Axial chiral nitrogen-containing heteroaromatic amide ligand as well as preparation method and application thereof

Abstract

The invention discloses an axially chiral nitrogen-containing heteroaromatic ring amide ligand as well as a preparation method and application thereof. The axial chiral nitrogen-containing heteroaromatic ring amide ligand has a structure shown in a general formula (I), the structure shown in the general formula (I) is formed by connecting an axial chiral binaphthyl structure part A and a quinoline or phenanthroline part B through an amido bond, a nitrogen-containing heteroaromatic ring amide part can be chelated and coordinated with transition metal ions, and the binaphthyl structure provides a chiral environment for the ligand. A complex formed in situ by the axially chiral nitrogen-containing heteroaromatic amide ligand and palladium salt in a reaction system shows good catalytic activity and enantioselectivity in an intramolecular amination alkylation reaction for catalyzing olefin, and has a very good application prospect. The invention belongs to the field of asymmetric synthetic chemistry.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of asymmetric synthesis chemistry, and particularly relates to a new type of axially chiral nitrogen-containing heteroaromatic ring amide ligand, a preparation method and use thereof. The catalyst formed by the ligand and a transition metal can be used for synthesizing chiral nitrogen-containing heterocyclic compounds by intramolecular amination alkylation of olefins, and has good catalytic activity and enantioselectivity. BACKGROUND

[0002] The chiral nitrogen-containing heteroaromatic ring amide ligand is a kind of chiral ligand with chelating ability, and plays an important role in reactions of asymmetric catalysis of carbon-carbon bond and carbon heteroatom bond. Most of the chiral sources of the known chiral nitrogen-containing heteroaromatic ring amide ligand are structures with central chirality. This kind of nitrogen-containing heteroaromatic ring amide can be coordinated with transition metals to form metal complexes to catalyze asymmetric synthesis reactions, so the design, synthesis and application of this kind of ligand have always been concerned. For example, in 2003, Xingquan Hu's group reported a class of NOBIN and BINOL-derived phosphite containing pyridine amide axially chiral ligand D for Cu(I)-catalyzed addition of chalcone, with an ee value as high as 97% (J. Org. Chem, 2003, 68, 4542-4545). In 2025, Ma Dazhao and Xue Xiaosong's group reported NOBIN-derived amide ligand E, which realized the enantioselective coupling reaction of aryl iodide with sulfoximine with an ee value as high as 97% (Nat. Commun. 2025, 16, 231).

[0003]

[0004] As an advantage chiral skeleton, the axially chiral binaphthyl has a wide application in the field of asymmetric catalysis. Many excellent chiral ligands and catalysts (such as chiral phosphoric acid, chiral amine, chiral bisphosphine, chiral cyclopentadiene, etc.) are developed based on these two types of axially chiral skeletons. However, there are few reports on axially chiral nitrogen-containing heteroaromatic ring amide ligands based on binaphthyl. Binaphthyl has unique axially chiral structure and multi-site adjustable characteristics. Its rigid skeleton and tight chiral environment are key factors for asymmetric induction. Designing and developing new axially chiral nitrogen-containing heteroaromatic ring amide ligands based on binaphthyl is expected to provide new advantage chiral ligands for asymmetric catalytic synthesis reactions and new methods for synthesis of chiral molecules, and the related research results have important practical value in asymmetric synthesis chemistry. SUMMARY

[0005] The purpose of the present application is to provide a new type of axially chiral nitrogen-containing heteroaromatic ring amide ligand.

[0006] Another purpose of the present application is to provide a synthesis method of the above-mentioned axially chiral nitrogen-containing heteroaromatic ring amide ligand.

[0007] The application also provides the use of the above-mentioned axially chiral nitrogen-containing heteroaromatic ring amide ligand, i.e. after in-situ forming a complex catalyst with a transition metal compound, it is applied to the synthesis of chiral nitrogen-containing heterocyclic compounds by the intramolecular amination alkylation reaction of olefins.

[0008] The application provides an axially chiral nitrogen-containing heteroaromatic ring amide ligand, characterized in that the axially chiral nitrogen-containing heteroaromatic ring amide ligand has the following general formula (I):

[0009]

[0010] In the general formula (I), A is an axially chiral part of the ligand;

[0011] The chiral part marked with * is in R configuration or S configuration, or is racemic;

[0012] The axially chiral part of the ligand is A;

[0013] The nitrogen-containing heteroaromatic ring part B of the ligand can be selected from B-1 or B-2 or B-3 at random;

[0014] R 1 is selected from any one of alkyl, alkoxy, hydroxyl, siloxy, phenyl, substituted phenyl, amine, substituted amine;

[0015] R 2 and R 3 are respectively and independently selected from any one of hydrogen, halogen, phenyl, substituted phenyl;

[0016] R 4 is selected from alkyl.

[0017] In a preferred experimental scheme of the application, when the R 1 is alkyl, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl or benzyl; when the R 1 is alkoxy, the alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, n-pentyloxy, isopentyloxy, neopentyloxy or benzyloxy; when the R 1 is siloxy, the siloxy is trimethylsiloxy, triethylsiloxy, tri-n-propylsiloxy, triisopropylsiloxy, tri-n-butyisiloxy, triisobutyisiloxy, tri-n-pentyisiloxy, triisopentyisiloxy or tri-neopentyisiloxy; when the R 1 is substituted phenyl, the substituted phenyl is methyl-substituted phenyl, trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, ethyl-substituted phenyl, t-butyl-substituted phenyl or fluorine-substituted phenyl; when the R 1When the substituted amine group is substituted, the substituted amine group is a methyl-substituted amine group, an ethyl-substituted amine group, a n-propyl-substituted amine group, an iso-propyl-substituted amine group, a n-butyl-substituted amine group, an iso-butyl-substituted amine group, a n-pentyl-substituted amine group, an iso-pentyl-substituted amine group, a neopentyl-substituted amine group, a benzyl-substituted amine group, or a phenyl-substituted amine group;

[0018] In a preferred embodiment of the present application, when the R 2 , R 3 is a substituted phenyl group, the substituted phenyl group is a methyl-substituted phenyl group, an ethyl-substituted phenyl group, an iso-propyl-substituted phenyl group, a t-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 t-butyloxy-substituted phenyl group, a fluorine-substituted phenyl group, a chlorine-substituted phenyl group, a bromine-substituted phenyl group, or an iodine-substituted phenyl group; when the R 2 , R 3 is a halogen, the halogen is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom;

[0019] In a preferred embodiment of the present application, when the R 4 is an alkyl group, the alkyl group is a methyl group, an ethyl group, a n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl group, a sec-butyl group, a t-butyl group, a n-pentyl group, an iso-pentyl group, a neopentyl group, or a hexyl group.

[0020] The present application also provides a preparation method of the axial chiral nitrogen-containing heteroaromatic ring amide ligand, characterized by comprising the following steps:

[0021] (1) reacting compound a1 and compound b1 in an organic solvent under nitrogen or inert gas to prepare compound C-1 under the action of a condensing agent;

[0022]

[0023] (2) reacting compound a1 and compound b2 in an organic solvent under nitrogen or inert gas to prepare compound C-2 under the action of a condensing agent;

[0024]

[0025] (3) reacting compound a1 and compound b3 in an organic solvent under nitrogen or inert gas to prepare compound C-3 under the action of a condensing agent.

