Chiral phenol dioxane ligands and intermediates, their preparation methods, and their applications in asymmetric catalytic reactions

Abstract

This invention discloses a chiral phenol bis(nitrile) ligand Bf-2NO and an intermediate Bf. The invention involves a condensation reaction between various substituted proline amides or hydroxyproline 1 and phenol-2,5-dicarboxaldehyde 2 to generate intermediate Bf. Then, the nitrogen atom in intermediate Bf undergoes a nitrogenooxidation reaction under the action of the oxidant m-chloroperoxybenzoic acid to generate the chiral phenol bis(nitrile) ligand Bf-2NO. This type of ligand contains a phenolic group and a nitrile group (the hydroxyl oxygen atom of phenol and the oxygen atom of the nitrile group are electron-rich coordination sites). It can form a seven-membered ring coordination with Lewis metals, thereby generating a chiral ligand-metal complex, which can be used as a chiral ligand in asymmetric catalytic reactions. This invention is simple and easy to operate, the raw materials are inexpensive and readily available, the ligand prepared by this invention can react in various organic solvents, has good air stability, wide applicability, and good compatibility with various substituents.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chiral chemistry and asymmetric catalytic synthesis, in particular to a chiral phenolic bis-nitrogen oxygen ligand and intermediates, a preparation method thereof and application thereof in asymmetric catalytic reaction. BACKGROUND

[0002] Chiral pharmaceuticals are the frontier of the pharmaceutical industry, and the Nobel Prize in Chemistry in 2001 and 2021 was awarded to the main contributors of chiral catalysis.

[0003] The key preparation technology of chiral drugs is selected as one of the "ten chemical technology inventions that change the world" proposed by IUPAC. The design and synthesis of superior chiral ligands play a key role in the development of asymmetric catalytic reactions, and are the most attractive and challenging targets in asymmetric catalysis. In addition, an economically viable synthetic route is also crucial for superior chiral ligands so that they can be widely used. In particular, the N-oxide of amine is a highly polar substance, and the N-oxide of amine can be easily prepared by N-oxidation of pyridine compounds or tertiary amines. The oxygen atom generated in the N-oxide belongs to an electron-rich coordination site. Therefore, the unique properties of the electron pair of the N-oxide provide an opportunity to form complexes with a variety of metals. Some studies focus on the development of new chiral amine N-oxide ligands for metal-catalyzed reactions.

[0004] In the N-oxide derived from tertiary amine, if the parent tertiary amine contains three different groups, then the nitrogen center on the corresponding N-oxyl group will generate a stable chiral center. In this context, therefore, we designed and developed a new type of chiral tertiary amine-derived chiral phenolic-bis-nitrogen oxygen ligand Bf-2NO, and tested their application in the asymmetric Friedel-Crafts alkylation reaction of indole. Based on the design and synthesis of metal complexes of the new type of phenolic bis-nitrogen oxygen ligand, our design idea refers to the tridentate ligand chelation catalytic mechanism of the "lobster" biomimetic model: the bis-nitrogen oxygen group is analogous to the two crab legs of the "lobster", and the hydroxyl group of the phenol is analogous to the mouth of the "lobster" (as shown in Figure 1 and Figure 2 ). SUMMARY

[0005] The application aims to provide a chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO and an intermediate Bf and a preparation method and application thereof, which is an important chiral phenolic bis-nitrogen-oxygen ligand, the ligand comprises a phenolic group and a nitrogen-oxygen group (the oxygen atoms of the hydroxyl group of the phenolic group and the nitrogen-oxygen group belong to electron-rich coordination sites), can form a seven-membered ring coordination with a Lewis metal, thereby generating a chiral ligand metal complex, and is applied as a chiral ligand in an asymmetric catalytic reaction. Therefore, the application has important application value in the field of asymmetric catalytic synthesis, and the synthesis method is very economical and simple. The chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO also has good air stability, wide applicability, and good compatibility with various substituents.

[0006] The application also finds that the chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO is applied in an asymmetric catalytic indole Friedel-Crafts alkylation reaction.

[0007] The application is achieved in the following manner: a chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO and an intermediate Bf, characterized in that the chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO has a structure as shown in a general formula (I), and the intermediate Bf has a structure as shown in a general formula (II).

[0008]

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

[0010] A preparation method of the chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO and the intermediate Bf, characterized in that: a condensation reaction is first performed on a corresponding proline amide or hydroxyproline amide 1 and phenol-2,5-diformaldehyde 2 to generate the required intermediate Bf, and then a nitrogen oxidation reaction is performed on the nitrogen atom in the intermediate Bf under the action of an oxidant m-chloroperoxybenzoic acid to generate the chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO.

