Chiral binuclear copper complex with benzo [c] cinnoline skeleton and preparation method thereof

Abstract

The invention discloses a chiral binuclear copper complex with a benzo [c] cinnoline skeleton and a preparation method of the chiral binuclear copper complex. The binuclear copper complex has a structure as shown in a general formula V. The preparation method is simple, a series of chiral binuclear copper complexes can be rapidly prepared, and the binuclear copper complexes not only have stable structures, but also can be applied to asymmetric catalytic reactions, and have economic practicability and industrial application prospects. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a chiral binuclear copper complex and a preparation method thereof, in particular to a preparation method of a chiral binuclear copper complex of bisoxazoline or bisimidazoline based on a benzo[c]cinnoline skeleton. Background Art

[0002] Asymmetric catalysis is a hot topic in the current research field of organic synthetic chemistry. Despite the large number of chiral ligands, there are still few ligands with a "dominant structure" skeleton, and it is very important to further develop new chiral ligands. Chiral oxazoline or imidazoline ligands are easy to synthesize, and chiral raw materials are not only cheap and easy to obtain but also widely available. In addition, due to the strong coordination ability of chiral oxazoline or imidazoline ligands, they are widely used in the preparation of various metal complexes and a variety of asymmetric catalytic reactions. Benzo[c]cinnoline is also a very important structural unit. Due to its unique properties and biological activity, it is widely used, such as in antibacterial, herbicidal, anticancer preparations, cytotoxic activity and many functional materials. It is worth noting that the benzo[c]cinnoline skeleton can be used as a bridging unit of a binuclear ligand, and its N=N bond exhibits good coordination ability with transition metals. In 2018, Zhang Wanbin et al. (Chem.Soc.Rev., 2018, 47, 1783-1810) summarized asymmetric catalytic reactions of various binuclear ligands containing chiral oxazoline and various metal precursors. In 2018, Daniel Seidel et al. summarized chiral binuclear metal complexes containing chiral oxazoline skeletons (Beilstein J.Org.Chem.2018, 14, 2002-2011). In 2020, T.Don Tilley et al. summarized binuclear copper complexes containing naphthyridine skeletons (Acc.Chem.Res.2020, 53, 1944-1956). However, there are fewer reports on chiral binuclear copper complexes with clear structures, and the synthesis is difficult. The reports on using chiral binuclear copper complexes with clear structures for asymmetric catalytic reactions and achieving better reaction effects are more limited. Therefore, it is of great significance to develop, design and synthesize chiral binuclear copper complexes with novel skeletons and use them to solve challenging problems in the field of asymmetric catalysis. Summary of the invention

[0003] The present invention aims at the above-mentioned deficiencies in the prior art and provides a chiral binuclear copper complex of bisoxazoline or bisimidazoline based on a benzo[c]cinnoline skeleton and a synthesis method thereof. A series of novel chiral binuclear copper complexes are prepared by using the nitrogen-nitrogen double bond of benzo[c]cinnoline as a bridging unit. The novel chiral binuclear copper complex not only has a stable structure, but also can be used as a catalyst for asymmetric catalytic reactions, and has economical practicality and industrial application prospects.

[0004] In a first aspect of the present invention, a chiral binuclear complex is provided, having a structure as shown in Formula V,

[0005]

[0006] In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from: hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-7 membered heteroaryl;

[0007] R 1 , R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-7 membered heteroaryl; or R 1 , R 2 , R 3 , R 4 Together with the connected carbon, it forms a 3-8 membered ring (preferably a 3-8 membered saturated carbocyclic ring, more preferably a 4-6 membered saturated carbocyclic ring);

[0008] or, for R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 6-10 Aryl 4-7 membered heterocyclic ring, substituted or unsubstituted 4-7 membered heteroaryl;

[0009] X is a coordinated anion selected from chloride, bromide, iodide, carboxylate, tetrafluoroborate, hexafluorophosphate, and trifluoromethanesulfonate;

[0010] Y is O or NR, wherein R is selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-7 membered heteroaryl;

[0011] The above substitutions are each independently substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 6-10 Aryl.

[0012] In another preferred embodiment, R 1 , R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0013] In another preferred embodiment, R 1 , R 2 , R 3 , R 4 are independently selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, benzyl.

[0014] In another preferred embodiment, R 1 , R 2 , R 3 , R 4 Each of the groups is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl and benzyl.

[0015] In another preferred embodiment, R 1 Not equal to R 2 In another preferred embodiment, R 3Not equal to R 4 .

[0016] When R 1 , R 2 When R 3 , R 4 When the same, the attached carbon is an achiral carbon.

[0017] In another preferred embodiment, the chiral binuclear complex has a structure shown in Formula II:

[0018]

[0019] R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 substituted or unsubstituted phenyl, substituted or unsubstituted benzo 5-6 membered heterocyclic ring, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, phenyl;

[0020] X, Y, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The definition of is as mentioned above.

[0021] In another preferred embodiment, R 11 , R 12 , R 13 , R 14 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, trifluoromethoxy, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 4-7 membered heteroaryl. In another preferred embodiment, R 15 , R 16are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

[0022] In another preferred embodiment, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from: hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0023] In another preferred embodiment, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 3-8 Cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 In another preferred embodiment, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0024] In another preferred embodiment, R 5 , R 6 , R 7 , R 8 , R 9 , R 10are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, trifluoromethoxy, F, Cl, Br, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, substituted or unsubstituted C 6-10 Aryl.

[0025] In another preferred embodiment, X is a coordinated anion selected from chloride, bromide, iodide, formate, acetate, propionate, butyrate, tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate; and / or

[0026] Y is O or NR, wherein R is selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0027] In another preferred embodiment, R 1 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, benzyl.

[0028] In another preferred embodiment, R 2 Selected from hydrogen, C 3-6 Cycloalkyl, phenyl, benzyl.

[0029] In another preferred embodiment, R 3 Selected from hydrogen, C 3-6 Cycloalkyl, phenyl, benzyl.

[0030] In another preferred embodiment, R 4 Selected from hydrogen, C 3-6 Cycloalkyl, phenyl, benzyl.

[0031] In another preferred embodiment, R 5 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy.

[0032] In another preferred embodiment, R 6 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0033] In another preferred embodiment, R 7 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy.

[0034] In another preferred embodiment, R 8 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy.

[0035] In another preferred embodiment, R 9 independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0036] In another preferred embodiment, R 10 Selected from hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl, C 1-4 Alkoxy.

[0037] In another preferred embodiment, R 11 Selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl.

[0038] In another preferred embodiment, R 12 is selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzo 5-6 membered heterocycle, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

[0039] In another preferred embodiment, R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl, C 1-4 Alkoxy.

[0040] In another preferred embodiment, X is a coordinated anion selected from chloride, bromide, iodide, formate, acetate, propionate, and butyrate.

[0041] In another preferred embodiment, Y is O or NR, wherein R is selected from H, C 1-4 Alkyl, phenyl, 5-6 membered heteroaryl.

[0042] In another preferred embodiment, the chiral binuclear complex is selected from the following group: C1-C45 compounds.

[0043] The chiral binuclear copper complex of the present invention is based on benzo[c]cinnoline containing a nitrogen-nitrogen double bond as a basic skeleton. In a preferred embodiment, the chiral binuclear copper complex contains two oxazolines, and the oxazolines have at least one chiral center carbon of (S) or (R) configuration. In another preferred embodiment, the chiral binuclear copper complex contains a basic skeleton of two imidazolines, and the imidazolines have at least one chiral center carbon of (S) or (R) configuration.