[0026]

[0027] In the present application, the organic solvent in steps (1), (2) and (3) is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, trichloromethane, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide;

[0028] The inert gas in steps (1), (2) and (3) is one or more of argon, helium, neon and krypton;

[0029] The condensing agent in steps (1), (2) and (3) is one or more of dicyclohexyl carbodiimide, diisopropyl carbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, 2-(1H-benzotriazol-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-oxyl tris(dimethylamino) phosphonium hexafluorophosphate, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate and (3H-1,2,3-triazolo[4,5-b]pyridine-3-oxyl)tris-1-pyrrolidinyl hexafluorophosphate, 4-dimethylaminopyridine;

[0030] The temperature of the reaction in steps (1), (2) and (3) is -30-70℃;

[0031] The time of the reaction in steps (1), (2) and (3) is 1-72 hours;

[0032] In the present application, the molar ratio of compound a1 to compound b1 in step (1) is 1:5-5:1;

[0033] In the present application, the molar ratio of compound a1 to compound b2 in step (2) is 1:5-5:1;

[0034] The preparation method of the one kind of axial chiral nitrogen-containing heteroaromatic ring amide ligand, the feeding ratio of compound a1 and compound b3 in step (3) is 1:5-5:1 in mole ratio.

[0035] In the present application, after the synthesis reactions in steps (1), (2) and (3) are completed, a step of reducing pressure and dissolving is further included.

[0036] In the present application, after the synthesis reactions in steps (1), (2) and (3) are completed, a step of post-treatment is further included, which can be a conventional post-treatment step in the art, and the post-treatment step includes one or more steps of extraction, washing, drying and column chromatography.

[0037] In the present application, the extractant in steps (1), (2) and (3) can be a conventional extractant in the field of organic synthesis, including ethyl acetate, dichloromethane, chloroform and diethyl ether. The washing solution can be a conventional washing solution in the art, such as saturated sodium chloride solution. The drying agent can be a conventional drying agent in the art, 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 in the column chromatography can be a conventional eluent in the field of organic synthesis, such as a mixture of one or more of petroleum ether, ethyl acetate, dichloromethane or methanol.

[0038] The present application further provides a synthesis method of a chiral nitrogen-containing heterocyclic compound, characterized in that the synthesis method of the chiral nitrogen-containing heterocyclic compound comprises the following steps: under a reaction gas, the axial chiral nitrogen-containing heteroaromatic ring amide ligand is complexed with a palladium salt and a base in an organic solvent, and compound 1 is subjected to the following reaction to obtain compound 2.

[0039]

[0040] wherein, R 5 -R 9 is selected from an alkyl group, an alkoxy group, a halogen atom or hydrogen;

[0041] X in the compound 1 is a chlorine atom, a bromine atom or an iodine atom;

[0042] The chirality marked with * is in S configuration or R configuration or racemic.

[0043] In the present application, the synthesis method of the chiral amido amide compound is characterized in that when R 5 -R 9 is an alkyl group, the alkyl group is a methyl group, an ethyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a cyclopentyl group or a cyclohexyl group; and when R 5 -R 9When R is an alkoxy group, the alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an i-propoxy group, a n-butyloxy group, an i-butyloxy group, a n-pentyloxy group, an i-pentyloxy group, a neopentyloxy group; when R 5 -R 9 When R is a halogen atom, the halogen atom is a chlorine atom, a bromine atom or an iodine atom;

[0044] In the present application, the reaction gas is one or more of oxygen, carbon monoxide, carbon dioxide, nitrogen, and air.

[0045] In the present application, the organic solvent is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, trichloromethane, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0046] In the present application, the metal palladium salt is at least one of bis(triphenylphosphine)palladium chloride, tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(acetonitrile)dichloropalladium, [1,3-bis(diphenylphosphino)propane]dichloropalladium, tetrakis(triphenylphosphine)palladium, palladium acetylacetonate, 1,1'-bis(di-tert-butylphosphino)ferrocene dichloropalladium, palladium acetate, palladium chloride, and palladium trifluoroacetate.

[0047] In the present application, the base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, cesium carbonate, 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.

[0048] In the present application, the molar concentration of the compound 1 in the organic solvent is 0.01-1.0 M.

[0049] In the present application, the molar ratio of the palladium salt to the base is 1:1-1:10.

[0050] In the present application, the molar ratio of the palladium salt to the axially chiral nitrogen-containing heteroaromatic amide ligand is 1:1-1:5.

[0051] In an embodiment of the present application, the reaction is followed by a post-treatment step, which can be a conventional post-treatment step in the field of organic synthesis, and the post-treatment step includes a column chromatography separation step.

[0052] The term "er" refers to the enantiomeric ratio.

[0053] The positive and progressive effects of this invention are as follows:

[0054] This invention provides a novel axially chiral nitrogen-containing heterocyclic amide ligand, characterized by a binaphthylamine axial chiral unit and nitrogen-containing coordinating groups such as quinoline and phenanthroline. The synthesis method of this ligand uses 1,1'-binaphthylamine (BINAM), 1,1'-binaphthol (BINOL), 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) and their derivatives, along with quinoline carboxylic acid or phenanthroline-2-carboxylic acid, as starting materials, to obtain the target molecule through the construction of amide bonds. The target molecule of this invention has a concise and clear structure, is simple to operate, and can be prepared in large quantities. It has potential application value in asymmetric catalytic synthesis.

[0055] The novel axially chiral nitrogen-containing heterocyclic amide ligands provided by this invention can form complexes in situ with palladium salts in the reaction system as chiral ligands. They exhibit good yields, enantioselectivity, and good substrate versatility in the intramolecular amination and alkylation reactions of olefins, and have great prospects for industrial applications. Attached Figure Description

[0056] Figure 1 The C-1-14 NMR spectrum of the axially chiral nitrogen-containing heterocyclic amide ligand provided in the embodiments of the present invention;

[0057] Figure 2 The C-1-14 NMR spectrum of the axially chiral nitrogen-containing heterocyclic aromatic amide ligand provided in the embodiments of the present invention;

[0058] Figure 3 The C-1-1 NMR spectrum of the axially chiral nitrogen-containing heterocyclic amide ligand provided in the embodiments of the present invention;

[0059] Figure 4 C-1-1 NMR spectrum of axially chiral nitrogen-containing heterocyclic aromatic amide ligands provided in embodiments of the present invention;

[0060] Figure 5 The C-2-7 NMR spectrum of the axially chiral nitrogen-containing heterocyclic amide ligand provided in the embodiments of the present invention;

[0061] Figure 6 C-2-7 NMR spectrum of axially chiral nitrogen-containing heterocyclic amide ligands provided in embodiments of the present invention;

[0062] Figure 7 The C-2-1 proton NMR spectrum of the axially chiral nitrogen-containing heterocyclic amide ligand provided in the embodiments of the present invention;

[0063] Figure 8The axial chirality nitrogen-containing heteroaromatic ring amide ligand C-2-1 nuclear magnetic carbon spectrum provided by the embodiment of the present application is shown in the following figure:

[0064] Figure 9 The axial chirality nitrogen-containing heteroaromatic ring amide ligand C-2-10 nuclear magnetic hydrogen spectrum provided by the embodiment of the present application is shown in the following figure:

[0065] Figure 10 The axial chirality nitrogen-containing heteroaromatic ring amide ligand C-2-10 nuclear magnetic carbon spectrum provided by the embodiment of the present application is shown in the following figure:

[0066] Figure 11 The axial chirality nitrogen-containing heteroaromatic ring amide ligand C-3-1 nuclear magnetic hydrogen spectrum provided by the embodiment of the present application is shown in the following figure:

[0067] Figure 12 The axial chirality nitrogen-containing heteroaromatic ring amide ligand C-3-1 nuclear magnetic carbon spectrum provided by the embodiment of the present application is shown in the following figure: DETAILED DESCRIPTION

[0068] The present application will be further described in detail by specific embodiments, but the scope of the present application is not limited thereby.

