Binaphthalene structure-assisted chiral pyridine oxazoline ligand as well as preparation method and application thereof

Abstract

The invention discloses a binaphthalene structure-assisted chiral pyridine oxazoline ligand as well as a preparation method and application thereof. The binaphthyl structure-assisted chiral pyridine oxazoline ligand has a structure shown in a general formula (I): # imgabs0 # general formula (I) has an axial chiral binaphthyl structure and a pyridine oxazoline structure, the binaphthyl structure has an important influence on enantioselectivity of a reaction, and the pyridine oxazoline structure is a structural unit which contains or does not contain a carbon chiral center and can be coordinated with metal ions. The binaphthyl structure-assisted chiral pyridine oxazoline ligand and palladium salt are in-situ formed in a reaction system to form a complex, and in catalysis of amination acetyl oxidation reaction of a biphenyl amino olefin compound and kinetic resolution reaction of a racemic biaryl amino olefin compound, the chiral pyridine oxazoline ligand and the palladium salt form a complex in situ. The catalyst has good catalytic activity, excellent enantioselectivity and good substrate universality, has a good kinetic resolution effect, and has a good industrial application prospect. The invention belongs to the field of asymmetric synthetic chemistry.

Description

Technical Field

[0001] The present invention belongs to the field of asymmetric synthesis chemistry, and specifically relates to a class of chiral pyridine oxazoline ligands assisted by a binaphthyl structure, a preparation method and a use thereof. The catalyst formed by such ligands and palladium salts can be used for the amination acetoxylation reaction of unactivated olefins to synthesize diversely substituted biaryl-bridged seven-membered nitrogen heterocyclic compounds and axially chiral amino alcohols with high optical purity, and has high regioselectivity and enantioselectivity. Background Art

[0002] Both nitrogen-containing heterocycles and biaryl units are widely present in natural products and bioactive molecules. Fusing these two substructures into a medium-sized biaryl-bridged ring forms a class of cyclic compounds with remarkable structures, conformations and biological properties. In fact, biaryl-bridged ring compounds are also widely present in natural products, bioactive molecules and organic catalysts, such as vancomycin, RO4929097, LY-411575, Paullones and axially chiral aminosulfonamides, etc. (D.L. Boger, et.al. Chem. Rev. 2017, 117, 11952–11993; G.K. Schwartz, et.al. Anticancer Res. 2013, 33, 1307-1316; E.M. Parker, et.al. J. Biol. Chem. 2004, 279, 12876-12882; C. Kunick, et.al. Curr. Top. Med. Chem. 2011, 11, 1320–1332; K. Maruoka, et.al. J. Am. Chem. Soc. 2011, 133, 18130–18133).

[0003] The asymmetric amination difunctionalization reaction of alkenes catalyzed by transition metals is an effective approach for constructing nitrogen-containing heterocyclic compounds with additional functional groups. For example, in 2008, the Chemler research group reported a complex prepared from a pyridine bisoxazoline ligand and copper trifluoromethanesulfonate for the enantioselective intramolecular 5-exo amination oxidation reaction of unactivated alkenes, obtaining five-membered nitrogen-containing heterocyclic compounds in excellent yields and with an enantiomeric ratio of up to 96:4 (R.S. Chemler, et al. J. Am. Chem. Soc. 2008, 130, 17638–17639). In 2018, the Liu Guosheng research group developed an enantioselective intramolecular 6-endo amination acetoxylation reaction of unactivated alkenes catalyzed by palladium, synthesizing a series of diversely substituted β-acetoxypiperidines with an enantiomeric ratio of up to 99:1. Notably, the introduction of the bulky diphenylmethyl group at the C6 position of the pyridine ring is crucial for enhancing the reactivity of the palladium catalyst and the enantioselective control of the amination acetoxylation products (G. Liu, et al. J. Am. Chem. Soc. 2018, 140, 7415–7419). To date, the asymmetric amination difunctionalization reaction of unactivated alkenes is generally limited to the construction of five- and six-membered nitrogen-containing heterocyclic compounds, and it is difficult to construct seven-membered nitrogen-containing heterocyclic compounds. The main reason may be that the reaction transition state for forming seven-membered ring products is energetically unfavorable and the lack of effective chiral ligands that can simultaneously promote the reaction, control regioselectivity and enantioselectivity. Therefore, designing and developing novel chiral ligands and catalysts for the amination acetoxylation reaction of biaryl amino alkenes to achieve the synthesis of diversely substituted biaryl-bridged seven-membered nitrogen heterocyclic compounds and axially chiral amino alcohols with high optical purity has high practical application value. Summary of the Invention

[0004] An object of the present invention is to provide a novel class of chiral pyridine oxazoline ligands (I) assisted by a binaphthyl structure.

[0005] Another object of the present invention is to provide a synthesis method of the above chiral ligand.

[0006] The object of the present invention also lies in providing the use of the above chiral ligand, that is, forming a catalyst with a palladium salt for the asymmetric synthesis of diversely substituted biaryl-bridged seven-membered nitrogen heterocyclic compounds and axially chiral amino alcohols.

[0007] The present invention provides a chiral pyridine oxazoline ligand assisted by a binaphthyl structure, characterized in that the chiral pyridine oxazoline ligand is shown as the following general formula (Ⅰ):

[0008]

[0009] In the general formula (Ⅰ):

[0010] The absolute configuration of the chiral center in the axially chiral structure or oxazoline structure marked with * is the R configuration or the S configuration;

[0011] n is the number of methylene groups where the oxygen atom in the binaphthalene structure is covalently bonded to the pyridine ring, and n is 0 or 1;

[0012] R 1 Selected from any one of hydroxyl, C 1-6 alkyl, C 1-6 alkyloxy, phenyl, substituted phenyl, alkylacyloxy, carbonate group;

[0013] R 2 –R 3 Each is independently selected from any one of hydrogen, halogen, C 1-6 alkyl, phenyl, substituted phenyl;

[0014] R 4 –R 5 Each is independently selected from any one of hydrogen, C 1-6 alkyl, phenyl, substituted phenyl.

[0015] In a preferred experimental scheme of the present invention, when the R 1 is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; R 1 is C 1-6 alkyloxy, the C 1-6 alkyloxy is methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy or hexyloxy; when the R 1 is substituted phenyl, the substituted phenyl is methyl-substituted phenyl, ethyl-substituted phenyl, isopropyl-substituted phenyl, tert-butyl-substituted phenyl, neopentyl-substituted phenyl, adamantyl-substituted phenyl, trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, tert-butoxy-substituted phenyl, fluoro-substituted phenyl, chloro-substituted phenyl, p-phenyl-substituted phenyl; when the R 1 is alkylacyloxy, the alkylacyloxy is methylacyloxy, ethylacyloxy, n-propylacyloxy, isopropylacyloxy, n-butylacyloxy, isobutylacyloxy, sec-butylacyloxy, tert-butylacyloxy, n-pentylacyloxy, isopentylacyloxy, neopentylacyloxy, hexylacyloxy, benzylacyloxy; when the R 1When the carbonate group is present, the carbonate group is a methyl carbonate group, an ethyl carbonate group, a n-propyl carbonate group, an isopropyl carbonate group, a n-butyl carbonate group, an isobutyl carbonate group, a sec-butyl carbonate group, a tert-butyl carbonate group, a n-pentyl carbonate group, an isopentyl carbonate group, a neopentyl carbonate group, or a benzyl carbonate group;

[0016] In a preferred experimental scheme of the present invention, when the R 2 –R 3 is a C 1-6 alkyl group, the alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, or a hexyl group; when the R 2 –R 3 is a substituted phenyl group, the substituted phenyl group is a phenyl group substituted with a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a neopentyl group, an adamantyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a tert-butoxy group, a fluorine atom, or a chlorine atom;

[0017] In a preferred experimental scheme of the present invention, when the R 4 –R 5 is an alkyl group, the alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, or a hexyl group; when the R 4 –R 5 is a substituted phenyl group, the substituted phenyl group is a phenyl group substituted with a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a neopentyl group, an adamantyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a tert-butoxy group, a fluorine atom, or a chlorine atom.