[0044] The second aspect of the present invention provides a method for preparing the chiral binuclear copper complex according to the first aspect, wherein Y is O, and the chiral binuclear copper complex has a structure shown in Formula I, and the method comprises the following steps:

[0045]

[0046] Step (a): Reductive coupling of the compound of formula S1 to obtain the compound of formula S2;

[0047] Step (b): reacting a compound of formula S2 with a chiral amino alcohol to obtain a compound of formula S3;

[0048] Step (c): oxidizing the compound of formula S3 to obtain the compound of formula S4;

[0049] Step (d): the compound of formula S4 is activated by a hydroxyl activator and then subjected to an intramolecular cyclization reaction to obtain a cyclization product, which is then reacted with a copper salt to obtain a chiral binuclear copper complex dichloromethane as shown in formula I;

[0050] Alternatively, Y is O, the chiral binuclear copper complex has a structure shown in Formula II, and the method comprises the following steps:

[0051]

[0052] Step (e): Reductive coupling of the compound of formula S5 to obtain the compound of formula S6;

[0053] Step (f): oxidizing the compound of formula S6 to obtain the compound of formula S7;

[0054] Step (g): reacting a compound of formula S7 with a compound of formula S8 to obtain a cyclized product, and then reacting the product with a copper salt to obtain a chiral binuclear copper complex dichloromethane represented by formula II;

[0055] Alternatively, Y is NR, R is H, and the method comprises the following steps:

[0056]

[0057] Step (h): Compound S7 is treated with Meerwin salt or HCl to generate an imine ester intermediate, which is reacted with chiral diamine S9 or S 10 The cyclized product is synthesized by reaction, and then reacted with copper salt to obtain a chiral binuclear copper complex shown in formula I or II; dichloromethane

[0058] In various types, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 The definition of is as above; Z is F, Cl, Br or I.

[0059] In another preferred embodiment, the method comprises the following steps:

[0060] Step (a): in an organic solvent, under the action of a metal catalyst, reducing and coupling the compound of formula S1 to obtain a compound of formula S2, the reaction temperature is 10-80° C., and the reaction time is 6-48 hours;

[0061] Step (b): reacting a compound of formula S2 and a chiral amino alcohol in the presence of a base to obtain a compound of formula S3, the reaction temperature being 100-200° C. and the reaction time being 2-72 hours;

[0062] Step (c): oxidizing the compound of formula S3 to the compound of formula S4 in an organic solvent under the action of an oxidant, the reaction temperature is 20-120° C., and the reaction time is 12-72 hours;

[0063] Step (d): activating the compound of formula S4 with a hydroxyl activator in an organic solvent containing a base and then subjecting it to an intramolecular cyclization reaction, the reaction temperature being 20-80° C. and the reaction time being 1-24 hours; after the reaction is completed, separating the cyclization product by column chromatography and reacting it with a copper salt in dichloromethane to obtain the chiral binuclear copper complex I, the reaction temperature being 20-40° C. and the reaction time being 1-12 hours;

[0064] In another preferred embodiment, the method comprises the following steps:

[0065] Step (e): in an organic solvent, in the presence of a metal catalyst, reducing and coupling the compound of formula S5 to obtain a compound of formula S6, the reaction temperature being 10-60° C. and the reaction time being 12-72 hours;

[0066] Step (f): oxidizing the compound of formula S6 to the compound of formula S7 in an organic solvent under the action of an oxidant, the reaction temperature is 60-140° C., and the reaction time is 12-72 hours;

[0067] Step (g): in an organic solvent, the compound of formula S7 and the compound of formula S8 react under the catalysis of Lewis acid, the reaction temperature is 100-160° C., and the reaction time is 12-72 hours; after the reaction is completed, the cyclization product is separated by column chromatography and reacted with copper salt in dichloromethane to obtain the chiral binuclear copper complex II, the reaction temperature is 20-40° C., and the reaction time is 1-12 hours;

[0068] In another preferred embodiment, the method comprises the following steps:

[0069] Step (h): In an organic solvent, the compound of formula S7 is treated with Meerwin salt (Et3OBF4) or HCl (alcohol solution) to generate an imidate intermediate, and then reacted with a chiral diamine S9 or S 10 The reaction is to synthesize imidazoline at a reaction temperature of 20-80°C and a reaction time of 6-24 hours; after the reaction is completed, the cyclized product is separated by column chromatography and reacted with a copper salt in dichloromethane to obtain the chiral binuclear copper complex I or II at a reaction temperature of 20-40°C and a reaction time of 1-12 hours. Furthermore, the method further comprises obtaining R-substituted imidazoline (i.e., Y=NR, R is substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 4-7 membered heteroaryl).

[0070] In another preferred embodiment, in the step (a), the organic solvent is one or a mixed solvent of two or more selected from the group consisting of methanol, ethanol, isopropanol, hexamethylphosphoric triamide, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0071] In another preferred embodiment, the metal catalyst is one or a combination of two or more of Pd(OAc)2, PdCl2, Pd2(dba)3, Pd(dba)2, Pd(CH3CN)Cl2, dpppNiCl2, Ni(PPh3)2Cl2, NiCl2, NiBr2, NiI2, NiCl2·DME or NiBr2·DME.

[0072] In another preferred embodiment, in the step (b), the chiral amino alcohol has at least one chiral central carbon with (S) or (R) configuration, and is selected from: (S)-phenylalaninol, (S)-phenylglycinol, (S)-valeric alcohol, (S)-tert-leucinol, (S)-hexylaminoethanol, (S)-leucinol, (S)-isoleucinol, (S)-aminopropanol, (S)-cyclohexylglycinol, (1R,2S)-2-amino-1,2-diphenylethanol, (S)-2-amino-1,1,3-triphenyl-1-propanol, (S)-2-amino-1,1,2-triphenylethanol or (S)-2-amino-3,3-dimethyl-1,1-diphenyl-1-butanol and enantiomers thereof.

[0073] In another preferred embodiment, in the step (b), the base is sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, sodium, butyl lithium, lithium diisopropylamide, benzyl lithium, sec-butyl lithium or tert-butyl lithium.

[0074] In another preferred embodiment, in the step (c), the organic solvent is one or a mixed solvent of two or more selected from tetrahydrofuran, toluene, benzene, xylene, trimethylbenzene, chlorobenzene or dichlorobenzene.

[0075] In another preferred embodiment, in the step (c), the oxidant is tert-butyl hypochlorite, iodobenzene diacetate (diacetoxyiodobenzene), Dess-Martin reagent, potassium permanganate, sodium dichromate, potassium dichromate or potassium perchlorate.

[0076] In another preferred embodiment, in the step (d), the base is triethylamine, diisopropylethylamine, dicyclohexylethylamine, triethylenediamine, pyridine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate or potassium hydroxide.

[0077] In another preferred embodiment, in the step (d), the organic solvent is one or a mixed solvent of two or more selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ether, tetrahydrofuran, toluene, benzene, xylene, trimethylbenzene, chlorobenzene or dichlorobenzene.

[0078] In another preferred embodiment, in the step (d), the hydroxyl activating agent is thionyl chloride, methanesulfonyl chloride, phenylsulfonyl chloride or p-toluenesulfonyl chloride.

[0079] In another preferred embodiment, in the step (d), the copper salt is CuCl, CuBr, CuI, Cu(OAc), cuprous tetrafluoroborate, cuprous hexafluorophosphate or cuprous trifluoromethanesulfonate.

[0080] In another preferred embodiment, in the step (e), the organic solvent is one or a mixed solvent of two or more selected from the group consisting of methanol, ethanol, isopropanol, hexamethylphosphoric triamide, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0081] In another preferred embodiment, in the step (e): the metal catalyst is one or a combination of two or more of Pd(OAc)2, PdCl2, Pd2(dba)3, Pd(dba)2, Pd(CH3CN)Cl2, dpppNiCl2, Ni(PPh3)2Cl2, NiCl2, NiBr2, NiI2, NiCl2·DME or NiBr2·DME.

[0082] In another preferred embodiment, in the step (f), the organic solvent is one or a mixed solvent of two or more selected from tetrahydrofuran, toluene, benzene, xylene, trimethylbenzene, chlorobenzene or dichlorobenzene.

