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

Abstract

The invention discloses a chiral furan dinitrogen oxygen ligand Fu-2NO and an intermediate Fu, various substituted prolinamide or hydroxyprolinamide 1 and furan-2, 5-dicarboxaldehyde 2 are subjected to a condensation reaction to generate the intermediate Fu, nitrogen atoms in the intermediate Fu are subjected to a nitrogen oxidation reaction under the action of an oxidizing agent m-chloroperoxybenzoic acid, and the chiral furan dinitrogen oxygen ligand Fu-2NO is obtained. And the chiral furan dinitrogen oxygen ligand Fu-2NO is generated. The ligand contains a furan group and a nitrogen-oxygen group, and can form six-membered ring coordination with Lewis metal, so that a chiral ligand metal compound is generated, and the chiral ligand metal compound is applied as a chiral ligand in an asymmetric catalytic reaction. The method is simple and easy to operate, the raw material synthesis is cheap and easy to obtain (the chiral source is economic and easy-to-obtain chiral proline or proline), 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 furan dinitrogen oxide ligand and 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. The Nobel Prizes in Chemistry in 2001 and 2021 were awarded to the main contributors to chiral catalysis. There are currently about 2,000 drugs in use in the world, of which chiral drugs account for more than 50%. Among the 250 drugs commonly used in clinical practice, there are as many as 200 chiral drugs.

[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 furan-diazolyl ligand Fu-2NO and tested their application in the asymmetric Friedel-Crafts alkylation of indole. Based on the design and synthesis of a new type of furan-diazolyl ligand metal complex, our design idea refers to the tridentate ligand chelation catalytic mechanism of the "hairy crab" biomimetic model: the dizolyl oxy group is likened to the two crab legs of the "hairy crab", and the oxygen atom of furan is likened to the mouth of the "hairy crab" (such as Figure 1 and Figure 2 shown). Summary of the invention

[0005] The purpose of the present invention is to provide a chiral furan dinitrogen oxide ligand Fu-2NO and an intermediate Fu and a preparation method and application thereof, which is an important type of chiral furan dinitrogen oxide ligand, and the ligand comprises a furan group and a nitroxide group (the oxygen atom of furan and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), and can form a six-membered ring coordination with a Lewis metal, thereby generating a chiral ligand metal complex, and is used as a chiral ligand in an asymmetric catalytic reaction. Therefore, it has important application value in the field of asymmetric catalytic synthesis, and its synthesis method is very economical and simple. It also has good air stability, wide applicability, and good compatibility for various substituents.

[0006] The present invention also finds the application of chiral furan dinitrogen oxide ligand Fu-2NO in asymmetric catalytic indole Friedel-Crafts alkylation reaction.

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

[0008]

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

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

[0011] The synthetic route is as follows:

[0012]

[0013] Application of intermediate Fu in the synthesis of chiral furan dinitrogen oxide ligand Fu-2NO.

[0014] Application of chiral furanyl dinitrogen oxide ligand Fu-2NO in asymmetric catalytic Friedel-Crafts alkylation of indole.

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

[0016] Easy to synthesize Multichiral Center Very good stereo and electronic control effect

[0017] By adopting the above technical scheme, various substituted proline amides or hydroxyproline amides 1 and furan-2,5-dicarboxaldehyde 2 first undergo condensation reaction to generate an intermediate Fu, and then the nitrogen atom in the intermediate Fu undergoes nitrogen oxidation reaction under the action of the oxidant meta-chloroperbenzoic acid to generate a chiral furan dinitrogen oxide ligand Fu-2NO, which contains a furan group and a nitrogen oxide group (the oxygen atom of furan and the oxygen atom of the nitrogen oxide group belong to electron-rich coordination sites), and can form a six-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 with various substituents. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 and Figure 2 The design idea and creative diagram of the chiral furan dinitrogen oxide ligand synthesized by the present invention;

[0019] Figure 2 In the above, the dinitrogen oxide groups are likened to the two legs of the "hairy crab", and the oxygen atoms of furan are likened to the mouth of the "hairy crab".

