A bipyridine chiral tetradentate bis-oxime ligand, a preparation method thereof, and an application thereof in an asymmetric catalytic reaction

Abstract

The present invention relates to the field of chiral chemistry and asymmetric catalysis technology, and provides a bipyridine chiral tetradentate bis-oxime ligand, a preparation method thereof, and an application in an asymmetric catalytic reaction. The bipyridine chiral tetradentate bis-oxime ligand provided by the present invention contains a bipyridine group and an oxime group, and can form a six-membered ring coordination with a Lewis metal, thereby generating a chiral ligand-metal complex, which can be used as a chiral ligand in an asymmetric catalytic reaction. The ligand provided by the present invention can react in various organic solvents, has good air stability, wide applicability, good compatibility with various substituents, and the preparation method is simple. The target product can be obtained only through two steps of condensation and nitroxidation reactions. The raw materials used are cheap and easily available, and the preparation cost is low. It has important application value in the field of asymmetric catalytic synthesis.

Description

Technical Field

[0001] The present invention relates to the technical field of chiral chemistry and asymmetric catalysis, and particularly relates to a bipyridine chiral tetradentate bis(oxime) ligand, a preparation method thereof, and an application thereof in an asymmetric catalytic reaction. Background Art

[0002] Chiral compounds are isomers (R / S) with different configurations. Their molecular structures are similar, and their properties are almost the same in an achiral environment. However, in living organisms, when interacting with enzymes in the organisms, they will exhibit different or even completely opposite properties. For example, (S)-asparagine has a bitter taste, while (R)-asparagine is sweet; another typical example is the "seal baby" phenomenon that occurred in countries such as the UK, Australia, Canada, Japan, and Brazil in the 1960s of the last century, which is a tragedy caused by insufficient understanding of the chiral drug "Thalidomide". Through later research on chiral drugs, it was found that: (S)-Thalidomide has strong teratogenic effects, while (R)-Thalidomide has sedative and analgesic effects. From the above, it can be seen the importance of studying the chirality of substances. To meet the needs of society, the development and research of chiral substances provide impetus for new chiral drugs, chiral materials, chiral dyes, chiral fragrances, etc. Chiral drug molecules can often improve the drug efficacy or / and reduce side effects. Chiral pharmaceuticals are a cutting-edge field in the pharmaceutical industry. Currently, the total number of drugs used in the world is about 2,000, and chiral drugs account for more than 70%. Among the 250 commonly used drugs in clinical practice, up to 200 are chiral drugs.

[0003] Among the "Top Ten Chemical Technology Inventions that Changed the World" proposed by IUPAC, the key preparation technology of chiral drugs was successfully selected. Superior chiral ligands often exhibit higher reaction selectivity, faster reaction efficiency, broader substrate generality, and higher stereoselectivity in asymmetric catalysis. The design and synthesis of superior chiral ligands play a crucial role in the development of asymmetric catalytic reactions. Therefore, the synthesis of superior chiral ligands is the most attractive and challenging goal in asymmetric catalysis. In addition, an economically feasible synthesis route is also crucial for the popularization of superior ligands. Among many compounds, N-oxides of amines are highly polar substances, and N-oxides of amines can be easily obtained through the N-oxidation reaction of pyridine compounds or tertiary amines. In N-oxides, the oxygen atom belongs to an electron-rich coordination site. Therefore, the unique property of the electron pair of N-oxides provides potential opportunities for this type of compound to form complexes with various metals. However, there are still relatively few chiral amine N-oxide ligands with simple synthesis methods and wide usability at present. Therefore, it is particularly important to develop new chiral amine N-oxide ligands for metal-catalyzed reactions. Summary of the Invention

[0004] In view of this, the present invention provides a bipyridine chiral tetradentate bis(oxime) ligand, a preparation method thereof, and an application thereof in an asymmetric catalytic reaction. The bipyridine chiral tetradentate bis(oxime) ligand provided by the present invention is a novel C2-axis symmetric ligand, which can be used as a chiral ligand in an asymmetric catalytic reaction, has good air stability, wide applicability, good compatibility with various substituents, and its synthesis method is very economical and simple, and has important application value in the field of asymmetric catalytic synthesis.

[0005] In order to achieve the above-mentioned invention purpose, the present invention provides the following technical solutions:

[0006] A bipyridine chiral tetradentate bis(oxime) ligand having the structure shown in Formula I:

[0007]

[0008] In Formula I: Ar is phenyl, alkyl-substituted phenyl, halogenated phenyl or 3,5-bis(trifluoromethyl)phenyl.

[0009] Preferably, in the alkyl-substituted phenyl, the number of carbon atoms of the alkyl is 1 to 5; the halogenated phenyl is fluorinated phenyl or chlorinated phenyl.

[0010] Preferably, the bipyridine chiral tetradentate bis(oxime) ligand includes any one of the following structures:

[0011]

[0012] The present invention also provides a preparation method of the bipyridine chiral tetradentate bis(oxime) ligand according to the above scheme, including the following steps:

[0013] Mix a compound having the structure shown in Formula A, a compound having the structure shown in Formula B and an alcohol solvent for a condensation reaction to obtain an intermediate; the intermediate has the structure shown in Formula C;

[0014]

[0015] In Formula A and Formula C: the type of Ar is the same as that in Formula I;

[0016] Mix the intermediate, m-chloroperbenzoic acid and a halogenated alkane solvent for a nitrogen oxidation reaction to obtain a bipyridine chiral tetradentate bis(oxime) ligand having the structure shown in Formula I.

