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

Abstract

The invention discloses an axially chiral nitrogen-containing heteroaromatic ring sulfonamide ligand as well as a preparation method and application thereof. The axially chiral nitrogen-containing heteroaromatic ring sulfonamide ligand has a structure shown in a general formula (I), wherein an axially chiral part A of a # imgabs0 # ligand is selected from A-1 or A-2; and the nitrogen-containing heteroaromatic ring part B of the ligand is selected from B-1 or B-2. The axially chiral nitrogen-containing heteroaromatic ring sulfonamide ligand and a transition metal compound form a complex catalyst in situ in a reaction system, and in the reaction of catalyzing free radical coupling of halogenated amide and amine to synthesize a chiral amino amide compound, good to excellent yield, enantioselectivity and good substrate universality are shown; good industrial application prospects are realized. 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 novel class of axially chiral nitrogen-containing heteroaromatic sulfonamide ligands, their preparation methods and uses. The catalysts formed by such ligands and transition metals can be used in the asymmetric radical coupling reaction of racemic alkyl halides and amine compounds to synthesize chiral amino amide compounds, and have high catalytic activity and enantioselectivity. Background Art

[0002] Chiral nitrogen-containing heteroaromatic sulfonamide ligands (such as pyridine sulfonamide, quinoline sulfonamide, etc.) are a class of chiral ligands with chelating ability and play an important role in the reactions of asymmetric catalytic construction of carbon-carbon bonds and carbon-heteroatom bonds. Most of the chiral sources of the currently known chiral nitrogen-containing heteroaromatic sulfonamide ligands have a structure with central chirality, such as chiral cyclohexanediamine, chiral oxazoline, chiral 1,2-diphenylethylenediamine, and cinchona alkaloid derivatives. Such nitrogen-containing heteroaromatic sulfonamides can not only coordinate with transition metals to form metal complexes for catalytic asymmetric synthesis reactions but also act as organic small molecule catalysts to achieve various asymmetric catalytic transformations. Therefore, the design, synthesis, and application of such ligands / catalysts have always attracted much attention. For example, in 2015, the Nakamura group reported a cinchona alkaloid-derived chiral organic small molecule catalyst (D) for the asymmetric addition of thiols to isatin-derived ketimines with an ee value of up to 97% (Nakamura, S. et al. Org. Lett. 2015, 17, 106 - 109). In 2016, the Nakamura group reported the enantioselective conjugate addition reaction of malonic acid-derived thioesters with coumarin-3-carboxylic acid catalyzed by a cinchona alkaloid-derived chiral quinoline sulfonamide (E), and chiral δ-lactone compounds were synthesized with a yield of up to 99% and an enantioselectivity of 94% (Nakamura, S. et al. Adv. Synth. Catal. 2016, 358, 1029–1034). In 2018, the Kowalczyk and Boratyński groups reported a chiral cyclohexanediamine-derived quinoline sulfonamide (F) for the catalytic asymmetric Michael hemiacetal reaction (Kowalczyk & Boratyński et al. Catal. Sci. Technol. 2018, 8, 4358–4363). In 2022, the Liu Xinyuan group reported a quinoline sulfonamide ligand (G) derived from the chiral 1,2-diphenylethylenediamine skeleton, realizing the asymmetric coupling reaction of alkyl halides with alkenyl boronic esters (Liu, X.-Y. & Li, Z.-L. et al. J. Am. Chem. Soc. 2022, 144, 6442 - 6452). In 2023, the Liu Xinyuan group used a complex formed by a cinchona alkaloid-derived quinoline sulfonamide (E) as a chiral ligand and a transition metal copper salt to catalyze the stereoconvergent N-alkylation reaction of alkylamines, and various chiral amino amide derivatives were synthesized with a yield of up to 99% and an enantioselectivity of 98%. At the same time, a chiral oxazoline-derived quinoline sulfonamide ligand (H) and cuprous iodide can catalyze the asymmetric coupling reaction of α-carbonyl chlorides with aromatic amines.(Liu, X.-Y. et al. Nature 2023, 618, 294 - 300; Liu, X.-Y. et al. J. Am. Chem. Soc. 2023, 145, 14686 - 14696;).

[0003]

[0004] Axially chiral binaphthyl and spiroindane skeletons, as two types of dominant chiral skeletons, have extensive applications in the field of asymmetric catalysis. Many excellent chiral ligands and catalysts (such as chiral phosphoric acid, chiral amine, chiral diphosphine, chiral cyclopentadiene, etc.) have been developed based on these two types of axially chiral skeletons. However, axially chiral nitrogen-containing heteroaromatic sulfonamide ligands based on binaphthyl and spiroindane skeletons have been rarely reported. Binaphthyl and spiroindane have unique axially chiral structures and multi-site adjustable characteristics. Their rigid structural skeletons and tight chiral environments are the key factors for asymmetric induction. Using binaphthyl and spiroindane as chiral sources to design and develop new axially chiral nitrogen-containing heteroaromatic sulfonamide ligands is expected to provide new dominant chiral ligands for asymmetric catalytic synthesis reactions (especially radical coupling reactions), provide new methods for the synthesis of chiral molecules, and the relevant research results have important practical value in asymmetric synthesis chemistry. Summary of the Invention

[0005] The purpose of the present invention is to provide a novel axially chiral nitrogen-containing heteroaromatic sulfonamide ligand.

[0006] Another purpose of the present invention is to provide a synthesis method of the above axially chiral nitrogen-containing heteroaromatic sulfonamide ligand.

[0007] The purpose of the present invention also lies in providing the use of the above axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, that is, after in-situ forming a complex catalyst in combination with a transition metal compound, it is applied to the reaction of catalytic radical coupling of haloamides and amines to synthesize chiral amino amide compounds.

[0008] The present invention provides an axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, which is characterized in that the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand has the structure of the following general formula (Ⅰ):

[0009]

[0010]

[0011] In the general formula (Ⅰ):

[0012] The chirality marked with * is of R configuration or S configuration, or is racemic;

[0013] The axially chiral part A of the ligand can be arbitrarily selected from A-1 or A-2;

[0014] The nitrogen-containing heteroaromatic moiety B of the ligand can be optionally selected from B-1 or B-2;

[0015] R 1 is selected from any one of alkyl, alkoxy, hydroxyl, siloxy, phenyl, substituted phenyl, substituted amino, and carbonyl;

[0016] R 2 -R 7 are each independently selected from any one of hydrogen, halogen, alkyl, substituted phenyl, aryl, heteroaryl, nitro, ester group, cyano group, aldehyde group, and alkoxy;

[0017] R 8 is selected from any one of hydroxyl, alkoxy, amino, and substituted amino;

[0018] R 9 -R 18 are each independently selected from any one of hydrogen, halogen, alkyl, aryl, and heteroaryl.