[0011] The synthesis route is as follows:

[0012]

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

[0014] Application of the intermediate Bf in synthesis of the chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO.

[0015] Application of the chiral phenolic bis-nitrogen-oxygen ligand Bf-2NO in an asymmetric catalytic Friedel-Crafts alkylation reaction involving indole. ​​

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

[0017] Our design: tertiary amine derived C2 symmetric chiral phenol bisnitrogen oxide ligand

[0018]

[0019] By adopting the above technical scheme, various substituted prolinamides or hydroxyprolinamides 1 are first subjected to condensation reaction with phenol-2,5-diformaldehyde 2 to generate intermediate Bf, and then the nitrogen atom in the intermediate Bf is subjected to nitrogen oxidation reaction under the action of oxidant meta-chloroperoxybenzoic acid to generate chiral phenol bisnitrogen oxide ligand Bf-2NO. The ligand contains a phenol group and a nitrogen oxide group (the oxygen atoms of the hydroxyl group of the phenol and the nitrogen oxide group belong to electron-rich coordination sites), can form a seven-membered ring coordination with a Lewis metal, thereby generating a chiral ligand metal complex, which is applied as a chiral ligand in an asymmetric catalytic reaction. The present application is simple and easy to operate, and the raw materials are cheap and easy to synthesize (the chiral source is an economically available chiral proline or proline). The ligand prepared by the present application can be reacted in various organic solvents, has good air stability, and has wide applicability and good compatibility with various substituents. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 and Figure 2 Design idea and creativity of the chiral phenol bisnitrogen oxide ligand Bf-2NO synthesized by the present application;

[0021] Figure 2 In the formula, the bisnitrogen oxide group is analogous to two crab legs of a lobster, and the hydroxyl group of the phenol is analogous to the mouth of the lobster.

[0022] Figure 3 and Figure 4 Spectrum data of the chiral phenol bisnitrogen oxide ligand Bf-01-2NO of the embodiment of the present application;

[0023] Figure 5 and Figure 6 Spectrum data of the chiral phenol bisnitrogen oxide ligand Bf-05-2NO of the embodiment of the present application;

[0024] Figure 7 and Figure 8 Spectrum data of the chiral phenol bisnitrogen oxide ligand intermediate Bf-1 of the embodiment of the present application;

[0025] Figure 9 Single crystal graphs of the chiral phenol bisnitrogen oxide ligand intermediates Bf-23 and Bf-26 of the embodiment of the present application. DETAILED DESCRIPTION

[0026] (I) Synthesis of chiral phenolic bis-N-oxyl ligand intermediate Bf

[0027]

[0028] Chiral phenolic bis-N-oxyl ligand intermediate Bf-1: The starting material hydroxyprolinamide la (2.5 eq) and phenol-2,5-diformaldehyde (1 eq, 0.78 mmol) 2 were dissolved in an appropriate amount of absolute ethanol, and refluxed for 10 h. After the reaction solution was treated, the intermediate Bf-1 was obtained by column chromatography purification, white solid, yield 79%, 15:1 dr. The results of nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: 1 HNMR (CD3OD, 400 MHz) 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, 100 MHz) 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 chiral phenolic bis-N-oxyl ligand Bf-02-2NO~Bf-10-2NO prepared by the examples is the same as ligand Bf-01-2NO, the same feeding ratio as ligand Bf-01-2NO, ligand Bf-02-2NO~Bf-10-2NO can be obtained, and the reaction yield is shown in Table 2, but it should be emphasized that the examples are intended to illustrate but not limit the scope of the present application. The compounds of the present application are not limited to the content represented in Table 1.

[0030] The chiral phenolic bis-N-oxyl ligand intermediate Bf-2 prepared in this example: white solid; yield 77%, 17:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: 1H NMR (CD3OD, 400 MHz) 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, 100 MHz) 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] The present example prepared chiral phenol bis-nitrogen oxide ligand intermediate Bf-3: white solid; yield 81%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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 = 8.4 Hz, 4H), 7.13 (d, J = 8.4 Hz, 4H); 13 C NMR (CD3OD, 100 MHz) 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 is a chemical structure of preparing chiral phenol bis-nitrogen oxide ligand intermediate Bf

[0033]

