Axial chiral N-heterocyclic carbene ligand as well as preparation method and application thereof

Abstract

The invention discloses an axially chiral N-heterocyclic carbene ligand as well as a preparation method and application thereof. The axially chiral N-heterocyclic carbene ligand has a structure as shown in a general formula (I), wherein an axially chiral part A of the ligand is any one of A-1 or A-2; the part B of the ligand is any one of B-1 and B-2 or is the same as A; and the anion X part of the ligand is any one of chlorine, bromine, iodine, tetrafluoroborate or hexafluorophosphate. The axially chiral N-heterocyclic carbene ligand and a transition metal compound are subjected to in-situ complexation in a reaction system to form a complex catalyst, and the complex catalyst shows good yield and enantioselectivity in amylene amide substrate intramolecular amination and arylation reaction and has a good industrial application prospect. The invention belongs to the field of asymmetric synthetic chemistry.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric synthetic chemistry, specifically relating to a novel class of axially chiral nitrogen heterocyclic carbene ligands, their preparation methods, and applications. The catalysts formed by these ligands and palladium salts can be used for asymmetric amination and arylation reactions of pentenamide substrates to synthesize chiral five-membered fused-to-five-membered N-fused heterocyclic compounds, exhibiting good catalytic activity and enantioselectivity. Background Technology

[0002] Axially chiral biaryl structures are not only widely found in natural products and drug molecules, but also serve as the core framework for many chiral ligands and catalysts, playing a crucial role in asymmetric synthesis. Since Noyori et al. pioneered the development of the 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) ligand (BINAP), many novel axially chiral ligands have been continuously developed and widely applied in transition metal-catalyzed asymmetric synthetic reactions (Noyori, R. et al. J. Am. Chem. Soc. 1979, 101, 3129-3131; Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029-3070). Research on N-heterocyclic carbenes (NHCs) began in 1968, with Wanzlick, and Its existence was first reported. It wasn't until 1991, when Arduengo's team successfully isolated the first stable crystalline NHC, that it attracted widespread attention in the chemical community. Compared to traditional phosphine ligands, NHCs have significant advantages: high chemical stability, simple synthesis and storage; strong σ-electron-donating ability, enabling them to form stable complexes with transition metals, thus efficiently promoting the activation of challenging substrates; and unique steric hindrance and electronic structure endowing them with rapid reductive elimination properties (Bertrand, G. et al. Chem. Rev. 2000, 100, 39-91). In the past two decades, NHC metal complexes have made breakthrough progress in catalytic construction of C-C bonds, CN bonds, and CH bond activation, becoming an important tool in modern organic synthesis chemistry (Yoon, J. et al. Chem. Soc. Rev. 2021, 50, 589-618). For example, in recent years, Shi Shiliang's research group has designed and developed a class of fit-inducible, sterically hindered chiral NHC ligands (ANIPE and SIPE series) based on the excellent chiral induction ability of C2 symmetrical chiral aniline fragments. These ligands are characterized by their large size and good flexibility, and exhibit wide applicability in asymmetric metal-catalyzed reactions (Shi, S.-L. et al. Acc. Chem. Res. 2025, 58, 13, 2157–2177). The structural diversity of NHCs provides endless possibilities for their functional expansion. Nevertheless, designing novel NHC ligands with novel framework structures remains a core challenge in this field. Transition metal-catalyzed asymmetric amination and arylation reactions of pentenamide substrates are one of the most efficient methods for constructing N-fused heterocycles. Among them, N-fused heterocycle structures, as an important class of organic molecular frameworks, have become highly promising and advantageous frameworks for innovative drug development due to their unique structure and properties, and have important application prospects (Williams, R. M et al. Chem. Rev. 2013, 113, 6816-6863). Currently, the chiral ligands suitable for this type of reaction are mainly chiral bisoxazoline and pyridine oxazoline ligands. The catalytic system is relatively simple and the types of reactions it can catalyze are limited. The enantioselectivity of some reactions needs to be improved (Gong, L.-Z. et al. Org. Chem. Front., 2014, 1, 473–476). K. et al. Chem. Soc. Rev., 2007, 36, 1142-1152; Zhang, J. et al. Chem. Soc. Rev., 2024, 53, 883-971). Developing novel chiral carbene ligands and catalysts for the synthesis of N-fused heterocyclic skeletons has high practical application value. Summary of the Invention

[0003] The purpose of this invention is to provide a novel class of axially chiral nitrogen heterocyclic carbenes (I).

[0004] Another objective of this invention is to provide a method for synthesizing the above-mentioned chiral ligands.