[0069] The instruments and experimental material information used in the following embodiments are as follows:

[0070] All chemical reagents are purchased commercial reagents, and the reagent sources are Adamas, Bide Pharmaceutical, Leyan, Bailingwei, etc. reagent company. Thin layer chromatography (TLC) uses SHF254 silica gel plate, and the column chromatography uses Notai silica gel powder (300-400 mesh), and TLC uses UV light (254 nm). 1 H NMR and 13 C NMR is characterized by Bruker AVANCE III 400MHz nuclear magnetic resonance instrument, and the solvent is deuterated chloroform or deuterated dimethyl sulfoxide. The unit of chemical shift is ppm, and the unit of coupling constant is Hz, 1 In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, m represents multiplet, and br represents broad peak. In 13 In C NMR, δ represents chemical shift. The enantiomeric ratio (e.r.) is determined by Shimadzu LC-20A high performance liquid chromatography and large Cel Chiralpak, Chiralcel chiral column.

[0071] Example 1:

[0072]

[0073] To a dry 100 mL Schlenk flask was added compound a1-1 (0.57 g, 2.0 mmol), b1-1 (0.48 g, 2.8 mmol), EDCI (0.48 g, 2.8 mmol), DMAP (0.48 g, 2.8 mmol), the reaction system was replaced with nitrogen three times and anhydrous DCM (15 mL) was added by syringe under a nitrogen atmosphere, the reaction was stirred at 40 °C for 12 h. After the reaction was completed, it was cooled to room temperature, the organic solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (4:1) as the eluent to obtain white solid C-1-1, 762 mg, yield 84%; 1 H NMR (400 MHz, Chloroform-d) δ 13.01 (s, 1H), 9.01 (d, J = 9.2 Hz, 1H), 8.90 (dd, J = 7.2, 1.6 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.07 - 8.04 (m, 2H), 7.94 (t, J = 8.0 Hz, 2H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.38 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.35 (ddd, J = 7.6, 4.0, 2.0 Hz, 2H), 7.29 - 7.19 (m, 3H), 7.15 (dd, J = 8.4, 4.4 Hz, 1H), 7.06 (d, J = 7.2, 1H), 3.68 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.0, 155.8, 148.4, 145.1, 137.4, 136.8, 134.6, 134.2, 133.5, 132.1, 131.1, 130.2, 129.5, 129.1, 128.6, 128.3, 128.1, 127.9, 127.2, 126.5, 126.2, 125.8, 125.5, 124.6, 124.1, 122.5, 122.1, 120.6, 120.0, 114.7, 57.0.

[0074] Example 2:

[0075]

[0076] Preparation method was the same as example 1, yellow solid, 747 mg, yield 80%; 1H NMR (400 MHz, Chloroform-d) δ 13.12 (s, 1H), 8.98 (d, J = 9.2 Hz, 1H), 8.91 (dd, J = 7.2, 1.6 Hz, 1H), 8.05 (d, J = 9.6 Hz, 2H), 7.98 (d, J = 8.8 Hz, 1H), 7.91 (t, J = 8.8 Hz, 2H), 7.83 (dd, J = 8.4, 1.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.39 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.31 (ddd, J = 8.0, 6.4, 1.2 Hz, 1H), 7.27 (dd, J = 4.4, 2.0 Hz, 1H), 7.24 - 7.12 (m, 5H), 2.47 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.1, 150.8, 148.5, 145.1, 137.3, 136.8, 134.6, 134.1, 133.5, 132.1, 131.2, 129.8, 129.5, 129.0, 128.3, 128.2, 128.1, 127.8, 126.9, 126.5, 126.3, 126.1, 125.6, 125.3, 124.6, 123.8, 123.0, 122.3, 120.6, 120.4, 43.4.

[0077] Example 3:

[0078]

[0079] Preparation method same as example 1, white solid, 937 mg, yield 86%; 1H NMR (400 MHz, Chloroform-d) δ 13.1 (s, 1H), 8.99 (d, J = 8.8 Hz, 1H), 8.91 (dd, J = 7.2, 1.6 Hz, 1H), 8.07 (dd, J = 8.4, 2.0 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.26 - 7.20 (m, 2H), 7.18 (dd, J = 7.6, 3.6 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 2.47 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.1, 151.0, 148.4, 145.0, 137.4, 136.8, 134.1, 133.3, 133.1, 132.2, 131.3, 130.6, 130.0, 129.6, 128.8, 128.6, 128.5, 128.2 (2C), 127.1, 126.5, 126.3, 126.0, 124.9, 124.8, 122.3 (2C), 121.4, 120.7, 117.4, 43.1.

[0080] Example 4:

[0081]

[0082] Preparation method was the same as example 1, brown solid, 969 mg, yield 77%; 1H NMR (400 MHz, Chloroform-d) δ 13.20 (s, 1H), 9.02 (d, J = 9.2 Hz, 1H), 8.90 (dd, J = 7.6, 1.6 Hz, 1H), 8.09 (dd, J = 8.4, 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 8.4, 1.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.38 (dd, J = 4.4, 2.0 Hz, 1H), 7.29 (dd, J = 9.2, 2.4 Hz, 1H), 7.22 (dd, J = 9.2, 2.4 Hz, 1H), 7.19 (dd, J = 8.0, 3.2 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 2.47 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.2, 151.1, 148.4, 145.0, 137.5, 137.3, 134.2, 133.0, 132.4, 132.2, 131.7, 130.6, 130.2, 130.1, 130.0, 129.6, 128.7 (2C), 128.3, 127.9, 127.7, 126.9, 126.6, 125.0, 123.4, 121.7, 121.3, 120.8, 118.8, 117.5, 43.1.

[0083] Example 5:

[0084]

[0085] Preparation method was the same as example 1, yellow solid, 1.10 g, yield 89%; 1H NMR (400 MHz, Chloroform-d) δ 13.26 (s, 1H), 9.08 (d, J = 9.2 Hz, 1H), 8.94 (dd, J = 7.6, 1.6 Hz, 1H), 8.18 - 8.14 (m, 3H), 8.08 (d, J = 8.8 Hz, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 1.6 Hz, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.55 - 7.32 (m, 11H), 7.29 (d, J = 8.8 Hz, 1H), 7.12 (dd, J = 8.4, 4.4 Hz, 1H), 2.56 (s, 6H). 13 CNMR (101 MHz, Chloroform-d) δ 164.2, 150.9, 148.5, 145.0, 141.1, 141.0, 137.3, 137.2, 137.0, 136.2, 134.1, 133.8, 132.6, 132.2, 131.4, 129.9, 129.8, 128.9 (2C), 128.7, 128.2, 127.3, 127.2 (2C), 127.1, 126.9, 126.5, 126.4, 126.0, 125.8, 125.6, 125.4, 122.7, 122.4, 120.7 (2C), 43.4.