[0034] This example prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-5: white solid; yield 80%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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 = 8.8 Hz, 4H), 7.17 (d, J = 8.4 Hz, 4H); 13 C NMR (CD3OD, 100 MHz) δ: 14.7, 19.1, 24.3, 27.6, 28.0, 54.4, 64.7, 81.3, 123.8, 127.9, 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 prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-7: white solid; yield 71%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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 = 8.8 Hz, 4H), 7.17 (d, J = 8.4 Hz, 4H); 13C NMR (CDC13, 100 MHz) 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 prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-11: white solid; yield 77%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CDC13, 400 MHz) 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 (CDC13, 100 MHz) 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 prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-16: white solid; yield 78%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1H NMR (CDC13, 400 MHz) 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 (CDC13, 100 MHz) δ: 19.0, 24.3, 27.8, 54.4, 54.5, 64.8, 82.1, 113.8, 123.3, 126.1, 127.8, 128.6, 129.8, 153.6, 158.4, 173.9; HRMS (ESI-TOF) m / z: Calcd. for C 33 H 36 N4NaO5 [M + Na] + : 591.2578; Found: 591.2581.

[0038] The present example prepared chiral phenol bis-nitrogen oxygen ligand intermediate Bf-17: white solid; yield 75%, >20: 1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CDC13, 400 MHz) 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 = 7.6 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 7.00-7.04 (m, 4H); 13 C NMR (CDC13, 100 MHz) δ: 19.1, 20.1, 24.3, 27.6, 54.4, 64.7, 81.3, 120.7, 123.7, 124.3, 126.9, 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 prepared chiral phenol bis-nitrogen oxide ligand intermediate Bf-20: white solid; yield 72%, >20: 1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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, 100 MHz) δ: 19.0, 24.3, 27.7, 54.4, 64.8, 81.8, 115.2 (d, J CF = 23.1 Hz), 123.4, 126.2 (d, J CF = 9.2 Hz), 128.0, 129.7, 132.3, 132.4 (d, J CF = 3.1 Hz), 161.8 (d, J CF = 244.2 Hz), 174.1; HRMS (ESI-TOF) m / z: Calcd. for C 31 H 30 F2N4NaO3[M+Na] + : 567.2178; Found: 567.2172.

[0040] This example prepared chiral phenol bis-nitrogen oxide ligand intermediate Bf-23: white solid; yield 71%, 19: 1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (DMSO-d6, 400 MHz) 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), 2.84-2.90 (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, 100 MHz) 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. for C 31 H 30 Br2N4NaO3[M+Na] + : 687.0577; Found: 687.0584.

[0041] This example prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-25: white solid; yield 71%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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, 100 MHz) 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 prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-26: white solid, yield 73%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1H NMR (DMSO-d6, 400 MHz) 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 = 7.6 Hz, 2H), 7.09-7.13 (m, 2H), 7.27-7.31 (m, 4H), 7.43 (d, J = 8.0 Hz, 4H), 10.98 (br s, 1H); 13 C NMR (DMSO-d6, 100 MHz) 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 prepared chiral phenol bis-nitrogen ligand intermediate Bf-27: white solid, yield 70%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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, 2H), 4.52-4.54 (m, 2H), 6.04 (s, 2H), 6.45-6.49 (m, 1H), 6.80 (d, J = 8.0 Hz, 2H), 7.12-7.16 (m, 2H), 7.23-7.32 (m, 8H); 13 C NMR (CD3OD, 100 MHz) 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 prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-28: white solid, yield 75%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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 = 7.6 Hz, 2H), 7.03 (d, J = 8.4 Hz, 4H), 7.14 (d, J = 8.8 Hz, 4H); 13 C NMR (CD3OD, 100 MHz) 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. for C 32 H 34 N4NaO3 [M + Na] + : 545.2523; Found: 545.2523.

[0045] This example prepared chiral phenol bisnitrogen oxide ligand intermediate Bf-29: white solid, yield 70%, >20:1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results as follows: 1 H NMR (CD3OD, 400 MHz) 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 = 7.6 Hz, 4H), 7.04-7.08 (m, 2H), 7.15-7.20 (m, 4H); 13 C NMR (CD3OD, 100 MHz) 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 of chiral phenolic bis-nitrogen oxide ligand Bf-2NO

[0047]

[0048] Chiral phenolic bis-nitrogen oxide ligand Bf-2NO: The intermediate Bf (100 mg, 1 eq) prepared above was dissolved in an appropriate amount of chloroform, and m-chloroperbenzoic acid (2.5 eq) was added at room temperature. The reaction was allowed to proceed for 20 min. After the reaction was completed, the reaction solution was purified by column chromatography to obtain white solid Bf-01-2NO, melting point: 237.1-237.8 °C; total yield 51%, 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.03 (s, 3H), 2.41-2.49 (m, 2H), 2.56-2.63 (m, 2H), 3.49 (d, J = 11.6 Hz, 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, 100 MHz) 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 chiral phenolic bis-nitrogen oxide ligands Bf-02-2NO ~ Bf-26-2NO prepared by the examples is the same as that of ligand Bf-01-2NO, and the same feeding ratio as that of ligand Bf-01-2NO can be used to obtain ligands Bf-02-2NO ~ Bf-26-2NO, and the reaction yield is shown in Table 2, but it should be emphasized that the examples are intended to illustrate but not limit the scope of the present application. The compounds of the present application are not limited to the content represented in Table 2.