[0005] Another objective of this invention is to provide the use of the above-mentioned chiral ligands, namely, to form catalysts with palladium salts for the asymmetric synthesis of N-fused-ring heterocyclic compounds.

[0006] A chiral nitrogen heterocyclic carbene ligand, characterized in that the chiral nitrogen heterocyclic carbene ligand has the structure of the following general formula (Ⅰ):

[0007]

[0008]

[0009] In the general formula (Ⅰ):

[0010] Chirality marked with * indicates R configuration or S configuration;

[0011] The anion X portion of the axially chiral nitrogen heterocyclic carbene ligand is selected from any one of chloride, bromine, iodine, tetrafluoroborate, or hexafluorophosphate.

[0012] The axially chiral portion A of the axially chiral nitrogen heterocyclic carbene ligand is either A-1 or A-2;

[0013] The B portion of the axially chiral nitrogen heterocyclic carbene ligand is either B-1 or B-2 or the same as A;

[0014] R 1 It is selected from any one of alkyl, alkoxy, hydroxy, phenyl, and substituted phenyl groups;

[0015] R 2 Each is independently selected from hydrogen, alkyl, phenyl, or substituted phenyl;

[0016] R 3 Each of the following is independently selected from hydrogen, halogen, alkyl, alkoxy, phenyl, substituted phenyl, naphthyl, anthraceneyl, phenanthryl, and heteroaryl;

[0017] R 4 -R 8 Each of the following is independently selected from hydrogen, halogen, and alkyl groups.

[0018] In this invention, the axially chiral nitrogen heterocyclic carbene ligand is 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; 1When 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 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.

[0019] When the R 2 When R is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, or tert-butyl; 2 When the substituted phenyl group is used, the substituted phenyl group is a methyl-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;

[0020] When the R 3 When R 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; 3 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, or tert-butyloxy; when the 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 3 When the heteroaryl group is a furanyl, thiophene, indolyl, or pyridinyl group;

[0021] When the R 4 -R 8 When the alkyl group is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;

[0022] When the R 4 -R 8 When the halogen is halogen, the halogen is fluorine, chlorine, or bromine.

[0023] The method for preparing the axially chiral nitrogen heterocyclic carbene ligand in this invention is characterized by the following steps:

[0024] (1) Compound 2 is prepared by reacting compound 1 with glyoxal and paraformaldehyde in an acid under the presence of nitrogen or an inert gas in an organic solvent.

[0025]

[0026] (2) Compound 4 is prepared by reacting compound 3, triethyl orthoformate and ammonium salt in an organic solvent under nitrogen or inert gas.

[0027]

[0028] (3) Compound 5 and compound 6 are reacted in an organic solvent under nitrogen or inert gas to prepare compound 7 by the action of ammonium salt;

[0029]

[0030] (4) Compound 5 is reacted with imidazole in the presence of an ammonium salt in an organic solvent under nitrogen or an inert gas to prepare compound 8;

[0031]

[0032] In this invention, the method for preparing an axially chiral nitrogen heterocyclic carbene ligand is characterized in that the organic solvents 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;

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

[0034] The acid mentioned in steps (1), (2), (3) and (4) is selected from one of formic acid, acetic acid, tetrafluoroboric acid, hydrochloric acid, hydrogen bromide or hexafluorophosphoric acid;

[0035] The ammonium salts mentioned in steps (1), (2), (3) and (4) are selected from one of ammonium chloride, ammonium sulfate, ammonium tetrafluoroborate or ammonium bromide;

[0036] The preparation method of the axial chiral nitrogen heterocyclic carbene ligand, wherein the reaction temperature of the synthesis steps (1), (2), (3) and (4) is 25 to 120 °C;

[0037] The preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the reaction time of the synthesis steps (1), (2), (3) and (4) is 8-72 hours;

[0038] In the preparation method of the axially chiral nitrogen heterocyclic carbene ligand, the feeding ratio of compound 1, glyoxal and paraformaldehyde in step (1) is 2:1:0.5 to 3:1:0.5 molar ratio;

[0039] In the preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the molar ratio of compound 3 to triethyl orthoformate in step (2) is 1:10 to 1:20.

[0040] In the preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the molar ratio of compound 5 to compound 6 in step (3) is 1:1 to 1:2.

[0041] In the preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the molar ratio of compound 5 to imidazole in step (4) is 2:1 to 2.5:1.