[0020] Figure 3 and Figure 4 The spectrum data of the chiral furan dinitrogen oxide ligand Fu-01-2NO of the embodiment of the present invention;

[0021] Figure 5 and Figure 6 The spectrum data of the chiral furan dinitrogen oxide ligand Fu-06-2NO of the embodiment of the present invention;

[0022] Figure 7 and Figure 8 The spectral data of the chiral furan dinitrogen oxide ligand intermediate Fu-1 according to an embodiment of the present invention;

[0023] Fig. 9 This is a single crystal image of compound Fu-22 according to an embodiment of the present invention. DETAILED DESCRIPTION

[0024] (I) Synthesis and preparation of chiral furan dinitrogen oxide ligand intermediate Fu

[0025]

[0026] Chiral furan dinitrogen oxide ligand intermediate Fu-1: The raw material hydroxyproline amide 1a (2.5eq) and furan-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 Fu-1 as a white solid with a yield of 81% and >20:1dr. The results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 HNMR(CDCl3,400MHz)δ:1.77-1.85(m,4H),2.08-2.14(m,4H),2.69-2.75(m,2H),3.31-3.36(m,2H),3 .90-3.94(m,2H),5.63(s,2H),6.01(s,2H),7.05-7.09(m,2H),7.20-7.24(m,4H),7.30-7.32(m,4H); 13 C NMR (CDCl3, 100MHz) δ: 23.8, 26.2, 54.3, 63.6, 76.2, 107.5, 120.6, 124.6, 128.1, 136.1, 151.2, 173.6; HRMS (ESI-TOF) m / z: Calcd.for C 28 H 28 N4NaO3[M+Na] + :491.2054;Found:491.2055.

[0027] Table 1 shows the chemical structure of the intermediate Fu in the preparation of chiral furan dinitrogen oxide ligands

[0028]

[0029] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-5: white solid, yield 70%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.88-1.93(m,4H),2.13(s,6H),2.16-2.23(m,4H),2.88-2.94(m,2H),3.35-3.40(m,2 H),4.07-4.10(m,2H),5.30(s,2H),6.09(s,2H),6.69(d,J=7.6Hz,2H),7.06-7.10(m,2H),7.15-7.20(m,4H); 13C NMR (CDCl3, 100MHz) δ: 17.9, 25.1, 27.9, 56.1, 64.4, 78.6, 108.8, 126.8, 127.7, 128.3, 131.2, 134.2, 136.1, 152.6, 174.0; HRMS (ESI-TOF) m / z: Calcd.for C 30 H 32 N4NaO3[M+Na] + :519.2367;Found:519.2363.

[0030] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-7: white solid, yield 73%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.78-1.85(m,4H),2.06-2.15(m,4H),2.67-2.74(m,2H),3.31-3.36 (m,2H),3.89-3.92(m,2H),5.59(s,2H),6.03(s,2H),7.17-7.20(m,4H),7.27-7.29(m,4H); 13 C NMR (CDCl3, 100MHz) δ: 23.3, 25.8, 53.9, 63.1, 75.6, 107.1, 120.9, 127.6, 129.3, 134.2, 150.6, 173.1; HRMS (ESI-TOF) m / z: Calcd.forC 28 H 26 Cl2N4NaO3[M+Na] + :559.1274;Found:559.1275.

[0031] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-9: white solid, yield 72%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.78-1.85(m,4H),2.08-2.15(m,4H),2.67-2.73(m,2H),3.31-3.36 (m,2H),3.88-3.91(m,2H),5.60(s,2H),6.03(s,2H),7.22-7.25(m,4H),7.32-7.35(m,4H); 13C NMR (CDCl3, 100MHz) δ: 22.7, 25.2, 53.2, 62.5, 74.9, 106.5, 116.4, 120.5, 130.0, 134.1, 149.9, 172.5; HRMS (ESI-TOF) m / z: Calcd.forC 28 H 26 Br2N4NaO3[M+Na] + :647.0264;Found:647.0263.