[0050] The present example prepared chiral phenolic bisnitrogen oxide ligand Bf-02-2NO: white solid, melting point: 226.6-227.1℃; total yield 50%, 11:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test and the like are as follows: 1 H NMR (CD3OD, 400 MHz) 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 = 12.0 Hz, 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, 100 MHz) 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, 124.8, 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 is the chemical structure of preparing chiral phenolic bisnitrogen oxide ligand Bf-2NO

[0052]

[0053] The present example prepared chiral phenolic bisnitrogen oxide ligand Bf-03-2NO: white solid, melting point: 235.5-236.2℃; total yield 49%, 13:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry test and the like are as follows: 1H NMR (CD3OD, 400 MHz) 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 = 12.4 Hz, 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 = 8.0 Hz, 2H), 7.12-7.14 (m, 2H), 7.32 (s, 2H); 13 C NMR (CD3OD, 100 MHz) 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, 128.0, 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 prepared chiral phenol bis-nitrogen oxide ligand Bf-04-2NO: white solid, melting point: 216.1-216.6 °C; total yield 47%, 9: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.03 (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 = 7.6 Hz, 4H); 13C NMR (DMSO-d6, 100 MHz) 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. for C 31 H 32 N4NaO5[M+Na] + : 563.2265; Found: 563.2269.

[0055] The chiral phenol bisnitrogen oxide ligand Bf-05-2NO was prepared in this example: white solid, melting point: 227.7-228.3 °C; overall yield 50%, 10:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (DMSO-d6, 400 MHz) δ: 2.04 (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 = 8.0 Hz, 4H); 13 C NMR (DMSO-d6, 100 MHz) 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] The chiral phenol bisnitrogen oxide ligand Bf-06-2NO was prepared in this example: white solid, melting point: 220.3-221.0 °C; overall yield 51%, 11:1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1H NMR (DMSO-d6, 400 MHz) 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 = 8.4 Hz, 3H); 13 C NMR (DMSO-d6, 100 MHz) 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, 120.9, 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] The present example prepared chiral phenol bis-nitrogen ligand Bf-07-2NO: white solid, melting point: 212.4-213.5 °C; total yield 52%, 15: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry test, etc. as follows: 1 H NMR (DMSO-d6, 400 MHz) 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 = 8.4 Hz, 3H); 13C NMR (CDC13, 100 MHz) 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, 121.7, 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. for C 39 H 48 N4NaO5[M+Na] + : 675.3517; Found: 675.3517.

[0058] The chiral phenol bisnitrogen oxide ligand Bf-08-2NO was prepared in this example: white solid, melting point: 218.8-219.2 °C; overall yield 53%, 12: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1 H NMR (CDC13, 400 MHz) δ: 2.10 (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 = 8.8 Hz, 4H), 7.11 (s, 2H), 7.28 (d, J = 8.8 Hz, 4H); 13 C NMR (CDC13, 100 MHz) 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. for C 33 H 36 N4NaO7[M+Na] + : 623.2476; Found: 623.2476.

[0059] The chiral phenol bisnitrogen oxide ligand Bf-09-2NO was prepared in this example: white solid, melting point: 244.4-255.3 °C; overall yield 54%, 15: 1 dr; results of nuclear magnetic resonance and high resolution mass spectrometry tests, etc. are as follows: 1H NMR (CD3OD, 400 MHz) 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, 100 MHz) 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, 124.2, 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] The present example prepared chiral phenol bis-nitrogen oxygen ligand Bf-10-2NO: white solid, melting point: 197.8-198.4 °C; total yield 46%, 7: 1 dr; nuclear magnetic resonance and high resolution mass spectrometry test results, etc. as follows: 1 H NMR (CD3OD, 400 MHz) 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, 100 MHz) 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 = 23.1 Hz), 115.5 (d, J CF = 23.2 Hz), 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] In this embodiment, chiral phenol bis(oxo) ligand Bf-23-2NO was prepared as a white solid with an overall yield of 30% (7:1 dr). High-resolution mass spectrometry (HRMS) results are as follows: HRMS (ESI-TOF) m / z: Calcd. for C 31 H 30 Br2N4NaO5[M+Na] + :719.0475; Found:719.0472.