[0017] Preferably, the molar ratio of the compound having the structure shown in Formula A to the compound having the structure shown in Formula B is 2 to 3:1; the alcohol solvent is one or more of ethanol, methanol, isopropanol and n-butanol; the condensation reaction is carried out under reflux conditions, and the time of the condensation reaction is 6 to 24 h.

[0018] Preferably, the molar ratio of the m-chloroperbenzoic acid to the compound having the structure shown in Formula B is 2-3:1; the temperature of the nitrogen oxidation reaction is room temperature, and the time is 25-60 min; the haloalkane solvent is chloroform.

[0019] The present invention also provides an application of the bipyridine chiral tetradentate bis-nitroxide ligand described in the above solution in an asymmetric catalytic reaction.

[0020] Preferably, the asymmetric catalytic reaction is an asymmetric Michael addition cyclization reaction participated by 5-aminopyrazole compounds.

[0021] Preferably, the bipyridine chiral tetradentate bis-nitroxide ligand is used in combination with a metal Lewis acid; the bipyridine chiral tetradentate bis-nitroxide ligand and the metal Lewis acid coordinate to form a chiral ligand-metal complex.

[0022] The present invention also provides an intermediate for synthesizing the bipyridine chiral tetradentate bis-nitroxide ligand, which has the structure shown in Formula C:

[0023]

[0024] In Formula C: Ar is phenyl, alkyl-substituted phenyl, halogenated phenyl or 3,5-bis(trifluoromethyl)phenyl.

[0025] The present invention provides a bipyridine chiral tetradentate bis-nitroxide ligand, which has the structure shown in Formula I (the specific structure is shown above). The C2 axis symmetry can provide the same chiral environment on both sides of the metal center. In this context, the present invention designs and develops a new type of C2 axis symmetric bipyridine chiral tetradentate bis-nitroxide ligand, and uses the asymmetric catalytic Michael addition cyclization reaction participated by 5-aminopyrazole compounds as a template reaction to test its application in asymmetric catalytic reactions. Based on the design and synthesis of the novel C2 axis symmetric bipyridine chiral tetradentate bis-nitroxide ligand, the design idea of the present invention refers to the chelation catalytic mechanism of the tetradentate ligand of the "crab" bionic model: the bis-nitroxide group is analogous to the two pincers of the "crab", and the N atoms in the bipyridine are analogous to the two eyes of the "crab" (as Figures 1 to 2 shown), and the main structural characteristics of the finally obtained ligand are as follows: C2 axis symmetry; being both rigid and flexible, easy to regulate; being both hard and soft, coordinating with many types of metals; interaction between nitrogen-oxygen and hydrogen bonds.

[0026] The bipyridine chiral tetradentate bis-nitroxide ligand provided by the present invention contains a bipyridine group and a nitroxide group, wherein the nitrogen atoms in the bipyridine and the oxygen atoms in the nitroxide group are electron-rich coordination sites, and can coordinate with metals (Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , Zn 2+etc.) form a six-membered ring coordination to generate a chiral ligand metal complex, which is used as a chiral ligand in asymmetric catalytic reactions. Moreover, this type of ligand can react in various organic solvents, has good air stability, wide applicability, and good compatibility with various substituents.

[0027] The present invention also provides a preparation method of the bipyridine chiral tetradentate bis(oxime) ligand described in the above solution. The target product can be obtained by the present invention through two steps of condensation and nitrogen oxidation reactions, and the raw materials used are cheap and easy to obtain, with low preparation costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 shows the structural characteristics of the bipyridine chiral tetradentate bis(oxime) ligand of the present invention;

[0029] Figure 2 is a schematic diagram of the design concept of the bipyridine chiral tetradentate bis(oxime) ligand of the present invention;

[0030] Figure 3 is the 1H NMR spectrum of the bipyridine chiral tetradentate bis(oxime) ligand L1 prepared in Example 1;

[0031] Figure 4 is the 13C NMR spectrum of the bipyridine chiral tetradentate bis(oxime) ligand L1 prepared in Example 1;

[0032] Figure 5 shows the yields and dr values of the ligands prepared in Examples 1 to 2;

[0033] Figure 6 is the 1H NMR spectrum of compound 3a prepared in the 10th group of experiments in Example 3;

[0034] Figure 7 is the 13C NMR spectrum of compound 3a prepared in the 10th group of experiments in Example 3;

[0035] Figure 8 is the HPLC spectrum of the racemate (rac-3a) of compound 3a;

[0036] Figure 9 is the HPLC spectrum of compound 3a prepared in the 10th group of experiments;

[0037] Figure 10 shows the synthetic route and the ball-and-stick model of compound 3f in Example 4;

[0038] Figure 11 shows the yields and Ee values of compounds 3b to 3j synthesized in Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention provides a bipyridine chiral tetradentate bis-oxime ligand having the structure shown in Formula I:

[0040]

[0041] In Formula I: Ar is phenyl, alkyl-substituted phenyl, halogenated phenyl or 3,5-bis(trifluoromethyl)phenyl.

[0042] In the present invention, in the alkyl-substituted phenyl, the number of carbon atoms of the alkyl is preferably 1-5. Specifically, the alkyl-substituted phenyl is preferably methyl-substituted phenyl; the halogenated phenyl is preferably fluorinated phenyl or chlorinated phenyl.