[0032] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-13: white solid, yield 79%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.11-1.15(m,6H),1.78-1.85(m,4H),2.08-2.14(m,4H),2.50-2.56(m,4H),2.69-2.76(m, 2H),3.31-3.36(m,4H),3.91-3.94(m,2H),5.59(s,2H),6.01(s,2H),7.05(d,J=8.8Hz,4H),7.19(d,J=8.4Hz,4H); 13 C NMR (CDCl3, 100MHz) δ: 14.4, 23.8, 26.2, 27.3, 54.3, 63.6, 76.4, 107.5, 120.8, 127.4, 133.6, 140.8, 151.3, 173.5; HRMS (ESI-TOF) m / z: Calcd.for C 32 H 36 N4NaO3[M+Na] + :547.2680;Found:547.2674.

[0033] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-17: white solid, yield 82%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.21(s,18H),1.80-1.83(m,4H),2.09-2.13(m,4H),2.69-2.75(m ,2H),3.31-3.36(m,2H),3.91-3.94(m,2H),5.60(s,2H),6.04(s,2H),7.22-7.27(m,8H); 13C NMR (CDCl3, 100MHz) δ: 23.8, 26.2, 30.3, 33.4, 54.2, 63.5, 76.3, 107.5, 120.3, 124.9, 133.5, 147.6, 151.3, 173.6; HRMS (ESI-TOF) m / z: Calcd.for C 36 H 44 N4NaO3[M+Na] + :603.3306;Found:603.3307.

[0034] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-22: white solid, yield 75%, 10:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:0.54(s,3H),0.55(s,3H),0.99(s,3H),1.01(s,3H),1. 08-1.11(m,12H),1.79-1.84(m,4H),2.03-2.11(m,2H),2.14-2.22(m,2H),2.4 3-2.50(m,2H),2.75-2.88(m,4H),3.23-3.29(m,2H),4.18-4.21(m,2H),4.97 (s,2H),5.97(s,2H),6.97-6.99(m,2H),7.03-7.05(m,2H),7.16-7.20(m,2H); 13 C NMR(CDCl3,100MHz)δ:23.5,23.6,24.8,24.9,25.5,28.6,28.7,28.8,56.5,64.7,79.7,108 .7,123.6,124.3,129.1,129.6,146.3,148.9,152.9,174.8; HRMS(ESI-TOF)m / z:Calcd.forC 40 H 52 N4NaO3[M+Na] + :659.3932;Found:659.3937.

[0035] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-23: white solid, yield 76%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(CDCl3,400MHz)δ:1.10-1.14(m,6H),2.09-2.15(m,2H),2.33-2.40(m,2H),2.49-2.55(m,4H),2.77-2.80(m,2H),3.35(d ,J=10.0Hz,2H),4.10-4.14(m,2H),4.32-4.35(m,2H),5.54(s,2H),6.03(s,2H),7.04(d,J=8.4Hz,4H),7.15(d,J=8.8Hz,4H); 13 C NMR (CDCl3, 100MHz) δ: 14.4, 27.3, 35.9, 61.0, 62.1, 70.5, 75.5, 107.9, 120.9, 127.5, 133.3, 141.1, 150.7, 173.1; HRMS (ESI-TOF) m / z: Calcd.forC 32 H 36 N4NaO5[M+Na] + :579.2578;Found:579.2575.

[0036] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-24: white solid, yield 80%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:1.77-1.85(m,4H),2.08-2.14(m,4H),2.23(s,6H),2.69-2.75(m,2H),3.30-3. 35(m,2H),3.90-3.93(m,2H),5.58(s,2H),6.00(s,2H),7.01(d,J=8.0Hz,4H),7.18(d,J=7.2Hz,4H); 13 C NMR (CDCl3, 100MHz) δ: 19.9, 23.8, 26.2, 54.3, 63.6, 76.4, 107.4, 120.8, 128.6, 133.4, 134.5, 151.3, 173.4; HRMS (ESI-TOF) m / z: Calcd.for C 30 H 32 N4NaO3[M+Na] + :519.2367;Found:519.2362.