[0083] In another preferred embodiment, in the step (f), the oxidant is tert-butyl hypochlorite, iodobenzene diacetate, Dess-Martin reagent, potassium permanganate, sodium dichromate, potassium dichromate or potassium perchlorate.

[0084] In another preferred embodiment, in the step (g), the organic solvent is one or a mixed solvent of two or more selected from tetrahydrofuran, toluene, benzene, xylene, trimethylbenzene, chlorobenzene or dichlorobenzene.

[0085] In another preferred embodiment, in the step (g), the Lewis acid is zinc chloride, zinc bromide, aluminum chloride, ferric chloride, boron trichloride, niobium pentachloride, boron trifluoride, aluminum bromide, titanium tetraisopropoxide, cupric chloride, ferric bromide, tin tetrachloride, titanium tetrachloride, or silver trifluoromethanesulfonate.

[0086] In another preferred embodiment, in the step (g), the copper salt is CuCl, CuBr, CuI, Cu(OAc), cuprous tetrafluoroborate, cuprous hexafluorophosphate or cuprous trifluoromethanesulfonate.

[0087] In another preferred embodiment, in the step (h), the organic solvent is one or a mixed solvent of two or more selected from tetrahydrofuran, toluene, benzene, xylene, trimethylbenzene, chlorobenzene or dichlorobenzene.

[0088] In another preferred embodiment, in the step (h), the acid used in the acidic condition is p-toluenesulfonic acid, pyridine p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, or benzenesulfonic acid.

[0089] In another preferred embodiment, in the step (h), the chiral diamine has at least one chiral center carbon of (S) or (R) configuration, and is selected from: (S)-3-phenylpropane-1,2-diamine, (2S)-propane-1,2-diamine, (1S)-1-phenyl-1,2-ethylenediamine, (1R,2R)-1,2-dicyclohexylethane-1,2-diamine, (1S,2S)-(+)-1,2-cyclohexanediamine, (1R,2R)-1,2-diphenylethylenediamine and enantiomers thereof.

[0090] In another preferred embodiment, in the step (h), the copper salt is CuCl, CuBr, CuI, Cu(OAc), cuprous tetrafluoroborate, cuprous hexafluorophosphate or cuprous trifluoromethanesulfonate.

[0091] In another preferred embodiment, in the step (a), the molar ratio of the metal catalyst to the compound of formula S1 is 0.001-0.5:1, preferably 0.01-0.5:1, and more preferably 0.05-0.25:1.

[0092] In another preferred embodiment, in the step (b), the molar ratio of the chiral amino alcohol to the compound of formula S2 is 2-5:1, 3-5:1 or 4-5:1; the molar ratio of the base to the compound of formula S2 is 0.1-2:1, 0.5-1.5:1 or 1-2:1.

[0093] In another preferred embodiment, in the step (c), the molar ratio of the oxidant to the compound of formula S3 is 2-6:1, 3-5:1 or 4-5:1, preferably 2-5:1 or 2.5-4:1.

[0094] In another preferred embodiment, in the step (d), the molar ratio of the base to the compound of formula S4 is 2 to 20:1.

[0095] 5-15:1, 8-12:1 or 10-18:1; the molar ratio of the hydroxyl activator to the compound of formula S4 is 2-8:

[0096] 1. 3-7:1 or 4-6:1, 4.5-5:1.

[0097] In another preferred embodiment, in the step (e), the molar ratio of the metal catalyst to the compound of formula S5 is 0.001-0.5:1, preferably 0.01-0.5:1, and more preferably 0.05-0.25:1.

[0098] In another preferred embodiment, in the step (f), the molar ratio of the oxidant to the compound of formula S3 is 2-6:1, 3-5:1 or 4-5:1.

[0099] In another preferred example, in the step (g), the ratio of the compound of formula S8 to the compound of formula S7 is 2-5:1, 3-5:1 or 4-5:1; the ratio of the Lewis acid to the compound of formula S7 is 2-10:1, 2-8:1, 3-7:1, 4-6:1 or 4.5-5:1.

[0100] In another preferred embodiment, in the step (h), the formula S9 or S 10 The ratio of the compound to the compound of formula S7 is 2-5:1, 3-5:1 or 4-5:1; the ratio of the acid used in the acidic conditions to the compound of formula S7 is 1-4:1 or 2-3:1.

[0101] The third aspect of the present invention provides the use of the chiral binuclear complex described in the first aspect as a chiral ligand or a chiral catalyst for asymmetric synthesis reactions.

[0102] In another preferred embodiment, it is used as a catalyst for asymmetric propargyl substitution reaction.

[0103] The preparation method of the invention is simple, and can provide a chiral binuclear copper complex of bisoxazoline or bisimidazoline based on a benzo[c]cinnoline skeleton. The novel chiral binuclear copper complex not only has a stable structure, but also can be used as a catalyst for asymmetric catalytic reactions, and has economical practicality and industrial application prospects.

[0104] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they are not listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1 This is the X-ray crystal diffraction pattern of the chiral binuclear copper complex C1 based on the benzo[c]cinnoline skeleton obtained in Example 1.

[0106] Specific implementation methods

[0107] The inventors of the present application have conducted extensive and in-depth research and have prepared a chiral binuclear copper complex of bisoxazoline or bisimidazole based on a benzo[c]cinnoline skeleton by using a simple reaction. The chiral binuclear copper complex can be used for asymmetric catalytic reactions and has economical practicality and industrial application prospects.

[0108] the term

[0109] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0110] In the present invention, the term "C 1-6 ” means having 1, 2, 3, 4, 5 or 6 carbon atoms, “C 3-8 ” means having 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. 4-7 membered means having 4, 5, 6 or 7 ring atoms, and so on.

[0111] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0112] The term "alkyl" refers to a saturated linear or branched hydrocarbon moiety, such as -CH3, -CH2CH3, -CH2CH2CH3, -C(CH3)3 or -CH(CH3)2. The term "haloalkyl" refers to a halogen-substituted alkyl group, such as trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

[0113] The term "alkoxy" refers to a group formed by linking an alkyl group with an oxygen atom, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2. The term "haloalkoxy" refers to an alkoxy group substituted with a halogen, such as trifluoromethoxy, difluoromethoxy, trifluoroethoxy, and the like.

[0114] The term "cycloalkyl" denotes a saturated cyclic hydrocarbon moiety, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0115] The term "heterocyclyl" refers to a saturated or unsaturated, non-aromatic cyclic group containing at least one (e.g. 1, 2, 3 or 4) ring heteroatom (e.g. N, O or S), for example dioxolane, tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothiophenyl, morpholinyl.

[0116] The term "aryl" refers to a hydrocarbyl moiety containing one or more aromatic rings, including but not limited to phenyl, naphthyl, pyrenyl, anthracenyl, phenanthrenyl.

[0117] The term "heteroaryl" refers to an aromatic cyclic group containing 1, 2 or 3 ring heteroatoms selected from N, O, S, for example furanyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridinyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl, pyranyl.

[0118] Advantages of the present invention

[0119] (1) The present invention provides a novel chiral binuclear copper complex having a benzo[c]cinnoline skeleton and containing two oxazolines or bisimidazoles.

[0120] (2) The present invention provides a simple and feasible method for preparing a chiral binuclear copper complex of bisoxazoline or bisimidazole based on a benzo[c]cinnoline skeleton.

[0121] (3) The present invention provides a novel chiral binuclear copper complex which not only has a stable structure but can also be used as a catalyst for asymmetric catalytic reactions and has economical practicality and industrial application prospects.

[0122] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually performed under normal conditions or according to the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and weight parts.

[0123] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0124] The following examples were synthesized based on the chemical formula shown below.

[0125]

[0126]

[0127] Example 1: Preparation of chiral binuclear copper complex C1 of bisoxazoline based on benzo[c]cinnoline skeleton

[0128] Step (a1): from methyl 2-amino-3-bromobenzoate S 1a Preparation of 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a .