[0043] In the present invention, the bipyridine chiral tetradentate bis-oxime ligand preferably includes any one of the following structures:

[0044]

[0045] The present invention also provides a preparation method of the bipyridine chiral tetradentate bis-oxime ligand described in the above solution, including the following steps:

[0046] Mix a compound having the structure shown in Formula A, a compound having the structure shown in Formula B and an alcohol solvent for a condensation reaction to obtain an intermediate; the intermediate has the structure shown in Formula C;

[0047]

[0048] In Formula A and Formula C: the type of Ar is the same as that in Formula I;

[0049] Mix the intermediate, m-chloroperoxybenzoic acid and a halogenated alkane solvent for a nitrogen oxidation reaction to obtain a bipyridine chiral tetradentate bis-oxime ligand having the structure shown in Formula I.

[0050] In the present invention, the synthesis route of the bipyridine chiral tetradentate bis-oxime ligand is as follows:

[0051]

[0052] The synthesis method will be described in detail below in combination with the synthesis route.

[0053] In the present invention, a compound having the structure shown in Formula A, a compound having the structure shown in Formula B, and an alcohol solvent are mixed for a condensation reaction to obtain an intermediate. In the present invention, the compound having the structure shown in Formula A is a (1S,3S,5S)-2-azabicyclo[3,3,0]octane-3-carboxamide compound, and the compound having the structure shown in Formula B is 2,2'-bipyridine-6,6'-dicarboxaldehyde; the molar ratio of the compound having the structure shown in Formula A to the compound having the structure shown in Formula B is preferably 2 to 3:1, more preferably 2.5:1; the alcohol solvent is preferably one or more of ethanol, methanol, isopropanol, and n-butanol, more preferably absolute ethanol; the condensation reaction is preferably carried out under reflux conditions, and the time of the condensation reaction is preferably 6 to 24 h.

[0054] After the condensation reaction is completed, the present invention preferably performs flash column chromatography on the obtained reaction solution. The eluent for the flash column chromatography is preferably methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is preferably 1:20 to 1:2 to obtain the intermediate.

[0055] After obtaining the intermediate, the present invention mixes the intermediate, m-chloroperbenzoic acid, and a halogenated alkane solvent for a nitrogen oxidation reaction to obtain a bipyridine chiral tetradentate bis-nitroxide ligand having the structure shown in Formula I. In the present invention, the molar ratio of m-chloroperbenzoic acid to the compound having the structure shown in Formula B is preferably 2 to 3:1, more preferably 2.1:1; the temperature of the nitrogen oxidation reaction is preferably room temperature, and the time is preferably 5 to 60 min, more preferably 25 min; the halogenated alkane solvent is preferably chloroform.

[0056] After the nitrogen oxidation reaction is completed, the present invention preferably removes the solvent from the obtained reaction solution and purifies it by dry loading column chromatography to obtain a bipyridine chiral tetradentate bis-nitroxide ligand having the structure shown in Formula I; the eluent for the column chromatography purification is preferably methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is preferably 1:10 to 1:1.

[0057] The present invention also provides the application of the bipyridine chiral tetradentate bis-nitroxide ligand described in the above scheme in an asymmetric catalytic reaction; the asymmetric catalytic reaction is preferably an asymmetric Michael addition cyclization reaction participated by 5-aminopyrazole compounds; in the application process, the bipyridine chiral tetradentate bis-nitroxide ligand is used in combination with a metal Lewis acid; the bipyridine chiral tetradentate bis-nitroxide ligand coordinates with the metal ion in the metal Lewis acid to form a chiral ligand-metal complex; the metal ions in the metal Lewis acid preferably include Mn 2+ 、Fe 2+ 、Co 2+ 、Ni 2+ 、Cu 2+ and Zn 2+One or more of those in. In a specific embodiment of the present invention, the metal Lewis acid is preferably Ni(OTf) 2 . In a specific embodiment of the present invention, the asymmetric Michael addition cyclization reaction involving the 5-aminopyrazole compound is specifically an asymmetric Michael addition cyclization reaction between the 5-aminopyrazole compound and the α,β-unsaturated 2-acylimidazole compound. Among them, the dosage of the bipyridine chiral tetradentate bis(oxime) ligand is preferably 5.5% to 11% of the molar amount of the α,β-unsaturated 2-acylimidazole compound. The reaction solvent is preferably dichloromethane, chloroform, tetrahydrofuran or acetonitrile; the asymmetric Michael addition cyclization reaction does not require inert gas protection.

[0058] In the present invention, the structural formula of the 5-aminopyrazole compound is preferably as shown in Formula D.

[0059]

[0060] Ar in Formula D is phenyl, halogenated phenyl or thienyl; the halogenated phenyl is preferably fluorophenyl or chlorophenyl; R in Formula D is preferably alkyl, and the number of carbon atoms of the alkyl is preferably 1 to 10, more preferably 1 to 5, and specifically preferably isobutyl.

[0061] In the present invention, the structure of the α,β-unsaturated 2-acylimidazole compound is preferably as shown in Formula E:

[0062]

[0063] R in Formula E 1 is alkyl, and the number of carbon atoms of the alkyl is preferably 1 to 10, more preferably 1 to 5, and further preferably methyl or isopropyl; R in Formula E 2 is preferably phenyl, substituted phenyl or naphthyl; the substituent in the substituted phenyl is preferably alkyl, alkoxy or alkynyl. The number of carbon atoms of the alkyl is preferably 1 to 10, more preferably 1 to 5, and further preferably methyl. The number of carbon atoms of the alkoxy is preferably 1 to 10, more preferably 1 to 5, and further preferably methoxy. The alkynyl is preferably ethynyl.