[0018] The present invention also provides a preparation method of the chiral pyridine oxazoline ligand assisted by the binaphthyl structure, and the characteristics thereof include one or more of the following steps:

[0019] (1) In an organic solvent, under nitrogen or an inert gas, compound 1 and compound 2 are reacted under the action of a condensing agent to prepare intermediate 3; intermediate 3 is reacted under the action of a fluorinating reagent and a base to prepare compound 4;

[0020]

[0021] wherein R 1 is one of a hydroxyl group, a C 1-6 alkyl group, a phenyl group, and a substituted phenyl group;

[0022] The absolute configuration of the axially chiral structure marked with * is the R configuration or the S configuration; the absolute configurations of the two centrally chiral carbon atoms marked with * are the R,R configuration, the S,S configuration, the R,S configuration, or the S,R configuration;

[0023] (2) In an organic solvent, under nitrogen or an inert gas, compound 4a and compound 5 are reacted under the action of a base to prepare compound 6;

[0024]

[0025] X of compound 5 is a chlorine atom or a bromine atom, and R 6 is respectively selected from any one of 1-6 C-alkyl, alkyl acyl, and alkoxy acyl;

[0026] In a preferred experimental scheme of the present invention, when the R 6 is C 1-6 alkyl, the C 1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl; when the R 6 is alkyl acyl, the alkyl acyl is methyl acyl, ethyl acyl, n-propyl acyl, isopropyl acyl, n-butyl acyl, isobutyl acyl, sec-butyl acyl, tert-butyl acyl, n-pentyl acyl, isopentyl acyl, neopentyl acyl, hexyl acyl, benzyl acyl; when the R 6 is alkoxy acyl, the alkoxy acyl is methoxy acyl, ethoxy acyl, n-propoxy acyl, isopropoxy acyl, n-butoxy acyl, isobutoxy acyl, sec-butoxy acyl, tert-butoxy acyl, n-pentyloxy acyl, isopentyloxy acyl, neopentyloxy acyl, hexyloxy acyl, benzyloxy acyl;

[0027] (3) In an organic solvent, under nitrogen or an inert gas, compound 7 and compound 8 are reacted under the catalytic action of a copper salt and a ligand to prepare intermediate 9; intermediate 9 is reacted under basic conditions to prepare intermediate 10; intermediate 10 reacts with compound 2 under the action of an acid to generate compound 11.

[0028]

[0029] In the present invention, the inert gas includes one or more of argon, helium, neon, and krypton;

[0030] In the present invention, the condensing agent is a condensing agent commonly used in the field of organic synthesis, including dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazol-1,1,3,3-tetramethyluronium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyloxy-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(endo-5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate, benzotriazol-1-oxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, and (3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)tris-pyrrolidinium hexafluorophosphate, 4-dimethylaminopyridine, or a combination of several thereof;

[0031] In the present invention, the organic solvent is a solvent commonly used in the field of organic synthesis, and the organic solvent is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, methyl tert-butyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, benzene, toluene, xylene, mesitylene, trifluorotoluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide;

[0032] In the present invention, the fluorinating agent is a solvent commonly used in the field of organic synthesis, and the fluorinating agent is one or more of diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, sulfur tetrafluoride, pyridine-2-sulfonyl fluoride, perfluorobutanesulfonyl fluoride, N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, and 1,3-bis(2,6-diisopropylphenyl)-2,2-difluoroimidazoline;

[0033] In the present invention, the base is a base commonly used in the field of organic synthesis, and the base includes sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, calcium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and pyridine;

[0034] In the present invention, the copper salt is a copper salt conventionally used in the field of organic synthesis, and the copper salts include copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide, copper acetate, copper acetylacetonate, copper perchlorate, copper trifluoroacetate, copper tetrafluoroborate, copper tetraethylacetonitrile hexafluorophosphate, cuprous cyanide, cuprous thiocyanate, cuprous 2 - thiophenecarboxylate, cuprous oxide; preferably cuprous chloride, cuprous bromide or cuprous iodide;

[0035] In the present invention, the ligand is a ligand conventionally used in the field of organic synthesis, and the ligands include one or more of phenylformic acid, naphthylformic acid, pyridylformic acid, quinolinylformic acid, furylformic acid or thiophenylformic acid;

[0036] In the present invention, the acid is an acid conventionally used in the field of organic synthesis, and the acids include one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, phenylformic acid, naphthylformic acid, pyridylformic acid, quinolinylformic acid, furylformic acid, thiophenylformic acid, p - toluenesulfonic acid, methanesulfonic acid or chlorosulfonic acid;

[0037] In the present invention, the molar concentrations of the reaction compounds 1, 4a and 7 in the organic solvent are 0.01 - 2 mol / L, for example, 0.5 mol / L;

[0038] In the present invention, after the synthesis reaction is completed, it further includes solvent stripping under reduced pressure;

[0039] In the present invention, after the synthesis reaction is completed, it further includes a quenching process, and the solution used for quenching can be a conventional quenching solution for this type of reaction in the field of organic synthesis, such as saturated ammonium chloride solution or sodium hydroxide solution;

[0040] In the present invention, after the synthesis reaction is completed, it further includes a post - treatment step, and the post - treatment step can be a conventional post - treatment step in this field, and the post - treatment step includes one or more of extraction, washing, drying, and column chromatography steps;

[0041] In the present invention, the extractant can be a conventional extractant in the field of organic synthesis, including ethyl acetate, dichloromethane, chloroform, and ether. The solution used for washing can be a conventional washing solution in this field, such as saturated sodium chloride solution; the drying can use conventional desiccants in this field, such as anhydrous sodium sulfate and anhydrous magnesium sulfate; the column chromatography can be a conventional silica gel column chromatography in the field of organic synthesis, and the eluent used for column chromatography can be a conventional eluent in the field of organic synthesis, such as a mixture of one or more of petroleum ether, dichloromethane, ethyl acetate or methanol.

[0042] The present invention also provides a method for synthesizing a biaryl-bridged heptacyclic nitrogen heterocyclic compound, which comprises the following steps: Under a reaction gas, the biaryl structure-assisted chiral pyridine oxazoline ligand (I) and a palladium salt are complexed in an organic solvent, and then an oxidant is added. Compounds 12 and 13 are subjected to the following reaction at the required reaction temperature for the required reaction time to obtain compound 14;

[0043]

[0044] The present invention also provides a kinetic resolution reaction of a racemic biaryl amino olefin, which comprises the following steps: Under a reaction gas, the biaryl structure-assisted chiral pyridine oxazoline ligand (I) and a palladium salt are complexed in an organic solvent, and then an oxidant is added. Compounds 15 and compound 13 are subjected to the following reaction at the required reaction temperature for the required reaction time to obtain compound 16; The remaining compound 15 reacts under the action of a reducing agent, a base and an oxidant to generate compound 17;

[0045]

[0046] Wherein, R 7 is selected from phenylsulfonyl or substituted phenylsulfonyl;

[0047] R 8 –R 13 is selected from hydrogen, alkyl, phenyl, ester group, cyano or halogen;

[0048] R 14 –R 15 is selected from hydrogen, alkyl, phenyl or halogen;

[0049] The absolute configurations of the chiral axis and chiral center marked with * are S configuration or R configuration.

[0050] In the present invention, when the R 7 is a substituted phenylsulfonyl, the substituted phenylsulfonyl is p-methylphenylsulfonyl, p-ethylphenylsulfonyl, 4-n-propylphenylsulfonyl, 4-isopropylphenylsulfonyl, 4-n-butylphenylsulfonyl, p-tert-butylphenylsulfonyl, 4-isopentylphenylsulfonyl, p-methoxyphenylsulfonyl, 2,4,6-trimethylphenylsulfonyl, 2,4,6-tri-tert-butylphenylsulfonyl or p-nitrophenylsulfonyl;

[0051] In the present invention, when the R 8 –R 13 is an alkyl, the alkyl is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl;

[0052] In the present invention, when the R 14 –R 15When the alkyl group is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl;

[0053] In the present invention, the palladium salt is palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, palladium trifluoroacetate, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium chloride, bis(triphenylphosphine)palladium chloride, allylpalladium chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, [1,3-bis(diphenylphosphino)propane]dichloropalladium, 1,1'-bis(diphenylphosphino)ferrocene dichloride (II) dichloromethane complex, 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium or bis(dibenzylideneacetone)palladium; preferably palladium acetate, palladium acetylacetonate or palladium bromide;

[0054] The oxidant is oxygen, diacetoxyiodobenzene, hydrogen peroxide, tert-butyl hydroperoxide, cumene hydroperoxide, manganese dioxide, potassium permanganate, 1,4-benzoquinone, m-chloroperbenzoic acid or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone;

[0055] In the present invention, the organic solvent is a solvent commonly used in the field of organic synthesis, including methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, mesitylene, trifluorotoluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide; preferably toluene, 1,2-dichloroethane;

[0056] In the present invention, the reducing agent is a solvent commonly used in the field of organic synthesis, including sodium borohydride, sodium acetoxyborohydride, sodium cyanoborohydride, N,N-dimethylaminoborohydride lithium, lithium aluminum hydride, trimethylsilane, trichlorosilane, borane tetrahydrofuran solution and diisopinocampheylborane;

[0057] In the present invention, the base is a base commonly used in the field of organic synthesis, and the base includes sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, calcium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and pyridine;

[0058] In the present invention, the gas is oxygen, nitrogen or air;

[0059] In the present invention, the molar concentrations of compounds 12 and 13 in the reaction formula in the organic solvent are 0.01 - 5.0 M; for example, 0.1 M;

[0060] In the present invention, the molar concentrations of compounds 15 and 13 in the reaction formula in the organic solvent are 0.01 - 5.0 M; for example, 0.1 M;

[0061] In the present invention, in the amination acetoxylation reaction and kinetic resolution reaction of the above-mentioned biaryl amino olefin compounds, the molar ratio of the palladium salt to the binaphthyl structure-assisted chiral pyridine oxazoline ligand is 1:5 - 5:1; for example, 1:2;

[0062] In the present invention, the reaction temperature is -50 - 50 °C; for example, 0 °C;

[0063] In the present invention, the reaction time is 1 - 180 hours; for example, 48 hours;

[0064] In the embodiments of the present invention, after the reaction is completed, a post-treatment step is further included. The post-treatment step can be a conventional post-treatment step in the field of organic synthesis, and the post-treatment step includes a column chromatography step.