[0129] Under anhydrous and oxygen-free conditions, 2-amino-3-bromobenzoic acid methyl ester S was added 1a(23.0g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), nickel chloride (II) glycol dimethyl ether NiCl2·DME (2.2g, 10mmol) and degassed N,N-dimethylformamide (100mL). The reaction mixture was then reacted at room temperature for 24h. Column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) was used for separation and purification to obtain a white solid 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a (12.1 g, 80% yield).

[0130] Step (b1): from 2,2'-diamino-3,3'-biphenyl dicarboxylic acid methyl ester S 2a Preparation of N 3 ,N 3 '-Bis((S)-2-hydroxy-1-tert-butylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3a .

[0131] Under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S was added 2a (3.0 g, 10 mmol), (S)-tert-leucine (5.86 g, 50 mmol) and NaH (120 mg, 5 mmol). The reaction system was reacted at 150°C for 6 h, and S was monitored by TLC. 2a After complete conversion, the product was separated and purified by column chromatography (dichloromethane / methanol=100 / 1) to obtain a white solid N 3 ,N 3 '-Bis((S)-2-hydroxy-1-tert-butylethyl)-2,2'-diamino-3,3'-biphenyldicarboxylate S 3a (4.0 g, 85% yield).

[0132] Step (c1): From N 3 ,N 3 '-Bis((S)-2-hydroxy-1-tert-butylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3a Preparation of N 4 ,N 7 -Bis((S)-2-hydroxy-1-tert-butylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4a .

[0133] Under anhydrous and oxygen-free conditions, S 3a(4.0 g, 8.5 mmol) was dissolved in anhydrous toluene (150 mL), diacetoxy iodobenzene (6.0 g, 18.7 mmol) was slowly added, and the reaction mixture was reacted at 80°C for 24 h. Finally, it was separated and purified by column chromatography (dichloromethane / methanol = 100 / 1), and the yellow solid N 4 ,N 7 -Bis((S)-2-hydroxy-1-tert-butylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4a (2.2 g, 56% yield).

[0134] Step (d1): From N 4 ,N 7 -Bis((S)-2-hydroxy-1-tert-butylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4a A chiral binuclear copper complex C1 containing two oxazolines and having a benzo[c]cinnoline skeleton was prepared.

[0135] Under anhydrous and oxygen-free conditions, S 4a (2.2g, 4.8mmol) was dissolved in 1,2-dichloroethane (150mL). Sulfonyl chloride (1.74mL, 23.9mmol) was slowly added dropwise to the reaction system, and the suspension was heated at 80°C for 2h. After cooling to room temperature, it was quenched with a saturated solution of NaHCO3 and extracted with dichloromethane (40mL×3). The organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered, concentrated and dried to obtain a crude product which was directly used in the next step. Then NaOH (764.6mg, 19.1mmol) and EtOH (100mL) were added to the crude product and heated to reflux for 2h. The crude product was quickly separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The obtained crude product was dissolved in dichloromethane (100mL), and CuI (3.64g, 19.1mmol) was added, and the reaction system quickly turned red and black. The mixture was stirred at room temperature overnight, and the excess CuI was removed by filtration. The corresponding chiral binuclear copper complex C1 (1.62 g, 42% total yield in 3 steps) was obtained by separation and purification through column chromatography (dichloromethane / methanol=200 / 1). Figure 1 The X-ray crystal diffraction pattern of the chiral binuclear copper complex C1 of the bisoxazoline of benzo[c]cinnoline skeleton is shown.

[0136] HRMS (ESI) m / z: calculated C 26 H 30 N4O2Cu2I + [MI] + :683.0000; Actual measurement:682.9999.

[0137] Example 2: Preparation of chiral binuclear copper complex C2 based on benzo[c]cinnoline skeleton

[0138] Step (a2): from methyl 2-amino-3-bromobenzoate S 1a Preparation of 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a .

[0139] Place a magnetic stirring bar in a dry three-necked round-bottom flask and add 2-amino-3-bromobenzoic acid methyl ester S under anhydrous and oxygen-free conditions. 1a (23.0g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), nickel chloride NiCl2 (1.3g, 10mmol) and degassed N,N-dimethylacetamide (80mL). The reaction mixture was then reacted at room temperature for 24h. After the reaction was completed, it was extracted with dichloromethane (200mL×3), the organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered and concentrated. It was separated and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to obtain a white solid 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a (10.9 g, 72% yield).

[0140] Step (b2): from 2,2'-diamino-3,3'-biphenyl dicarboxylic acid methyl ester S 2a Preparation of N 3 ,N 3 '-Bis((S)-2-hydroxy-1-benzylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3b .

[0141] In a 50 mL sealed tube equipped with a magnetic stirring bar, under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S was added. 2a (900.4 mg, 3 mmol), (S)-phenylalaninol (2.3 g, 15 mmol) and NaH (36 mg, 1.5 mmol). The reaction system was reacted at 150°C for 6 h, and S was monitored by TLC. 2a After complete conversion, the reaction was quenched with water (10 mL). The organic matter was extracted with dichloromethane (40 mL × 3), and the organic layer was washed with saturated NaCl, dried over anhydrous NaSO4, filtered and concentrated. The white solid N was obtained by separation and purification by column chromatography (dichloromethane / methanol = 100 / 1). 3 ,N 3 '-Bis((S)-2-hydroxy-1-benzylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S3b (1.2 g, 72% yield).

[0142] Step (c2): From N 3 ,N 3 '-Bis((S)-2-hydroxy-1-benzylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3b Preparation of N 4 ,N 7 -Bis((S)-2-hydroxy-1-benzylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4b .

[0143] Under anhydrous and oxygen-free conditions, S 3b (1.2 g, 2.2 mmol) was dissolved in anhydrous toluene (150 mL), diacetoxy iodobenzene (1.5 g, 4.8 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 24 h. After the reaction was completed, a yellow solid was precipitated. After filtering the yellow solid product, the mother liquor was concentrated under reduced pressure. The yellow solid N was separated and purified by column chromatography (dichloromethane / methanol = 20 / 1) and the combined yellow solid was 4 ,N 7 -Bis((S)-2-hydroxy-1-benzylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4b (723.9 mg, 63% yield).

[0144] Step (d2): From N 4 ,N 7 -Bis((S)-2-hydroxy-1-benzylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4b A chiral binuclear copper complex C2 containing two oxazolines and having a benzo[c]cinnoline skeleton was prepared.

[0145] Under anhydrous and oxygen-free conditions, S 4b(723.9mg, 1.4mmol) was dissolved in 1,2-dichloroethane (30mL). Sulfonyl chloride (0.49mL, 6.8mmol) was slowly added dropwise to the reaction system, and the suspension was heated at 80°C for 2h. After cooling to room temperature, it was quenched with a saturated solution of NaHCO3 and extracted with dichloromethane (30mL×3). The organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered, concentrated and dried to obtain a crude product which was directly used in the next step. Then NaOH (216.6mg, 5.4mmol) and EtOH (40mL) were added to the crude product and heated to reflux for 2h. The crude product was quickly separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The obtained crude product was dissolved in dichloromethane (30mL), and CuI (1.02g, 5.4mmol) was added, and the reaction system quickly turned red and black. The mixture was stirred at room temperature overnight, and the excess CuI was removed by filtration. The corresponding chiral binuclear copper complex C2 (456.2 mg, 3 steps 38% total yield) was obtained by separation and purification through column chromatography (dichloromethane / methanol=200 / 1).

[0146] HRMS (ESI) m / z: calculated C 32 H 26 N4O2Cu2I + [MI] + :750.9687; Actual measurement:750.9686.

[0147] Example 3: Chiral binuclear copper complex C of bisoxazoline based on benzo[c]cinnoline skeleton 17 Preparation

[0148] Step (a3): from methyl 2-amino-3-bromobenzoate S 1a Preparation of 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a .