[0064] In the present invention, the reaction formula for the asymmetric Michael addition cyclization reaction between the 5-aminopyrazole compound and the α,β-unsaturated 2-acylimidazole compound is as follows:

[0065]

[0066] The present invention also provides an intermediate for synthesizing the bipyridine chiral tetradentate bis(oxime) ligand, which has the structure shown in Formula C:

[0067]

[0068] In formula C: The type of Ar is the same as that in formula I.

[0069] Next, in combination with the embodiments of the present invention, the technical solutions in the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts shall fall within the protection scope of the present invention.

[0070] Example 1 Synthesis of Bipyridine Chiral Tetradentate Bis(oxime) Ligand L 1 Synthesis

[0071] The synthesis route is as follows, where the Ar group in Compound 1 is a phenyl group.

[0072]

[0073] Add Compound 1 (2.5 equiv, 25 mmol) to a round-bottom flask equipped with a magnetic stir bar, then add Compound 2 (1.0 equiv, 10 mmol), and finally add an appropriate amount of absolute ethanol to dissolve. Subsequently, heat under reflux in an oil bath for 6 h, and then perform flash column chromatography (the eluent is methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is 1:20) to obtain an intermediate. Add the intermediate and m-chloroperoxybenzoic acid (2.1 equiv) to a reaction tube, and add an appropriate amount of chloroform to dissolve. The reaction system is stirred at room temperature for 25 min. The reaction solution is concentrated by rotary evaporation, and purified by dry loading column chromatography (the eluent is methanol and dichloromethane, and the volume ratio of methanol to dichloromethane is 1:10) to obtain a white solid L1, melting point: 182.5 - 184.3 °C; total yield 42%, >20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (400 MHz, CD 3 OD) δ 8.30 (dd, J = 7.9, 1.0 Hz, 2H), 7.98 (t, J = 7.8 Hz, 2H), 7.78 (dd, J = 7.7, 1.0 Hz, 2H), 7.48 - 7.42 (m, 4H), 7.30 - 7.23 (m, 4H), 7.17 - 7.09 (m, 2H), 6.84 (s, 2H), 4.89 (m, 2H), 4.65 (m, 2H), 3.39 - 3.31 (m, 2H), 2.89 (dt, J = 14.0, 10.5 Hz, 2H), 2.27 - 2.16 (m, 4H), 2.13 - 2.03 (m, 2H), 1.95 - 1.85 (m, 2H), 1.73 - 1.60 (m, 6H); 13 C NMR (100 MHz, CD 3OD) δ 170.0, 156.6, 151.9, 139.4, 136.3, 130.4, 128.8, 127.7, 123.2, 122.7, 94.7, 87.2, 78.8, 43.3, 33.7, 32.2, 30.4, 25.6; HRMS(APCI) m / z calcd for C 40 H 41 N 6 O 4 + (M + H) + 669.3184, found 669.3156. Figure 3 is the 1H NMR spectrum of the bipyridine chiral tetradentate bis(oxime) ligand L1; Figure 4 is the 13C NMR spectrum of the bipyridine chiral tetradentate bis(oxime) ligand L1.

[0074] Example 2

[0075] Other conditions are the same as in Example 1, except that the Ar group in Compound 1 is 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl or 3,5-bis(trifluoromethyl)phenyl, and the resulting products are the bipyridine chiral tetradentate bis(oxime) ligands L2, L3, L4, L5, respectively; the yields and dr values of the resulting products are shown in Figure 5 , and the structural identification data of each product are as follows:

[0076] In this example, the bipyridine chiral tetradentate bis(oxime) ligand L2 was prepared: white solid, melting point: 178.9 - 180.5 °C; total yield 39%, >20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 1H NMR(400 MHz, CD 3 OD) δ 8.32 (d, J = 7.9 Hz, 2H), 7.98 (t, J = 7.8 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.33 - 7.27 (m, 4H), 7.03 (m, 4H), 6.79 (s, 2H), 4.89 (m, 2H), 4.65 (m, 2H), 3.35 (m, 2H), 2.89 (dt, J = 13.9, 10.4 Hz, 2H), 2.31 - 2.03 (m, 12H), 1.91 (m, 2H), 1.76 - 1.59 (m, 6H); 13 13C NMR(100 MHz, CD 3OD) δ 169.9, 156.6, 151.9, 139.3, 137.9, 133.7, 130.8, 128.8, 123.1, 122.8, 94.7, 87.4, 78.8, 43.3, 33.7, 32.2, 30.4, 25.6, 20.8; HRMS(APCI) m / z calcd for C 42 H 45 N 6 O 4 + (M + H) + 697.3497, found 697.3467.

[0077] In this example, the bipyridine chiral tetradentate bis(oxime) ligand L3 was prepared: white solid, melting point: 182.1 - 183.7 °C; total yield 39%, >20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR (400 MHz, CD 3 OD) δ 8.31 (dd, J = 8.0, 1.0 Hz, 2H), 8.00 (t, J = 7.8 Hz, 2H), 7.77 (dd, J = 7.6, 1.0 Hz, 2H), 7.50 - 7.44 (m, 4H), 7.06 - 6.99 (m, 4H), 6.84 (s, 2H), 4.90 - 4.88 (m, 2H), 4.66 (m, 2H), 3.35 (s, 2H), 2.90 (m, 2H), 2.22 (m, 4H), 2.09 (m, 2H), 1.98 - 1.88 (m, 2H), 1.75 - 1.61 (m, 6H); 13 C NMR (100 MHz, CD 3 OD) δ 170.0, 163.2, 160.8, 156.6, 151.7, 139.4, 132.5, 132.4, 128.9, 125.2, 125.1, 123.3, 117.2, 117.0, 94.7, 87.3, 78.7, 43.3, 33.7, 32.2, 30.4, 25.6; 19 F NMR (376 MHz, CD 3 OD) δ -116.3; HRMS(APCI) m / z calcd for C 40 H 39 F 2 N 6 O 4 + (M + H) + 705.2995, found 705.2963.