[0037] This example prepares the chiral furan dinitrogen oxide ligand intermediate Fu-25: white solid, yield 73%, 12:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows:1 H NMR(CDCl3,400MHz)δ:2.12-2.18(m,2H),2.31-2.38(m,2H),2.75-2.78(m,2H),3.34(d,J=10.0Hz,2H),4.09-4.13(m,2H) ,4.34-4.36(m,2H),5.60(s,2H),6.09(s,2H),7.06-7.10(m,2H),7.15-7.18(m,2H),7.20-7.23(m,3H),7.61-7.62(m,2H); 13 C NMR (CDCl3, 100MHz) δ: 36.0, 61.0, 62.2, 70.3, 75.0, 108.1, 118.6, 121.8, 123.3, 127.8, 129.5, 137.1, 150.5, 173.3; HRMS (ESI-TOF) m / z: Calcd.for C 28 H 26 Br2N4NaO5[M+Na] + :679.0162;Found:679.0160.

[0038] (II) Synthesis and preparation of chiral furan dinitrogen oxide ligand Fu-2NO

[0039]

[0040] Chiral furan dinitrogen oxide ligand Fu-01-2NO: The intermediate Fu (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 Fu-01-2NO, melting point: 224.1-224.9 ° C; total yield 55%, 20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR (CDCl3, 400MHz) δ: 2.59-2.71 (m, 4H), 3.75-3.78 (m, 2H), 3.93 (d, J = 15.2Hz, 2 H),4.50(s,2H),4.70-4.73(m,2H),6.19(s,2H),6.72(s,2H),7.16-7.24(m,10H); 13 C NMR (CDCl3, 100MHz) δ: 36.6, 71.2, 74.5, 76.4, 82.5, 116.6, 123.1, 127.8, 129.7, 134.6, 146.7, 167.5; HRMS (ESI-TOF) m / z: Calcd.for C28 H 28 N4NaO7[M+Na] + :555.1850;Found:555.1854.

[0041] The preparation method of the chiral furan dinitrogen oxide ligands Fu-02-2NO to Fu-13-2NO prepared in the examples is the same as that of the furan dinitrogen oxide ligand Fu-01-2NO, and the feed ratio is the same as that of the ligand Fu-01-2NO, and the ligands Fu-02-2NO to Fu-13-2NO 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.

[0042] Table 2 shows the chemical structure of the chiral furan dinitrogen oxide ligand Fu-2NO.

[0043]

[0044] This example prepares chiral furan dinitrogen oxide ligand Fu-02-2NO: white solid, melting point: 262.8-263.2°C; total yield 54%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.17-1.20(m,6H),2.58-2.64(m,6H),2.73-2.79(m,2H),3.83(d,J=12.4Hz,2H), 4.26-4.31(m,2H),4.62(s,4H),6.71(s,2H),6.85(s,2H),7.18(d,J=8.8Hz,4H),7.29(d,J=8.0Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 14.6, 28.0, 35.4, 70.2, 75.5, 76.8, 83.2, 117.0, 124.3, 128.5, 132.2, 144.1, 146.5, 167.4; HRMS (ESI-TOF) m / z: Calcd.for C 32 H 36 N4NaO7[M+Na] + :611.2476;Found:611.2475.

[0045] This example prepares chiral furan dinitrogen oxide ligand Fu-03-2NO: white solid, melting point: 262.9-263.4°C; total yield 54%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR (CD3OD, 400MHz) δ: 1.28 (s, 18H), 2.58-2.64 (m, 2H), 2.74-2.80 (m, 2H), 3.85 (d, J = 12.4Hz, 2H), 4.26 -4.31(m,2H),4.61-4.65(m,4H),6.72(s,2H),6.85(s,2H),7.34(d,J=8.8Hz,4H),7.41(d,J=8.8Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 30.3, 34.1, 35.4, 70.2, 75.6, 76.7, 83.1, 117.0, 123.9, 126.0, 132.0, 146.6, 150.9, 167.3; HRMS (ESI-TOF) m / z: Calcd.for C 36 H 44 N4NaO7[M+Na] + :667.3102;Found:667.3104.