[0042] In this invention, the complex formed by the complexation of the axially chiral nitrogen heterocyclic carbene ligand and the transition metal compound is characterized in that the complex is formed by the in-situ complexation of the axially chiral nitrogen heterocyclic carbene ligand and the transition metal compound in the reaction system, wherein 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 hexafluorophosphate tetraacetonitrile, nickel iodide, nickel chloride, nickel trifluoromethanesulfonate, ferric chloride, ferric bromide, ferrous trifluoromethanesulfonate, tetra(triphenylphosphine)palladium, tris(dibenzylacetone)dipalladium, palladium acetate, palladium chloride, palladium acetylacetonate, nickel chloride, nickel acetate, bis(1,5-cyclooctadiene)nickel, or bis(1,5-cyclooctadiene)iridium.

[0043] A method for synthesizing chiral N-fused heterocyclic compounds, characterized in that the method comprises the following steps:

[0044] Under a reaction gas, the axially chiral nitrogen heterocyclic carbene ligand complexes with a palladium salt and a base in an organic solvent to react compound 9 or 11 with the following formula to obtain compound 10 or 12.

[0045]

[0046] Among them, R 9 -R 10 Selected from alkyl, alkoxy, phenyl, substituted phenyl, or halogen;

[0047] R 11 Selected from alkyl, phenyl, or substituted phenyl groups;

[0048] R 12 -R 17 Selected from alkyl, alkoxy, phenyl, substituted phenyl, or halogen;

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

[0050] In this invention, the method for synthesizing chiral N-fused heterocyclic compounds is characterized in that, when R... 9 -R 10 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 9 -R 10 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; when the R 9 -R 10 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, or a bromine-substituted phenyl group; when R 9 -R 10 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine;

[0051] When R 11 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 11 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, or a bromine-substituted phenyl group.

[0052] When R 12 -R 17 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 12 -R 17 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; when the R 12 -R 17 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, or a bromine-substituted phenyl group; when R 12 -R17 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine;

[0053] The reacting gas is one or more of oxygen, carbon monoxide, carbon dioxide, nitrogen, and air;

[0054] 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.

[0055] The palladium salt is selected from at least one of palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, palladium trifluoroacetate, tetra(triphenylphosphine)palladium, di(triphenylphosphine)palladium chloride, tri(dibenzylacetone)palladium, or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0056] 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;

[0057] The molar concentration of compound 9 in the organic solvent is 0.01–1.0 M;

[0058] The molar concentration of compound 11 in the organic solvent is 0.01–1.0 M;

[0059] The molar ratio of the palladium salt to the base is 1:1 to 1:30;

[0060] The molar ratio of the palladium salt to the axially chiral nitrogen heterocyclic carbene ligand is 1:1 to 1:3. In an embodiment of the present invention, the reaction further includes a post-treatment step, which can be a conventional post-treatment step in the field of organic synthesis, including a column chromatography step.

[0061] The term "er" refers to the enantiomeric ratio.

[0062] The positive and progressive effects of this invention are as follows:

[0063] This invention provides a novel axially chiral nitrogen-containing heterocyclic carbene ligand, characterized by a binahnethinyl axially chiral source and an imidazole group. The ligand is synthesized using 1,1'-bi-2-naphthol (BINOL) and substituted BINOL, along with glyoxal, formaldehyde, or imidazole and their derivatives, as starting materials, under the influence of acid, ammonium salt, or triethyl orthoformate. The target molecule of this invention has a concise and clear structure, is easy to operate experimentally, and can be prepared on a large scale. It has potential applications in the design of novel axially chiral ligands and the synthesis of N-fused heterocyclic compounds.

[0064] The novel axially chiral nitrogen heterocyclic carbene ligand provided by this invention can be used as a chiral ligand to form a catalyst with palladium salt in the reaction system, catalyzing the asymmetric amination and arylation reaction of pentenamide compounds to synthesize fused nitrogen heterocyclic compounds, and exhibiting good yield and enantioselectivity (up to 95:5). Attached Figure Description

[0065] Figure 1 The 1H NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand 2a provided in an embodiment of the present invention;

[0066] Figure 2 The carbon NMR spectrum of axially chiral nitrogen heterocyclic carbene ligand 2a provided in an embodiment of the present invention;

[0067] Figure 3 The 2c 1H NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0068] Figure 4 The 2c carbon NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0069] Figure 5 The 2d 1H NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0070] Figure 6 The 2d carbon NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0071] Figure 7 The 1H NMR spectrum of axially chiral nitrogen heterocyclic carbene ligand 4a provided in an embodiment of the present invention;

[0072] Figure 8 The carbon NMR spectrum of axially chiral nitrogen heterocyclic carbene ligand 4a provided in an embodiment of the present invention;

[0073] Figure 9 The 4b NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in this embodiment of the invention;

[0074] Figure 10The 4b carbon NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0075] Figure 11 The 4c ​​1H NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in an embodiment of the present invention;