[0149] Place a magnetic stirring bar in a dry three-necked round-bottom flask and add 2-amino-3-bromobenzoic acid methyl ester S under anhydrous and oxygen-free conditions. 1a(23.0g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), nickel bromide (II) glycol dimethyl ether NiBr2·DME (1.54g, 5mmol) and degassed hexamethylphosphoric acid triamide (50mL). Then the reaction mixture was reacted at room temperature for 24h. After the reaction was completed, it was extracted with dichloromethane (200mL×3), the organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered and concentrated. It was separated and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to obtain a white solid 2,2'-diamino-3,3'-biphenyl dicarboxylic acid methyl ester S 2a (8.8 g, 58% yield).

[0150] Step (b3): ​​from 2,2'-diamino-3,3'-biphenyl dicarboxylic acid methyl ester S 2a Preparation of N 3 ,N 3 '-Bis((1R,2S)-2-hydroxy-1,2-diphenyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3c .

[0151] In a 50 mL sealed tube equipped with a magnetic stirring bar, under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S was added. 2a (900.4 mg, 3 mmol), (1R, 2S)-2-amino-1,2-diphenylethanol (1.9 g, 9 mmol) and sodium methoxide (324.1 mg, 6 mmol). The reaction system was reacted at 180°C for 12 h, and S was monitored by TLC. 2a After complete conversion, the reaction was quenched with water (10 mL). The organic matter was extracted with dichloromethane (40 mL × 3), and the organic layer was washed with saturated NaCl, dried over anhydrous NaSO4, filtered and concentrated. The white solid N was obtained by separation and purification by column chromatography (dichloromethane / methanol = 200 / 1). 3 ,N 3 '-Bis((1R,2S)-2-hydroxy-1,2-diphenyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3c (1.1 g, 58% yield).

[0152] Step (c3): From N 3 ,N 3 '-Bis((1R,2S)-2-hydroxy-1,2-diphenyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3c Preparation of N 4 ,N 7-Bis((1R,2S)-2-hydroxy-1,2-diphenyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4c .

[0153] Under anhydrous and oxygen-free conditions, S 3c (1.1 g, 1.7 mmol) was dissolved in anhydrous toluene (150 mL), potassium permanganate (0.81 g, 5.1 mmol) was slowly added, and the reaction mixture was reacted at 40°C for 12 h. After the reaction was completed, a yellow solid was precipitated. The yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. The yellow solid N 4 ,N 7 -Bis((1R,2S)-2-hydroxy-1,2-diphenyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4c (593.5 mg, 53% yield).

[0154] Step (d3): From N 4 ,N 7 -Bis((1R,2S)-2-hydroxy-1,2-diphenyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4c Preparation of a chiral binuclear copper complex C containing two oxazolines and a benzo[c]cinnoline skeleton 17 .

[0155] Under anhydrous and oxygen-free conditions, S 4c (593.5mg, 0.9mmol) was dissolved in 1,2-dichloroethane (20mL). And p-toluenesulfonyl chloride (0.86g, 4.5mmol) was slowly added dropwise to the reaction system, and the suspension was heated at 70°C for 4h. After cooling to room temperature, it was quenched with a saturated solution of NaHCO3 and extracted with dichloromethane (30mL×3). The organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered, concentrated and dried to obtain a crude product and used directly in the next step. Then potassium carbonate (621.9mg, 4.5mmol) and EtOH (20mL) were added to the crude product and heated to reflux for 2h. The crude product was quickly separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The obtained crude product was dissolved in dichloromethane (30mL), and CuI (0.68g, 3.6mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred at room temperature overnight, and the excess CuI was removed by filtration. The corresponding chiral binuclear copper complex C was obtained by separation and purification by column chromatography (dichloromethane / methanol=200 / 1). 17 (343.6 mg, 38% overall yield over 3 steps).

[0156] HRMS (ESI) m / z: calculated C 42 H 30 N4O2Cu2I + [MI] + :875.0000; Actual measurement:875.0001.

[0157] Example 4: Chiral binuclear copper complex C of bisoxazoline based on benzo[c]cinnoline skeleton 20 Preparation

[0158]

[0159] Step (a4): from methyl 2-amino-3-bromobenzoate S 1a Preparation of 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a .

[0160] Place a magnetic stirring bar in a dry three-necked round-bottom flask and add 2-amino-3-bromobenzoic acid methyl ester S under anhydrous and oxygen-free conditions. 1a (23.0g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), Ni(PPh3)2Cl2 (2.0g, 3mmol) and degassed N,N-dimethylformamide (100mL). The reaction mixture was then reacted at room temperature for 24h. After the reaction was completed, it was extracted with dichloromethane (200mL×3), the organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered and concentrated. It was separated and purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1) to obtain a white solid 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a (6.8 g, 45% yield).

[0161] Step (b4): from 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S 2a Preparation of N 3 ,N 3 '-Bis((S)-2-hydroxy-2,2-diphenyl-1-tert-butylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3d .

[0162] In a 50 mL sealed tube equipped with a magnetic stirring bar, under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyldicarboxylic acid methyl ester S was added. 2a(900.4 mg, 3 mmol), (S)-(-)-2-amino-3,3-dimethyl-1,1-diphenyl-1-butanol (4.0 g, 15 mmol) and butyl lithium (96 mg, 1.5 mmol). The reaction system was reacted at 140°C for 9 h, and S was monitored by TLC. 2a After complete conversion, the reaction was quenched with water (10 mL). The organic matter was extracted with dichloromethane (40 mL × 3), and the organic layer was washed with saturated NaCl, dried over anhydrous NaSO4, filtered and concentrated. The white solid N was obtained by separation and purification by column chromatography (dichloromethane / methanol = 200 / 1). 3 ,N 3 '-Bis((S)-2-hydroxy-2,2-diphenyl-1-tert-butylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3d (1.6 g, 69% yield).

[0163] Step (c4): From N 3 ,N 3 '-Bis((S)-2-hydroxy-2,2-diphenyl-1-tert-butylethyl)-2,2'-diamino-3,3'-biphenyldicarboxamide S 3d Preparation of N 4 ,N 7 -Bis((S)-2-hydroxy-2,2-diphenyl-1-tert-butylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4d .

[0164] Under anhydrous and oxygen-free conditions, S 3d (1.6 g, 2.1 mmol) was dissolved in anhydrous toluene (100 mL), tert-butyl hypochlorite (0.5 g, 4.62 mmol) was slowly added, and the reaction mixture was reacted at 80°C for 24 h. After the reaction was completed, a yellow solid was precipitated. After filtering the yellow solid product, the mother liquor was concentrated under reduced pressure. The yellow solid N 4 ,N 7 -Bis((S)-2-hydroxy-2,2-diphenyl-1-tert-butylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4d (971.4 mg, 60% yield).

[0165] Step (d4): From N 4 ,N 7 -Bis((S)-2-hydroxy-2,2-diphenyl-1-tert-butylethyl)-benzo[c]cinnoline-4,7-dicarboxamide S 4d Preparation of a chiral binuclear copper complex C containing two oxazolines and having a benzo[c]cinnoline skeleton 20.

[0166] Under anhydrous and oxygen-free conditions, S 4d (971.4mg, 1.26mmol) was dissolved in 1,2-dichloroethane (30mL). Methanesulfonyl chloride (721.7mg, 6.3mmol) was slowly added dropwise to the reaction system, and the suspension was heated at 80°C for 2h. After cooling to room temperature, it was quenched with a saturated solution of NaHCO3 and extracted with dichloromethane (30mL×3). The organic layer was washed with saturated NaCl, dried with anhydrous NaSO4, filtered, concentrated and dried to obtain a crude product which was directly used in the next step. KOH (353.5mg, 6.3mmol) and EtOH (40mL) were then added to the crude product and heated to reflux for 2h. The crude product was quickly separated by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The obtained crude product was dissolved in dichloromethane (30mL), and CuI (0.72g, 3.78mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred at room temperature overnight, and the excess CuI was removed by filtration. The corresponding chiral binuclear copper complex C was obtained by separation and purification by column chromatography (dichloromethane / methanol=200 / 1). 20 (323.4 mg, 23% overall yield over 3 steps).