[0078] This example prepares the bipyridine chiral tetradentate bis(oxime) ligand L4: white solid, melting point: 172.4 - 174.2 °C; total yield 38%, >20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(400MHz,CD 3 OD)δ8.28(d,J=7.9Hz,2H),8.00(t,J=7.8Hz,2H),7.79(d,J=7.6Hz,2H),7.49-7.40(m,4H),7.27-7.15(m,4H),6.85(s,2H),4.85(m,2H),4.65(m,2H),3.37-3.31(m,2H),2.90(dt,J=14.0,10.5Hz,2H),2.27-2.15(m,4H),2.08-1.98(m,2H),1.95-1.87(m,2H),1.73-1.58(m,6H); 13 CNMR(100MHz,CD 3 OD)δ169.9,156.6,151.6,139.4,135.0,132.8,130.4,129.0,123.9,123.3,94.8,86.9,78.7,43.2,33.7,32.3,30.4,25.6;HRMS(APCI)m / z calcd forC 40 H 39 Cl 2 N 6 O 4 + (M+H) + 737.2404,found 737.2393.

[0079] This example prepares the bipyridine chiral tetradentate bis(oxime) ligand L5: white solid, melting point: 173.0 - 174.6 °C; total yield 36%, >20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry tests are as follows: 1 H NMR(400MHz,CD 3 OD)δ8.27(dd,J=8.0,1.0Hz,2H),8.13(d,J=1.6Hz,4H),8.05(t,J=7.8Hz,2H),7.85(dd,J=7.7,1.0Hz,2H),7.65(d,J=1.6Hz,2H),7.20(s,2H),4.92-4.89(m,2H),4.68(m,2H),3.37(m,2H),2.94(m,2H),2.24(m,4H),2.07-1.88(m,4H),1.76-1.62(m,6H);13 C NMR (100 MHz, CD 3 OD) δ 170.7, 156.5, 150.8, 139.6, 138.3, 133.9, 133.5, 129.3, 125.4, 123.4, 122.7, 122.2, 120.4, 106.8, 94.8, 86.3, 78.5, 43.2, 33.6, 32.3, 30.4, 25.5; 19 F NMR (376 MHz, CD 3 OD) δ -64.8; HRMS (APCI) m / z calcd for C 44 H 37 F 12 N 6 O 4 + (M + H) + 941.2679, found 941.2641.

[0080] Example 3

[0081] To demonstrate the application value of the bipyridine chiral tetradentate bis(oxazoline) ligand of the present invention in an asymmetric catalytic system, the Michael addition cyclization reaction of 5-aminopyrazole (Compound 1a) and α,β-unsaturated 2-acylimidazole (Compound 2a) was selected as the template reaction, and the chiral complexes were in-situ generated by using the bipyridine chiral tetradentate bis(oxazoline) ligands L1 - L5 and the Lewis acid Ni(OTf) 2 to verify the asymmetric catalytic effect of the bipyridine chiral tetradentate bis(oxazoline) ligand. However, it should be emphasized that the bipyridine chiral tetradentate bis(oxazoline) ligand of the present invention is not limited to being used as a chiral ligand only in the Michael addition cyclization reaction of 5-aminopyrazole compounds.

[0082] The synthetic route and the ligand structures used in this example are as follows:

[0083]

[0084] The specific reaction process is as follows: Compound 1a, Compound 2a, Ni(OTf) 2 , the bipyridine chiral tetradentate bis(oxazoline) ligand and the solvent were mixed and reacted at room temperature for 24 h. After the reaction was completed, rapid column chromatography separation was carried out (the chromatographic column was a chiral IC column, and the eluent was 20% isopropanol + 80% n-hexane, both were volume fractions), the yield was calculated, and the ee value of the product (Compound 3a) was determined by HPLC analysis (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, column temperature 40 °C).

[0085] A total of 10 groups of experiments were carried out. In the 1st to 5th groups of experiments, the chiral ligands used were L1, L2, L3, L4, and L5 respectively. The amount of compound 1a used was 0.12 mmol, the amount of compound 2a used was 0.10 mmol, the amount of Ni(OTf) 2 was 10 mol% of compound 2a, the amount of the bipyridine chiral tetradentate bis(oxime) ligand was 10 mol% of compound 2a, the amount of the solvent used was 1 mL, and the solvents used were all dichloromethane.

[0086] In the 6th to 9th groups of experiments, the ligand used was L1, and other conditions were the same as those in the 1st group of experiments, except that the solvents were replaced with chloroform, 1,2-dichloroethane (DEC), tetrahydrofuran (THF), and acetonitrile (MeCN) respectively.

[0087] In the 10th group of experiments, the ligand used was L1, and other conditions were the same as those in the 1st group of experiments, except that the amount of Ni(OTf) 2 was changed to 5 mol% of compound 2a, and the amount of ligand L1 was changed to 5.5 mol% of compound 2a.

[0088] The product yields and Ee values of each group of experiments are shown in Table 1.