[0019] In a preferred experimental scheme of the present invention, 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-butoxy, isobutoxy, n-pentyloxy, isopentyloxy, neopentyloxy, or benzyloxy; when the R 1 is siloxy, the siloxy is trimethylsilyloxy, triethylsilyloxy, tri-n-propylsilyloxy, triisopropylsilyloxy, tri-n-butylsilyloxy, triisobutylsilyloxy, tri-n-pentylsilyloxy, triisopentylsilyloxy, or trineopentylsilyloxy; when the R 1 is substituted phenyl, the substituted phenyl is methyl-substituted phenyl, trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, ethyl-substituted phenyl, tert-butyl-substituted phenyl, or fluoro-substituted phenyl; when the R 1 is substituted amino, the substituted amino is methyl-substituted amino, ethyl-substituted amino, n-propyl-substituted amino, isopropyl-substituted amino, n-butyl-substituted amino, isobutyl-substituted amino, n-pentyl-substituted amino, isopentyl-substituted amino, neopentyl-substituted amino, benzyl-substituted amino, or phenyl-substituted amino.

[0020] In a preferred experimental scheme of the present invention, when the R 2 -R 7 are each independently alkyl, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl; when the R2 -R 7 When -R are each independently an alkoxy group, the alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group; when the R 2 -R 7 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-butoxy-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 7 is an aryl group, the aryl group is a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group or a pyrenyl group; when the R 2 -R 7 are each independently a heteroaryl group, the heteroaryl group is a furyl group, a thiophenyl group, an indolyl group or a pyridyl group.

[0021] In a preferred experimental scheme of the present invention, when the R 8 is an alkoxy group, the alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group; when R 8 is a substituted amino group, the substituted amino group is a methyl-substituted amino group, an ethyl-substituted amino group, an isopropyl-substituted amino group, a phenyl-substituted amino group or a benzyl-substituted amino group.

[0022] In a preferred experimental scheme of the present invention, when the R 9 -R 18 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, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group or a hexyl group; when the R 9 -R 18 is an aryl group, the aryl group is a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group or a pyrenyl group; when the R 9 -R 18 is a heteroaryl group, the heteroaryl group is a furyl group, a thiophenyl group, an indolyl group or a pyridyl group.

[0023] The present invention also provides a preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, and the characteristics thereof include the following steps:

[0024] (1) In an organic solvent, under nitrogen or an inert gas, react compound a1 with compound b1 under the action of a base to prepare compound C-1;

[0025]

[0026] (2) In an organic solvent, under nitrogen or an inert gas, react compound a1 with compound b2 under the action of a base to prepare compound C-2;

[0027]

[0028] (3) In an organic solvent, under nitrogen or an inert gas, react compound a2 with compound b1 under the action of a base to prepare compound C-3;

[0029]

[0030] (4) In an organic solvent, under nitrogen or an inert gas, react compound a2 with compound b2 under the action of a base to prepare compound C-4.

[0031]

[0032] In the present invention, the organic solvent described in steps (1), (2), (3) and (4) 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;

[0033] The inert gas described in steps (1), (2), (3) and (4) includes one or more of argon, helium, neon and krypton;

[0034] The base described in steps (1), (2), (3) and (4) is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, 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;

[0035] For the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the reaction temperature of steps (1), (2), (3) and (4) is -30 to 70 °C;

[0036] For the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the reaction time of steps (1), (2), (3) and (4) is 1 to 72 hours;

[0037] In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a1 to compound b1 in step (1) is a molar ratio of 1:5 to 5:1;

[0038] In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a1 to compound b2 in step (2) is a molar ratio of 1:5 to 5:1;

[0039] In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a2 to compound b1 in step (3) is a molar ratio of 1:5 to 5:1;

[0040] In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a2 to compound b2 in step (4) is a molar ratio of 1:5 to 5:1.

[0041] In the present invention, after the synthesis reactions described in steps (1), (2), (3) and (4) are completed, it further includes solvent removal under reduced pressure.

[0042] In the present invention, after the synthesis reactions described in steps (1), (2), (3) and (4) are completed, it further includes a post-treatment step. The post-treatment step can be a conventional post-treatment step in the art. The post-treatment step includes one or more steps of extraction, washing, drying, and column chromatography.

[0043] In the present invention, the extractant described in steps (1), (2), (3) and (4) 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 the art, such as saturated sodium chloride solution; the drying can be carried out using conventional desiccants 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 for 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.

[0044] The present invention also provides a complex, which is characterized in that the complex is formed by in-situ complexation of an axially chiral nitrogen-containing heteroaromatic sulfonamide ligand and a transition metal compound in a reaction system. The transition metal compound is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, copper bromide, copper chloride, copper trifluoromethanesulfonate, copper acetylacetonate, copper tetraethylacetonitrile hexafluorophosphate, nickel iodide, nickel chloride, nickel trifluoromethanesulfonate, ferric trichloride, ferric tribromide, ferrous trifluoromethanesulfonate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, and palladium chloride.

[0045] The present invention also provides a method for synthesizing chiral amino amide compounds, which is characterized in that the method for synthesizing chiral amino amide compounds comprises the following steps: under a reaction gas, the axially chiral nitrogen-containing heterocyclic sulfonamide ligand is complexed with a copper salt and a base in an organic solvent, and compound 1 and compound 2 are subjected to the following reaction to obtain compound 3.

[0046]

[0047] Wherein, R 19 -R 21 is selected from alkyl, substituted phenyl, aryl;

[0048] X in the compound 1 is a chlorine atom, a bromine atom or an iodine atom;

[0049] The chirality marked with * is of S configuration, R configuration or racemic.

[0050] In the present invention, the method for synthesizing chiral amino amide compounds is characterized in that when R 19 -R 21 is alkyl, the alkyl is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; when the R 19 -R 21 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, fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl; when R 19 -R 21 is aryl, the aryl is naphthyl, anthryl, phenanthryl or pyrenyl.

[0051] In the present invention, the reaction gas is one or more of oxygen, carbon monoxide, carbon dioxide, nitrogen, air.