[0167] HRMS (ESI) m / z: calculated C 50 H 46 N4O2Cu2I + [MI] + :987.1252; measured:987.1253.

[0168] Example 5: Chiral binuclear copper complex C of bisoxazoline based on benzo[c]cinnoline skeleton 22 Preparation.

[0169] Step (e1): from 2-amino-3-bromobenzonitrile S 5a Preparation of 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a .

[0170] Under anhydrous and oxygen-free conditions, 2-amino-3-bromobenzonitrile S was added 5a(19.7g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), nickel chloride (II) glycol dimethyl ether NiCl2·DME (2.2g, 10mmol) and degassed N,N-dimethylformamide (100mL). The reaction mixture was then reacted at room temperature for 24h. Column chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) was used for separation and purification to obtain a yellow solid 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a (5.6 g, 48% yield).

[0171] Step (f1): from 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a Preparation of benzo[c]cinnoline-4,7-dicarbonitrile S 7a .

[0172] Under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a (5.6 g, 23.9 mmol) was dissolved in anhydrous toluene (300 mL), diacetoxy iodobenzene (16.9 g, 52.6 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 48 h. After the reaction was completed, a yellow solid was precipitated, and the yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. Finally, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1), and the yellow solid benzo[c]cinnoline-4,7-dicarbonitrile S was obtained by merging. 7a (3.8 g, 70% yield).

[0173] Step (g1): From benzo[c]cinnoline-4,7-dicarbonitrile S 7a Preparation of chiral binuclear copper C 22 .

[0174] Add benzo[c]cinnoline-4,7-dicarbonitrile S into the dried sealed tube. 7a (115.1mg, 0.5mmol), (1R, 2S)-1-amino-2-indanol (216.3mg, 1.5mmol), dry ZnCl2 (272.6mg, 2mmol) and anhydrous chlorobenzene (25mL). The reaction system was placed in an argon atmosphere and the mixture was stirred at 140°C for 24h under reflux. After the reaction was completed, the solvent was removed by decompression and the crude product was obtained by column chromatography (dichloromethane / methanol = 50 / 1). The obtained crude product was dissolved in dichloromethane (10mL) and CuI (380mg, 2mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred overnight, the excess CuI was filtered off, and the corresponding chiral binuclear copper C was separated and purified by column chromatography (dichloromethane / methanol = 150 / 1) to obtain the corresponding chiral binuclear copper C22 (88.4 mg, 20% overall yield for 2 steps).

[0175] HRMS (ESI) m / z: calculated C 32 H 22 N4O2Cu2I + [MI] + :746.9374; measured:746.9378.

[0176] Example 6: Chiral binuclear copper complex C of bisoxazoline based on benzo[c]cinnoline skeleton 31 Preparation.

[0177] Step (e2): from 2-amino-5-tert-butyl-3-bromobenzonitrile S 5b Preparation of 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile 6b .

[0178] Place a magnetic stirring bar in a dry three-necked round-bottom flask and add 2-amino-5-tert-butyl-3-bromobenzonitrile S under anhydrous and oxygen-free conditions. 5b (68.8g, 271.8mmol), manganese powder (44.8g, 815.4mmol), 4,4'-dimethyl-2,2'-bipyridine (10.0g, 54.4mmol), nickel bromide (II) ethylene glycol dimethyl ether NiBr2·DME (4.2g, 13.6mmol) and degassed N,N-dimethylacetamide (200mL). The reaction mixture was then reacted at room temperature for 24h. After the reaction was completed, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 40 / 1-10 / 1) to obtain a yellow solid 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b (24.7 g, 53% yield).

[0179] Step (f2): from 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b Preparation of 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile 7b .

[0180] Under anhydrous and oxygen-free conditions, 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b(16.7 g, 48 mmol) was dissolved in anhydrous toluene (800 mL), diacetoxy iodobenzene (32.5 g, 100.9 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 24 h. After the reaction was completed, a yellow solid was precipitated, and the yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. Finally, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1), and the yellow solid 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S was obtained. 7b (13.2 g, 80% yield).

[0181] Step (g2): From 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S 7b Preparation of chiral binuclear copper C 31 .

[0182] Add 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S into the dried sealed tube. 7b (68.5mg, 0.2mmol), (1R, 2S)-1-amino-6-bromo-2-indanol (114.0mg, 0.5mmol), dried ZnBr2 (135.1mg, 0.6mmol) and anhydrous chlorobenzene (10mL). The reaction system was placed in an argon atmosphere and the mixture was stirred at 130°C for 24h under reflux. After the reaction was completed, the solvent was removed by decompression and the crude product was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The obtained crude product was dissolved in dichloromethane (10mL) and CuI (152mg, 0.8mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred overnight, the excess CuI was filtered off, and the corresponding chiral binuclear copper C was separated and purified by column chromatography (dichloromethane / methanol = 100 / 1) to obtain the corresponding chiral binuclear copper C 31 (37.3 mg, 16% overall yield for 2 steps).

[0183] HRMS (ESI) m / z: calculated C 40 H 36 Br2N4O2Cu2I + [MI] + :1014.8836; measured:1014.8843.

[0184] Example 7: Chiral binuclear copper complex C of bisoxazoline based on benzo[c]cinnoline skeleton 33 Preparation.

[0185] Step (e3): from 2-amino-5-tert-butyl-3-bromobenzonitrile S 5b Preparation of 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile 6b .

[0186] Place a magnetic stirring bar in a dry three-necked round-bottom flask and add 2-amino-5-tert-butyl-3-bromobenzonitrile S under anhydrous and oxygen-free conditions. 5b (68.8g, 271.8mmol), manganese powder (44.8g, 815.4mmol), 4,4'-dimethyl-2,2'-bipyridine (10.0g, 54.4mmol), NiBr2 (3.0g, 13.6mmol) and degassed dimethyl sulfoxide (200mL). The reaction mixture was then reacted at room temperature for 24h. After the reaction was completed, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 40 / 1-10 / 1) to obtain a yellow solid 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b (28.4 g, 61% yield).

[0187] Step (f3): from 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b Preparation of 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile 7b .

[0188] Under anhydrous and oxygen-free conditions, 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b (16.7 g, 48 mmol) was dissolved in anhydrous toluene (800 mL), diacetoxy iodobenzene (32.5 g, 100.9 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 24 h. After the reaction was completed, a yellow solid was precipitated, and the yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. Finally, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1), and the yellow solid 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S was obtained. 7b (13.2 g, 80% yield).

[0189] Step (g3): From 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S 7b Preparation of chiral binuclear copper C 33 .

[0190] Add 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S into the dried sealed tube. 7b(171.2mg, 0.5mmol), (1R, 2S)-1-amino-6-cyclohexyl-2-indanol (114.0mg, 2.5mmol), dried aluminum chloride (333.4mg, 2.5mmol) and trimethylbenzene (20mL). The reaction system was placed in an argon atmosphere and the mixture was stirred at 150°C for 16h under reflux. After the reaction was completed, the solvent was removed by decompression and the crude product was obtained by column chromatography (petroleum ether / ethyl acetate = 1 / 1). The obtained crude product was dissolved in dichloromethane (10mL), and CuI (475.0mg, 2.5mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred overnight, the excess CuI was filtered off, and the corresponding chiral binuclear copper C was separated and purified by column chromatography (dichloromethane / methanol = 100 / 1) to obtain the corresponding chiral binuclear copper C 33 (109.3 mg, 19% overall yield for 2 steps).

[0191] HRMS (ESI) m / z: calculated C 52 H 58 N4O2Cu2I + [MI] + :1023.2191; Actual measurement:1023.2196.

[0192] Example 8: Chiral binuclear copper complex C based on bisimidazoline skeleton 37 Preparation.