[0089] Table 1 Product yields and Ee values

[0090]

[0091]

[0092] It can be seen from Table 1 that the bipyridine chiral tetradentate bis(oxime) ligand of the present invention can react in various organic solvents, and the product yields and Ee values are relatively high.

[0093] The product structure identification data of compound 3a prepared in the 10th group of experiments are as follows: 3a: pale yellow solid, melting point: 151.9 - 153.5 °C; total yield 97%, and the results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance, and high resolution mass spectrometry tests are as follows: HPLC: 98% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 9.74 min, tr(minor) = 8.38 min; [α] D 20 =-16.2 (c = 0.2, CH 2 Cl 2 ). 1 HNMR (400 MHz, CDCl 3) δ 7.49 - 7.43 (m, 2H), 7.19 - 7.12 (m, 3H), 7.12 - 7.07 (m, 3H), 7.06 - 7.00 (m, 3H), 6.98 (d, J = 1.0 Hz, 1H), 6.86 (d, J = 1.0 Hz, 1H), 4.36 (dd, J = 9.2, 2.1 Hz, 1H), 4.02 (s, 3H), 3.88 (dd, J = 17.0, 2.2 Hz, 1H), 3.02 (dd, J = 17.1, 9.2 Hz, 1H), 1.75 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 156.7, 146.8, 144.3, 143.7, 142.9, 134.1, 129.0, 128.8, 128.5, 127.3, 127.1, 126.7, 126.6, 126.3, 105.0, 60.0, 37.5, 34.9, 34.3, 30.0. HRMS (APCI) m / z calcd for C 26 H 28 N 5 + (M + H) + 410.2399, found 410.2333.

[0094] Figure 6 1H NMR spectrum of compound 3a prepared for the 10th group of experiments Figure 7 13C NMR spectrum of compound 3a prepared for the 10th group of experiments Figure 8 HPLC spectrum of the racemate (rac - 3a) of compound 3a Figure 9 HPLC spectrum of compound 3a prepared for the 10th group of experiments

[0095] Example 4

[0096] In this example, the generality of the ligand was investigated. The ligands used were all L1. The experimental conditions were the same as those in the 10th group of experiments in Example 3, except that compounds 1a and 2a were replaced, and compounds 3b - 3j were obtained respectively. The synthetic route and the ball - and - stick model of compound 3f are as Figure 10 shown. The product structures, yields, and Ee values of compounds 3a - 3j are as Figure 11 shown; the substituents in the reactant structures are the same as those at the corresponding positions in the products and are not shown here. The results of Example 4 show that the chiral tetradentate bis - N - oxide ligand provided by the present invention has a wide substrate adaptability and good compatibility with various substituents.

[0097] The structure identification data of each product are as follows:

[0098] Preparation of this Example 3b: Pale yellow solid, melting point: 165.6 - 167.2 °C; total yield 85%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: HPLC: 96% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 8.10 min, tr(minor) = 7.21 min; [α] D 20 = -58.5 (c = 0.2, CH 2 Cl 2 ). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.57 - 7.42 (m, 2H), 7.20 (m, 2H), 7.16 - 7.03 (m, 4H), 6.99 - 6.88 (m, 3H), 4.40 (dd, J = 9.2, 2.5 Hz, 1H), 4.09 (s, 3H), 3.91 (d, J = 16.9 Hz, 1H), 3.16 (dd, J = 17.1, 9.2 Hz, 1H), 1.83 (s, 9H). 13 13C NMR (100 MHz, CDCl 3 ) δ 163.4, 161.0, 146.8, 144.3, 143.0, 142.7, 130.2, 130.2, 128.9, 128.8, 128.3, 128.2, 127.3, 126.9, 126.2, 115.4, 115.2, 104.7, 60.0, 37.5, 34.3, 30.0. 19 19F NMR (376 MHz, CDCl 3 ) δ -115.4. HRMS (APCI) m / z calcd for C 26 H 27 FN 5 + (M + H) + 428.2245, found 428.2239.

[0099] This example prepares 3c: a pale yellow solid, melting point: 71.9 - 73.5 °C; total yield 89%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: HPLC: 95% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 16.19 min, tr(minor) = 10.75 min; [α] D 20 = -9.0 (c = 0.1, CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl3) δ 7.22 (m, 2H), 7.14 - 6.95 (m, 9H), 4.30 (t, J = 8.0 Hz, 1H), 4.14 (s, 3H), 3.45 (d, J = 8.0 Hz, 2H), 1.82 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 157.3, 145.8, 144.2, 143.1, 142.8, 133.6, 133.5, 131.7, 129.5, 129.0, 128.8, 128.1, 127.5, 126.4, 126.3, 107.5, 59.9, 37.5, 35.5, 34.8, 30.0. HRMS (APCI) m / z calcd for C 26 H 27 ClN 5 + (M + H) + 444.1950, found 444.1941.

[0100] This example prepares 3d: a pale yellow solid, melting point: 171.1 - 172.7 °C; total yield 91%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: HPLC: 98% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 10.90 min, tr(minor) = 9.11 min; [α] D 20 = -43.5 (c = 0.2, CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3) δ 7.24 - 7.17 (m, 2H), 7.17 - 7.05 (m, 5H), 6.96 (s, 1H), 6.92 - 6.86 (m, 2H), 4.44 (dd, J = 9.5, 1.9 Hz, 1H), 4.10 (s, 3H), 4.04 - 3.93 (m, 1H), 3.16 (dd, J = 17.2, 9.6 Hz, 1H), 1.83 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 156.6, 146.6, 144.1, 142.5, 139.6, 136.8, 128.8, 128.8, 127.4, 127.3, 126.8, 126.3, 124.1, 123.9, 104.3, 60.1, 37.6, 34.7, 33.9, 29.9. HRMS (APCI) m / z calcd for C 24 H 26 N 5 S + (M + H) + 416.1903, found 416.1898.