[0052] In the present invention, the organic solvent is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

[0053] In the present invention, the copper salt is selected from at least one of copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide, copper acetate, copper acetylacetonate, copper perchlorate, copper trifluoroacetate, copper tetrafluoroborate, tetraethylacetonitrile copper hexafluorophosphate, cuprous cyanide, copper thiocyanate, copper thiophene-2-carboxylate, and cuprous oxide.

[0054] In the present invention, 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, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and pyridine.

[0055] In the present invention, the molar concentration of Compound 1 in the organic solvent is 0.01 - 1.0 M.

[0056] In the present invention, the molar concentration of Compound 2 in the organic solvent is 0.01 - 1.0 M.

[0057] In the present invention, the molar ratio of the copper salt to the base is 1:1 - 1:10.

[0058] In the present invention, the molar ratio of the copper salt to the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand is 1:1 - 1:5.

[0059] In the embodiment 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.

[0060] The term "e.r." refers to the enantiomeric ratio.

[0061] The positive and progressive effects of the present invention are as follows:

[0062] The present invention provides a novel axially chiral nitrogen-containing heteroaromatic sulfonamide ligand. The main structural features are the presence of a binaphthyl or spirodihydroindene axially chiral unit and groups such as pyridine sulfonamide and quinoline sulfonamide. The synthesis method of this ligand uses binaphtholamine (NOBIN), binaphthyl diamine (BINAM), or 1,1'-spirodihydroindene-7,7'-diol (SPINOL) and pyridine sulfonyl chloride, quinoline sulfonyl chloride as starting materials, and the target molecule is obtained through the construction of a sulfonamide bond. The structure of the target molecule of the present invention is simple and clear, the experimental operation is simple, and it can be prepared on a large scale. It has potential application value in asymmetric catalytic synthesis.

[0063] The novel axially chiral nitrogen-containing heteroaromatic sulfonamide ligand provided by the present invention can form a complex in situ with a copper salt as a chiral ligand in a reaction system, and shows good to excellent yields, enantioselectivity and good substrate generality in the catalytic radical coupling reaction of haloamides with alkylamines or aromatic amines, and has good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 1H NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-1-2 provided by the embodiment of the present invention;

[0065] Figure 2 13C NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-1-2 provided by the embodiment of the present invention;

[0066] Figure 3 1H NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-2-2 provided by the embodiment of the present invention;

[0067] Figure 4 13C NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-2-2 provided by the embodiment of the present invention;

[0068] Figure 5 1H NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-3-4 provided by the embodiment of the present invention;

[0069] Figure 6 13C NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-3-4 provided by the embodiment of the present invention;

[0070] Figure 7 1H NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-4-1 provided by the embodiment of the present invention;

[0071] Figure 8 13C NMR spectrum of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand C-4-1 provided by the embodiment of the present invention; DETAILED DESCRIPTION OF THE INVENTION

[0072] The present invention will be further described in detail below through specific embodiments, but the scope of the present invention is not limited thereby.

[0073] The information of the instruments and experimental materials used in the following examples is as follows:

[0074] All chemical reagents were purchased as commercial reagents, and the reagents were sourced from reagent companies such as Adamas, Bidepharm, Leyan, and J&K. Thin layer chromatography (TLC) was performed using SHF254 silica gel plates, and the silica gel powder used for column chromatography was Notai silica gel powder (300-400 mesh). TLC was carried out using UV light (254 nm). 1 HNMR and13 13C NMR was characterized using a Bruker AVANCEⅢ 400 MHz nuclear magnetic resonance instrument. The solvents were deuterated chloroform, deuterated methanol, or deuterated dimethyl sulfoxide. 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 br represents a broad peak. 13 In 13C NMR, δ represents the chemical shift. The enantiomeric ratio (e.r.) was determined by Shimadzu LC-20A high performance liquid chromatography and Daicel Chiralpak and Chiralcel chiral columns.

[0075] Example 1:

[0076]

[0077] Compound a1-1 (0.57 g, 2.0 mmol) and b1-1 (0.55 g, 2.4 mmol) were added to a dry 100 mL Schlenk flask. The reaction system was purged with nitrogen three times, and anhydrous CH3CN (15 mL) and pyridine (0.47 g, 6.0 mmol) were added via syringe under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was washed with 1 M hydrochloric acid and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the organic solvents were removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) as the eluent to obtain 952 mg of white solid C-1-1, with a yield of 99%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.50 (s, 1H), 8.14–8.11 (m, 2H), 8.04–7.98 (m, 3H), 7.92–7.88 (m, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 8.2, 1.3 Hz, 1H), 7.40 (dd, J = 8.2, 7.3 Hz, 1H), 7.36–7.32 (m, 2H), 7.12–7.08 (m, 2H), 6.99 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 6.62–6.57 (m, 2H), 6.01 (dd, J = 8.4, 1.1 Hz, 1H). 1313C NMR (101 MHz, DMSO-d6) δ 153.58, 150.83, 141.88, 136.71, 136.09, 134.47, 134.35, 133.94, 132.94, 131.37, 130.85, 129.41, 128.63, 128.31, 128.17, 128.10, 127.53, 126.77, 126.64, 126.06, 125.50, 125.34, 124.75, 123.72, 122.94, 122.68, 122.60, 118.18, 113.05.

[0078] Example 2:

[0079]

[0080] Compound a1-2 (0.6 g, 2 mmol) and b1-1 (0.55 g, 2.4 mmol) were added to a dry 100 mL Schlenk flask. The reaction system was purged with nitrogen three times and anhydrous CH3CN (15 mL) and pyridine (0.47 g, 6 mmol) were added via syringe under a nitrogen atmosphere. Subsequently, the reaction mixture was stirred at 90 °C for 12 hours. After cooling to room temperature, the reaction mixture was washed with 1 M hydrochloric acid and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the organic solvents were removed. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) as the eluent to obtain white solid C-1-2, 975 mg, yield 99%; 1 1H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.12 (dd, J = 7.4, 1.4 Hz, 1H), 8.06 (dd, J = 4.4, 1.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.87–7.82 (m, 2H), 7.64 (dd, J = 8.2, 1.4 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.32–7.28 (m, 2H), 7.16 (dd, J = 8.2, 4.2 Hz, 1H), 7.07–7.0 (m, 3H), 6.67–6.62 (m, 2H), 6.34 (d, J = 8.8 Hz, 1H), 3.57 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 154.80, 150.29, 142.46, 136.92, 135.72, 134.12, 133.82, 133.08, 132.92, 131.49, 130.48, 129.53, 128.61, 128.00, 127.91, 127.42, 126.70, 126.18, 125.91, 125.06, 124.89, 124.46, 124.42, 124.01, 123.30, 121.62, 117.08, 112.39, 56.12.