[0065] The term "er" refers to the enantiomeric ratio

[0066] The positive and progressive effects of the present invention are as follows:

[0067] The present invention provides a novel binaphthyl structure-assisted chiral pyridine oxazoline ligand. The main structural feature is that it has a binaphthyl structure unit and a pyridyl oxazoline coordination unit. The first synthesis method of this ligand is as follows: Under the action of a condensing agent, axially chiral pyridinecarboxylic acid and amino alcohol undergo a condensation reaction to construct an amide bond; subsequently, under the action of a fluorinating reagent and a base, an oxazoline ring is constructed through a nucleophilic substitution reaction. The second synthesis method of this ligand is as follows: Using the ligand containing a phenolic hydroxyl group in the binaphthyl structure obtained by the first synthesis method as a raw material, a ligand with diversified modification of the phenolic hydroxyl group is synthesized by reacting with a halogenating reagent under alkaline conditions. The third synthesis method of this ligand is as follows: 1) Using 1,1'-bi-2-naphthol (BINOL) or substituted BINOL and 6-bromo-2-cyanopyridine as starting materials, a carbon-oxygen bond is constructed through a coupling reaction under the catalytic action of a copper salt and a ligand; 2) Under alkaline conditions, after the axially chiral pyridine cyanide undergoes base hydrolysis of the cyano group, an oxazoline ring is constructed by reacting with an amino alcohol under the catalytic action of an acid. The target molecule of the present invention has a simple and clear structure, simple experimental operation, and can be prepared on a large scale. It has potential application value in the design of novel axially chiral ligands and the synthesis of biaryl-bridged heptacyclic nitrogen heterocyclic compounds and axially chiral amino alcohol compounds with chiral axes and chiral centers.

[0068] The complex formed in situ by the novel binaphthalene structure-assisted chiral pyridine oxazoline ligand provided by the present invention and palladium salt exhibits good catalytic activity, excellent enantioselectivity, good substrate generality, good kinetic resolution effect, and good industrial application prospects in the amination acetoxylation reaction of biaryl amino olefin compounds and the kinetic resolution reaction of racemic biaryl amino olefin compounds. Description of the Drawings

[0069] Figure 1 1H NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 4a-5 provided in the embodiment of the present invention;

[0070] Figure 2 13C NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 4a-5 provided in the embodiment of the present invention;

[0071] Figure 3 1H NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 6a provided in the embodiment of the present invention;

[0072] Figure 4 13C NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 6a provided in the embodiment of the present invention;

[0073] Figure 5 1H NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 11b provided in the embodiment of the present invention;

[0074] Figure 6 13C NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 11b provided in the embodiment of the present invention;

[0075] Figure 7 1H NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 11e provided in the embodiment of the present invention;

[0076] Figure 8 13C NMR spectrum of the binaphthalene framework-assisted pyridine oxazoline ligand 11e provided in the embodiment of the present invention;

[0077] Figure 9 1H NMR spectrum of the biaryl bridge 7-membered nitrogen heterocyclic compound 14a provided in the embodiment of the present invention;

[0078] Figure 10 13C NMR spectrum of the biaryl bridge 7-membered nitrogen heterocyclic compound 14a provided in the embodiment of the present invention;

[0079] Figure 11 1H NMR spectrum of the biaryl bridge 7-membered nitrogen heterocyclic compound 16a containing axial chirality and central chirality provided in the embodiment of the present invention;

[0080] Figure 1213C NMR spectrum of the biaryl-bridged 7-membered azacycle compound 16a containing axial chirality and central chirality provided by the embodiment of the present invention;

[0081] Figure 13 1H NMR spectrum of the axially chiral amino alcohol compound 17a provided by the embodiment of the present invention;

[0082] Figure 14 13C NMR spectrum of the axially chiral amino alcohol compound 17a provided by the embodiment of the present invention. Detailed implementation manners

[0083] The present invention will be further described in detail below through specific embodiments, but the scope of the present invention is not limited thereby.

[0084] The information of the instruments and experimental materials used in the following embodiments is as follows:

[0085] All chemical reagents were purchased as commercial reagents, and the reagents were sourced from reagent companies such as Adamas, Bide Pharmatech, and J&K Scientific. Thin-layer chromatography (TLC) was performed using SHF254 silica gel plates, and the silica gel column chromatography used Norit silica gel (300 - 400 mesh). TLC was carried out using UV light (254 nm). 1 1H NMR and 13 13C NMR were characterized using a Bruker AVANCEⅢ 400 MHz nuclear magnetic resonance instrument, and the solvent was deuterated chloroform. The unit of chemical shift is ppm, and the unit of coupling constant is Hz. 1 In 1H NMR, δ represents the chemical shift, s represents a singlet, d represents a doublet, t represents a triplet, q represents a quartet, m represents a multiplet, and hept represents a heptet. In 13 13C NMR, δ represents the chemical shift. High-resolution mass spectrometry was performed using a JEOC AccuTOF LC-plus 4G device, and the ion source was ESI. The enantiomeric ratio (er) was determined by Shimadzu LC-20A high-performance liquid chromatography and Daicel Chiralpak and Chiralcel chiral columns.

[0086] Example 1:

[0087]

[0088] Select a dry 50 mL round-bottom flask. After adding a magnetic stir bar of appropriate size, add 1a (2.105 g, 5 mmol), DCC (2.060 g, 10.0 mmol), and HOBT (1.350 g, 10.0 mmol) in sequence. Then add 20 mL of dry THF solvent to dissolve. Next, add 2a (1.370 g, 10.0 mmol) in batches to the reaction flask. Stir at room temperature for 12 hours. Monitor the reaction by TLC to check if it is complete. After the raw materials are completely converted, add water to quench the reaction. Then extract the reaction solution with dichloromethane (3 × 40 mL) solvent. Wash the combined organic layers with water multiple times, and finally wash with brine. Dry over anhydrous sodium sulfate, filter, remove some solvents under reduced pressure, and then separate by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain white solid 3a (2.052 g, yield 76%). Select a dry 50 mL Schlenk tube. After adding a magnetic stir bar of appropriate size and compound 3a (1.620 g, 3.0 mmol), add 20 mL of dry DCM solvent to dissolve. Subsequently, transfer it to a -78 °C low-temperature bath. Dropwise add DAST (792 μL, 6.0 mmol) to the reaction system. Continue to stir for 1 hour. Then quickly add K 2 CO 3 (1.382 g, 10 mmol) to the reaction system. After stirring for 10 minutes, transfer the reaction flask to room temperature and continue to stir for 12 hours. Monitor the reaction by TLC to check if it is complete. After the raw materials are completely converted, add water to quench the reaction. Then extract the reaction solution with dichloromethane (3 × 30 mL) solvent. Wash the combined organic layers with water multiple times. Dry over anhydrous sodium sulfate, filter, remove some solvents under reduced pressure, and then separate by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain white solid 4a-1 (1.456 g, yield 93%). 1 HNMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.41–7.26 (m, 10H), 7.22 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.45–5.33 (m, 3H), 5.31 (d, J = 14.4 Hz, 1H), 4.84 (dd, J = 10.0, 8.4 Hz, 1H), 4.36 (t, J = 8.4 Hz, 1H). 13 C NMR (101 MHz, CDCl 3)δ163.8,157.8,154.6,151.6,145.7,141.8,137.5,134.1,134.0,131.3,130.0,129.8,129.3,128.9,128.4,128.3,127.9,127.6,127.0,126.6,125.1,125.0,124.6,123.4,123.1(2C),117.8,116.6,115.2,115.1,75.5,71.4,70.4.HRMS(ESI-TOF)m / z Calcd.for C 35 H 27 N 2 O 3 + [M+H] + :523.2016;Found:523.2013.

[0089] Example 2:

[0090]

[0091] The preparation method was the same as that of Example 1, white solid, 472 mg, total yield 79%; 1 H NMR(400MHz,CDCl 3 )δ8.00(dd,J=8.8,2.0Hz,1H),7.97(d,J=7.6Hz,1H),7.94(d,J=9.2Hz,1H),7.89(d,J=8.0Hz,2H),7.52(t,J=7.6Hz,1H),7.45(d,J=9.2Hz,1H),7.42–7.27(m,15H),7.23(ddd,J=8.4,6.8,1.6Hz,1H),7.11(d,J=8.4Hz,1H),6.92(d,J=7.6Hz,1H),5.50(d,J=8.0Hz,1H),5.42–5.31(m,3H),5.27(d,J=8.0Hz,1H). 13 C NMR(101MHz,CDCl 3)δ163.1,158.0,154.6,151.6,145.7,141.5,140.1,137.5,134.1,134.0,131.2,130.0,129.8,129.2,129.0(2C),128.7,128.4,128.2,128.0,127.5,127.0,126.6,126.0,125.1,125.0,124.6,123.4,123.2(2C),117.8,116.6,115.2,115.1,89.8,79.2,71.3.HRMS(ESI-TOF)m / z Calcd.forC 41 H 31 N 2 O 3 + [M+H] + :599.2329;Found:599.2336.