[0046] This example prepares chiral furan dinitrogen oxide ligand Fu-04-2NO: white solid, melting point: 243.1-243.7°C; total yield 52%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.28 (s, 6H), 2.57-2.62 (m, 2H), 2.72-2.78 (m, 2H), 3.83 (d, J = 12.4Hz, 2H), 4.24-4.28 (m,2H),4.56-4.60(m,4H),6.73(s,2H),6.87(s,2H),7.10(d,J=3.6Hz,2H),7.16-7.24(m,4H),7.27(s,4H); 13 C NMR (CD3OD, 100MHz) δ: 20.0, 35.4, 70.3, 75.2, 76.7, 83.0, 117.1, 121.2, 124.7, 128.3, 129.0, 134.5, 139.5, 146.4, 167.3; HRMS (ESI-TOF) m / z: Calcd.forC 30 H 32 N4NaO7[M+Na] + :583.2163;Found:583.2163.

[0047] This example prepares chiral furan dinitrogen oxide ligand Fu-05-2NO: white solid, melting point: 245.0-245.7°C; total yield 51%, 14:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR (CD3OD, 400MHz) δ: 2.59-2.65 (m, 2H), 2.73-2.80 (m, 2H), 3.80 (d, J = 12.4Hz, 2H), 4.27-4.32 ( m,2H),4.56-4.64(m,4H),6.77(s,2H),6.88(s,2H),7.34(d,J=9.2Hz,4H),7.41(d,J=9.2Hz,4H); 13 CNMR(CD3OD,100MHz)δ:35.4,70.1,75.6,76.9,82.9,117.2,124.1,125.5,129.0,129.1,132.8,133.4,146.3,167.2; HRMS(ESI-TOF)m / z:Calcd.for C 28 H 26 Cl2N4NaO7[M+Na] + :623.1071;Found:623.1071.

[0048] This example prepares chiral furan dinitrogen oxide ligand Fu-06-2NO: white solid, melting point: 210.1-210.9°C; total yield 57%, 15:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CDCl3,400MHz)δ:2.02-2.09(m,2H),2.31-2.40(m,2H),2.55-2.65(m,4H),2.62-3.64(m,2H),3 .73-3.80(m,2H),3.87-3.91(m,2H),6.14(s,2H),6.70(s,2H),7.16-7.19(m,3H),7.25-7.26(m,7H); 13 CNMR(CDCl3,100MHz)δ:21.9,23.8,70.1,76.4,81.9,114.9,121.5,126.4,128.6,134.1,146.3,167.2; HRMS(ESI-TOF)m / z:Calcd.for C 28 H 28 N4NaO5[M+Na] + :523.1952;Found:523.1955.

[0049] This example prepares chiral furan dinitrogen oxide ligand Fu-07-2NO: white solid, melting point: 204.5-204.9°C; total yield 53%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.23-2.27(m,2H),2.38-2.44(m,2H),2.52-2.64(m,4H),3.82-3.86(m,2H),4 .09-4.16(m,2H),4.38-4.41(m,2H),6.69(s,2H),6.83(s,2H),7.08-7.12(m,4H),7.41-7.44(m,4H); 13 CNMR(CD3OD,100MHz)δ:22.6,24.7,70.7,77.5,83.2,115.9(d,J CF =23.0Hz),117.1,127.4,127.5(d,J CF =9.0Hz),130.6,130.7,146.9,161.9(d,J CF =246.1Hz),168.2; HRMS(ESI-TOF)m / z:Calcd.for C 28 H 26 F2N4NaO5[M+Na] + :559.1763;Found:559.1760.

[0050] This example prepares chiral furan dinitrogen oxide ligand Fu-08-2NO: white solid, melting point: 218.0-218.7°C; total yield 52%, 19:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.21-2.27(m,2H),2.38-2.45(m,2H),2.53-2.63(m,4H),3.80-3.84(m,2H),4.05 -4.12(m,2H),4.34-4.37(m,2H),6.76(s,2H),6.86(s,2H),7.35(d,J=8.8Hz,4H),7.44(d,J=8.4Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 22.6, 24.5, 70.5, 77.3, 82.6, 116.8, 125.7, 129.2, 132.9, 133.5, 146.8, 167.9; HRMS (ESI-TOF) m / z: Calcd.for C 28 H26 Cl2N4NaO5[M+Na] + :591.1172;Found:591.1167.