[0081] Example 3:

[0082]

[0083] The preparation method was the same as that of Example 2. It was a yellow solid, 82 mg, with a yield of 75%; 1 H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.59 (dd, J = 4.4, 1.8 Hz, 1H), 8.07 (s, 1H), 7.96–7.93 (m, 1H), 7.91–7.89 (m, 1H), 7.78 (dd, J = 8.4, 1.8 Hz, 1H), 7.75–7.72 (m, 2H), 7.66 (dd, J = 7.3, 1.5 Hz, 1H), 7.58–7.50 (m, 4H), 7.45–7.40 (m, 2H), 7.40–7.33 (m, 3H), 7.27 (s, 1H), 7.12–7.04 (m, 3H), 6.92 (dd, J = 8.1, 7.3 Hz, 1H), 6.84 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 6.77–6.73 (m, 2H), 2.90 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 153.29, 150.58, 142.14, 141.29, 140.73, 138.06, 137.81, 135.74, 133.42, 133.10, 132.44, 132.26, 130.88, 130.58, 130.45, 130.05, 129.58, 129.33, 128.41, 128.16, 128.15, 128.09, 127.68, 127.57, 127.30, 127.08, 126.57, 126.37, 126.23, 126.06, 125.87, 125.77, 125.04, 124.76, 121.35, 60.18.

[0084] Example 4:

[0085]

[0086] The preparation method is the same as that of Example 2, white solid, 600 mg, yield 98%; 1 H NMR(400MHz,Chloroform-d)δ8.49(s,1H),8.14(d,J=9.0Hz,1H),8.06(dd,J=7.2,1.6Hz,1H),7.98(d,J=8.9Hz,1H),7.88–7.83(m,1H),7.75(d,J=8.5Hz,1H),7.58(dd,J=8.1,1.4Hz,1H),7.52–7.44(m,2H),7.32(ddd,J=8.1,6.8,1.2Hz,1H),7.25–7.20(m,1H),7.10–7.00(m,3H),6.88(d,J=9.0Hz,1H),6.73(ddd,J=8.3,6.8,1.3Hz,1H),6.62(dd,J=8.5,1.0Hz,1H),6.47(d,J=8.6Hz,1H),3.44(s,3H),2.21(s,3H). 13 C NMR(101MHz,Chloroform-d)δ159.86,154.52,142.37,136.54,135.76,134.31,133.64,132.93,132.74,131.63,130.05,128.84,128.45,127.95,127.92,127.34,126.66,126.36,126.15,125.83,125.60,125.13,125.05,124.08,124.04,123.41,122.53,117.20,112.15,56.01,25.86.

[0087] Example 5:

[0088]

[0089] The preparation method is the same as that of Example 2, white solid, 280 mg, yield 99%; 11H NMR (400 MHz, Chloroform-d) δ 8.31 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.04 (dd, J = 7.3, 1.4 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.88–7.84 (m, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.61 (dd, J = 8.2, 1.4 Hz, 1H), 7.48–7.42 (m, 2H), 7.32 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.25–7.17 (m, 2H), 7.05 (dddd, J = 8.3, 6.8, 4.1, 1.2 Hz, 2H), 6.81 (d, J = 9.1 Hz, 1H), 6.76 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 6.64 (dd, J = 8.5, 1.1 Hz, 1H), 6.50 (dd, J = 8.6, 1.1 Hz, 1H), 3.41 (s, 3H), 2.66 (hept, J = 6.9 Hz, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.09 (d, J = 6.9 Hz, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 167.32, 154.55, 142.05, 136.89, 135.79, 134.40, 133.69, 132.93, 132.59, 131.65, 129.93, 128.71, 128.38, 127.92, 127.29, 126.76, 126.57, 126.12, 125.91, 125.85, 125.31, 125.14, 124.18, 124.14, 123.41, 120.17, 117.32, 112.36, 56.11, 35.92, 21.46, 21.31.

[0090] Example 6:

[0091]

[0092] The preparation method was the same as that of Example 2. White solid, 285 mg, yield 98%; 11H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.12 (dd, J = 7.3, 1.3 Hz, 1H), 8.04 (dd, J = 4.3, 1.5 Hz, 1H), 7.99 (t, J = 1.4 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.65 (dd, J = 8.0, 1.2 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.15 (dd, J = 8.4, 4.0 Hz, 1H), 7.11–7.00 (m, 3H), 6.69–6.65 (m, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.29 (d, J = 8.4 Hz, 1H), 3.56 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 154.82, 150.30, 142.40, 136.80, 135.78, 134.57, 133.65, 133.19, 132.59, 131.48, 130.77, 129.84, 129.50, 127.99, 127.93, 127.78, 127.65, 127.52, 126.90, 125.47, 124.93, 124.60, 123.69, 123.43, 121.67, 119.12, 116.35, 112.31, 56.11.

[0093] Example 7:

[0094]

[0095] The preparation method was the same as that of Example 2. White solid, 426 mg, yield 99%; 11H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 8.26 (dd, J = 4.4, 1.6 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.01 (dd, J = 7.4, 1.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 8.2, 1.8 Hz, 1H), 7.48 (dd, J = 8.2, 1.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.34–7.29 (m, 2H), 7.19 (d, J = 9.2 Hz, 1H), 7.15 (dd, J = 8.2, 4.2 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.07–7.03 (m, 1H), 6.98–6.94 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 6.51–6.47 (m, 1H), 6.14 (d, J = 8.4 Hz, 1H), 2.51 (s, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 150.64, 149.69, 142.49, 136.75, 135.55, 133.88, 133.45, 133.31, 133.21, 131.65, 129.83, 129.74, 128.48, 128.36, 127.97, 127.69, 127.26, 127.09, 126.58, 126.31, 126.16, 125.36, 125.10, 124.65, 124.56, 123.15, 121.98, 121.45, 118.65, 43.46.

