitrogen oxide ligand Bf-04-2NO: white solid, melting point: 216.1-216.6°C; total yield 47%, 9:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(DMSO-d6,400MHz)δ:2.03(s,3H),2.13-2.24(m,4H),2.30-2.34(m,2H),2.44-2.48(m,2H),3.61-3.65(m,2H),3.90 -3.97(m,2H),4.48-4.52(m,2H),6.80(s,2H),7.03(s,2H),7.15-7.19(m,2H),7.25-7.29(m,4H),7.36(d,J=7.6Hz,4H); 13C NMR(DMSO-d6,100MHz)δ:20.4,20.5,22.2,22.6,23.2,25.0,25.2,65.3,69.4,77.7,85.1,114.4,120.1,122.7 ,123.8,124.5,125.2,126.9,129.3,131.0,136.0,136.4,159.7,168.3,169.7; HRMS(ESI-TOF)m / z:Calcd.forC 31 H 32 N4NaO5[M+Na] + :563.2265;Found:563.2269.

[0055] This example prepares chiral phenol dinitrogen oxide ligand Bf-05-2NO: white solid, melting point: 227.7-228.3°C; total yield 50%, 10:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(DMSO-d6,400MHz)δ:2.04(s,3H),2.17-2.19(m,4H),2.23(s,6H),2.30-2.33(m,2H),2.44-2.49(m,2H) ,3.60(s,2H),3.88-3.95(m,2H),4.45-4.49(m,2H),6.73(s,2H),7.02-7.10(m,6H),7.24(d,J=8.0Hz,4H); 13 C NMR(DMSO-d6,100MHz)δ:20.5,20.6,21.0,22.3,23.2,24.6,25.0,31.2,36.2,65.2,69.4,77.7,85.2,114.5,119.4, 123.9,124.5,129.6,129.7,133.5,133.9,136.2,136.5,159.7,162.8,168.3,169.8; HRMS(ESI-TOF)m / z:Calcd.for C 33 H 36 N4NaO5[M+Na] + :591.2578;Found:591.2578.

[0056] This example prepares chiral phenol dinitrogen oxide ligand Bf-06-2NO: white solid, melting point: 220.3-221.0°C; total yield 51%, 11:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(DMSO-d6,400MHz)δ:1.14-1.15(m,12H),2.06(s,3H),2.14-2.20(m,4H),2.34-2.40(m,4H),2.79-2.88(m,2H),3.66 -3.68(m,2H),3.91-3.98(m,2H),4.47-4.50(m,2H),6.81(s,2H),7.02(s,2H),7.17-7.22(m,5H),7.37(d,J=8.4Hz,3H); 13 C NMR(DMSO-d6,100MHz)δ:20.4,20.7,22.3,23.0,24.0,24.1,24.2,24.3,25.2,33.4,33.5,65.0,69.7,77.7,85.2,120.1,1 20.9,123.6,124.6,125.5,126.4,127.0,127.2,133.8,134.1,147.2,159.8,168.1,169.7; HRMS(ESI-TOF)m / z:Calcd.for C 37 H 44 N4NaO5[M+Na] + :647.3204;Found:647.3202.

[0057] This example prepares chiral phenol dinitrogen oxide ligand Bf-07-2NO: white solid, melting point: 212.4-213.5°C; total yield 52%, 15:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.25(s,18H),2.08(s,3H),2.22-2.24(m,2H),2.41-2.54(m,6H),3.93-3.95(m,2H),4 .01-4.05(m,2H),4.47-4.49(m,2H),6.96(s,2H),7.12(s,2H),7.35(d,J=8.8Hz,5H),7.45(d,J=8.8Hz,3H); 13C NMR(CD3OD,100MHz)δ:18.9,19.4,21.8,22.4,22.8,24.2,24.6,24.8,30.3,30.5,34.0,65.1,70.0,77.8,84.9,120.1,12 1.7,123.4,125.4,125.6,125.8,127.6,129.1,131.5,133.2,149.6,157.7,167.7,169.4; HRMS(ESI-TOF)m / z:Calcd.forC 39 H 48 N4NaO5[M+Na] + :675.3517;Found:675.3517.