[0101] This example prepares 3e: a pale yellow solid, melting point: 108.4 - 110.0 °C; total yield 92%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance, high resolution mass spectrometry, etc. are as follows: HPLC: 96% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 9.31 min, tr(minor) = 8.42 min; [α] D 20 = -31.5 (c = 0.2, CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 - 7.41 (m, 2H), 7.20 - 7.15 (m, 2H), 7.13 - 7.08 (m, 1H), 7.00 (s, 1H), 6.91 (s, 4H), 6.85 (s, 1H), 4.34 (dd, J = 9.2, 1.9 Hz, 1H), 4.01 (s, 3H), 3.90 (d, J = 17.0 Hz, 1H), 3.00 (dd, J = 17.0, 9.2 Hz, 1H), 2.15 (s, 3H), 1.76 (s, 9H). 13 C NMR (100 MHz, CDCl 3) δ 156.6, 146.7, 143.7, 139.7, 136.1, 134.1, 129.5, 128.8, 128.5, 127.2, 127.1, 126.5, 126.2, 105.2, 59.9, 37.5, 34.9, 33.8, 30.0, 21.1. HRMS(APCI) m / z calcd for C 27 H 30 N 5 + (M + H) + 424.2496, found 424.2486.

[0102] This example prepared 3f: pale yellow solid, melting point: 73.5 - 75.1 °C; total yield 93%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance, and high resolution mass spectrometry tests are as follows: HPLC: 96% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 11.69 min, tr(minor) = 10.85 min; [α] D 20 = -79.0 (c = 0.3, CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.64 - 7.51 (m, 2H), 7.28 - 7.23 (m, 2H), 7.21 - 7.15 (m, 1H), 7.08 (s, 1H), 7.04 - 6.97 (m, 2H), 6.93 (s, 1H), 6.77 - 6.67 (m, 2H), 4.40 (dd, J = 9.0, 2.0 Hz, 1H), 4.08 (s, 3H), 3.95 (d, J = 17.0 Hz, 1H), 3.69 (s, 3H), 3.07 (dd, J = 16.7, 9.0 Hz, 1H), 1.83 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 158.3, 146.7, 144.3, 143.6, 134.8, 134.1, 128.9, 128.5, 128.3, 127.1, 126.5, 126.2, 114.1, 105.3, 59.9, 55.2, 37.5, 33.4, 30.0. HRMS(APCI) m / z calcd for C 27 H 30 N 5 O +(M+H) + 440.2455, found 440.2438.

[0103] 3 g of the product was prepared in this example: a pale yellow solid, melting point: 93.2 - 94.8 °C; total yield 94%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry are as follows: HPLC: 98% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 9.16 min, tr(minor) = 8.46 min; [α] D 20 = -46.0 (c = 0.2, CH 2 Cl 2 ). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.52 (m, 2H), 7.36 - 7.31 (m, 2H), 7.29 - 7.22 (m, 2H), 7.22 - 7.15 (m, 1H), 7.10 - 7.03 (m, 3H), 6.95 (s, 1H), 4.44 (dd, J = 9.2, 2.2 Hz, 1H), 4.09 (s, 3H), 3.95 (d, J = 17.0 Hz, 1H), 3.10 (dd, J = 17.0, 9.2 Hz, 1H), 2.98 (s, 1H), 1.84 (s, 9H). 13 13C NMR (100 MHz, CDCl 3 ) δ 156.4, 146.8, 144.1, 143.7, 143.7, 133.9, 132.6, 129.0, 128.5, 127.4, 127.3, 126.5, 126.4, 120.4, 104.3, 83.7, 77.1, 60.0, 37.5, 34.6, 34.2, 29.9. HRMS (APCI) m / z calcd for C 28 H 28 N 5 + (M+H) + 434.2399, found 434.2332.

[0104] This example was prepared for 3 h: pale yellow solid, melting point: 62.4 - 64.0 °C; total yield 90%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: HPLC: 98% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 80:20, flow rate 1.0 mL / min, tr(major) = 10.58 min, tr(minor) = 12.08 min; [α] D 20 = -28.5 (c = 0.2, CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 - 7.43 (m, 2H), 7.25 - 7.17 (m, 2H), 7.17 - 7.10 (m, 1H), 7.05 (s, 1H), 6.91 (s, 1H), 6.25 (s, 2H), 4.34 (dd, J = 8.7, 2.7 Hz, 1H), 4.03 (s, 3H), 3.89 (d, J = 17.0 Hz, 1H), 3.67 (s, 3H), 3.56 (s, 6H), 3.04 (dd, J = 17.2, 8.7 Hz, 1H), 1.74 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 153.2, 146.4, 144.2, 143.8, 138.3, 136.5, 134.2, 128.9, 128.5, 127.2, 126.8, 126.3, 105.4, 104.1, 60.8, 59.9, 55.9, 37.5, 34.3, 29.8. HRMS (APCI) m / z calcd for C 29 H 34 N 5 O 3 + (M + H) + 500.2656, found 500.2647.