[0096] Example 8:

[0097]

[0098] The preparation method was the same as that of Example 2. It was a white solid, 150 mg, with a yield of 99%; 11H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.23–8.20 (m, 2H), 8.03 (dd, J = 7.2, 1.2 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 8.4, 1.6 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.25–7.22 (m, 2H), 7.20 (dd, J = 4.9, 3.5 Hz, 1H), 7.13 (dd, J = 8.8, 2.0 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H), 6.42 (dd, J = 9.0, 2.2 Hz, 1H), 5.91 (d, J = 9.2 Hz, 1H), 2.51 (s, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 150.63, 150.27, 142.42, 136.73, 135.78, 133.96, 133.27, 132.68, 132.17, 131.83, 130.06, 129.89, 129.36, 129.10, 129.03, 128.05, 127.81, 126.56, 126.23, 125.57, 124.83, 121.70, 120.78, 119.85, 119.32, 117.07, 43.34.

[0099] Example 9:

[0100]

[0101] The preparation method was the same as that of Example 2. A yellow solid, 280 mg, with a yield of 95%; 11H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 1H), 8.19 (dd, J = 5.6, 1.6 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.83 (dd, J = 8.7, 4.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.4, 5.7 Hz, 2H), 7.29 (dd, J = 10.0, 7.5 Hz, 2H), 7.18 (dd, J = 8.4, 4.0 Hz, 1H), 7.14–7.02 (m, 7H), 6.77 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 8.4, 6.8 Hz, 1H), 6.39 (d, J = 8.4 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 150.54, 142.22, 140.48, 140.38, 136.98, 135.89, 133.75, 133.47, 133.37, 132.95, 131.69, 130.76, 130.29, 129.38, 129.12, 128.66, 128.51, 128.06, 127.94, 127.92, 127.82, 127.27, 127.14, 126.51, 126.47, 126.28, 126.12, 125.45, 125.31, 124.97, 124.82, 123.55, 121.63.

[0102] Example 10:

[0103]

[0104] The preparation method was the same as that of Example 2. It was a white solid, 130 mg, with a yield of 85%; 11H NMR (400 MHz, Chloroform-d) δ 8.61–8.49 (m, 1H), 8.34 (d, J = 6.6 Hz, 1H), 8.18 (td, J = 3.7, 3.1, 1.7 Hz, 2H), 8.07 (dd, J = 7.3, 1.5 Hz, 1H), 7.95 (d, J = 4.5 Hz, 1H), 7.84–7.80 (m, 2H), 7.66–7.60 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 7.8, 1.2 Hz, 1H), 7.31–7.28 (m, 1H), 7.08–7.03 (m, 3H), 6.99–6.89 (m, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.77–6.73 (m, 1H), 6.49 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.32 (dd, J = 8.5, 1.0 Hz, 1H), 2.19 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 152.49, 150.55, 142.21, 140.31, 137.52, 136.95, 136.79, 136.68, 136.44, 135.95, 135.84, 133.36, 133.34, 131.85, 129.36, 129.07, 128.73, 128.55, 128.38, 128.19, 127.93, 127.78, 127.76, 127.21, 126.49, 126.39, 126.35, 125.29, 125.25, 125.06, 124.97, 124.77, 123.75, 122.94, 121.60, 21.10.

[0105] Example 11:

[0106]

[0107] The preparation method was the same as that of Example 2. It was a white solid, 190 mg, with a yield of 97%; 11H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 8.25–8.21 (m, 2H), 7.97 (d, J = 9.2 Hz, 1H), 7.94–7.90 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 11.2, 8.4 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.32 (dd, J = 8.4, 6.8 Hz, 1H), 7.19–7.14 (m, 2H), 7.07 (t, J = 8.1 Hz, 2H), 6.71 (dd, J = 8.4, 6.8 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 1.68 (s, 3H). 13 13C NMR (101 MHz, Chloroform-d) δ 150.41, 142.36, 137.04, 135.96, 135.87, 133.58, 133.33, 132.86, 132.53, 131.42, 131.28, 130.57, 129.35, 128.71, 128.58, 128.25, 128.10, 127.96, 127.53, 126.57, 126.33, 126.12, 125.56, 125.21, 124.98, 124.95, 124.48, 123.33, 121.87, 19.74.

[0108] Example 12:

[0109]

[0110] Compound A-1-1 (0.06 g, 0.2 mmol) was added to a dry 25 mL Schlenk flask. The reaction system was purged with nitrogen three times and anhydrous THF (2 mL) and pyridine (0.05 g, 0.6 mmol) were added via syringe under a nitrogen atmosphere. Then, B-2-1 (0.06 g, 0.24 mmol) was slowly added dropwise to the reaction solution in an ice-water bath. The reaction solution was then transferred to room temperature and stirred for 12 hours. Thereafter, the reaction mixture was washed with 1 M hydrochloric acid and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and the organic solvents were removed. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (2:1) as the eluent to obtain 68 mg of white solid C-2-1, with a yield of 80%; 11H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.36 (s, 1H), 8.27 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.95–7.90 (m, 2H), 7.88 (d, J = 9.0 Hz, 1H), 7.84 (dd, J = 8.2, 1.2 Hz, 1H), 7.78 (td, J = 7.7, 1.7 Hz, 1H), 7.71 (dt, J = 7.8, 1.1 Hz, 1H), 7.45–7.30 (m, 3H), 7.21 (dtd, J = 8.3, 6.8, 1.2 Hz, 2H), 7.01 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 6.87 (dd, J = 8.6, 1.2 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H). 13 13C NMR (101 MHz, DMSO-d6) δ 157.09, 153.74, 150.00, 138.63, 134.08, 133.79, 133.22, 131.42, 130.53, 128.79, 128.49, 128.37, 128.35, 127.43, 126.85, 126.75, 126.26, 125.85, 125.59, 124.40, 122.94, 122.80, 122.01, 118.92, 113.71.

[0111] Example 13:

[0112]

[0113] The preparation method was the same as that of Example 12. White solid, 90 mg, yield 75%; 1 1H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 9.2 Hz, 1H), 8.02–7.94 (m, 3H), 7.84 (dd, J = 18.2, 8.2 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.51–7.40 (m, 2H), 7.36 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7.14 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.07–6.96 (m, 2H), 6.96–6.85 (m, 2H), 6.47 (d, J = 8.4 Hz, 1H), 3.76 (s, 3H). 1313C NMR (101 MHz, Chloroform-d) δ 156.44, 154.68, 149.54, 137.15, 133.69, 133.01, 132.82, 131.51, 131.10, 129.14, 129.10, 128.04, 127.98, 126.96, 126.51, 126.28, 126.23, 125.31, 124.83, 124.38, 123.64, 122.23, 121.66, 116.40, 113.44, 56.60.