[0058] This example prepares chiral phenol dinitrogen oxide ligand Bf-08-2NO: white solid, melting point: 218.8-219.2°C; total yield 53%, 12:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.10(s,3H),2.27-2.40(m,4H),2.45-2.50(m,2H),2.55-2.62(m,2H),3.71(s,6H),3.77-3.83 (m,2H),4.01-4.07(m,2H),4.49-4.53(m,2H),6.76(s,2H),6.81(d,J=8.8Hz,4H),7.11(s,2H),7.28(d,J=8.8Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 18.9, 19.2, 21.8, 22.7, 22.9, 24.6, 24.9, 54.6, 65.2, 69.1, 77.8, 84.9, 113.8, 113.9, 114. 0,125.1,125.3,127.9,128.0,128.4,131.5,157.8,158.4,158.8,168.1,169.6; HRMS(ESI-TOF)m / z:Calcd.forC 33 H 36 N4NaO7[M+Na] + :623.2476;Found:623.2476.

[0059] This example prepares chiral phenol dinitrogen oxide ligand Bf-09-2NO: white solid, melting point: 244.4-255.3°C; total yield 54%, 15:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(CD3OD,400MHz)δ:2.12(s,3H),2.21-2.27(m,8H),2.39-2.43(m,2H),2.48-2.56(m,4H),3.88-3.91(m, 2H),4.01-4.08(m,2H),4.45-4.47(m,2H),6.95(s,2H),7.01-7.03(m,2H),7.13-7.17(m,6H),7.40(s,2H); 13 C NMR(CD3OD,100MHz)δ:18.9,19.3,20.1,21.8,22.4,22.9,24.3,24.6,24.8,65.2,69.7,77.7,84.8,119.4,119.7,120.9,122.9,1 24.2,127.2,128.4,128.6,128.7,131.4,135.3,135.6,138.8,139.0,139.1,157.7,167.8,169.5; HRMS(ESI-TOF)m / z:Calcd.for C 33 H 36 N4NaO5[M+Na] + :591.2578;Found:591.2575.

[0060] This example prepares chiral phenol dinitrogen oxide ligand Bf-10-2NO: white solid, melting point: 197.8-198.4°C; total yield 46%, 7:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.12(s,3H),2.29-2.41(m,4H),2.49-2.55(m,2H),2.61-2.68(m,2H),3.79-3 .85(m,2H),4.04-4.11(m,2H),4.52-4.56(m,2H),6.82(s,2H),7.01-7.12(m,7H),7.35-7.43(m,3H); 13 C NMR(CD3OD,100MHz)δ:18.8,19.1,21.7,22.7,22.9,24.6,24.8,65.2,69.1,77.7,84.6,115.3(d,J CF =23.1Hz),115.5(d,J CF =23.2Hz),117.1,119.2,125.7(d,J CF=9.1Hz),126.6,127.7,131.5,131.8,160.2(d,J CF =229.5Hz),161.8(d,J CF =227.4Hz),168.1,169.1,169.5; HRMS(ESI-TOF)m / z:Calcd.for C 31 H 30 F2N4NaO5[M+Na] + :599.2076;Found:599.2072.

[0061] This example prepares chiral phenol dinitrogen oxide ligand Bf-23-2NO: white solid, total yield 30%, 7:1dr; high resolution mass spectrometry test results are as follows: HRMS (ESI-TOF) m / z: Calcd.for C 31 H 30 Br2N4NaO5[M+Na] + :719.0475;Found:719.0472.