[0193] Step (e4): from 2-amino-3-bromobenzonitrile S 5a Preparation of 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a .

[0194] Under anhydrous and oxygen-free conditions, 2-amino-3-bromobenzonitrile S was added 5a (19.7g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), nickel chloride (II) glycol dimethyl ether NiCl2·DME (3.3g, 15mmol), degassed dimethyl sulfoxide (50mL) and N,N-dimethylacetamide (50mL). The reaction mixture was then reacted at room temperature for 24h. Column chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) was used for separation and purification to obtain a yellow solid 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a (4.7 g, 40% yield).

[0195] Step (f4): from 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a Preparation of benzo[c]cinnoline-4,7-dicarbonitrile S 7a.

[0196] Under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a (5.6 g, 23.9 mmol) was dissolved in anhydrous toluene (300 mL), diacetoxy iodobenzene (16.9 g, 52.6 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 48 h. After the reaction was completed, a yellow solid was precipitated, and the yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. Finally, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1), and the yellow solid benzo[c]cinnoline-4,7-dicarbonitrile S was obtained by merging. 7a (3.8 g, 70% yield).

[0197] Step (h1): From benzo[c]cinnoline-4,7-dicarbonitrile S 7a Preparation of chiral binuclear copper C 37 .

[0198] In dichloromethane (10 mL), benzo[c]cinnoline-4,7-dicarbonitrile S 7a (115.1 mg, 0.5 mmol) was treated with Meerwin salt (Et3OBF4) (115.1 mg, 1.5 mmol) to generate an imidate intermediate, and the solvent of the reaction system was removed. Then (S)-3-phenylpropane-1,2-diamine (225.3 mg, 1.5 mmol), dry ZnCl2 (272.6 mg, 2 mmol) and anhydrous chlorobenzene (15 mL) were added, the reaction temperature was 130 ° C, and the reaction time was 14 hours. After the reaction was completed, the solvent was removed by decompression, and the crude product was obtained by column chromatography (dichloromethane / methanol = 100 / 1). The obtained crude product was dissolved in dichloromethane (10 mL), and CuI (380 mg, 2 mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred overnight, the excess CuI was filtered to remove, and the corresponding chiral binuclear copper C was separated and purified by column chromatography (dichloromethane / methanol = 150 / 1) to obtain. 37 (88.4 mg, 20% overall yield for 2 steps).

[0199] HRMS (ESI) m / z: calculated C 32 H 28 N6Cu2I + [MI] + :749.0002; Actual measurement:749.0012.

[0200] Example 9: Chiral binuclear copper complex C based on bisimidazoline skeleton 38 Preparation.

[0201] Step (e5): From 2-amino-3-bromobenzonitrile S 5a Preparation of 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a .

[0202] Under anhydrous and oxygen-free conditions, 2-amino-3-bromobenzonitrile S was added 5a (19.7g, 100mmol), manganese powder (16.5g, 300mmol), 4,4'-dimethyl-2,2'-bipyridine (3.7g, 20mmol), NiI2 (3.8g, 12mmol) and degassed N,N-dimethylformamide (100mL). The reaction mixture was then reacted at room temperature for 24h. Column chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) was used for separation and purification to obtain a yellow solid 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a (4.4 g, 38% yield).

[0203] Step (f5): from 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a Preparation of benzo[c]cinnoline-4,7-dicarbonitrile S 7a .

[0204] Under anhydrous and oxygen-free conditions, 2,2'-diamino-3,3'-biphenyl dicarbonitrile S 6a (5.6 g, 23.9 mmol) was dissolved in anhydrous toluene (300 mL), diacetoxy iodobenzene (16.9 g, 52.6 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 48 h. After the reaction was completed, a yellow solid was precipitated, and the yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. Finally, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1), and the yellow solid benzo[c]cinnoline-4,7-dicarbonitrile S was obtained by merging. 7a (3.8 g, 70% yield).

[0205] Step (h2): From benzo[c]cinnoline-4,7-dicarbonitrile S 7a Preparation of chiral binuclear copper C 38 .

[0206] In dichloromethane (10 mL), benzo[c]cinnoline-4,7-dicarbonitrile S 7a(115.1 mg, 0.5 mmol) was treated with Meerwin salt (Et3OBF4) (115.1 mg, 1.5 mmol) to generate an imidate intermediate, and the solvent of the reaction system was removed. Then (S)-3-phenylpropane-1,2-diamine (300.4 mg, 2 mmol), dried aluminum chloride (333.4 mg, 2.5 mmol) and trimethylbenzene (20 mL) were added, the reaction temperature was 120 ° C, and the reaction time was 14 hours. After the reaction was completed, the solvent was removed by decompression, and the crude product was obtained by column chromatography (dichloromethane / methanol = 100 / 1). The obtained crude product was dissolved in N, N-dimethylformamide (5 mL), and K2CO3 (333.4 mg, 2.5 mmol) and iodomethane (333.4 mg, 2.5 mmol) were added. The reaction temperature was 80 ° C, and the reaction time was 6 hours. After the reaction was completed, the solvent was removed by decompression, and the methylated imidazoline ligand was obtained by column chromatography (dichloromethane / methanol = 200 / 1). The obtained methylated imidazoline ligand was dissolved in dichloromethane (10 mL), and CuI (380 mg, 2 mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred overnight, the excess CuI was filtered off, and the corresponding chiral binuclear copper C was separated and purified by column chromatography (dichloromethane / methanol = 150 / 1) to obtain. 38 (63.4 mg, 14% overall yield over 3 steps).

[0207] HRMS (ESI) m / z: calculated C 34 H 32 N6Cu2I + [MI] + :777.0311; Actual measurement:777.0316.

[0208] Example 10: Chiral binuclear copper complex C based on bisimidazoline skeleton 44 Preparation.

[0209] Step (e6): From 2-amino-5-tert-butyl-3-bromobenzonitrile S 5b Preparation of 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile 6b .

[0210] Place a magnetic stirring bar in a dry three-necked round-bottom flask and add 2-amino-5-tert-butyl-3-bromobenzonitrile S under anhydrous and oxygen-free conditions. 5b(68.8g, 271.8mmol), manganese powder (44.8g, 815.4mmol), 4,4'-dimethyl-2,2'-bipyridine (10.0g, 54.4mmol), dpppNiCl2 (5.9g, 10.8mmol) and degassed hexamethylphosphoric acid triamide (100mL). Then the reaction mixture was reacted at room temperature for 24h. After the reaction was completed, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 40 / 1-10 / 1) to obtain a yellow solid 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b (27.2 g, 58% yield).

[0211] Step (f6): from 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b Preparation of 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile 7b .

[0212] Under anhydrous and oxygen-free conditions, 2,2'-diamino-5,5-di-tert-butyl-3,3'-biphenyl dicarbonitrile S 6b (16.7 g, 48 mmol) was dissolved in anhydrous toluene (800 mL), diacetoxy iodobenzene (32.5 g, 100.9 mmol) was slowly added, and the reaction mixture was reacted at 80 ° C for 24 h. After the reaction was completed, a yellow solid was precipitated, and the yellow solid product was filtered and the mother liquor was concentrated under reduced pressure. Finally, it was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1-1 / 1), and the yellow solid 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S was obtained. 7b (13.2 g, 80% yield).

[0213] Step (h3): From 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S 7b Preparation of chiral binuclear copper C 44 .

[0214] In THF (10 mL), 2,9-di-tert-butyl-benzo[c]cinnoline-4,7-dicarbonitrile S 7b(171.2 mg, 0.5 mmol) was treated with Meerwin salt (Et3OBF4) (115.1 mg, 1.5 mmol) to generate an imidate intermediate, and the solvent of the reaction system was removed. Then (1R, 2S)-2,3-dihydro-1H-indene-1,2-diamine (222.3 mg, 1.5 mmol), dry boron trifluoride (135.6 mg, 2 mmol) and anhydrous toluene (10 mL) were added, the reaction temperature was 100 ° C, and the reaction time was 10 hours. After the reaction was completed, the solvent was removed by decompression, and the crude product was obtained by column chromatography (dichloromethane / methanol = 100 / 1). The obtained crude product was dissolved in dichloromethane (10 mL), and CuI (380 mg, 2 mmol) was added, and the reaction system quickly turned red and black. The mixed system was stirred overnight, the excess CuI was removed by filtration, and the corresponding chiral binuclear copper C was obtained by separation and purification by column chromatography (dichloromethane / methanol=150 / 1). 44 (83.88 mg, 17% overall yield for 2 steps).