[0076] Figure 12 The 4c ​​carbon NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0077] Figure 13 The 1H NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand 7a provided in an embodiment of the present invention;

[0078] Figure 14 The carbon NMR spectrum of 7a axially chiral nitrogen heterocyclic carbene ligand provided in an embodiment of the present invention;

[0079] Figure 15 The 1H NMR spectrum of the fused nitrogen heterocyclic bicyclic compound 7b provided in this embodiment of the invention;

[0080] Figure 16 The carbon NMR spectrum of the fused nitrogen heterocyclic bicyclic compound 7b provided in the embodiments of the present invention;

[0081] Figure 17 The 7e NMR carbon spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0082] Figure 18 The 7e 1H NMR spectrum of the axially chiral nitrogen heterocyclic carbene ligand provided in the embodiments of the present invention;

[0083] Figure 19 The carbon NMR spectrum of 10a, a fused nitrogen heterocyclic bicyclic compound, provided in an embodiment of the present invention;

[0084] Figure 20 The 1H NMR spectrum of the fused nitrogen heterocyclic bicyclic compound 10a provided in this embodiment of the invention; Detailed Implementation

[0085] The present invention will be further described in detail below through specific embodiments, but this does not limit the scope of the present invention.

[0086] The information on the instruments and experimental materials used in the following embodiments is as follows:

[0087] All chemical reagents were purchased commercially available from companies such as Adamas, Bidex Pharmaceuticals, and Bailingwei. Thin-layer chromatography (TLC) was performed using SHF254 silica gel plates, and silica gel column chromatography used Nortech silica gel (300-400 mesh). TLC was performed using UV light (254nm). 1 HNMR and 13CNMR was characterized using a Bruker AVANCE III 400MHz NMR instrument, with deuterated chloroform or deuterated dimethyl sulfoxide as the solvent. Chemical shifts are expressed in ppm, and coupling constants are expressed in Hz. 1 In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, sept represents septet, and m represents multiplet. 13 In CNMR, δ represents chemical shift. High-resolution mass spectrometry was performed using a JEOC AccuTOF LC-plus 4G instrument with an ESI ion source. Enantiomer ratios (er) were determined using Shimadzu LC-20A high-performance liquid chromatography and Daicel Chiralpak and Chiralcel chiral columns.

[0088] Example 1:

[0089]

[0090] Using a dry 25 mL Schlenk tube, dissolve paraformaldehyde (15.0 mg, 0.5 mmol) in 3 mL of toluene, then add 2'-(2-amino-2-phenylethoxy)-[1,1'-binaphthyl]-2-phenol 1a (202.8 mg, 0.5 mmol). Stir and heat the mixture until a clear solution forms. After cooling to 0 °C, add 2'-(2-amino-2-phenylethoxy)-[1,1'-binaphthyl]-2-phenol 1a (202.8 mg, 0.5 mmol) again. Then, add dropwise 0.17 mL of 3M tetrafluoroboric acid aqueous solution (0.5 mmol). After removing the cooling device, add dropwise glyoxal (0.06 mL, 40% aqueous solution, 0.5 mmol). Stir the reaction mixture at 40 °C for 18 hours. After dilution with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 30 / 1-20 / 1) to give a yellow solid 2a, 494.4 mg, with a yield of 53%. 1H NMR (400MHz, CDCl3) δ8.63(s,1H),8.03(d,J=8.8Hz,2H),7.89(d,J=8.0Hz,2H),7.72(d,J=8.8H z,2H),7.66(d,J=8.0Hz,2H),7.40(d,J=8.8Hz,3H),7.38–7.34(m,1H),7.32(d,J=7.2Hz,2H),7. 30–7.24(m,9H),7.23(s,1H),7.15(d,J=8.4Hz,2H),7.07–7.00(m,6H),6.85–6.78(m,4H),5.55 (s,2H),5.28(dd,J=5.2,3.6Hz,2H),4.69(dd,J=10.4,5.2Hz,2H),4.57(dd,J=10.8,3.6Hz,2H); 13 C NMR (101MHz, CDCl3) δ153.5,151.8,134.5,134.0,133.9,133.4,131.5,130.0,129.8,129.4,128.8,128.5,128.1, 127.7,126.7,125.0,124.9,124.8,123.3,120.6,117.9,116.1,114.9,113.9,69.3,68.1,62.9; HRMS(ESI-TOF)m / z Calcd.for C 59 H 45 N2O4 + [M-BF4] + :845.3374; Found:845.3371.