[0062] This example prepares chiral phenol dinitrogen oxide ligand Bf-26-2NO: white solid, total yield 31%, 5:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(DMSO-d6,400MHz)δ:2.24-2.31(m,2H),2.39-2.45(m,2H),2.52-2.62(m,4H),3.86-3.90(m,2H),4.0 4-4.09(m,2H),4.47-4.51(m,2H),7.00(s,2H),7.17-7.22(m,3H),7.27-7.31(m,7H),7.42-7.45(m,3H); 13 C NMR(DMSO-d6,100MHz)δ:21.7,22.5,22.9,24.4,24.7,24.8,65.2,69.4,77.7,84.8,117.9,122.5,123.6,1 24.1,126.5,127.0,128.6,128.7,128.8,131.1,135.5,135.7,167.9,169.4; HRMS(ESI-TOF)m / z:Calcd.for C 30 H 30 N4NaO5[M+Na] + :549.2108;Found:549.2101.

[0063] (III) Application of chiral phenol dinitrogen oxide ligand Bf-2NO in asymmetric catalytic Friedel-Crafts alkylation of indole

[0064] Formula (1) of the present invention generates a chiral phenol dinitrogen oxide ligand Bf-2NO, which contains a phenol group and a nitroxide group (the hydroxyl oxygen atom of the phenol and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), and can form a seven-membered ring coordination with a 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 oxide ligand of the present invention is not limited to being used as a chiral ligand in asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0065] Example 1: Application of chiral phenol dinitrogen oxide ligand Bf-2NO with various substituents in the asymmetric catalytic Friedel-Crafts alkylation of indole 4 and 2,3-dioxypyrrolidine olefin 5

[0066] In order to demonstrate the application value of the developed chiral phenol dinitrogen oxide ligand Bf-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidine olefin 5 as the template reaction, and selected 12 compounds in Compound Table 2 as chiral phenol dinitrogen oxide ligands Bf-2NO to in situ generate chiral complexes with Lewis acid Ni(OTf)2 to verify the asymmetric catalytic effect of chiral phenol dinitrogen oxide ligand Bf-2NO (Table 3).

[0067] Table 3 shows the application of chiral phenol dinitrogen oxide ligand Bf-2NO with various substituents in asymmetric catalytic reactions

[0068]

[0069] Experimental conclusion: The asymmetric catalytic Friedel-Crafts alkylation template reaction of indole 4 and 2,3-dioxypyrrolidine olefin 5 was selected as the evaluation index. The experimental results show that the chiral phenol dinitrogen oxide ligand Bf-2NO with various substituents shown in formula (1) shows asymmetric catalytic effect in the Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidine olefin 5, and can be developed into a new chiral phenol dinitrogen oxide ligand, which is worthy of further in-depth study.

Claims

1. A chiral phenol dinitrogen oxide ligand Bf-2NO and an intermediate Bf, characterized in that: The chiral phenol dinitrogen oxide ligand Bf-2NO has a structure as shown in the general formula (I), and the intermediate Bf has a structure as shown in the general formula (II); In the formula, R 1 is hydroxyl or hydrogen; R is methyl or hydrogen; Ar is a benzene ring substituted with fluorine, isopropyl, tert-butyl, methoxy, methyl or hydrogen; The chiral phenol dinitrogen oxide ligand Bf-2NO is specifically one of the following structural formulas: The intermediate Bf of the chiral phenol dinitrogen oxide ligand is specifically one of the following structural formulas:

2. A method for preparing the chiral phenol dinitrogen oxide ligand Bf-2NO and the intermediate Bf as claimed in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with phenol-2,5-dicarboxaldehyde 2 to generate the desired intermediate Bf, and then the nitrogen atom in the intermediate Bf undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperbenzoic acid to generate a chiral phenol dinitrogen oxide ligand Bf-2NO; The synthetic route is as follows: In the formula, R 1 is hydroxyl or hydrogen; R is methyl or hydrogen; Ar is a benzene ring substituted with fluorine, isopropyl, tert-butyl, methoxy, methyl or hydrogen.

3. Use of the intermediate Bf as claimed in claim 1 in the synthesis of chiral phenol dinitrogen oxide ligand Bf-2NO.

4. Use of the chiral phenol dinitrogen oxide ligand Bf-2NO as claimed in claim 1 in asymmetric catalytic Friedel-Crafts alkylation reaction involving indole.

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