[0092] Example 3:

[0093]

[0094] The preparation method was the same as that of Example 1, white solid, 417 mg, total yield 83%; 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J = 9.2Hz,1H),7.93(d,J = 8.8Hz,1H),7.88(d,J = 8.0Hz,2H),7.87(d,J = 8.0Hz,1H),7.46(t,J = 8.0Hz,1H),7.40(d,J = 9.2Hz,1H),7.40–7.35(m,2H),7.34–7.27(m,3H),7.21(ddd,J = 8.4,6.8,1.2Hz,1H),7.09(d,J = 8.4Hz,1H),6.85(d,J = 8.0Hz,1H),5.43(br,1H),5.34(d,J = 14.4Hz,1H),5.28(d,J = 14.0Hz,1H),4.40(dd,J = 10.4,8.8Hz,1H),4.28(t,J = 8.4Hz,1H),4.07(dd,J = 10.4,8.4Hz,1H),0.93(s,9H). 13 C NMR(101MHz,CDCl 3)δ162.4,157.5,154.6,152.2,146.0,137.3,134.1,134.0,131.1,129.9,129.8,129.2,128.3,128.2,127.5,126.6,125.2,125.0,124.6,123.4,122.9,122.7,117.9,116.7,115.2,115.1,75.4,71.3,69.5,34.1,26.0.HRMS(ESI-TOF)m / z Calcd.for C 33 H 31 N 2 O 3 + [M+H] + :503.2329;Found:503.2337.

[0095] Example 4:

[0096]

[0097] The preparation method was the same as that of Example 1, white solid, 429 mg, total yield 80%; 1 H NMR(400MHz,CDCl 3 )δ7.99(d,J = 8.8Hz,1H),7.94(d,J = 8.8Hz,1H),7.88(dd,J = 8.0,1.7Hz,2H),7.80(d,J = 7.6Hz,1H),7.48–7.18(m,13H),7.10(d,J = 8.4Hz,1H),6.85(d,J = 7.6Hz,1H),5.34(d,J = 14.0Hz,1H),5.29(d,J = 14.0Hz,1H),4.67–4.56(m,1H),4.39(t,J = 8.8Hz,1H),4.20(t,J = 7.6Hz,1H),3.28(dd,J = 14.0,5.2Hz,1H),2.71(dd,J = 13.6,9.2Hz,1H). 13 C NMR(101MHz,CDCl 3)δ163.1,157.8,154.5,151.6,145.8,137.8,137.5,134.1,133.9,131.2,130.0,129.8,129.3,129.2,128.7,128.3,128.2,127.5,126.7,126.6,125.1,125.0,124.6,123.4,122.9,122.8,117.8,116.7,115.2,115.1,72.7,71.3,68.1,41.7.HRMS(ESI-TOF)m / z Calcd.for C 36 H 29 N 2 O 3 + [M+H] + :537.2173;Found:537.2169.

[0098] Example 5:

[0099]

[0100] The preparation method was the same as that of Example 1, white solid, 534 mg, total yield 68%; 1 H NMR(400MHz,CDCl 3 )δ8.04(s,1H),7.94(d,J = 8.0Hz,1H),7.84(s,1H),7.79(d,J = 8.0Hz,1H),7.74(d,J = 8.0Hz,1H),7.67(d,J = 8.0Hz,2H),7.55–7.39(m,7H),7.37–7.15(m,11H),6.56(d,J = 8.0Hz,1H),5.48(s,1H),5.31(t,J = 9.2Hz,1H),4.74(d,J = 14.8Hz,1H),4.75–4.69(m,1H),4.66(d,J = 14.4Hz,1H),4.23(t,J = 8.4Hz,1H),1.35(s,18H). 13 C NMR(101MHz,CDCl 3)δ163.8,158.4,154.6,150.7,150.6,149.1,144.8,141.9,136.6,135.7,135.4,134.7,133.6,133.2,131.7,131.5,130.3,129.9,129.3,129.1,128.9,128.3,128.1,127.8,126.9,126.8,125.8,125.7(2C),125.6,124.9,123.9,123.7,122.5,122.4,116.5,75.5,75.3,70.3,34.7(2C),31.5(2C).HRMS(ESI-TOF)m / z Calcd.for C 55 H 50 N 2 O 3 + [M+H] + :787.3894;Found:787.3887.

[0101] Example 6:

[0102]

[0103] The preparation method was the same as that of Example 1, white solid, 395 mg, total yield 76%; 1 H NMR(400MHz,CDCl 3 )δ7.97(d,J = 9.2Hz,1H),7.93(d,J = 5.2Hz,1H),7.92–7.87(m,3H),7.54(d,J = 8.4Hz,1H),7.45(d,J = 7.6Hz,1H),7.43(d,J = 6.0Hz,1H),7.41–7.15(m,10H),7.13(d,J = 8.4Hz,1H),6.69(d,J = 8.0Hz,1H),5.43(dd,J = 10.4,8.4Hz,1H),5.32(d,J = 7.2Hz,1H),5.28(s,J = 14.4Hz,1H),4.88(dd,J = 10.4,8.8Hz,1H),4.38(t,J = 8.8Hz,1H),2.14(s,3H). 13 C NMR(101MHz,CDCl 3)δ163.8,158.3,153.2,145.7,141.9,137.4,135.2,133.8,133.4,132.4,132.3,129.8,129.6,128.9,128.8,128.2,128.0,127.9,127.7,127.0,126.9,126.1,126.0,125.3,124.9,124.2,123.0(2C),122.8,115.1,75.6,71.5,70.4,20.5.HRMS(ESI-TOF)m / z Calcd.for C 36 H 29 N 2 O 2 + [M+H] + :521.2224;Found:521.2222.

[0104] Example 7:

[0105]

[0106] The preparation method was the same as that of Example 1, white solid, 435 mg, total yield 73%; 1 H NMR(400MHz,CDCl 3 )δ8.05(d,J = 8.4Hz,1H),7.98(d,J = 8.4Hz,1H),7.95(d,J = 8.0Hz,1H),7.81(d,J = 9.2Hz,1H),7.80(d,J = 8.0Hz,1H),7.70(d,J = 8.4Hz,1H),7.50–7.41(m,2H),7.39–7.22(m,10H),7.13(d,J = 9.2Hz,1H),6.93(s,1H),6.88–6.80(m,3H),6.56(d,J = 8.0Hz,1H),5.43(dd,J = 10.0,8.4Hz,1H),5.19(d,J = 14.8Hz,1H),5.06(d,J = 14.8Hz,1H),4.88(dd,J = 10.0,8.4Hz,1H),4.39(t,J = 8.4Hz,1H),2.02(s,3H). 13 C NMR(101MHz,CDCl 3)δ163.8,158.5,153.2,145.7,142.0,141.9,140.2,137.4,137.0,134.9,133.3,132.9,131.8,130.0,129.7,129.0,128.9,128.4,128.1(2C),127.9,127.4,127.2,127.0,126.9,126.8,126.4,126.0,125.9,125.8,123.8,122.9,122.8,122.5,114.2,75.6,71.0,70.5,21.3.HRMS(ESI-TOF)m / z Calcd.for C 42 H 33 N 2 O 2 + [M+H] + :597.2537;Found:597.2531.

[0107] Example 8:

[0108]

[0109] A dry 25 mL sealed tube was selected. After adding a magnetic stir bar of appropriate size and compound 4a-1 (52.2 mg, 0.10 mmol), 5 mL of dry DMF solvent was added for dissolution. The reaction flask was transferred to an ice-water bath and stirred for 10 minutes. Then, NaH (6.0 mg, 0.15 mmol) was added to the reaction system in portions. After stirring for 1 hour, CH 3 I (31 μL, 0.5 mmol) was quickly added to the reaction flask, and the stopper was quickly tightened. Subsequently, the reaction flask was transferred to room temperature and stirred for 24 hours. TLC was used to monitor whether the reaction was complete. After the raw materials were completely converted, a small amount of water was added to quench the excess NaH in the reaction. Then, the reaction solution was extracted with dichloromethane (3 × 10 mL) solvent. The combined organic layers were washed with water multiple times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove part of the solvent, and then separated by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain white solid 6a (50 mg, yield 93%). 1 HNMR(400MHz,CDCl 3)δ8.02(d,J=9.2Hz,1H),7.95(d,J=9.2Hz,1H),7.94(d,J=8.0Hz,1H),7.90(d,J=8.8Hz,1H),7.88(d,J=9.2Hz,1H),7.49(d,J=6.4Hz,1H),7.46(d,J=4.8Hz,1H),7.43(d,J=8.8Hz,1H),7.39–7.24(m,8H),7.23(d,J=4.8Hz,1H),7.22–7.19(m,1H),7.17(d,J=8.4Hz,1H),6.85(d,J=8.0Hz,1H),5.43(dd,J=10.0,8.8Hz,1H),5.37(d,J=14.8Hz,1H),5.32(d,J=14.4Hz,1H),4.88(dd,J=10.0,8.8Hz,1H),4.39(t,J=8.4Hz,1H),3.77(s,3H). 13 C NMR(101MHz,CDCl 3 )δ163.8,158.6,155.1,153.6,145.7,141.9,137.2,134.2(2C),129.7,129.6(2C),129.3,128.9,128.1(2C),127.9,127.0,126.6(2C),125.5,125.4,124.0,123.7,122.9(2C),120.4,119.4,115.2,114.0,75.6,71.6,70.4,56.8.HRMS(ESI-TOF)m / zCalcd.for C 36 H 29 N 2 O 3 + [M+H] + :537.2173;Found:537.2166.