[0105] The 3i prepared in this example: pale yellow solid, melting point: 94.6 - 96.2 °C; total yield 94%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: HPLC: 95% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 10.50 min, tr(minor) = 9.41 min; [α] D 20 = -65.7 (c = 0.2, CH 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 - 7.61 (m, 2H), 7.56 (m, 1H), 7.52 - 7.46 (m, 2H), 7.35 (s, 1H), 7.28 (m, 3H), 7.16 - 7.11 (m, 2H), 7.10 - 7.04 (m, 1H), 6.96 (s, 1H), 6.81 (s, 1H), 4.53 (dd, J = 9.2, 1.9 Hz, 1H), 3.99 (m, 4H), 3.08 (dd, J = 16.9, 9.2 Hz, 1H), 1.79 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 146.9, 144.1, 143.9, 140.2, 134.0, 133.6, 132.6, 128.8, 128.7, 128.5, 128.0, 127.6, 127.2, 126.5, 126.0, 125.9, 125.8, 125.6, 104.7, 60.0, 37.5, 34.8, 34.3, 30.0. HRMS (APCI) m / z calcd for C 30 H 30 N 5 + (M + H) + 460.2496, found 460.2488.

[0106] This example prepared 3j: a pale yellow solid, melting point: 91.3 - 92.9 °C; total yield 96%. The results of high performance liquid chromatography, optical rotation, nuclear magnetic resonance and high resolution mass spectrometry tests are as follows: HPLC: 96% ee (Chiralpak IC column, 254 nm, hexane / isopropanol = 95:5, flow rate 1.0 mL / min, tr(major) = 7.63 min, tr(minor) = 6.71 min; [α] D 20 = -81.5 (c = 0.3, CH 2 Cl 2 ). 1 1H NMR (400 MHz, CDCl 3 ) δ 7.61 - 7.48 (m, 2H), 7.25 (m, 2H), 7.22 - 7.15 (m, 4H), 7.15 - 7.06 (m, 4H), 5.98 (m, 1H), 4.43 (dd, J = 9.1, 2.3 Hz, 1H), 3.94 (d, J = 16.9 Hz, 1H), 3.16 (dd, J = 16.9, 9.1 Hz, 1H), 1.82 (s, 9H), 1.51 (d, J = 6.7 Hz, 3H), 1.45 - 1.36 (m, 3H). 13 13C NMR (100 MHz, CDCl 3 ) δ 157.1, 146.7, 143.7, 142.8, 134.1, 129.5, 128.8, 128.5, 127.3, 127.1, 126.7, 126.6, 120.0, 105.1, 59.9, 48.7, 34.4, 30.0, 24.0, 23.9. HRMS (APCI) m / z calcd for C 28 H 32 N 5 + (M + H) + 438.2652, found 438.2646.

[0107] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A bipyridine chiral tetradentate bis(oxime) ligand, characterized in that, it has the structure shown in Formula I: In Formula I: Ar is phenyl, alkyl-substituted phenyl, halogenated phenyl or 3,5-bis(trifluoromethyl)phenyl; in the alkyl-substituted phenyl, the number of carbon atoms of the alkyl is 1-5.

2. The bipyridine chiral tetradentate bis(oxime) ligand according to claim 1, characterized in that, the halogenated phenyl is fluorophenyl or chlorophenyl.

3. The bipyridine chiral tetradentate bis(oxime) ligand according to claim 1 or 2, characterized in that, the bipyridine chiral tetradentate bis(oxime) ligand includes any one of the following structures:

4. The preparation method of the bipyridine chiral tetradentate bis(oxime) ligand according to any one of claims 1 to 3, characterized in that, it includes the following steps: Mix the compound with the structure shown in Formula A, the compound with the structure shown in Formula B and an alcohol solvent for a condensation reaction to obtain an intermediate; the intermediate has the structure shown in Formula C; In Formula A and Formula C: the type of Ar is the same as that in Formula I; Mix the intermediate, m-chloroperbenzoic acid and a halogenated alkane solvent for a nitrogen oxidation reaction to obtain the bipyridine chiral tetradentate bis(oxime) ligand with the structure shown in Formula I.

5. The preparation method according to claim 4, characterized in that, the molar ratio of the compound with the structure shown in Formula A to the compound with the structure shown in Formula B is 2-3:1; the alcohol solvent is one or more of ethanol, methanol, isopropanol and n-butanol; the condensation reaction is carried out under reflux conditions, and the time of the condensation reaction is 6-24 h.

6. The preparation method according to claim 4, characterized in that, the molar ratio of m-chloroperbenzoic acid to the compound with the structure shown in Formula B is 2-3:1; the temperature of the nitrogen oxidation reaction is room temperature, and the time is 5-60 min; the halogenated alkane solvent is chloroform.

7. The application of the bipyridine chiral tetradentate bis(oxime) ligand according to any one of claims 1 to 3 in an asymmetric catalytic reaction; the asymmetric catalytic reaction is an asymmetric Michael addition cyclization reaction participated by 5-aminopyrazole compounds.

8. The application according to claim 7, characterized in that, the bipyridine chiral tetradentate bis(oxime) ligand is used in combination with a metal Lewis acid; the bipyridine chiral tetradentate bis(oxime) ligand and the metal Lewis acid coordinate to form a chiral ligand-metal complex.

9. An intermediate for synthesizing the bipyridine chiral tetradentate bis(oxime) ligand, characterized in that, it has the structure shown in Formula C: In Formula C: Ar is phenyl, alkyl-substituted phenyl, halogenated phenyl or 3,5-bis(trifluoromethyl)phenyl; in the alkyl-substituted phenyl, the number of carbon atoms of the alkyl is 1-5.

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