[0091] Example 2:

[0092]

[0093] The preparation method is the same as in Example 1, yielding 490 mg of yellow solid 2b, with a yield of 53%. 1H NMR (400MHz, CDCl3) δ8.59(s,1H),8.02(d,J=9.2Hz,2H),7.89(d,J=8.0Hz,4H),7.73(d,J=8.8Hz,2H) ,7.66(d,J=8.0Hz,2H),7.39(d,J=9.2Hz,3H),7.36(d,J=9.2Hz,1H),7.32(d,J=7.2Hz,2H),7.30–7.2 2(m,10H),7.14(d,J=8.4Hz,2H),7.07–6.99(m,4H),6.85–6.77(m,4H),6.70(t,J=7.6Hz,4H),5.55(s ,1H),5.49(s,1H),5.26(t,J=3.6Hz,2H),4.67(dd,J=10.4,5.2Hz,2H),4.56(dd,J=10.8,3.6Hz,2H); 13 C NMR (101MHz, CDCl3) δ153.5,151.9,134.5,134.0,133.9,133.5,131.5,130.0,129.8,129.4,128.8,128.5,128.1,128 .0,127.6,126.7,125.0,124.9,124.8,123.3,120.6,117.9,116.2,114.9,113.9,69.2,66.0,62.9; HRMS(ESI-TOF)m / z Calcd.for C 59 H 45 N2O4 + [M-BF4] + :845.3374; Found:845.3375.

[0094] Example 3:

[0095] The preparation method is the same as in Example 1, yielding 2c of yellow solid, 490.5mg, with a yield of 51%. 1H NMR(400MHz, CDCl3)δ8.47(s,1H),7.96(t,J=9.6Hz,4H),7.86(d,J=8.0Hz,2H), 7.73(d,J=8.0Hz,2H),7.43(d,J=9.2Hz,2H),7.37–7.30(m,6H),7.23(t,J=9.2H z,8H),7.09(d,J=8.4Hz,2H),7.02–6.94(m,6H),6.83–6.73(m,4H),5.38–5.30( m,2H),4.57(dd,J=10.8,4.0Hz,2H),4.56(dd,J=10.8,3.6Hz,2H),3.68(s,6H); 13 C NMR (101MHz, CDCl3) δ155.1,152.5,134.6,134.0,133.8(2C),130.1,129.9,129.7,129.5,129.2,128.8,128.3,128.3,1 27.9,126.8,126.7,125.2,125.0,124.3,123.7,120.3,119.8,119.0,114.2,113.8,69.7,62.4,56.6; HRMS(ESI-TOF)m / z Calcd.for C 61 H 49 N2O4 + [M-BF4] + :873.3687; Found:873.3691.

[0096] Example 4:

[0097] The preparation method is the same as in Example 1. The yellow solid was 2 days old, 449 mg, and the yield was 31%. 1H NMR (400MHz, CDCl3) δ8.72(s,1H),8.19(d,J=8.4Hz,2H),8.06(d,J=5.6Hz,4H),7.96(d,J=8.0Hz,2H),7.65(d ,J=8.4Hz,4H),7.58(d,J=8.4Hz,4H),7.50(d,J=7.2Hz,4H),7.38–7.29(m,8H),7.23(d,J=8.8Hz,2H),7.09(t ,J=8.8Hz,4H),7.04(d,J=8.0Hz,4H),6.88(t,J=7.6Hz,4H),6.13(d,J=7.6Hz,4H),5.87(s,2H),5.27(s,2H), 5.22(dd,J=9.6,4.0Hz,2H),3.65(dd,J=10.8,4.4Hz,2H),4.56(t,J=10.4Hz,2H),1.44(s,18H),1.14(s,18H); 13 C NMR (101MHz, CDCl3) δ152.0,151.8,150.9,149.5,138.0,134.9,134.2,134.1, 133.5,133.1,133.0,132.0,131.9,130.9,130.0,129.3,129.2,129.1,128.9,1 28.8,128.4(2C),127.2,127.0,126.4,126.3,126.1,125.8,125.7,125.0,124 .5,123.2,118.5,115.9,71.5,63.6,34.9,34.5,31.5,31.2; HRMS(ESI-TOF)m / z Calcd.for C 99 H 94 N2O4 + [M-BF4] + Found: 1374.7208; Found: 1374.7214.