[0110] Example 9:

[0111]

[0112] A dry 25 mL Schlenk tube was selected. After adding a magnetic stir bar of appropriate size, compound 4a-1 (52.2 mg, 0.10 mmol), NaH (6.0 mg, 0.15 mmol), and DMAP (1.2 mg, 10 mol%) were added in sequence. Then, 5 mL of dry dichloromethane solvent was added to dissolve. 5a (11 μL, 0.15 mmol) was added to the reaction system, and the mixture was stirred for 12 hours. TLC was used to monitor whether the reaction was complete. After the raw materials were completely converted, a small amount of water was added to quench the excess NaH in the reaction. Then, the reaction solution was extracted with dichloromethane (3 × 10 mL) solvent. The combined organic layers were washed with water multiple times, dried over anhydrous sodium sulfate, filtered, and partially concentrated under reduced pressure. Then, column chromatography separation (petroleum ether / ethyl acetate = 2:1) was carried out to obtain white solid 6b (40 mg, yield 71%). 1 HNMR(400MHz,CDCl 3 )δ8.02(d,J=8.8Hz,1H),7.96(d,J=2.4Hz,1H),7.93(d,J=8.4Hz,2H),7.85(d,J=8.0Hz,1H),7.49–7.39(m,4H),7.38–7.20(m,10H),6.87(d,J=8.0Hz,1H),5.42(dd,J=10.0,9.2Hz,1H),5.34(d,J=14.4Hz,1H),5.30(d,J=14.8Hz,1H),4.86(dd,J=10.0,8.8Hz,1H),4.37(t,J=8.4Hz,1H),1.75(s,3H). 13 C NMR(101MHz,CDCl 3 )δ169.2,163.7,158.2,153.5,147.0,145.6,141.8,137.3,133.8,133.7,131.8,130.3,129.3,129.2,128.9,128.2,127.9,127.8,126.9,126.8,126.7,126.2,125.7,125.5,125.2,124.1,123.0,122.9,122.0,118.6,114.7,75.5,71.6,70.4,20.6.HRMS(ESI-TOF)m / zCalcd.for C 37 H 29 N 2 O 4 + [M+H] + :565.2122;Found:565.2120.

[0113] Example 10:

[0114]

[0115] The preparation method was the same as that of Example 9, white solid, 49.9 mg, yield 86%; 1 H NMR(400MHz,CDCl 3 )δ8.04(d,J = 8.8Hz,1H),7.99–7.92(m,3H),7.86(d,J = 8.0Hz,1H),7.55(d,J = 8.8Hz,1H),7.49(t,J = 7.6Hz,1H),7.49–7.44(m,1H),7.41–7.33(m,4H),7.33–7.29(m,3H),7.29–7.24(m,3H),7.20(d,J = 8.4Hz,1H),6.98(d,J = 8.0Hz,1H),5.43(t,J = 9.2Hz,1H),5.36(d,J = 14.8Hz,1H),5.31(d,J = 14.4Hz,1H),4.88(t,J = 8.8Hz,1H),4.38(t,J = 8.4Hz,1H),3.53(s,3H). 13 C NMR(101MHz,CDCl 3 )δ163.8,158.2,153.9,153.6,147.2,145.7,141.9,137.4,133.8,133.7,131.9,130.5,129.5,129.3,128.9,128.2,128.1,127.9,127.0,126.9,126.4,125.9,125.5,125.1,124.1,123.1,123.0,121.4,117.8,114.6,75.6,71.4,70.4,55.3.HRMS(ESI-TOF)m / z Calcd.for C 37 H 29 N 2 O 5 + [M+H] + :581.2071; Found:581.2072.

[0116] Example 11:

[0117]

[0118] The preparation method was the same as that of Example 9, white solid, 55.5 mg, yield 91%; 1 H NMR(400MHz,CDCl 3)δ8.02(d,J=8.8Hz,1H),7.94(d,J=6.8Hz,1H),7.92(d,J=7.6Hz,2H),7.82(d,J=8.0Hz,1H),7.53(d,J=9.2Hz,1H),7.47(t,J=8.0Hz,1H),7.45–7.41(m,1H),7.38(d,J=8.8Hz,1H),7.35–7.17(m,10H),6.98(d,J=8.0Hz,1H),5.41(t,J=9.6Hz,1H),5.36(d,J=14.8Hz,1H),5.31(d,J=14.8Hz,1H),4.85(t,J=9.2Hz,1H),4.36(t,J=8.4Hz,1H),3.83(t,J=6.4Hz,2H),1.38–1.27(m,2H),0.61(t,J=7.2Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ163.8,158.2,153.5,153.4,147.1,145.6,141.8,137.3,133.8,133.7,131.9,130.4,129.4,129.3,128.8,128.2,127.9,127.8,126.9,126.8(2C),126.3,125.8,125.5,125.2,124.0,123.1,122.9,121.5,117.8,114.5,75.5,71.3,70.4,70.0,21.7,9.9.HRMS(ESI-TOF)m / z Calcd.for C 39 H 33 N 2 O 5 + [M+H] + :609.2384;Found:609.2378.

[0119] Example 12:

[0120]

[0121] Prepared in the same manner as in Example 9, white solid, 50.6 mg, yield 83%; 1 H NMR(400MHz,CDCl 3)δ8.03(d,J=8.8Hz,1H),7.95(d,J=8.8Hz,1H),7.93(d,J=8.4Hz,2H),7.83(d,J=8.0Hz,1H),7.53(d,J=8.8Hz,1H),7.47(t,J=7.6Hz,1H),7.46–7.42(m,1H),7.40–7.19(m,11H),6.98(d,J=8.0Hz,1H),5.42(t,J=9.2Hz,1H),5.36(d,J=14.8Hz,1H),5.31(d,J=14.8Hz,1H),4.87(t,J=9.2Hz,1H),4.57(hept,J=6.0Hz,1H),4.37(t,J=8.4Hz,1H),1.04(d,J=6.4Hz,3H),0.81(d,J=6.0Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ163.8,158.3,153.5,152.8,147.2,145.6,141.9,137.3,133.8,133.7,131.9,130.4,129.4,129.3,128.9,128.2,127.9,127.8,126.9,126.8(2C),126.3,125.8,125.6,125.4,124.0,123.1,122.9,121.6,117.9,114.5,75.5,72.7,71.3,70.4,21.5,21.2.HRMS(ESI-TOF)m / zCalcd.for C 39 H 33 N 2 O 5 + [M+H] + :609.2384;Found:609.2381.

[0122] Example 13:

[0123]

[0124] Prepared in the same manner as in Example 9, white solid, 57.2 mg, yield 92%; 1 H NMR(400MHz,CDCl 3)δ8.05(d, J = 8.8 Hz, 1H), 7.97(d, J = 8.4 Hz, 1H), 7.94(d, J = 8.8 Hz, 2H), 7.85(d, J = 8.0 Hz, 1H), 7.55(d, J = 8.8 Hz, 1H), 7.50(d, J = 8.0 Hz, 1H), 7.49–7.44(m, 1H), 7.40–7.25(m, 10H), 7.25–7.19(m, 1H), 6.99(dd, J = 8.0, 0.4 Hz, 1H), 5.44(dd, J = 10.0, 8.4 Hz, 1H), 5.37(d, J = 14.8 Hz, 1H), 5.33(d, J = 14.4 Hz, 1H), 4.89(dd, J = 10.4, 8.8 Hz, 1H), 4.39(t, J = 8.4 Hz, 1H), 3.68(dd, J = 10.4, 6.8 Hz, 1H), 3.64(dd, J = 9.2, 5.6 Hz, 1H), 1.66–1.54(m, 1H), 0.63(d, J = 1.6 Hz, 3H), 0.61(d, J = 1.6 Hz, 3H). 13 C NMR(101MHz, CDCl 3 )δ163.8, 158.2, 153.5(2C), 147.2, 145.6, 141.9, 137.4, 133.8, 133.7, 131.9, 130.4, 129.5, 129.3, 128.9, 128.2, 127.9(2C), 126.9, 126.8(2C), 126.4, 125.8, 125.5, 125.3, 124.1, 123.1, 122.9, 121.6, 117.8, 114.4, 75.5, 74.5, 71.3, 70.4, 27.6, 18.6(2C). HRMS(ESI-TOF) m / z Calcd. for C 40 H 35 N 2 O 5 + [M + H] + : 623.2541; Found: 623.2541.