[0086] Example 6:

[0087]

[0088] Preparation method same as example 1, yellow solid, 977 mg, yield 90%; 1H NMR (400 MHz, Chloroform-d) δ 13.17 (s, 1H), 9.00 (d, J = 9.2 Hz, 1H), 8.89 (dd, J = 7.2, 1.6 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.4, 2.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 - 7.61 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.47 - 7.37 (m, 5H), 7.35 (dd, J = 4.4, 2.0 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.29 - 7.17 (m, 3H), 7.05 (dd, J = 8.4, 4.4 Hz, 1H), 2.47 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.1, 150.8, 148.5, 145.0, 141.0, 137.3, 136.8, 136.1, 134.0, 133.8, 133.4, 132.1, 131.2, 129.9, 129.7, 128.9, 128.8, 128.4, 128.1 (2C), 127.1 (2C), 126.4, 126.3 (2C), 126.2, 125.8, 125.6, 125.5, 124.7, 122.5, 122.3, 120.7, 120.6, 43.3.

[0089] Example 7:

[0090]

[0091] Preparation method same as example 1, yellow solid, 825 mg, yield 72%; 1H NMR (400 MHz, Chloroform-d) δ 13.22 (s, 1H), 9.07 (d, J = 9.2 Hz, 1H), 8.93 (d, J = 7.2, 1.6 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.99 - 7.95 (m, 2H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.46 - 7.39 (m, 3H), 7.33 (d, J = 9.2 Hz, 1H), 7.28 - 7.22 (m, 2H), 7.09 (dd, J = 8.4, 4.4 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H), 2.51 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.1, 159.1, 150.6, 148.5, 145.0, 137.2, 136.8, 135.8, 134.0, 133.4 (2C), 132.1, 131.1, 130.0, 129.6, 128.8, 128.3, 128.1 (2C), 126.4, 126.3, 126.1, 125.8, 125.5, 124.8, 124.6, 122.7, 122.3, 120.7, 120.6, 114.3, 55.4, 43.3.

[0092] Example 8:

[0093]

[0094] Preparation method was the same as example 1, yellow solid, 1.11 g, yield 85%; 1H NMR(400MHz,Chloroform-d)δ13.24(s,1H),9.08(d,J=9.2Hz,1H),8.93(dd,J=7.6,1.6Hz,1 H),8.12(d,J=9.2Hz,1H),8.08(dd,J=7.6,2.0Hz,2H),8.05(dd,J=8.0,2.0Hz,2H),7.83(d,J =8.0,1.6Hz,1H),7.67–7.58(m,5H),7.53(d,J=9.2Hz,1H),7.45(dd,J=8.8,2.0Hz,1H),7.4 3–7.40(m,2H),7.35(d,J=8.8Hz,1H),7.25(d,J=8.8Hz,1H),7.17–7.09(m,5H),2.54(s,6H). 13 C NMR(101MHz,Chloroform-d)δ164.2,162.5(d,J C-F =247.5Hz), 162.4(d,J) C-F =247.5Hz),151.0,148.5,145.1,137.4,137.3(d,J C-F =4.0Hz), 137.1(d,J C-F =3.0Hz),137.1,136.3,135.3,134.1,133.7,132.5,132.2,131.4,129.9,129.8,128.8(d,J C-F =8.1Hz), 128.7, 128.6 (d, J) C-F =8.1Hz),128.2,126.9,126.5,126.3,125.9,125.7,125.5,125.3,122.8,122.3,120.8,120.7,115.8(d,J C-F =21.2Hz), 43.3. 19 F NMR(376MHz,Chloroform-d)δ-115.8,-115.8.

[0095] Example 9:

[0096]

[0097] The preparation method is the same as in Example 1, yielding a yellow solid, 1.13 g, with a yield of 84%. 1H NMR (400 MHz, Chloroform-d) δ 13.26 (s, 1H), 9.11 (d, J = 9.2 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 9.2 Hz, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.59 - 7.48 (m, 3H), 7.44 (d, J = 10.0 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 8.4, 4.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 2.55 (s, 6H). 13 CNMR (101 MHz, Chloroform-d) δ 164.1, 159.1 (2C), 150.6, 148.5, 144.9, 137.2, 136.8, 136.6, 135.8, 133.9, 133.5, 133.4 (2C), 132.2, 132.1, 131.5, 130.0, 129.7, 128.8, 128.5, 128.3, 128.1 (2C), 126.8, 126.4, 126.2, 125.8, 125.6, 125.4, 125.1, 124.8, 122.7, 122.6, 120.7, 120.6, 114.3, 55.3, 43.4.

[0098] Example 10:

[0099]

[0100] Preparation method same as example 1, white solid, 806 mg, yield 92%; 1H NMR (400 MHz, Chloroform-d) δ 13.08 (s, 1H), 9.09 (d, J = 9.2 Hz, 1H), 8.88 (dd, J = 7.2, 1.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.98 - 7.93 (m, 2H), 7.73 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 6.8 Hz, 1H), 7.41 (t, J = 6.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 4.4, 2.0 Hz, 1H), 7.28 - 7.21 (m, 2H), 7.10 (dd, J = 8.0, 4.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 2.17 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.1, 148.3, 144.9, 137.3, 136.2, 133.9, 133.6, 132.9, 132.8, 132.4, 132.1, 131.1, 129.2, 128.7, 128.5, 128.2, 128.1, 127.9, 126.7, 126.4, 126.3, 126.0, 125.6, 125.3, 125.1, 124.8, 122.0, 120.5, 20.3.

[0101] Example 11:

[0102]

[0103] Preparation method was the same as example 1, light yellow solid, 900 mg, yield 90%;1H NMR (400 MHz, Chloroform-d) δ 13.24 (s, 1H), 8.93 - 8.89 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.39 (dd, J = 4.4, 2.0 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.21 (td, J = 8.4, 1.2 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.13 (dd, J = 8.8, 3.2 Hz, 1H), 7.09 - 7.07 (m, 2H), 7.02 - 6.93 (m, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 163.8, 148.4, 145.0, 141.3, 141.2, 137.4, 137.2, 134.0, 133.5, 133.4, 133.1, 132.4, 132.1, 130.6, 128.8 (2C), 128.7, 128.6, 128.5, 128.2, 128.0, 127.5, 127.1, 126.8, 126.4, 126.2 (2C), 126.0, 124.7, 124.5, 121.5, 120.6.

[0104] Example 12:

[0105]

[0106] Preparation method was the same as example 1, white solid, 884 mg, yield 86%; 1H NMR (400 MHz, Chloroform-d) δ 13.24 (s, 1H), 8.96 (d, J = 9.2 Hz, 1H), 8.90 (dd, J = 7.6, 2.0 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.6, 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (ddd, J = 8.0, 6.4, 1.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 4.4, 2.0 Hz, 1H), 7.32 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.29 (ddd, J = 6.4, 4.4, 1.2 Hz, 1H), 7.20 (ddd, J = 8.4, 6.8, 1.6 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.12 (dd, J = 8.0, 2.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 7.6 Hz, 2H), 2.09 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.8, 148.4, 145.0, 141.2, 138.5, 137.4, 137.2, 136.3, 134.0, 133.5 (2C), 133.1, 132.2, 132.1, 130.6, 129.0, 128.8, 128.6, 128.5, 128.4 (2C), 128.2, 127.9, 127.0, 126.8, 126.4, 126.1 (2C), 126.0, 124.9, 124.4, 121.5, 120.6, 21.1.