[0098] Example 5:

[0099] The preparation method is the same as in Example 1, yielding a yellow solid 2e, 634.0 mg, with a yield of 37%. 1H NMR (400MHz, CDCl3) δ7.93(s,2H),7.91(d,J=8.0Hz,2H),7.83(s,2H),7.67(s,1H),7.61(d,J=7.6Hz,2H),7.5 4(s,2H),7.46(d,J=1.6Hz,5H),7.41(s,2H),7.33–7.27(m,5H),7.23(d,J=8.4Hz,2H),7.18(t,J=7.6Hz,2H), 7.12(d,J=6.8Hz,4H),7.05(t,J=7.6Hz,4H),6.49(d,J=7.6Hz,4H),5.71(d,J=2.0Hz,2H),5.47(s,2H),4.72( dd,J=7.6,4.4Hz,2H),4.01(dd,J=11.2,7.6Hz,2H),3.81(dd,J=11.2,4.4Hz,2H),1.39(s,36H),1.20(s,36H); 13 C NMR (101MHz, CDCl3) δ152.8,151.8,151.3,149.0,137.5,136.4,136.1,133.4, 133.0,132.9,132.0,131.5(2C),130.1,129.6,129.5,129.3,129.1,128.4,12 8.3,127.2(2C),127.1,126.9,126.2,126.1,125.4,124.8,124.2,123.7,122. 6,122.1,119.4,116.4,72.9,63.4,35.2,35.0,31.7,31.6; HRMS(ESI-TOF)m / z Calcd.for C 115 H 126 N2O + [M-BF4] + Found: 1598.9712; Found: 1598.9720.

[0100] Example 6:

[0101] The preparation method is the same as in Example 1, yielding 2f of a yellow solid, 499.3 mg, with a yield of 37%. 1H NMR (400MHz, CDCl3) δ7.97(s,1H),7.90(d,J=5.6Hz,4H),7.81(s,2H),7.68(d,J=5.6Hz,2H),7 .46(t,J=7.6Hz,2H),7.31(t,J=8.4Hz,2H),7.26–7.19(m,8H),7.19–7.16(m,2H),7.15–7.05(m ,14H),6.93(s,2H),6.55(d,J=8.4Hz,4H),5.90(d,J=3.6Hz,2H),5.32(s,2H),4.81(dd,J=8.0 ,3.6Hz,2H),4.03(t,J=11.2Hz,2H),3.80(dd,J=11.2,4.0Hz,2H),2.43(s,12H),2.22(s,12H); 13 CNMR(101MHz,CDCl3)δ152.5,148.8,138.8,138.3,137.9,136.8,136.1,1 35.5,133.4,133.3,133.0,131.8,131.5,130.7,130.1,130.1,129.8,129. 4,129.2,129.1,128.4,128.2,127.3,127.2(2C),127.1,126.1,125.3,124 .6,124.2,123.6,119.3,116.3,72.6,63.2,21.6,21.4; HRMS(ESI-TOF)m / z Calcd.for C 91 H 77 N2O + [M-BF4] + Found: 1261.5878; Found: 1261.5879.

[0102] Example 7:

[0103]

[0104] A dry 25 mL Schlenk tube was used. 3a (283.4 mg, 0.5 mmol, 1.0 equiv) and ammonium tetrafluoroborate (78.6 mg, 0.75 mmol, 1.5 equiv) were dissolved in triethyl orthoformate (0.5 M) under a nitrogen atmosphere. The mixture was stirred at 115 °C for 48 hours, then cooled to room temperature. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1-20 / 1) to give a yellow solid 4a, 184.4 mg, yield 56%. 1H NMR (400MHz, CDCl3) δ7.97(d,J=9.2Hz,1H),7.85(d,J=8.0Hz,1H),7.67(dd,J=8.8,5.2Hz,2H),7.4 0(d,J=9.2Hz,1H),7.36(d,J=7.6Hz,1H),7.34–7.29(m,4H),7.25(d,J=7.2Hz,2H),7.17(d,J=8.0Hz ,2H),7.15–7.10(m,2H),7.09(dd,J=7.6,6.0Hz,1H),7.01(d,J=7.6Hz,1H),6.88(s,2H),5.02(t,J =4.0Hz,1H),4.61(d,J=3.6Hz,2H),3.47–3.36(m,2H),3.36–3.25(m,2H),2.31(s,3H),1.93(s,6H); 13 CNMR(101MHz, CDCl3)δ157.6,154.0,152.0,140.5,133.8,133.7,133.3,131.4,130.5,130.0,130.0,129.7,129.6,129.5,128.7,128.5,1 28.3,128.2,127.6,126.8,124.8,124.8,124.5,123.5,118.1,116.6,115.1,114.5,69.9,61.3,50.3,48.0,21.1,17.4; HRMS(ESI-TOF)m / z Calcd.for C 40 H 37 N2O2 + [M-BF4] + :577.2850; Found:577.2849.