[0125] Example 14:

[0126]

[0127] Take a dry 100 mL sealed tube, add a magnetic stir bar of appropriate size, and then sequentially add compound 7a (1.430 g, 5.0 mmol), 8 (1.092 g, 6.0 mmol), CuBr (71.5 mg, 0.5 mmol), 2-pyridinecarboxylic acid (123 mg, 1 mmol), K 3 PO 4 (2.120 g, 10 mmol) into the reaction flask. Replace nitrogen three times, add 20 mL of dry DMSO solvent and quickly tighten the stopper. Transfer the reaction flask to an oil bath at 100 °C and stir for 24 hours. After cooling to room temperature, monitor the completion of the reaction by TLC. After the raw materials are completely converted, add water to quench the reaction, then extract the reaction solution with ethyl acetate (3×30 mL) solvent. Wash the combined organic layers with water multiple times, dry over anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and then separate by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain white solid 9a (1.630 g, yield 84%). Take a dry 50 mL Schlenk tube, sequentially add compound 9a (776 mg, 2.0 mmol) and MeONa (222 μL, 4.0 mmol), replace nitrogen three times, add 10 mL of dry MeOH solvent to dissolve and transfer to an oil bath at 50 °C and stir for 12 hours. Monitor the completion of the reaction by TLC. After the raw materials are completely converted, remove all the solvents under reduced pressure, add TsOH (34.4 mg, 0.2 mmol) and dry toluene solvent, transfer to an oil bath at 80 °C and stir for 2 hours, then add 2a (411 mg, 3.0 mmol), and continue to stir for 12 hours. After cooling to room temperature, monitor the completion of the reaction by TLC. After the raw materials are completely converted, add a small amount of water to quench the reaction, then extract the reaction solution with dichloromethane (3×20 mL) solvent. Wash the combined organic layers with water multiple times, dry over anhydrous sodium sulfate, filter, remove part of the solvent under reduced pressure, and then separate by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain white solid 11a (874 mg, total two-step yield 86%). 1 H NMR (400 MHz, CDCl 3)δ 7.96 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 7.6, 1.6 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 7.6, 0.8 Hz, 1H), 7.43 (dd, J = 8.0, 7.6 Hz, 1H), 7.41–7.37 (m, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.30–7.14 (m, 10H), 7.13 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H), 6.67 (dd, J = 8.4, 0.8 Hz, 1H), 5.23 (dd, J = 10.0, 8.4 Hz, 1H), 4.57 (dd, J = 10.4, 8.8 Hz, 1H), 4.16 (t, J = 8.8 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 )δ 163.5, 163.2, 152.4, 151.0, 144.1, 141.8, 140.0, 134.1, 133.9, 131.8, 130.9, 129.9, 129.0, 128.8, 128.2, 128.0, 127.8, 127.1, 127.0, 126.5, 125.9, 125.8, 124.8, 124.5, 123.3, 121.9, 119.4, 119.0, 115.6, 114.3, 77.4, 75.2, 70.2. HRMS (ESI-TOF) m / z Calcd. for C 40 H 35 N 2 O 5 + [M + H] + : 509.1860; Found: 509.1854.

[0128] Example 15:

[0129]

[0130] Prepared in the same manner as in Example 14, white solid, 276 mg, total yield 55%; 1 H NMR (400 MHz, CDCl 3)δ8.02(d,J=8.8Hz,1H),7.96(d,J=8.4Hz,1H),7.79(d,J=6.0Hz,1H),7.77(d,J=6.0Hz,1H),7.67(d,J=7.6Hz,1H),7.50(d,J=9.2Hz,1H),7.47(d,J=5.6Hz,1H),7.43(d,J=7.6Hz,1H),7.38(d,J=8.4Hz,1H),7.34(d,J=6.4Hz,1H),7.33(d,J=7.6Hz,1H),7.31(d,J=7.2Hz,1H),7.29–7.23(m,5H),7.18–7.11(m,2H),6.57(d,J=8.4Hz,1H),5.35(t,J=10.0Hz,1H),4.76(t,J=8.4Hz,1H),4.24(t,J=8.8Hz,1H),2.14(s,3H). 13 C NMR(101MHz,CDCl 3 )δ163.8,163.4,150.2,144.9,142.1,139.4,135.6,133.9,133.1,132.0,131.5,131.0,129.6,128.9,128.7,128.3,127.9,127.8,127.5,126.9,126.8,126.4,126.0,125.8,125.4,124.8,121.8,119.1,113.7,75.3,70.3,20.7.HRMS(ESI-TOF)m / z Calcd.forC 35 H 27 N 2 O 2 + [M+H] + :507.2067;Found:507.2058.

[0131] Example 16:

[0132]

[0133] The preparation method was the same as that of Example 14, white solid, 200 mg, total yield 38%; 1 H NMR(400MHz,CDCl 3)δ8.01(d,J=8.8Hz,1H),7.95(d,J=8.4Hz,1H),7.83(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,1H),7.66(d,J=7.2Hz,1H),7.51(d,J=9.2Hz,1H),7.48(d,J=5.6Hz,1H),7.46(d,J=5.6Hz,1H),7.44(d,J=7.6Hz,1H),7.36–7.23(m,7H),7.21(d,J=8.4Hz,1H),7.15(d,J=8.4Hz,1H),7.11(t,J=8.4Hz,1H),6.59(d,J=8.4Hz,1H),5.35(dd,J=10.0,8.4Hz,1H),4.77(dd,J=10.4,8.4Hz,1H),4.24(t,J=8.4Hz,1H),2.47(q,J=7.6Hz,2H),1.02(t,J=7.6Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ163.7,163.2,150.1,144.7,141.9,141.1,139.2,134.3,132.9,131.9,131.3,130.2,129.4,128.8,128.1(2C),127.7,127.6,127.3,126.8,126.7,126.6,126.5,126.2,125.6,125.3,124.8,121.7,119.0,113.8,75.2,70.1,26.9,14.9.HRMS(ESI-TOF)m / z Calcd.for C 36 H 29 N 2 O 2 + [M+H] + :520.2158;Found:521.2149.

[0134] Example 17:

[0135]

[0136] Prepared in the same manner as in Example 14, white solid, 59.6 mg, total yield 21%; 1 H NMR(400MHz,CDCl 3)δ7.93(d, J = 8.4 Hz, 1H), 7.88(d, J = 7.6 Hz, 1H), 7.86(d, J = 8.0 Hz, 1H), 7.84(d, J = 9.6 Hz, 1H), 7.70(d, J = 7.2 Hz, 1H), 7.57(d, J = 8.4 Hz, 1H), 7.42(t, J = 6.4 Hz, 1H), 7.39(t, J = 7.6 Hz, 1H), 7.36–7.28(m, 5H), 7.28–7.22(m, 4H), 7.19(d, J = 10.4 Hz, 1H), 7.16(d, J = 8.8 Hz, 1H), 6.89–6.83(m, 2H), 6.81(d, J = 8.0 Hz, 1H), 6.78(d, J = 7.2 Hz, 1H), 5.80(d, J = 8.4 Hz, 1H), 5.35(t, J = 9.4 Hz, 1H), 4.76(t, J = 8.8 Hz, 1H), 4.25(t, J = 10.0 Hz, 1H), 1.99(s, 3H). 13 C NMR(101MHz, CDCl 3 )δ163.6, 163.1, 149.9, 144.9, 142.0, 141.9, 139.7, 139.1, 137.3, 135.5, 133.2, 132.8, 130.6, 130.5(2C), 129.5, 128.8, 128.5, 128.3, 128.2, 127.9, 127.8, 127.5, 127.3, 127.1, 127.0, 126.9, 126.7, 126.3, 126.1, 125.7, 125.2, 120.4, 118.9, 113.5, 75.3, 70.3, 21.3. HRMS(ESI-TOF) m / z Calcd. for C 41 H 31 N 2 O 2 + [M + H] + : 583.2380;Found: 583.2372.

[0137] Example 18:

[0138]

[0139] Prepared in the same manner as in Example 8, white solid, 32 mg, total yield 61%; 1 H NMR(400MHz, CDCl 3)δ 7.99 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.45–7.40 (m, 1H), 7.38–7.10 (m, 11H), 6.74 (d, J = 8.4 Hz, 1H), 5.35 (t, J = 9.4 Hz, 1H), 4.77 (dd, J = 10.4, 8.8 Hz, 1H), 4.27 (t, J = 8.4 Hz, 1H), 3.65 (s, 3H). 13 C NMR (101 MHz, CDCl 3 )δ 163.8 (2C), 154.9, 150.4, 145.0, 142.0, 139.3, 134.4, 134.0, 131.5, 130.0, 129.7, 129.1, 128.9, 128.2, 127.9, 127.8, 126.9, 126.7, 126.4, 126.2, 125.7, 125.4, 125.2, 123.6, 121.5, 118.9, 117.8, 113.5, 113.3, 75.3, 70.3, 56.3. HRMS (ESI-TOF) m / z Calcd. for C 35 H 27 N 2 O 3 + [M + H] + : 523.2016; Found: 523.2018.

[0140] Example 19:

[0141]

[0142] The preparation method was the same as that of Example 9, white solid, 44 mg, total yield 72%; 1 H NMR (400 MHz, CDCl 3) δ 7.99 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 3.2 Hz, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.44–7.39 (m, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.34–7.29 (m, 3H), 7.29–7.22 (m, 4H), 7.21 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.34 (t, J = 9.4 Hz, 1H), 4.74 (t, J = 8.8 Hz, 1H), 4.24 (t, J = 8.4 Hz, 1H), 3.75–3.64 (m, 2H), 1.73–1.61 (m, 1H), 0.69 (d, J = 2.8 Hz, 3H), 0.67 (d, J = 2.8 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 163.6, 163.3, 153.3, 150.6, 147.0, 144.7, 142.0, 139.4, 133.8, 133.3, 131.6, 131.2, 130.3, 129.6, 128.8, 128.0, 127.8, 127.7, 126.9, 126.8, 126.7, 126.4, 126.2, 125.7, 125.3, 123.9, 122.6, 121.1, 119.1, 114.1, 75.2, 74.4, 70.2, 27.6, 18.6 (2C). HRMS (ESI-TOF) m / z Calcd. for C 39 H 33 N 2 O 5 + [M + H] + : 609.2341; Found: 609.2345.