[0215] HRMS (ESI) m / z: calculated C 40 H 40 N6Cu2I + [MI] + :857.1012; measured:857.1021.

[0216] Example 11: Use of Chiral Dinuclear Copper Complexes in Asymmetric Propargyl Amination

[0217] In this example, some representative chiral binuclear copper catalysts were selected to catalyze the asymmetric propargyl amination reaction. The reaction route is as follows.

[0218]

[0219] 1-9 S 11 and S 12 Reaction preparation S 13 As described below the experimental procedures.

[0220] Under argon atmosphere, C x (0.0020mmol, 2mol%) was placed in a 10mL Schlenk tube. Ag(CH3CN)4BF4 (3.58mg, 10mol%) was dissolved in H2O (0.1mL) and added to the Schlenk tube. Next, propargyl ester S 11 (23.2mg, 0.1mmol), aniline S 12(18.6 mg, 0.20 mmol), morpholine (6.96 μL, 40 mol%) and methanol (1 mL). The reaction system was stirred at room temperature for 24 hours, and the mixture was concentrated under reduced pressure. n-Hexane and EtOAc (n-Hexane / EtOAc = 250 / 1-100 / 1) were used as eluents to obtain S 13 It is a light yellow solid.

[0221] The reaction of 10 is basically the same, except that S 12 (0.3mmol), C 33 (2.5 mol%), react at room temperature for 36 hours.

[0222] The test results are shown in Table 1. The chiral binuclear copper complex of the present invention can be used to catalyze the asymmetric propargyl amination reaction. Most of the chiral binuclear copper complexes can obtain a yield of more than 70%, and the product S 13 The ee value can reach more than 90%.

[0223] Table 1 Catalytic test results

[0224]

[0225]

[0226] b1 H NMR yield. c The ee value of S13 was obtained by HPLC using chiral column IA-3. e Isolated yield.

[0227] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A chiral binuclear complex having a structure shown in formula V, In the formula, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from: hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-7 membered heteroaryl; R 1 , R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-7 membered heteroaryl; or R 1 , R 2 , R 3 , R 4 Together with the carbon to which it is attached, it forms a 3-8 membered ring; or, for in, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted C 6-10 Aryl 4-7 membered heterocyclic ring, substituted or unsubstituted 4-7 membered heteroaryl; X is a coordinated anion selected from chloride, bromide, iodide, carboxylate, tetrafluoroborate, hexafluorophosphate, and trifluoromethanesulfonate; Y is O or NR, wherein R is selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-7 membered heteroaryl; The above substitutions are each independently substituted by one or more substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 6-10 Aryl.

2. The chiral binuclear complex according to claim 1, characterized in that R 1 , R 2 , R 3 , R 4 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

3. The chiral binuclear complex according to claim 1, characterized in that It has the structure shown in formula II: R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 substituted or unsubstituted phenyl, substituted or unsubstituted benzo 5-6 membered heterocyclic ring, substituted or unsubstituted 5-6 membered heteroaryl; the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, phenyl; X, Y, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 The definition as in claim 1.

4. The chiral binuclear complex according to any one of claims 1 to 3, characterized in that R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from: hydrogen, halogen, substituted or unsubstituted benzyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

5. The chiral binuclear complex according to any one of claims 1 to 3, characterized in that X is a complex anion selected from chloride, bromide, iodide, formate, acetate, propionate, butyrate, tetrafluoroborate, hexafluorophosphate, trifluoromethanesulfonate; and / or Y is O or NR, wherein R is selected from H, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl.

6. The chiral binuclear complex according to any one of claims 1 to 3, characterized in that The chiral binuclear complex is selected from the group consisting of:

7. The method for preparing a chiral binuclear copper complex according to claim 1, characterized in that: Y is O, the chiral binuclear copper complex has a structure shown in Formula I, and the method comprises the following steps: Step (a): Reductive coupling of the compound of formula S1 to obtain the compound of formula S2; Step (b): reacting a compound of formula S2 with a chiral amino alcohol to obtain a compound of formula S3; Step (c): oxidizing the compound of formula S3 to obtain the compound of formula S4; Step (d): activating the compound of formula S4 with a hydroxyl activator and then subjecting it to an intramolecular cyclization reaction to obtain a cyclization product, and then reacting it with copper salt dichloromethane to obtain a chiral binuclear copper complex of formula I; Alternatively, Y is O, the chiral binuclear copper complex has a structure shown in Formula II, and the method comprises the following steps: Step (e): Reductive coupling of the compound of formula S5 to obtain the compound of formula S6; Step (f): oxidizing the compound of formula S6 to obtain the compound of formula S7; Step (g): reacting a compound of formula S7 with a compound of formula S8 to obtain a cyclized product, and then reacting the product with copper salt dichloromethane to obtain a chiral binuclear copper complex of formula II; Alternatively, Y is NR, wherein R is H, and the method comprises the following steps: Step (h): Compound S7 is treated with Meerwin salt or HCl to generate an imine ester intermediate, which is reacted with chiral diamine S9 or S 10 The cyclization product is synthesized by reaction, and then reacted with copper salt dichloromethane to obtain a chiral binuclear copper complex shown in formula I or II; In various types, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 The definition of is as in claim 1; Z is F, Cl, Br or I.

8. The preparation method according to claim 7, characterized in that: The preparation method has one or more of the following characteristics: The chiral amino alcohol has at least one chiral central carbon of (S) or (R) configuration, and is selected from: (S)-phenylalaninol, (S)-phenylglycinol, (S)-valeric alcohol, (S)-tert-leucinol, (S)-hexylamino alcohol, (S)-leucinol, (S)-isoleucinol, (S)-aminopropanol, (S)-cyclohexylglycinol, (1R,2S)-2-amino-1,2-diphenylethanol, (S)-2-amino-1,1,3-triphenyl-1-propanol, (S)-2-amino-1,1,2-triphenylethanol or (S)-2-amino-3,3-dimethyl-1,1-diphenyl-1-butanol and enantiomers thereof; The oxidant used in the oxidation is tert-butyl hypochlorite, iodobenzene diacetate, Dess-Martin reagent, potassium permanganate, sodium dichromate, potassium dichromate or potassium perchlorate; The hydroxyl activator is thionyl chloride, methanesulfonyl chloride, phenylsulfonyl chloride or p-toluenesulfonyl chloride; The copper salt is CuCl, CuBr, CuI, Cu(OAc), cuprous tetrafluoroborate, cuprous hexafluorophosphate or cuprous trifluoromethanesulfonate.

9. The preparation method according to claim 7, characterized in that: The preparation method has one or more of the following characteristics: In the step (b), the molar ratio of the chiral amino alcohol to the compound of formula S2 is 2 to 4:1; In the step (c), the molar ratio of the oxidant to the compound of formula S3 is 2 to 6:1; In the step (d), the molar ratio of the hydroxyl activating agent to the compound of formula S4 is 2 to 8:1; In the step (f), the molar ratio of the oxidant to the compound of formula S3 is 2 to 6:1; In the step (g), the molar ratio of the compound of formula S8 to the compound of formula S7 is 2 to 4:1; In the step (h), the formula S9 or S 10 The molar ratio of the compound to the compound of formula S7 is 2 to 4:

1.

10. The use of the chiral binuclear complex according to claim 1, characterized in that: Used as chiral ligand or chiral catalyst in asymmetric synthesis reactions.

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