[0114] Example 14:

[0115]

[0116] The preparation method was the same as that of Example 12. White solid, 70 mg, yield 65%; 1 1H NMR (400 MHz, Chloroform-d) δ 8.16–8.14 (m, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.73 (dd, J = 8.0, 3.9 Hz, 2H), 7.57 (td, J = 7.8, 1.7 Hz, 1H), 7.39 (ddd, J = 8.1, 6.6, 1.1 Hz, 1H), 7.24–7.10 (m, 4H), 7.06 (dd, J = 8.6, 3.5 Hz, 2H), 6.92 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 3.57 (s, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 156.52, 149.77, 142.63, 137.50, 133.73, 133.45, 132.74, 131.63, 130.61, 129.68, 128.18, 128.15, 127.07, 127.02, 126.67, 125.97, 125.62, 123.53, 122.89, 122.40, 121.89, 121.19, 118.31, 110.08.

[0117] Example 15:

[0118]

[0119] The preparation method was the same as that of Example 12. White solid, 86 mg, yield 72%; 11H NMR (400 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.7, 3.4 Hz, 2H), 7.73–7.62 (m, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.42–7.30 (m, 2H), 7.21–7.04 (m, 3H), 6.96 (d, J = 8.5 Hz, 1H), 6.80 (ddd, J = 8.3, 6.8, 1.4 Hz, 1H), 6.61 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 2.62 (s, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 156.32, 149.03, 148.92, 136.40, 133.62, 133.54, 132.00, 130.05, 129.67, 129.11, 128.61, 128.18, 127.55, 127.01, 126.59, 126.07, 125.84, 125.58, 125.56, 125.40, 123.59, 122.72, 120.77, 118.43, 43.52.

[0120] Example 16:

[0121]

[0122] The preparation method was the same as that of Example 12. White solid, 95 mg, yield 73%; 1 1H NMR (400 MHz, Chloroform-d) δ 8.12–8.03 (m, 2H), 7.92 (dd, J = 8.3, 1.3 Hz, 1H), 7.83 (q, J = 8.9 Hz, 3H), 7.70 (d, J = 8.5 Hz, 1H), 7.61 (dt, J = 7.8, 1.1 Hz, 1H), 7.55 (dd, J = 7.7, 1.7 Hz, 1H), 7.42 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.36 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H), 7.21 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.14 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H), 7.11–7.04 (m, 5H), 6.99 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.64 (dd, J = 8.5, 1.0 Hz, 1H), 6.60 (s, 1H). 13C NMR (101 MHz, Chloroform-d) δ 156.55, 149.77, 140.48, 140.34, 137.31, 133.92, 133.01, 132.82, 132.16, 130.62, 129.70, 129.28, 129.20, 128.68, 128.56, 128.11, 128.08, 128.04, 127.26, 126.92, 126.83, 126.55, 126.38, 126.20, 125.92, 125.38, 125.13, 121.60, 120.23.

[0123] Example 17:

[0124]

[0125] The preparation method was the same as that of Example 12. White solid, 85 mg, yield 78%; 1 H NMR (400 MHz, Chloroform-d) δ 8.80–8.78 (m, 2H), 8.28 (dt, J = 4.6, 1.2 Hz, 1H), 8.15 (d, J = 9.0 Hz, 1H), 8.09 (dt, J = 8.0, 1.1 Hz, 2H), 8.04 (td, J = 7.7, 1.7 Hz, 2H), 7.92 (dd, J = 8.8, 2.5 Hz, 2H), 7.89–7.80 (m, 3H), 7.73 (td, J = 7.7, 1.7 Hz, 1H), 7.67 (ddd, J = 7.5, 4.6, 1.3 Hz, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.40–7.30 (m, 3H), 7.15 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.01 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 6.84 (dd, J = 8.6, 1.1 Hz, 1H), 6.73–6.66 (m, 1H), 6.63 (s, 1H), 1.89 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 159.11, 156.49, 150.74, 150.11, 139.24, 137.87, 136.22, 132.72, 132.62, 132.47, 132.44, 130.94, 129.30, 129.29, 129.25, 128.98, 128.25, 128.10, 127.08, 127.01, 126.79, 125.49, 125.36, 125.28, 124.84, 124.51, 122.23, 122.00, 118.94, 19.87.

[0126] Example 18:

[0127]

[0128] The preparation method is the same as that of Example 2, white solid, 75 mg, yield 80%; 1 H NMR(400MHz,Chloroform-d)δ8.71(dd,J=4.2,1.8Hz,1H),8.39(dd,J=7.4,1.4Hz,1H),8.12(dd,J=8.4,2.0Hz,1H),7.95(dd,J=8.2,1.4Hz,1H),7.57(d,J=7.8Hz,1H),7.52(s,1H),7.41(dd,J=8.3,4.3Hz,1H),7.13(t,J=7.8Hz,1H),7.04–6.99(m,1H),6.96(t,J=7.7Hz,1H),6.61(d,J=7.3Hz,1H),6.52(d,J=7.9Hz,1H),4.95(s,1H),2.92(dd,J=8.8,5.8Hz,3H),2.64(dd,J=16.0,8.5Hz,1H),2.14(d,J=7.2Hz,2H),2.08–2.03(m,1H),1.99–1.94(m,1H). 13 C NMR(101MHz,Chloroform-d)δ152.44,151.38,145.53,145.20,143.01,137.29,136.95,136.64,133.76,133.45,131.46,129.97,129.28,128.80,128.46,125.43,122.24,121.47,119.70,117.37,114.12,58.71,37.75,37.07,31.09,30.85.

[0129] Example 19:

[0130]

[0131] The preparation method is the same as that of Example 2, yellow solid, 250 mg, yield 97%; 11H NMR (400 MHz, Chloroform-d) δ 8.79–8.68 (m, 1H), 8.42 (dd, J = 7.2, 1.4 Hz, 1H), 8.17 (dt, J = 8.2, 1.4 Hz, 1H), 7.97 (dd, J = 8.3, 1.3 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.46 (dd, J = 8.4, 4.2 Hz, 1H), 7.24 (d, J = 2.6 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 3.54 (s, 3H), 2.96–2.82 (m, 3H), 2.66 (dd, J = 16.0, 8.9 Hz, 1H), 2.17 (dt, J = 12.4, 9.7 Hz, 1H), 2.07 (q, J = 3.9, 3.0 Hz, 1H), 2.05–2.01 (m, 1H), 1.84 (dt, J = 12.8, 9.8 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 156.35, 152.49, 151.14, 145.37, 144.58, 143.31, 138.93, 137.72, 136.68, 136.52, 136.44, 133.54, 133.23, 133.15, 131.85, 130.15, 129.17, 128.80, 127.16, 125.42, 125.07, 122.94, 121.99, 120.69, 118.65, 117.48, 109.01, 59.21, 55.30, 37.79, 37.30, 31.16, 30.86.