[0143] Example 20: Optimization of the Aminoacetoxylation Reaction Conditions of Biaryl Amino Olefins (Screening of Solvents)

[0144]

[0145]

[0146]

[0147] Unless otherwise stated, reactions were performed on a 0.1 mmol scale in 1 mL of solvent. Example 21: Optimization of reaction conditions for aminoacetoxylation of biarylaminoolefins (screening of palladium salts)

[0148]

[0149]

[0150] Unless otherwise stated, reactions were carried out in 1 mL toluene solvent on a 0.1 mmol scale. Example 22: Optimization of reaction conditions for aminoacetoxylation of biarylaminoolefins (ligand screening)

[0151]

[0152]

[0153] Unless otherwise stated, reactions were performed on a 0.1 mmol scale in 1 mL of toluene solvent. Example 23: Aminoacetoxylation of Biarylaminoolefins

[0154]

[0155] Select a 10 mL reaction tube and add substrate 12 (0.1 mmol), 13 (0.2 mmol), Pd(OAc) 2 (10 mol%), ligand (I) (10 mol%), add 1 mL of toluene solvent, then screw the stopcock and stir for 1-180 hours. After the reaction is completed, the reaction solution is directly purified by silica gel column chromatography. The enantiomeric ratio of the product is analyzed by HPLC. The experimental results of the obtained biaryl bridged seven-membered nitrogen heterocycle of each substituent are shown in the table below.

[0156]

[0157]

[0158]

[0159] Example 54: Optimization of Kinetic Resolution Reaction Conditions for Racemic Biarylamino Olefins (Screening of Palladium Salts)

[0160]

[0161]

[0162] Unless otherwise stated, reactions were performed in 2 mL toluene solvent on a 0.2 mmol scale.

[0163] Example 55: Optimization of Kinetic Resolution Reaction Conditions of Racemic Biarylamino Olefins (Screening of Reaction Solvents)

[0164]

[0165]

[0166]

[0167] Unless otherwise stated, reactions were performed in 2 mL toluene solvent on a 0.2 mmol scale.

[0168] Example 56: Optimization of Kinetic Resolution Reaction Conditions of Racemic Biarylamino Olefins (Screening of Ligands)

[0169]

[0170]

[0171]

[0172] Unless otherwise stated, reactions were performed in 2 mL toluene solvent on a 0.2 mmol scale.

[0173] Example 57: Kinetic Resolution of Racemic Biarylamino Olefins

[0174]

[0175] Select a 10 mL reaction tube and add substrate 15 (0.2 mmol), 13 (0.12 mmol), Pd(OAc) 2 (10 mol%), ligand (I) (10 mol%), add 2 mL of toluene solvent to dissolve, then screw the stopcock, transfer to 30 ° C and stir for 24 hours. After the reaction is completed, the reaction solution is directly separated and purified by column chromatography to obtain compound 16 and optically pure compound 15. Select a 10 mL reaction tube, add optically pure compound 15, add 2 mL of tetrahydrofuran solvent to dissolve, add BH 3 After stirring THF (1M, 1mmol) for 6 hours, a certain amount of H 2 O 2 (30%, 1 mmol) and NaOH (2 M) solution were added and stirred for 6 hours. After the reaction was completed, sodium thiosulfate aqueous solution (1 M) was added to quench the reaction, and then dichloromethane (3×10 mL) was used for solvent extraction. The combined organic layer was washed with water several times, dried over anhydrous sodium sulfate, filtered, and part of the solvent was removed under reduced pressure. Then, the compound 17 was separated and purified by column chromatography to obtain the enantiomeric ratio of the product by HPLC analysis.

[0176] The experimental results of the biaryl-bridged seven-membered azacycles and axially chiral amino alcohols of each substituent obtained are shown in the following table.

[0177]

[0178]

[0179] Note: The er value of 16a-j is the ratio of the stereoisomers (R a , R:S a , S), the er value of 16k-l is the ratio of the stereoisomers (S a , R:R a , S), the er value of 17a-j is the ratio of the stereoisomers (S:R), and the er value of 17k-l is the ratio of the stereoisomers (R:S).

[0180] As described above, it is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by those skilled in the art within the technical scope disclosed by the present invention should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.

Claims

1. A chiral pyridine oxazoline ligand assisted by a binaphthyl structure, characterized in that: The chiral pyridine oxazoline ligand assisted by the binaphthyl structure is shown in the following general formula (I): In the general formula (I): The absolute configuration of the chiral center in the axial chiral structure or oxazoline structure marked with * is R configuration or S configuration; n is the number of methylene groups connected to the oxygen atom in the binaphthyl structure and the pyridine ring by covalent bonds, and n is 0 or 1; R 1 Selected from hydroxyl, C 1-6 Alkyl, C 1-6 Any one of an alkyloxy group, a phenyl group, a substituted phenyl group, an alkylacyloxy group, and a carbonate group; R 2 –R 3 are independently selected from hydrogen, halogen, C 1-6 Any of alkyl, phenyl, and substituted phenyl; R 4 –R 5 are independently selected from hydrogen, C 1-6 Any of an alkyl group, a phenyl group, and a substituted phenyl group.

2. The chiral pyridine oxazoline ligand assisted by a binaphthyl structure according to claim 1, characterized in that: When the R 1 C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; when the R 1 C 1-6 When the C 1-6 The alkyloxy group is methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, neopentyloxy or hexyloxy; when the R 1 When it is a substituted phenyl group, the substituted phenyl group is a methyl substituted phenyl group, an ethyl substituted phenyl group, an isopropyl substituted phenyl group, a tert-butyl substituted phenyl group, a neopentyl substituted phenyl group, an adamantyl substituted phenyl group, a trifluoromethyl substituted phenyl group, a methoxy substituted phenyl group, an ethoxy substituted phenyl group, a tert-butyloxy substituted phenyl group, a fluorine substituted phenyl group, a chlorine substituted phenyl group, or a p-phenyl substituted phenyl group; when R 1 When it is an alkyl acyloxy group, the alkyl acyloxy group is methyl acyloxy, ethyl acyloxy, n-propyl acyloxy, isopropyl acyloxy, n-butyl acyloxy, isobutyl acyloxy, sec-butyl acyloxy, tert-butyl acyloxy, n-pentyl acyloxy, isopentyl acyloxy, neopentyl acyloxy, hexyl acyloxy, benzyl acyloxy; when R 1 When it is a carbonate group, the carbonate group is methyl carbonate, ethyl carbonate, n-propyl carbonate, isopropyl carbonate, n-butyl carbonate, isobutyl carbonate, sec-butyl carbonate, tert-butyl carbonate, n-pentyl carbonate, isopentyl carbonate, neopentyl carbonate, or benzyl carbonate; When the R 2 –R 3 C 1-6 alkyl, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; when the R 2 –R 3 When it is a substituted phenyl group, the substituted phenyl group is a methyl substituted phenyl group, an ethyl substituted phenyl group, an isopropyl substituted phenyl group, a tert-butyl substituted phenyl group, a neopentyl substituted phenyl group, an adamantyl substituted phenyl group, a trifluoromethyl substituted phenyl group, a methoxy substituted phenyl group, an ethoxy substituted phenyl group, a tert-butyloxy substituted phenyl group, a fluorine substituted phenyl group, or a chlorine substituted phenyl group; When the R 4 –R 5 When R is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; when R 4 –R 5 When it is a substituted phenyl group, the substituted aryl group is a methyl substituted phenyl group, an ethyl substituted phenyl group, an isopropyl substituted phenyl group, a tert-butyl substituted phenyl group, a neopentyl substituted phenyl group, an adamantyl substituted phenyl group, a trifluoromethyl substituted phenyl group, a methoxy substituted phenyl group, an ethoxy substituted phenyl group, a tert-butyl substituted phenyl group, a fluorine substituted phenyl group, or a chlorine substituted phenyl group.

3. A method for preparing a chiral pyridine oxazoline ligand assisted by a binaphthyl structure as claimed in claim 1, characterized in that it comprises one or more of the following steps: (1) In an organic solvent, under nitrogen or inert gas, compound 1 and compound 2 are reacted in the presence of a condensing agent to prepare intermediate 3; intermediate 3 is reacted in the presence of a fluorinating agent and a base to prepare compound 4; Where R 1 Hydroxyl, C 1-6 One of alkyl, phenyl and substituted phenyl; The absolute configuration of the axial chiral structure marked with * is R configuration or S configuration; the absolute configuration of the two central chiral carbon atoms marked with * is R,R configuration, S,S configuration, R,S configuration or S,R configuration; (2) In an organic solvent, under nitrogen or inert gas, compound 4a is reacted with compound 5 in the presence of a base to prepare compound 6; In compound 5, X is a chlorine atom or a bromine atom, and R 6 C 1-6 Any of alkyl, alkylacyl, and alkyloxyacyl; (3) In an organic solvent, under nitrogen or inert gas, compound 7 and compound 8 are reacted under the catalytic action of copper salt and ligand to prepare intermediate 9, intermediate 9 is reacted under alkaline conditions to prepare intermediate 10, and intermediate 10 is reacted with compound 2 under the action of acid to produce compound 11.