[0107] Example 13:

[0108]

[0109] Preparation method was the same as example 1, brown solid, 955 mg, yield 80%; 1H NMR (400 MHz, Chloroform-d) δ 13.23 (s, 1H), 9.04 (d, J = 9.2 Hz, 1H), 8.87 (dd, J = 7.2, 1.6 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.08 (t, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.38 (dd, J = 4.0, 1.6 Hz, 1H), 7.32 (dd, J = 8.8, 2.0 Hz, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 7.20 (dd, J = 8.0, 4.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 18.8, 9.2 Hz, 2H), 3.65 (br, 2H). 13 CNMR (101 MHz, Chloroform-d) δ 164.5, 148.5, 145.1, 143.5, 137.8, 137.5, 134.2, 133.1, 132.5, 132.4, 131.4, 130.4, 130.3, 130.2, 120.0, 129.3, 129.0, 128.6, 128.4, 128.3, 127.2, 126.5, 126.0, 123.5, 121.4, 120.8, 119.5, 119.2, 116.1, 112.5.

[0110] Example 14:

[0111]

[0112] Preparation method same as example 1, yellow solid, 903 mg, 87% yield; 1H NMR (400 MHz, Chloroform-d) δ 13.19 (s, 1H), 9.02 (d, J = 9.2 Hz, 1H), 8.88 (dd, J = 7.6, 1.6 Hz, 1H), 8.09 - 8.04 (m, 2H), 8.02 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.83 (dd, J = 8.4, 1.6 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.29 - 7.23 (m, 2H), 7.19 (dd, J = 8.4, 4.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 9.2 Hz, 1H), 3.65 (s, 2H). 13 CNMR (101 MHz, Chloroform-d) δ 164.4, 148.5, 145.1, 143.5, 137.4, 137.3, 134.1, 133.2, 132.8, 132.3, 131.5, 130.2, 129.9, 129.3, 128.7, 128.3, 128.3, 126.9, 126.5, 126.3, 125.3, 125.2, 122.4, 121.3, 120.8, 119.5, 116.0, 113.3.

[0113] Example 15:

[0114]

[0115] Preparation method was the same as example 1, yellow solid, 790 mg, yield 90%; 1 H NMR (400 MHz, Chloroform-d) δ 13.22 (s, 1H), 9.01 (d, J = 8.8 Hz, 1H), 8.85 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 6.4 Hz, 1H), 7.85 (d, J = 5.6 Hz, 1H), 7.78 (dd, J = 8.4, 1.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.27 - 7.08 (m, 8H), 3.54 (br, 2H). 13C NMR (101 MHz, Chloroform-d) δ 164.4, 148.6, 145.1, 143.0, 137.3, 137.2, 134.7, 134.0, 133.0, 132.2, 131.5, 129.7, 129.1, 128.8, 128.3, 128.2 (2C), 128.0, 127.1, 126.7, 126.4, 125.6, 125.1, 124.4, 122.5, 122.4, 122.1, 120.7, 118.6, 113.2.

[0116] Example 16:

[0117]

[0118] Example 1. To a 100 mL round bottom flask was added compound C-1-1 (0.91 g, 2.0 mmol), BBr3(2.50 g, 10.0 mmol) was added at 0 °C, DCM (15 mL) was added via syringe and the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was quenched with water, extracted with dichloromethane (3 x 20 mL), dried over Na2S04and filtered. The organic solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as eluent to obtain C-1-16 as a white solid, 643 mg, 73% yield; 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.77 (s, 1H), 8.92 (d, J = 8.8 Hz, 1H), 8.72 (dd, J = 7.2, 1.6 Hz, 1H), 8.35 (dd, J = 8.4, 1.6 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 8.07 (dd, J = 8.0, 1.6 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H) 7.69 (t, J = 7.6 Hz, 1H), 7.63 (dd, J = 4.4, 2.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.42 - 7.39 (m, 2H), 7.25 (t, J = 7.2 Hz, 2H), 7.18 (ddd, J = 8.0, 6.4, 1.2 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 162.9, 153.7, 148.7, 144.1, 138.1, 136.4, 134.1, 133.6, 133.0, 132.9, 130.6, 130.0, 128.3, 128.2, 128.0 (2C), 127.9, 127.8, 126.8, 126.5, 126.2, 125.4, 124.6, 123.8, 122.9, 122.7, 121.7, 121.1, 118.8, 114.8.

[0119] Example 17:

[0120]

[0121] Preparation method as for Example 1, yellow solid, 589 mg, yield 63%; 1 H NMR (400 MHz, Chloroform-d) δ 12.77 (s, 1H), 8.87 (dd, J = 7.2, 1.6 Hz, 1H), 8.36 (dd, J = 8.8, 2.0 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.87 - 7.83 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.72 (dt, J = 8.0, 1.6 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.37 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.24 - 7.16 (m, 4H), 7.10 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.58 (s, 3H), 1.59 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.7, 158.8, 155.3, 144.9, 137.3, 135.8, 134.2, 134.0, 133.4, 132.0, 131.7, 129.9, 129.4, 128.1 (2C), 128.0, 127.9, 127.0, 126.4, 126.1, 126.0, 125.6, 125.4, 125.3, 125.0, 124.9, 123.8, 121.6, 119.3, 114.2, 56.7, 23.8.

[0122] Example 18:

[0123]

[0124] To a dry 100 mL Schlenk flask was added compound a1-1 (0.57 g, 2.0 mmol), b2-1 (0.54 g, 2.4 mmol), DMAP (0.17 g, 2.4 mmol), DCC (0.04 g, 0.2 mmol), the reaction system was replaced with nitrogen three times and anhydrous DCM (15 mL) was added by syringe under a nitrogen atmosphere, the reaction was stirred at 40 °C for 12 h. After the reaction was completed, it was cooled to room temperature, the organic solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as eluent to obtain white solid C-2-1, 676 mg, yield 67%; 1 H NMR (400 MHz, Chloroform-d) δ 10.52 (s, 1H), 9.12 (dd, J = 4.4, 2.0 Hz, 1H), 8.87 (d, J = 9.2 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 - 7.63 (m, 4H), 7.40 (t, J = 7.2 Hz, 1H), 7.27 - 7.13 (m, 5H), 4.03 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 162.9, 155.3, 149.8, 149.8, 146.0, 144.5, 137.5, 135.9, 134.7, 134.1, 133.4, 131.4, 130.4, 130.1, 129.4, 129.0, 128.7, 128.2, 128.1, 128.0, 126.9, 126.3 (2C), 126.2, 125.6, 124.9, 123.9, 123.4, 123.3, 121.4, 121.1, 117.45, 114.1, 56.7.