[0051] This example prepares chiral furan dinitrogen oxide ligand Fu-09-2NO: white solid, melting point: 236.9-237.8°C; total yield 50%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.17-1.21(m,6H),2.22-2.24(m,2H),2.40-2.42(m,2H),2.51-2.64(m,8H),3.81-3.85(m,2H), 4.05-4.12(m,2H),4.39-4.42(m,2H),6.68-6.69(m,2H),6.83-6.84(m,2H),7.20(d,J=8.0Hz,4H),7.30-7.33(m,4H); 13 C NMR (CD3OD, 100MHz) δ: 14.6, 22.5, 24.5, 28.0, 70.5, 77.2, 83.0, 116.6, 124.4, 128.5, 132.3, 144.1, 147.0, 168.0; HRMS (ESI-TOF) m / z: Calcd.for C 32 H 36 N4NaO5[M+Na] + :579.2578;Found:579.2577.

[0052] This example prepares chiral furan dinitrogen oxide ligand Fu-10-2NO: white solid, melting point: 250.7-251.5°C; total yield 47%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:2.21(s,6H),2.25-2.29(m,2H),2.44-2.50(m,2H),2.53-2.64(m,6H),3.89-3.90(m,2H),4.10-4.17(m ,2H),5.11(d,J=8.4Hz,2H),6.53(s,2H),6.72(d,J=3.2Hz,2H),6.93(d,J=3.6Hz,2H),7.15-7.19(m,2H),7.23-7.26(m,4H); 13C NMR(CD3OD,100MHz)δ:16.8,22.4,23.8,70.4,76.6,83.5,114.1,118.0,126.7,129 .1,131.1,132.7,136.8,144.8,152.7,164.1,168.0; HRMS(ESI-TOF)m / z:Calcd.for C 30 H 32 N4NaO5[M+Na] + :551.2265;Found:551.2266.

[0053] This example prepares chiral furan dinitrogen oxide ligand Fu-11-2NO: white solid, melting point: 235.0-235.7°C; total yield 53%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1 H NMR(CD3OD,400MHz)δ:1.20(s,6H),1.21(s,6H),2.21-2.24(m,2H),2.38-2.45(m,2H),2.53-2.61(m,4H),2.85-2.91(m,2H),3.8 1-3.85(m,2H),4.05-4.12(m,2H),4.39(d,J=8.8Hz,2H),6.68(s,2H),6.84(s,2H),7.23(d,J=8.4Hz,4H),7.33(d,J=7.6Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 22.5, 22.9, 24.5, 33.6, 70.6, 77.2, 83.0, 116.6, 124.5, 127.1, 132.3, 147.1, 148.7, 168.0; HRMS (ESI-TOF) m / z: Calcd.for C 34 H 40 N4NaO5[M+Na] + :607.2891;Found:607.2895.

[0054] This example prepares chiral furan dinitrogen oxide ligand Fu-12-2NO: white solid, melting point: 240.3-241.0°C; total yield 53%, >20:1dr; nuclear magnetic resonance and high-resolution mass spectrometry test results are as follows: 1H NMR(CD3OD,400MHz)δ:1.28(s,18H),2.19-2.25(m,2H),2.39-2.45(m,2H),2.53-2.61(m,4H),3.81-3.87(m,2H) ,4.05-4.12(m,2H),4.37-4.40(m,2H),6.69(s,2H),6.85(d,J=2H),7.34(d,J=8.8Hz,4H),7.41(d,J=8.8Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 22.6, 24.5, 30.2, 34.1, 70.6, 77.2, 82.9, 116.6, 124.1, 126.1, 132.1, 147.1, 150.9, 168.0; HRMS (ESI-TOF) m / z: Calcd.forC 36 H 44 N4NaO5[M+Na] + :635.3204;Found:635.3205.