[0105] Example 8:

[0106]

[0107] The preparation method is the same as in Example 7, yielding 250.8 mg of yellow solid 4b, with a yield of 54%. 1H NMR (400MHz, CDCl3) δ8.05(s,1H),7.95(d,J=8.4Hz,1H),7.69(s,1H),7.64(dd,J=8.4,2.0Hz,2H),7.62–7.55(m,6H),7.55– 7.52(m,1H),7.51–7.45(m,1H),7.35–7.26(m,4H),7.36(d,J=7.6Hz,2H),7.21(dd,J=6.0,2.0Hz,1H),7.04(s,1H),6.86(s, 2H),6.75(dd,J=7.6,1.6Hz,2H),5.34(d,J=6.8Hz,1H),4.51(dd,J=9.6,3.2Hz,1H),4.01(t,J=10.8Hz,1H),3.92–3.79(m,1 H),3.70(dd,J=11.2,3.6Hz,1H),3.65–3.50(m,2H),3.38–3.28(m,1H),2.36(s,3H),1.89(s,6H),1.41(s,9H),1.40(s,9H); 13 C NMR (101MHz, CDCl3) δ157.1,152.7,151.6,151.5,148.7,140.3,134.9,134.5,133.8, 133.0,132.8,132.2,132.0,131.7,130.4,130.1,130.0,129.6,129.5,129.1,128.9, 128.8,128.5,128.3,127.5,127.4,127.1,126.3,126.1,126.0,125.2,124.6,124.5, 123.0,116.4,71.6,62.6,50.7,47.5,34.8,34.8,31.4,21.2,17.4; HRMS(ESI-TOF)m / z Calcd.for C 60 H 61 N2O2 + [M-BF4] + :841.4728;Found:841.4722;

[0108] Example 9:

[0109]

[0110] The preparation method is the same as in Example 7, yielding 4c of yellow solid, 203.4 mg, with a yield of 61%. 11H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.77 (t, J = 9.2 Hz, 2H), 7.47 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.33–7.28 (m, 1H), 7.19 (dd, J = 6.4, 1.2 Hz, 2H), 7.17–7.14 (m, 2H), 7.12 (td, J = 8.4, 1.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 5.41 (d, J = 6.8 Hz, 1H), 4.32 (d, J = 10.0 Hz, 1H), 4.29–4.20 (m, 1H), 4.14 (dd, J = 10.4, 3.6 Hz, 1H), 3.63–3.51 (m, 1H) 3.34 (q, J = 11.6 Hz, 1H), 3.08–3.05 (m, 1H), 3.00–2.86 (m, 1H), 2.65 (sept, J = 6.8 Hz, 1H), 2.43 (sept, J = 6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H); 13 13C NMR (101 MHz, CDCl3) δ 157.9, 154.2, 152.0, 146.5, 146.4, 133.9 (2C), 131.7, 131.2, 130.0, 129.8, 128.9, 128.6, 128.2, 127.7, 126.7, 125.0, 124.9, 124.8, 124.7, 123.5, 118.0, 116.0, 115.2, 114.6, 53.7, 52.5, 46.8, 28.7, 24.6, 24.3, 14.6; HRMS (ESI-TOF) m / z Calcd. for C 38 H 41 N2O2 + [M - BF4] + : 557.3163; Found: 557.3163.

[0111] Example 10:

[0112]

[0113] Dry 25 mL Schlenk tubes were used to dissolve 5a (188.7 mg, 0.5 mmol, 1.0 equiv) and 6a (157.0 mg, 0.75 mmol, 1.5 equiv) in toluene (0.2 M) under a nitrogen atmosphere. The mixture was stirred at 120 °C for 72 hours, then cooled to room temperature. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1-20 / 1) to give a yellow solid 7a, 140.8 mg, yield 48%. 1 H NMR (400MHz, CDCl3) δ10.18(s,1H),8.83(dd,J=8.4,2.0Hz,1H),8.32(d,J=8.4Hz,1H),8.17(dd,J=8.0,1.6Hz,1H),7.9 6(dd,J=8.4,3.2Hz,2H),7.90(d,J=8.0Hz,1H),7.84(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.5 6(dd,J=8.0,6.8Hz,1H),7.51–7.45(m,2H),7.42(dd,J=8.4,4.0Hz,1H),7.38(d,J=9.2Hz,1H),7.24(t,J=7.2Hz,1H),6 .57(s,1H),5.97(d,J=13.6Hz,1H),5.93(d,J=13.2Hz,1H),5.32(d,J=14.0Hz,1H),5.03(d,J=14.4Hz,1H),3.67(s,3H). 13 C NMR (101MHz, CDCl3) δ154.3,150.3,146.1,137.3,136.7,135.0,133.9,133.5,132.9,132.7,131.6,130.9,130.0,129.8,129.5,128.8,12 8.5,128.3,128.2,127.3,127.1,127.0,126.9,126.5,124.1(2C),122.8,121.8,120.9,118.6,113.4,56.4,52.0,48.8; HRMS(ESI-TOF)m / z Calcd.for C 35 H 28 N3O + [M-Br] + :506.2227;Found:506.2232.