4. The method for preparing a chiral pyridine oxazoline ligand assisted by a binaphthyl structure according to claim 3, characterized in that: When the R 6 C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl; when the R 6 When R is an alkyl acyl group, the alkyl acyl group is methyl acyl, ethyl acyl, n-propyl acyl, isopropyl acyl, n-butyl acyl, isobutyl acyl, sec-butyl acyl, tert-butyl acyl, n-pentyl acyl, isopentyl acyl, neopentyl acyl, hexyl acyl, or benzyl acyl; when R 6 When it is an alkyloxyacyl group, the alkyloxyacyl group is methyloxyacyl, ethyloxyacyl, n-propyloxyacyl, isopropyloxyacyl, n-butyloxyacyl, isobutyloxyacyl, sec-butyloxyacyl, tert-butyloxyacyl, n-pentyloxyacyl, isopentyloxyacyl, neopentyloxyacyl, hexyloxyacyl, benzyloxyacyl; The condensing agent described in steps (1) and (2) is a condensing agent commonly used in the field of organic synthesis, including dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, 2-(1H-benzotriazolyl)-L-(1H-benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, One or more of benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-succinimidyl-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(endo-5-norbornene-2,3-dicarboximide)-1,1,3,3-tetramethyluronium tetrafluoroborate, benzotriazole-1-oxytris(dimethylamino)phosphine hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate, and (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxy)tris-1-pyrrolidinyl hexafluorophosphate; The organic solvent is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, mesitylene, trifluorotoluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide; The fluorination agent is one or more of diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, sulfur tetrafluoride, pyridine-2-sulfonyl fluoride, perfluorobutylsulfonyl fluoride, N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, and 1,3-bis(2,6-diisopropylphenyl)-2,2-difluoroimidazoline; The inert gas includes one or more of argon, helium, neon and krypton; The base is selected from one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, calcium hydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and pyridine; The copper salt is cupric chloride, cupric bromide, cuprous chloride, cuprous bromide, cuprous iodide, cupric acetate, copper acetylacetonate, copper perchlorate, copper trifluoroacetate, copper tetrafluoroborate, copper tetraacetonitrile hexafluorophosphate, cuprous cyanide, cuprous thiocyanate, cuprous thiophene-2-carboxylate, or cuprous oxide; preferably cuprous chloride, cuprous bromide, or cuprous iodide; The ligand includes one or more of phenylcarboxylic acid, naphthylcarboxylic acid, pyridylcarboxylic acid, quinolylcarboxylic acid, furanylcarboxylic acid or thienylcarboxylic acid; The acid includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, phenylformic acid, naphthylformic acid, pyridylformic acid, quinolylformic acid, furanylformic acid, thienylformic acid, p-toluenesulfonic acid, methanesulfonic acid or chlorosulfonic acid; In the preparation method of the chiral pyridine oxazoline ligand assisted by the binaphthyl structure, the feeding ratio of compound 1 to compound 2 is a molar ratio of 1:5 to 5:1; In the preparation method of the chiral pyridine oxazoline ligand assisted by the binaphthyl structure, the feeding ratio of compound 4a to compound 5 is a molar ratio of 1:5 to 5:1; In the preparation method of the chiral pyridine oxazoline ligand assisted by the binaphthyl structure, the feeding ratio of compound 7 to compound 8 is a molar ratio of 1:5 to 5:

1.

5. A method for synthesizing a biaryl-bridged seven-membered nitrogen heterocyclic compound comprises the following steps: complexing the chiral pyridine oxazoline ligand assisted by the binaphthyl structure as claimed in claim 1 with a palladium salt in an organic solvent under a reaction gas, then adding an oxidant, and reacting compounds 12 and 13 at a desired reaction temperature for a desired reaction time to obtain compound 14; in, R 7 is phenylsulfonyl or substituted phenylsulfonyl; R 8 –R 13 is hydrogen, alkyl, phenyl, ester, cyano or halogen; The absolute configurations of the chiral axes and chiral centers marked with * are S or R.

6. The method for preparing the biaryl-bridged seven-membered nitrogen heterocyclic compound according to claim 5, characterized in that: When the R 7 When it is a substituted phenylsulfonyl group, the substituted phenylsulfonyl group is p-methylphenylsulfonyl, p-ethylphenylsulfonyl, 4-n-propylphenylsulfonyl, 4-isopropylphenylsulfonyl, 4-n-butylphenylsulfonyl, p-tert-butylphenylsulfonyl, 4-isoamylphenylsulfonyl, p-methoxyphenylsulfonyl, 2,4,6-trimethylphenylsulfonyl, 2,4,6-tri-tert-butylphenylsulfonyl or p-nitrophenylsulfonyl; the R 8 –R 13 When it is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; The palladium salt is selected from one or more of palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, palladium trifluoroacetate, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium chloride, bis(triphenylphosphine)palladium chloride, allyl palladium chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, [1,3-bis(diphenylphosphino)propane]palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) dichloromethane complex, 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride, and bis(dibenzylideneacetone)palladium; preferably palladium acetate, palladium acetylacetonate or palladium bromide; The oxidant is oxygen, diacetoxyiodobenzene, hydrogen peroxide, tert-butyl peroxide, cumene hydroperoxide, manganese dioxide, potassium permanganate, 1,4-benzoquinone, m-chloroperbenzoic acid or 2,3-dichloro-5,6-dicyanobenzoquinone; The organic solvent is methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, mesitylene, trifluorotoluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide; preferably toluene and 1,2-dichloroethane; The reaction gas is oxygen, nitrogen or air; The molar concentration of the compounds 12 and 13 in the organic solvent is 0.01 to 5.0 M; The molar ratio of the palladium salt to the pyridine oxazoline ligand assisted by the binaphthyl structure is 1:5 to 5:1; The reaction temperature is -50 to 50°C; The reaction time is 1 to 180 hours.

7. A kinetic resolution reaction of a racemic biarylaminoolefin, comprising the following steps: complexing the chiral pyridine oxazoline ligand assisted by the binaphthyl structure as claimed in claim 1 with a palladium salt in an organic solvent under a reaction gas, then adding an oxidant, reacting compound 15 and compound 13 at a desired reaction temperature for a desired reaction time to obtain compound 16; the remaining compound 15 reacts under the action of a reducing agent, a base and an oxidant to produce compound 17; in, R 7 is phenylsulfonyl or substituted phenylsulfonyl; R 14 –R 15 is hydrogen, alkyl, phenyl or halogen; The absolute configurations of the chiral axes and chiral centers marked with * are S or R.

8. The kinetic resolution reaction of racemic biarylaminoolefins according to claim 7, characterized in that: When the R 7 When it is a substituted phenylsulfonyl group, the substituted phenylsulfonyl group is p-methylphenylsulfonyl, p-ethylphenylsulfonyl, 4-n-propylphenylsulfonyl, 4-isopropylphenylsulfonyl, 4-n-butylphenylsulfonyl, p-tert-butylphenylsulfonyl, 4-isoamylphenylsulfonyl, p-methoxyphenylsulfonyl, 2,4,6-trimethylphenylsulfonyl, 2,4,6-tri-tert-butylphenylsulfonyl or p-nitrophenylsulfonyl; when the R 14 –R 15 When it is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; The palladium salt is selected from one or more of palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, palladium trifluoroacetate, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium chloride, bis(triphenylphosphine)palladium chloride, allyl palladium chloride dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, tris(dibenzylideneacetone)dipalladium, [1,3-bis(diphenylphosphino)propane]palladium dichloride, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (II) dichloromethane complex, 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride and bis(dibenzylideneacetone)palladium; preferably palladium acetate, palladium acetylacetonate or palladium bromide; The oxidant is one or more of oxygen, diacetoxyiodobenzene, hydrogen peroxide, tert-butyl peroxide, cumene hydroperoxide, manganese dioxide, potassium permanganate, 1,4-benzoquinone, m-chloroperbenzoic acid or 2,3-dichloro-5,6-dicyanobenzoquinone; The organic solvent is methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, mesitylene, trifluorotoluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide; preferably toluene and 1,2-dichloroethane; The reducing agent is one of sodium borohydride, sodium acetoxyborohydride, sodium cyanoborohydride, N,N-dimethylamino lithium borohydride, lithium aluminum tetrahydride, trimethylsilane, trimethylchlorosilane, borane tetrahydrofuran solution and diisopinocamphenylborane; The base includes one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, calcium hydride, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and pyridine; The reaction gas is oxygen, nitrogen or air; The molar concentration of the compounds 15 and 13 in the organic solvent is 0.01 to 5.0 M; The molar ratio of the palladium salt to the pyridine oxazoline ligand assisted by the binaphthyl structure is 1:5 to 5:1; The reaction temperature is -50 to 50°C; The reaction time is 1 to 180 hours.

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