[0125] Example 19:

[0126]

[0127] Preparation method was the same as example 18, yellow solid, 886 mg, yield 76%; 1H NMR (400 MHz, Chloroform-d) δ 10.53 (s, 1H), 9.12 (dd, J = 4.4, 2.0 Hz, 1H), 8.93 (d, J = 8.8 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 10.0, 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.68 - 7.65 (m, 3H), 7.30 - 7.25 (m, 2H), 7.20 (ddd, J = 8.4, 6.4, 1.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 4.03 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 162.8, 155.2, 149.8, 149.5, 145.9, 144.4, 137.4, 135.9, 135.1, 133.8, 132.3, 131.9, 130.6, 130.1, 130.0, 129.5, 129.3, 128.9, 128.1, 128.1, 128.0, 127.7, 127.0, 126.1, 125.2, 123.8, 123.5, 123.3, 122.4, 121.0, 118.8, 116.6, 114.0, 56.6.

[0128] Example 20:

[0129]

[0130] Preparation method was the same as example 18, yellow solid, 812 mg, yield 70%; 1H NMR (400 MHz, Chloroform-d) δ 10.57 (s, 1H), 9.13 (dd, J = 4.4, 1.6 Hz, 1H), 8.91 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.18 (d, J = 8.4, 1.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.73 - 7.65 (m, 6H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.23 (s, 1H), 7.22 (t, J = 8.0 Hz, 2H), 4.05 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.0, 155.3, 149.8, 149.8, 146.0, 144.5, 141.2, 137.5, 137.5, 136.0, 134.9, 134.1, 132.6, 131.6, 130.5, 130.1, 129.5, 129.0 (2C), 128.9, 128.1, 128.0, 127.4, 127.3, 127.0, 126.8, 126.2, 126.1, 126.0, 125.6, 123.8, 123.5, 123.4, 122.0, 121.1, 117.4, 114.1, 56.7.

[0131] Example 21:

[0132]

[0133] Preparation method was the same as example 18, yellow solid, 1.07 g, yield 90%; 1H NMR(400MHz,Chloroform-d)δ10.54(s,1H),9.14(dd,J=4.4,1.6Hz,1H),8.90(d,J=9.2Hz,1H),8.50(d,J=8.0Hz,1 H),8.27(d,J=8.4Hz,1H),8.20(dd,J=8.0,1.6Hz,1H),8.14(s,1H),8.12(d,J=5.2Hz,2H),8.06(d,J=9.2Hz,1H),7. 84(d,J=8.4Hz,1H),7.76(d,J=8.8Hz,1H),7.71(d,J=8.8Hz,1H),7.68(d,J=9.2Hz,1H),7.67(t,J=4.4Hz,1H),7.6 0(d,J=8.0Hz,2H),7.49(dd,J=8.8,1.6Hz,1H),7.27(d,J=7.2Hz,3H),7.22–7.18(m,3H),4.05(s,3H),2.41(s,3H). 13 C NMR(101MHz,Chloroform-d)δ162.9,155.3,149.9,149.8,146.0,144.6,138.3,137.5(2C),137.1,136.0,134.7,134.1,132.5,131.6,130.5,130.1 ,129.7,129.5,129.0,128.2,128.0,127.2,127.0,126.8,126.3,126.0,1 25.8,125.6,123.8,123.4,123.3,121.8,121.1,117.4,114.1,56.7,21.3.

[0134] Example 22:

[0135]

[0136] The preparation method is the same as in Example 18. The product is a white solid, 622 mg, with a yield of 60%. 1H NMR (400 MHz, Chloroform-d) δ 10.56 (s, 1H), 9.07 (dd, J = 4.4, 1.6 Hz, 1H), 8.91 (d, J = 9.2 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.18 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (q, J = 8.8 Hz, 2H), 7.65 (dd, J = 8.0, 4.4 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 7.32 - 7.13 (m, 5H), 4.41 - 4.33 (m, 1H), 4.22 - 4.14 (m, 1H), 1.08 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 162.9, 154.9, 149.9, 149.8, 146.0, 144.6, 137.5, 135.8, 134.8, 134.2, 133.5, 131.3, 130.4, 130.1, 129.5, 128.9, 128.6, 128.2, 128.0, 126.9, 126.4, 126.2, 125.7, 124.8, 123.8, 123.5, 123.3, 121.3, 121.0, 118.0, 115.6, 65.00, 15.1.

[0137] Example 23:

[0138]

[0139] Preparation method was the same as example 18, yellow solid, 772 mg, yield 75%; 1H NMR (400 MHz, Chloroform-d) δ 10.33 (s, 1H), 9.17 (dd, J = 4.4, 2.0 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.39 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.15 (dd, J = 8.0, 1.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.45 - 7.38 (m, 4H), 7.31 - 7.24 (m, 4H), 6.99 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 162.6, 149.9, 149.5, 146.0, 144.5, 141.5, 140.9, 137.4, 135.8, 134.5, 134.1, 133.3, 133.2, 130.7, 130.3, 130.1, 129.4, 129.1, 128.9, 128.7 (2C), 128.2 (2C), 128.1, 127.5, 127.0, 126.9, 126.8, 126.6, 126.6, 126.1, 126.1, 125.4, 124.8, 123.4, 121.0, 120.9.

[0140] Example 24:

[0141]

[0142] Preparation method was the same as example 18, yellow solid, 665 mg, yield 68%; 1H NMR (400 MHz, Chloroform-d) δ 10.45 (s, 1H), 9.05 (dd, J = 4.4, 2.0 Hz, 1H), 8.99 (d, J = 9.2 Hz, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.97 (dd, J = 8.8, 2.8 Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.62 - 7.59 (m, 2H), 7.54 (d, J = 8.8 Hz, 1H), 7.43 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.38 (ddd, J = 8.4, 5.6, 2.4 Hz, 1H), 7.28 - 7.23 (m, 3H), 7.07 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 162.9, 150.0, 149.3, 145.8, 144.3, 137.4, 136.2, 135.7, 134.4, 133.3, 133.1, 132.6, 131.2, 130.8, 129.9, 129.3, 128.8, 128.7, 128.6, 128.2, 128.1, 128.0, 126.6, 126.6, 125.9 (3C), 125.6, 125.2, 125.0, 123.3, 120.8, 120.7, 20.4.

[0143] Example 25:

[0144]

[0145] Preparation method was the same as example 18, yellow solid, 454 mg, yield 45%; 1H NMR (400 MHz, Chloroform-d) δ 10.57 (s, 1H), 9.02 (d, J = 8.8 Hz, 1H), 8.92 (dd, J = 4.4, 2.0 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.12 (dd, J = 8.0, 1.6 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.92 (t, J = 4.8 Hz, 1H), 7.71 (t, J = 4.4 Hz, 1H), 7.67 (t, J = 4.4 Hz, 1H), 7.59 (dd, J = 8.0, 4.4 Hz, 1H), 7.40 - 7.29 (m, 4H), 7.24 - 7.17 (m, 3H), 0.91 (sept, J = 14.8, 7.6 Hz, 3H), 0.61 (d, J = 4.4 Hz, 9H), 0.59 (d, J = 4.0 Hz, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 162.7, 152.1, 145.0, 149.7, 145.9, 144.4, 137.3, 135.5, 135.2, 134.7, 133.4, 131.2, 130.3, 129.8, 129.5, 128.7, 128.4, 128.1, 128.0, 127.0, 126.4, 126.0, 125.9, 125.6, 124.6, 123.7, 123.4, 123.1, 120.8, 120.7, 120.5, 118.9, 17.6 (2C), 12.9.