[0055] This example prepares chiral furan dinitrogen oxide ligand Fu-13-2NO: white solid, melting point: 220.1-221.0°C, total yield 51%, 18:1dr; 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,2H),2.38-2.40(m,2H),2.54-2.62(m,4H),3.76(s,6H),3.81-3.86(m,2H) ,4.08-4.15(m,2H),4.40-4.42(m,2H),6.60(s,2H),6.80(s,2H),6.88(d,J=8.8Hz,4H),7.26(d,J=9.2Hz,4H); 13 C NMR (CD3OD, 100MHz) δ: 22.6, 24.6, 54.6, 70.7, 77.6, 83.5, 114.3, 117.0, 126.9, 127.0, 146.9, 159.5, 168.3; HRMS (ESI-TOF) m / z: Calcd.for C 30 H 32 N4NaO7[M+Na] + :583.2163;Found:583.2165.

[0056] This example prepares the chiral furan dinitrogen oxide ligand Fu-22-2NO: white solid, total yield 47%, 12:1dr; HRMS (ESI-TOF) m / z: Calcd.for C 40 H 52 N4NaO5[M+Na] + :691.3830;Found:691.3833.

[0057] (III) Application of chiral furan dinitrogen oxide ligand Fu-2NO in asymmetric catalytic Friedel-Crafts alkylation of indole

[0058] The formula (1) of the present invention generates a chiral furan dinitrogen oxide ligand Fu-2NO, which contains a furan group and a nitroxide group (the oxygen atom of the furan group and the oxygen atom of the nitroxide group belong to electron-rich coordination sites), and can form a six-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 nitroxide ligand of the present invention is not limited to being used as a chiral ligand in asymmetric catalytic Friedel-Crafts alkylation reaction of indole.

[0059] Example 1: Application of chiral furan dinitrogen oxide ligand Fu-2NO with various substituents in the asymmetric catalytic Friedel-Crafts alkylation of indole 4 and 2,3-dioxypyrrolidine olefin 5

[0060] Table 3 shows the application of chiral furan dinitrogen oxide ligand Fu-2NO with various substituents in asymmetric catalytic reactions

[0061]

[0062] In order to demonstrate the application value of the developed chiral furan dinitrogen oxide ligand Fu-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxopyrrolidine olefin 5 as the template reaction, and selected 14 compounds in Table 2 as chiral furan dinitrogen oxide ligand Fu-2NO to in situ generate chiral complexes with Lewis acid Ni(OTf)2 to verify the asymmetric catalytic effect of the chiral furan dinitrogen oxide ligand Fu-2NO (Table 3).

[0063] 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 furan dinitrogen oxide ligand Fu-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 furan dinitrogen oxide ligand, which is worthy of further in-depth study.

[0064] Example 2: Application of chiral ligand Fu-06-2NO to in situ formation of chiral complexes with various Lewis acids in the asymmetric catalytic Friedel-Crafts alkylation of indole 4 and 2,3-dioxypyrrolidine olefin 5

[0065] In order to demonstrate the application value of the developed chiral ligand Fu-06-2NO in asymmetric catalytic systems, we selected the Friedel-Crafts alkylation reaction involving indole 4 and 2,3-dioxopyrrolidine olefin 5 as the template reaction, and selected the chiral ligand Fu-06-2NO to generate chiral complexes with various Lewis acids in situ to verify the asymmetric catalytic effect of the chiral ligand Fu-06-2NO (Table 4).

[0066] Table 4 shows the application of chiral complexes generated in situ by chiral ligand Fu-06-2NO and various Lewis acids in asymmetric catalytic reactions

[0067]

[0068] 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 ligand Fu-06-2NO represented by formula (1) in situ generates chiral complexes with various Lewis acids for Friedel-Crafts alkylation reactions involving indole 4 and 2,3-dioxypyrrolidine olefin 5, and can be developed into a new advantageous chiral pyridine nitrogen oxygen ligand, which is worthy of further in-depth study.

Claims

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

2. A method for preparing the chiral furan dinitrogen oxide ligand Fu-2NO and the intermediate Fu as claimed in claim 1, characterized in that: The corresponding proline amide or hydroxyproline amide 1 first undergoes a condensation reaction with furan-2,5-dicarboxaldehyde 2 to generate the desired intermediate Fu, and then the nitrogen atom in the intermediate Fu undergoes a nitrogen oxidation reaction under the action of the oxidant m-chloroperbenzoic acid to generate a chiral furan dinitrogen oxide ligand Fu-2NO; The synthetic route is as follows:

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

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

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