[0132] Example 20:

[0133]

[0134] The preparation method was the same as that of Example 2, yellow solid, 19 mg, yield 70%; 11H NMR (400 MHz, Chloroform-d) δ 8.79 (dd, J = 4.3, 1.8 Hz, 1H), 8.43 (dd, J = 7.3, 1.4 Hz, 1H), 8.18 (dd, J = 8.4, 1.7 Hz, 1H), 7.99 (dd, J = 8.2, 1.5 Hz, 1H), 7.60 (dd, J = 8.2, 7.3 Hz, 1H), 7.56 (s, 1H), 7.48 (dd, J = 8.3, 4.2 Hz, 1H), 7.40–7.33 (m, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.99 (dd, J = 7.5, 1.1 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.56–6.43 (m, 1H), 6.36 (d, J = 7.8 Hz, 1H), 3.23 (s, 2H), 2.97–2.77 (m, 3H), 2.54 (dd, J = 15.8, 8.8 Hz, 1H), 2.18–2.00 (m, 3H), 1.80 (dddd, J = 12.5, 10.5, 8.9, 1.3 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 151.24, 145.43, 144.50, 143.30, 142.71, 137.50, 136.50, 135.92, 133.96, 133.29, 130.08, 129.02, 128.96, 128.82, 128.43, 125.39, 122.13, 121.23, 119.01, 115.26, 113.79, 59.05, 36.90, 35.73, 30.90, 30.76.

[0135] Example 21:

[0136]

[0137] The preparation method was the same as that of Example 2. Yellow solid, 60 mg, yield 90%; 11H NMR (400 MHz, Chloroform-d) δ 8.58 (dd, J = 4.3, 1.8 Hz, 1H), 8.40 (dd, J = 7.3, 1.4 Hz, 1H), 8.13 (dd, J = 8.3, 1.8 Hz, 1H), 7.94 (dd, J = 8.2, 1.4 Hz, 1H), 7.64–7.51 (m, 1H), 7.40 (dd, J = 8.3, 4.3 Hz, 1H), 7.25 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.17–7.12 (m, 1H), 7.01 (td, J = 7.7, 4.3 Hz, 2H), 6.97–6.85 (m, 2H), 3.02–2.87 (m, 3H), 2.75 (ddd, J = 16.0, 8.3, 3.7 Hz, 1H), 2.40 (dt, J = 12.8, 9.3 Hz, 1H), 2.22 (s, 6H), 2.21–2.12 (m, 1H), 2.06–1.95 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 151.29, 145.44, 145.04, 143.27, 141.84, 139.54, 137.83, 136.45, 133.72, 133.18, 130.22, 128.70, 128.62, 127.25, 125.41, 121.94, 120.99, 120.78, 119.81, 118.86, 60.38, 45.01, 39.71, 39.22, 31.33, 31.11.

[0138] Example 22:

[0139]

[0140] The preparation method was the same as that of Example 12. Yellow solid, 25 mg, yield 60%; 11H NMR (400 MHz, Chloroform-d) δ 8.64 (dt, J = 4.7, 1.2 Hz, 1H), 7.92 (dt, J = 7.9, 1.1 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.47–7.42 (m, 2H), 7.14 (td, J = 7.7, 6.5 Hz, 2H), 6.99 (dd, J = 7.5, 1.1 Hz, 1H), 6.77 (dd, J = 7.4, 1.0 Hz, 1H), 6.62 (s, 1H), 6.47 (d, J = 7.9 Hz, 1H), 3.24 (s, 2H), 3.02–2.89 (m, 4H), 2.23 (dddd, J = 12.3, 10.6, 9.0, 1.3 Hz, 1H), 2.16–2.10 (m, 2H), 1.86 (dddd, J = 12.5, 10.7, 9.5, 1.3 Hz, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 156.98, 149.98, 145.19, 145.16, 142.83, 137.88, 134.68, 133.91, 129.85, 128.76, 127.74, 126.91, 122.68, 121.13, 116.68, 115.88, 114.14, 58.85, 36.81, 35.44, 30.98, 30.80.

[0141] Example 23: Application of axially chiral nitrogen-containing heteroaromatic sulfonamide ligand-copper in the reaction of asymmetric catalytic synthesis of chiral amino amide derivatives.

[0142]

[0143] A 25 mL Schlenk flask was selected and charged with CuI (1.9 mg, 10 mol%), chiral quinoline sulfonamide ligand C-1-2 (15 mol%) and potassium phosphate (3.0 equiv.). The reaction flask was purged with nitrogen three times, and then tetrahydrofuran (1.0 mL) was added. The reaction system was stirred at room temperature for 1 hour. Subsequently, compound 1a (0.15 mmol) and compound 2a (0.1 mmol) were weighed and added to the reaction flask in sequence, and tetrahydrofuran (1.0 mL) was added. Then the reaction system was stirred at room temperature for 48 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filtrate was distilled under reduced pressure. The crude product was directly separated by silica gel column chromatography to obtain compound 3a. 11H NMR (400 MHz, Chloroform-d) δ 9.27 (s, 1H), 7.51–7.47 (m, 2H), 7.39–7.29 (m, 5H), 6.89–6.85 (m, 2H), 3.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J = 6.9 Hz, 1H), 1.74 (s, 1H), 1.42 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, Chloroform-d) δ 168.77, 156.22, 131.08, 128.77, 128.10, 127.57, 120.99, 114.18, 58.43, 55.52, 52.80, 19.72; The results of the examples of the obtained substituted amino amide compounds are shown in Table 1.

[0144] Table 1. Asymmetric Synthesis of Copper-Catalyzed Chiral Amino Amide Derivatives

[0145]

[0146] 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 conceived 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. An axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, characterized in that, The axially chiral nitrogen-containing heteroaromatic sulfonamide ligand has the structure of the following general formula (I): In the general formula (I): The chirality marked with * is in the R configuration or the S configuration, or is racemic; The axially chiral part A of the ligand can be arbitrarily selected from A-1 or A-2; The nitrogen-containing heteroaromatic part B of the ligand can be arbitrarily selected from B-1 or B-2; R 1 selected from any one of alkyl, alkoxy, hydroxyl, siloxy, phenyl, substituted phenyl, substituted amino and carbonyl; R 2 -R 7 each independently selected from any one of hydrogen, halogen, alkyl, substituted phenyl, aryl, heteroaryl, nitro, ester group, cyano, aldehyde group, and alkoxy group; R 8 selected from any one of a hydroxyl group, an alkoxy group, an amino group, and a substituted amino group; R 9 -R 18 Each independently selected from any one of hydrogen, halogen, alkyl, aryl, and heteroaryl.