[0146] Example 26:

[0147]

[0148] Preparation method same as example 18, yellow solid, 560 mg, yield 52%; 1H NMR (400 MHz, Chloroform-d) δ 10.31 (s, 1H), 9.20 (dd, J = 4.4, 1.6 Hz, 1H), 8.67 (d, J = 8.0 Hz, 1H), 8.44 (d, J = 8.9 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.22 (dd, J = 8.0, 1.6 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.97 - 7.91 (m, 3H), 7.82 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.4, 4.4 Hz, 1H), 7.45 (d, J = 4.0 Hz, 2H), 7.42 (t, J = 5.2 Hz, 1H), 7.32 (d, J = 3.6 Hz, 2H), 7.28 - 7.25 (m, 4H), 6.71 (d, J = 7.6 Hz, 2H), 2.11 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 162.6, 150.0, 149.7, 146.1, 144.6, 140.9, 138.6, 137.4, 136.4, 135.9, 134.5, 134.1, 133.2, 130.7, 130.3, 130.1, 129.5, 129.0 (2C), 128.7, 128.6, 128.4, 128.3, 128.2, 128.1, 127.1, 126.8, 126.7, 126.6, 126.2, 125.9, 125.8, 124.8, 123.4, 121.2, 121.0, 21.2.

[0149] Example 27:

[0150]

[0151] To a dry 100 mL Schlenk flask was added compound a1-2 (0.62 g, 2.0 mmol), b2-1 (0.54 g, 2.4 mmol), EDCI (0.50 g, 2.6 mmol, HOBt (0.35 g, 2.6 mmol), DIPEA (0.52 g, 4.0 mmol), the reaction system was replaced with nitrogen three times and anhydrous DCM (15 mL) was added by syringe under a nitrogen atmosphere, the reaction was stirred at 25 °C for 12 h. After the reaction was completed, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution, dichloromethane (3 x 20 mL) was extracted, the combined organic phase was washed with saturated brine, dried over Na2S04, filtered, and the organic solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) as eluent to obtain white solid C-1-1, 952 mg, yield 99%; the organic solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as eluent, yellow solid, 626 mg, yield 62%; 1 H NMR (400 MHz, Chloroform-d) δ 10.49 (s, 1H), 9.13 (dd, J = 4.4, 1.6 Hz, 1H), 8.78 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.20 (dd, J = 8.0, 1.6 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.95 (t, J = 7.2 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.75 (q, J = 8.8 Hz, 2H), 7.67 (dd, J = 8.4, 4.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.43 (ddd, J = 8.4, 5.2, 2.8 Hz, 1H), 7.28 - 7.23 (m, 3H), 7.14 (ddd, J = 8.8, 6.8, 1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 2.65 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 163.4, 150.5, 150.2, 149.8, 146.0, 144.7, 137.4, 135.9, 134.1, 134.0, 133.9, 131.5, 130.1, 130.0, 129.5, 129.0, 128.5, 128.3, 128.1, 127.9, 126.8, 126.6, 126.5, 126.4, 126.3, 125.8, 124.9, 123.8, 123.4, 122.6, 122.3, 121.4, 120.0, 43.8.

[0152] Example 28:

[0153]

[0154] Example 18. Into a 100 mL round bottom flask was added compound C-2-1 (1.01 g, 2.0 mmol), BBr3(1.50 g, 6.0 mmol) was added at 0 °C, DCM (15 mL) was added via syringe and the reaction was stirred at room temperature for 12 h. After the reaction was complete, the reaction mixture was quenched with water, extracted with dichloromethane (3 x 20 mL), dried over Na2S04, filtered and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as eluent. Compound C-2-10 was obtained as a white solid, 412 mg, 42% yield; 1 H NMR (400 MHz, Chloroform-d) δ 12.22 (s, 1H), 12.06 (s, 1H), 9.34 (dd, J = 4.4, 1.6 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.33 (dd, J = 8.0, 1.6 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.80 - 7.78 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.43 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.35 (t, J = 8.4 Hz, 2H), 7.28 - 7.18 (m, 2H), 7.09 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 161.6, 151.9, 145.0, 149.5, 145.3, 143.1, 138.0, 137.8, 134.6, 134.5, 134.3, 131.3, 130.1, 129.6, 129.2, 129.1, 128.2, 127.9 (2C), 127.3, 126.9, 126.4, 126.3, 124.8, 124.3, 123.6, 123.4, 120.9, 120.6, 119.9, 118.1.

[0155] Example 29:

[0156]

[0157] Into a dry 100 mL Schlenk flask was added compound a1-1 (0.57 g, 2.0 mmol), b3-1 (0.69 g, 4.0 mmol), EDCI (0.77 g, 4.0 mmol), DMAP (0.49 g, 4.0 mmol),), the reaction system was replaced with nitrogen three times and anhydrous DCM (15 mL) was added under a nitrogen atmosphere by syringe, the reaction was stirred at 25 °C for 12 hours. After the reaction was completed, it was cooled to room temperature, the organic solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (3:1) as the eluent, yellow solid, 726 mg, yield 80%; 1 H NMR (400 MHz, Chloroform-d) δ 10.41 (s, 1H), 9.08 (d, J = 9.2, Hz, 1H), 8.22 (d, J = 8.4, Hz, 1H), 8.21 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.47 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H), 7.40 - 7.36 (m, 2H), 7.30 (ddd, J = 8.0, 6.4, 1.6 Hz, 1H), 7.26 - 7.24 (m, 2H), 7.21 - 7.14 (m, 2H), 3.75 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 161.9, 155.5, 149.7, 146.0, 137.5, 134.7, 134.1, 133.3, 131.0, 130.9, 130.0, 129.6, 129.5, 129.2, 129.0, 128.3, 128.2, 127.9, 127.6, 127.3, 126.5, 126.0, 125.2, 124.7, 124.2, 121.6, 119.4, 118.4, 117.5, 114.0, 56.7.

[0158] Example 30: Application of axially chiral nitrogen-containing heteroaromatic ring amide ligand-palladium in asymmetric catalytic intramolecular amination alkylation reaction.

[0159]

[0160] A 25 mL Schlenk flask was selected and compound 1a (10.5 mg, 0.05 mmol), Pd(CF3CO2)2(10 mol%), chiral quinoline amide ligand C-2-1 (15 mol%), potassium carbonate (3.5 equiv.) and acetonitrile (1.0 mL) were added. MS (0.6 equiv). The reaction flask was replaced with nitrogen three times, then acetonitrile (1.0 mL) was added, and the reaction system was stirred at 40°C for 36 hours. After the reaction was completed, the reaction liquid was filtered with diatomite, and the filtrate was distilled under reduced pressure. The crude product was directly separated by silica gel column chromatography to obtain compound 2a, 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 7.8 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 4.67 - 4.62 (m, 1H), 3.18 (dd, J = 15.6, 8.5 Hz, 1H), 2.93 - 2.81 (m, 2H), 2.59 (dd, J = 16.6, 8.5 Hz, 1H), 2.51 - 2.45 (m, 1H), 2.04 - 1.93 (m, 1H); 13 CNMR (101 MHz, Chloroform-d) δ 171.6, 139.0, 134.1, 127.5, 125.2, 124.1, 114.5, 62.8, 36.2, 35.6, 29.2; the obtained partial axially chiral nitrogen-containing heteroaromatic ring amide ligand example results are shown in Table 1.