[0062] In this embodiment, chiral phenol bis(oxo) ligand Bf-26-2NO₂ was prepared as a white solid with an overall yield of 31% and a 5:1 dr ratio. The results of NMR and high-resolution mass spectrometry measurements 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] (Three), the application of chiral phenol bis nitroxide ligand Bf-2NO in asymmetric catalytic Friedel-Crafts alkylation of indole

[0064] The chiral phenol bis nitroxide ligand Bf-2NO of formula (1) of the present application contains phenol group and nitroxide group (the oxygen atom of hydroxyl group of phenol and the oxygen atom of nitroxide group belong to electron-rich coordination sites), which can form seven-membered ring coordination with Lewis metal, thereby generating chiral ligand metal complex, which is applied as dominant chiral ligand in asymmetric catalytic Friedel-Crafts alkylation of indole. It should be emphasized that the chiral pyridine nitroxide ligand of the present application is not limited to be applied as chiral ligand only in asymmetric catalytic Friedel-Crafts alkylation of indole.

[0065] Example 1: the application of chiral phenol bis nitroxide ligand Bf-2NO with various substituents in asymmetric catalytic Friedel-Crafts alkylation of indole 4 and 2,3-dioxypyrrolidene olefin 5

[0066] In order to prove the application value of the developed chiral phenol bis nitroxide ligand Bf-2NO in asymmetric catalytic system, the Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidene olefin 5 is selected as a template reaction, and 12 compounds in Table 2 are selected as chiral phenol bis nitroxide ligand Bf-2NO to generate chiral complex in situ with Lewis acid Ni(OTf)2, and the asymmetric catalytic effect of chiral phenol bis nitroxide ligand Bf-2NO is verified (Table 3).

[0067] Table 3: the application of chiral phenol bis nitroxide ligand Bf-2NO with various substituents in asymmetric catalytic reaction

[0068]

[0069] Experimental conclusion: the Friedel-Crafts alkylation template reaction of asymmetric catalytic indole 4 and 2,3-dioxypyrrolidene olefin 5 is selected as an evaluation index. The experimental results show that the chiral phenol bis nitroxide ligand Bf-2NO with various substituents of formula (1) shows asymmetric catalytic effect in the Friedel-Crafts alkylation reaction of indole 4 and 2,3-dioxypyrrolidene olefin 5, which can develop into a new chiral phenol bis nitroxide ligand, and is worth further research.

Claims

1. A chiral phenolic bis-nitrogen oxide ligand Bf-2NO and intermediate Bf, characterized by: ###0001### The chiral phenol bisnitrogen 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); wherein R is hydroxy or hydrogen; R is methyl or hydrogen; and Ar is a phenyl ring substituted with fluoro, isopropyl, t-butyl, methoxy, methyl or hydrogen. 1 wherein R is hydroxy or hydrogen; R is methyl or hydrogen; and Ar is a phenyl ring substituted with fluoro, isopropyl, t-butyl, methoxy, methyl or hydrogen.

2. A chiral phenolic bis-nitrogen oxide ligand Bf-2NO, characterized by: Specifically, one of the following structural formulas:

3. An intermediate Bf of chiral phenolic bisphosphine oxide ligand, characterized in that: Specifically, one of the following structural formulae:

4. A process for the preparation of the chiral phenolic bisphosphine oxide ligand Bf-2NO and intermediate Bf according to claim 1, characterized in that: The chiral phenol bisnitrogen 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); The synthesis route is as follows: wherein R is hydroxy or hydrogen; R is methyl or hydrogen; and Ar is a phenyl ring substituted with fluoro, isopropyl, t-butyl, methoxy, methyl or hydrogen. 1 wherein R is hydroxy or hydrogen; R is methyl or hydrogen; and Ar is a phenyl ring substituted with fluoro, isopropyl, t-butyl, methoxy, methyl or hydrogen.

5. Use of the intermediate Bf in claim 1 in the synthesis of the chiral phenol bisnitrogen oxide ligand Bf-2NO in claim 1.

6. Use of the chiral phenolic bisphosphine oxide ligand Bf-2NO according to claim 1 in asymmetric catalysis of indole- involved Friedel-Crafts alkylation reactions, characterized in that, The synthesis route is as follows:

5. Use of the intermediate Bf in claim 1 in the synthesis of the chiral phenol bisnitrogen oxide ligand Bf-2NO in claim 1. The synthesis route is as follows:

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