2. The axially chiral nitrogen-containing heteroaromatic sulfonamide ligand according to claim 1, characterized in that, When the R 1 is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, neopentyl or benzyl; when the R 1 is an alkoxy group, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentyloxy, isopentyloxy, neopentyloxy or benzyloxy; when the R 1 is a siloxy group, the siloxy group is trimethylsilyloxy, triethylsilyloxy, tri-n-propylsilyloxy, triisopropylsilyloxy, tri-n-butylsilyloxy, triisobutylsilyloxy, tri-n-pentylsilyloxy, triisopentylsilyloxy or trineopentylsilyloxy; when the R 1 is a substituted phenyl group, 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 is a substituted amino group, the substituted amino group is a methyl-substituted amino group, an ethyl-substituted amino group, an n-propyl-substituted amino group, an isopropyl-substituted amino group, an n-butyl-substituted amino group, an isobutyl-substituted amino group, an 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 -R 7 are each independently an alkyl group, 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 2 -R 7 are each independently an alkoxy group, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; when the R 2 -R 7 is a substituted phenyl group, the substituted phenyl group is a phenyl group substituted with methyl, ethyl, isopropyl, tert-butyl, neopentyl, adamantyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, fluoro, chloro, bromo or iodo; when the R 2 -R 7 is an aryl group, the aryl group is phenyl, naphthyl, anthryl, phenanthryl or pyrenyl; when the R 2 -R 7 are each independently a heteroaryl group, the heteroaryl group is furyl, thienyl, indolyl or pyridyl; When the R 8 is an alkoxy group, the alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group; when R 8 is a substituted amino group, the substituted amino group is a methyl-substituted amino group, an ethyl-substituted amino group, an isopropyl-substituted amino group, a phenyl-substituted amino group or a benzyl-substituted amino group; When the R 9 -R 18 is an alkyl group, 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 9 -R 18 is an aryl group, the aryl group is phenyl, naphthyl, anthryl, phenanthryl or pyrenyl; when the R 9 -R 18 is a heteroaryl group, the heteroaryl group is furyl, thienyl, indolyl or pyridyl.

3. A preparation method of an axially chiral nitrogen-containing heteroaromatic sulfonamide ligand as claimed in claim 1, characterized by including The following steps: (1) In an organic solvent, under nitrogen or an inert gas, react compound a1 with compound b1 under the action of a base to prepare compound C-1; (2) In an organic solvent, under nitrogen or an inert gas, react compound a1 with compound b2 under the action of a base to prepare compound C-2; (3) In an organic solvent, under nitrogen or an inert gas, react compound a2 with compound b1 under the action of a base to prepare compound C-3; (4) In an organic solvent, under nitrogen or an inert gas, react compound a2 with compound b2 under the action of a base to prepare compound C-4.

4. The preparation method of an axially chiral nitrogen-containing heteroaromatic sulfonamide ligand according to claim 3, characterized in that, The organic solvent in steps (1), (2), (3) and (4) is one or more of methanol, ethanol, isopropanol, n-butanol, acetone, dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethane, 1,2-dichloroethane, 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), (3) and (4) includes one or more of argon, helium, neon and krypton; The base in steps (1), (2), (3) and (4) is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, 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; In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the reaction temperature of the synthesis steps (1), (2), (3) and (4) is -30 to 70 °C; In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the reaction time of the synthesis steps (1), (2), (3) and (4) is 1 to 72 hours; In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a1 to compound b1 in step (1) is a molar ratio of 1:5 to 5:1; In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a1 to compound b2 in step (2) is a molar ratio of 1:5 to 5:1; In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a2 to compound b1 in step (3) is a molar ratio of 1:5 to 5:1; In the preparation method of the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand, the feeding ratio of compound a2 to compound b2 in step (4) is a molar ratio of 1:5 to 5:

1.

5. A complex formed by the combination of an axially chiral nitrogen-containing heteroaromatic sulfonamide ligand as described in claim 1 and a transition metal compound, characterized in that, The complex is formed by in-situ complexation of an axially chiral nitrogen-containing heteroaromatic sulfonamide ligand and a transition metal compound in a reaction system. The transition metal compound is selected from at least one of cuprous iodide, cuprous bromide, cuprous chloride, copper bromide, copper chloride, copper trifluoromethanesulfonate, copper acetylacetonate, copper tetraethylacetonitrile hexafluorophosphate, nickel iodide, nickel chloride, nickel trifluoromethanesulfonate, ferric trichloride, ferric tribromide, ferrous trifluoromethanesulfonate, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, and palladium chloride.

6. A method for synthesizing chiral amino amide compounds, characterized in that, The method for synthesizing chiral amino amide compounds comprises the following steps: Under a reaction gas, complex the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand as described in claim 1 with a copper salt and a base in an organic solvent, and react compound 1 with compound 2 as shown in the following formula to obtain compound 3. Among them, R 19 -R 21 is selected from alkyl, substituted phenyl, aryl; X in the compound 1 is a chlorine atom, a bromine atom, or an iodine atom. The chirality marked with * is in the S configuration, the R configuration, or is racemic.

7. The method for synthesizing chiral amino amide compounds according to claim 6, characterized in that, When R 19 -R 21 is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl; when the R 19 -R 21 is a substituted phenyl group, the substituted phenyl group is a phenyl group substituted with methyl, ethyl, isopropyl, tert-butyl, neopentyl, adamantyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, fluoro, chloro or bromo; when R 19 -R 21 is an aryl group, the aryl group is naphthyl, anthryl, phenanthryl or pyrenyl; The reaction 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, 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 metal copper salt is selected from at least one of 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, copper thiophene-2-carboxylate, and cuprous oxide. 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, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, and pyridine. The molar concentration of the compound 1 in the organic solvent is 0.01 - 1.0 M. The molar concentration of the compound 2 in the organic solvent is 0.01 - 1.0 M. The molar ratio of the copper salt to the base is 1:1 - 1:

10. The molar ratio of the copper salt to the axially chiral nitrogen-containing heteroaromatic sulfonamide ligand is 1:1 - 1:5.

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