[0161] Table 1. Axially chiral nitrogen-containing heteroaromatic ring amide ligand-palladium catalyzed intramolecular amination alkylation reaction of olefins

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] The above merely provides the specific implementation of the present application, but the protection scope of the present application is not limited to this. Any change or replacement within the technical range disclosed by the present application, which can be easily thought by any person skilled in the art, should be covered in the protection scope of the present application. Therefore, the protection scope of the present application should be subject to the protection scope of the claims.

Claims

1. A chiral nitrogen-containing heterocyclic amide ligand, characterized in that, The axially chiral nitrogen-containing heterocyclic amide ligand has the following general formula (Ⅰ): In the general formula (Ⅰ): The chirality marked with * indicates R configuration, S configuration, or racemic configuration; The axial chiral portion of the ligand is A; The nitrogen-containing heteroaromatic ring portion B of the ligand can be arbitrarily selected from B-1, B-2, or B-3; R 1 It is selected from any one of alkyl, alkoxy, hydroxy, siloxy, phenyl, substituted phenyl, amino, and substituted amino groups; R 2 and R 3 Each is independently selected from hydrogen, halogen, phenyl, or substituted phenyl; R 4 Selected from alkyl groups.

2. The axially chiral nitrogen-containing heterocyclic amide ligand according to claim 1, characterized in that, When the R 1 When R is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl, or benzyl; 1 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, n-pentyloxy, isopentyloxy, neopentyloxy, or benzyloxy; when the R 1 When the siloxy group is a siloxy group, the siloxy group is trimethylsiloxy, triethylsiloxy, tri-n-propylsiloxy, triisopropylsiloxy, tri-n-butylsiloxy, triisobutylsiloxy, tri-n-pentylsiloxy, triisopentylsiloxy, or trinepentylsiloxy; when the R 1 When the substituted phenyl group is used, the substituted phenyl group is a methyl-substituted phenyl group, a trifluoromethyl-substituted phenyl group, a methoxy-substituted phenyl group, an ethyl-substituted phenyl group, a tert-butyl-substituted phenyl group, or a fluorine-substituted phenyl group; when the R 1 When the substituted amino group is used, the substituted amino group is a methyl-substituted amino group, an ethyl-substituted amino group, a n-propyl-substituted amino group, an isopropyl-substituted amino group, a n-butyl-substituted amino group, an isobutyl-substituted amino group, a n-pentyl-substituted amino group, an isopentyl-substituted amino group, a neopentyl-substituted amino group, a benzyl-substituted amino group, or a phenyl-substituted amino group. When the R 2 and R 3 When the substituted phenyl group is used, 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, a bromine-substituted phenyl group, or an iodine-substituted phenyl group; when the R 2 and R 3 When the halogen is halogen, the halogen is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; When the R 4 When the alkyl group is alkyl, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl.

3. A method for preparing the axially chiral nitrogen-containing heterocyclic amide ligand as described in claim 1, characterized by comprising: The following steps are required: (1) Compound C-1 is prepared by reacting compound a1 and compound b1 in an organic solvent under nitrogen or inert gas with a condensing agent. (2) Compound C-2 is prepared by reacting compound a1 and compound b2 in an organic solvent under nitrogen or inert gas with a condensing agent. (3) Compound C-3 is prepared by reacting compound a1 and compound b3 in an organic solvent under nitrogen or inert gas with a condensing agent.

4. The method for preparing an axially chiral nitrogen-containing heterocyclic amide ligand according to claim 3, characterized in that, The organic solvents mentioned in steps (1), (2) and (3) are one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide; The inert gas in steps (1), (2) and (3) includes one or more of argon, helium, neon and krypton; The condensing agents mentioned in steps (1), (2), and (3) are condensing agents 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'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, and 2-(1H-benzotriazolyl-L-1-yl) One or more of the following: 1,1,3,3-tetramethylurea tetrafluoroborate, 2-succinimide-1,1,3,3-tetramethylurea tetrafluoroborate, 2-(intra-5-norbornene-2,3-dicarboxylimide)-1,1,3,3-tetramethylurea tetrafluoroborate, benzotriazol-1-oxytris(dimethylamino)phosphine hexafluorophosphate, benzotriazol-1-yl-oxytripyrrolylphosphine hexafluorophosphate, and (3H-1,2,3-triazol[4,5-b]pyridine-3-oxy)tri-1-pyrrolyl hexafluorophosphate, 4-dimethylaminopyridine; The catalysts mentioned in steps (1), (2) and (3) are one or more of 4-pyrrolidinylpyridine, N,N,N-trimethylaminopyridine, and 4-dimethylaminopyridine; The preparation method of the axially chiral nitrogen-containing heterocyclic amide ligand, wherein the reaction temperature of the synthesis steps (1), (2) and (3) is -30 to 70°C; The preparation method of the axially chiral nitrogen-containing heterocyclic amide ligand, wherein the reaction time of the synthesis steps (1), (2) and (3) is 1-72 hours; In the preparation method of the axially chiral nitrogen-containing heterocyclic amide ligand, the molar ratio of compound a1 to compound b1 in step (1) is 1:5 to 5:

1. In the preparation method of the axially chiral nitrogen-containing heterocyclic amide ligand, the molar ratio of compound a1 to compound b2 in step (2) is 1:5 to 5:

1. In the preparation method of the axially chiral nitrogen-containing heterocyclic amide ligand, the molar ratio of compound a1 to compound b3 in step (3) is 1:5 to 5:

1.

5. A method for synthesizing chiral nitrogen-containing heterocyclic compounds, characterized in that, The method for synthesizing chiral nitrogen-containing heterocyclic compounds includes the following steps: Under a reaction gas atmosphere, the axially chiral nitrogen-containing heterocyclic amide ligand as described in claim 1 is complexed with a palladium salt and a base in an organic solvent, and compound 1 is reacted according to the following formula to obtain compound 2; Among them, R 5 –R 9 Selected from alkyl, alkoxy, halogen atom or hydrogen; In compound 1, X is a chlorine atom, a bromine atom, or an iodine atom; The chirality marked with * indicates S configuration, R configuration, or racemic chirality.

6. The method for synthesizing chiral nitrogen-containing heterocyclic compounds according to claim 5, characterized in that, When R 5 –R 9 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 5 –R 9 When R is an alkoxy group, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, n-pentyloxy, isopentyloxy, or neopentyloxy; when R 5 –R 9 When the halogen atom is a halogen atom, the halogen atom is a chlorine atom, a bromine atom, or an iodine atom; The reacting gas is one or more of oxygen, carbon monoxide, carbon dioxide, nitrogen, and air; The organic solvent is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide. In this invention, the palladium salt is selected from at least one of bis(triphenylphosphine)palladium chloride, tris(dibenzylacetone)palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, bis(acetonitrile)palladium dichloride, [1,3-bis(diphenylphosphine)propane]palladium dichloride, tetra(triphenylphosphine)palladium, palladium acetylacetonate, 1,1'-bis(di-tert-butylphosphine)ferrocene dichloride palladium, palladium acetate, palladium chloride, and palladium trifluoroacetate; The base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, cesium carbonate, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, calcium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and pyridine; The molar concentration of compound 1 in the organic solvent is 0.01–1.0 M; The molar ratio of the palladium salt to the base is 1:1 to 1:10; The molar ratio of the palladium salt to the axially chiral nitrogen-containing heterocyclic amide ligand is 1:1 to 1:5.

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