[0114] Example 11:

[0115]

[0116] The preparation method is the same as in Example 10, yielding 170 mg of yellow solid 7b, with a yield of 46%. 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),8.71(dd,J=4.4,2.0Hz,1H),8.43(d,J=7.2Hz,1H),8.19(dd,J=8.0,2.0Hz,1H),7.95(s,1H),7.90( d,J=7.8Hz,2H),7.96(d,J=8.0Hz,2H),7.76(s,1H),7.60(d,J=7.2Hz,2H),7.57(d,J=8.0Hz,1H),7.55–7.51(m,1H),7.45(t,J=7.2Hz ,2H),7.42(d,J=4.4Hz,1H),7.41–7.37(m,2H),7.36–7.32(m,1H),7.32–7.28(m,1H),7.26–7.23(m,1H),7.13–7.01(m,4H),6.99(d,J =8.0Hz,2H),6.83(s,1H),5.93(d,J=13.6Hz,1H),5.83(d,J=13.2Hz,1H),5.38(d,J=14.8Hz,1H),5.04(d,J=15.2Hz,1H),3.03(s,3H); 13 C NMR (101MHz, CDCl3) δ153.3,150.1,146.1,139.7,139.5,138.0,136.9,136.8,136. 5,135.0,133.5,133.3,133.0,132.4,131.9,131.7,130.9,130.2,129.7,129.1,128 .8,128.7,128.5(2C),128.3,128.2,128.1,127.8(2C),127.7,127.5,127.2,127.1( 2C),126.3,126.0,125.0,123.6,121.6,120.4,60.8,49.7,48.3; HRMS(ESI-TOF)m / z Calcd.for C 35 H 28 N3O + [M-Br] + :658.2853; Found:658.2854.

[0117] Example 12:

[0118]

[0119] The preparation method is the same as in Example 10, yielding a yellow solid of 7c, 187.2mg, and a yield of 44%. 1 H NMR (400MHz, CDCl3) δ8.62(d,J=4.4Hz,1H),8.51(d,J=6.0Hz,1H),8.15(d,J=8.0Hz,1H),8.02(s,1H),7.93(d,J=5.2Hz,2 H),7.89–7.82(m,2H),7.82(d,J=7.2Hz,2H),7.55(d,J=8.0Hz,4H),7.48(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),7.36(d, J=8.0Hz,2H),7.28(s,1H),7.20(t,J=8.0Hz,1H),7.08(d,J=8.0Hz,2H),6.94(d,J=8.8Hz,1H),6.75(s,1H),6.00(d,J=13 .6Hz,1H),5.78(d,J=13.2Hz,1H),5.34(d,J=14.4Hz,1H),5.06(d,J=14.4Hz,1H),3.06(s,3H),1.39(s,9H),1.37(s,9H); 13 C NMR (101MHz, CDCl3) δ153.3,151.4,150.9,149.9,145.9,139.8,136.8,136.8,136.4,136.2, 134.9,134.84,133.5,133.1,132.8,132.3,131.7,131.6,130.8,130.3,129.7,129.3,128.7, 128.4,128.3,128.2,127.7,127.3,127.2,127.0(2C),126.2,126.1,126.0,125.8,125.7,12 5.6,124.8,123.5,121.5,120.8,60.8,49.7,48.2,34.8,34.7,31.5,31.4; HRMS(ESI-TOF)m / z Calcd.for C 55 H 52 N3O + [M-Br] + :770.4105;Found:770.4105.

[0120] Example 13:

[0121]

[0122] The preparation method was the same as in Example 10. The yellow solid was 209.4 mg after 7 days, with a yield of 47%. 1 H NMR (400MHz, CDCl3) δ9.16(s,1H),8.69(d,J=4.4Hz,1H),8.13(d,J=6.8Hz,1H),8.08(dd,J=8.4,1.6Hz,1H),8.00(s,1H),7.9 2(d,J=8.4Hz,1H),7.88(d,J=8.0Hz,1H),7.84(s,1H),7.75(d,J=9.2Hz,2H),7.71(d,J=8.4Hz,4H),7.68–7.60(m,4H),7.55(d ,J=7.2Hz,1H),7.53–7.41(m,8H),7.40–7.30(m,6H),7.29(s,1H),7.24–7.18(m,2H),7.16(d,J=7.6Hz,1H),7.01(d,J=8.4Hz, 1H),6.88(s,1H),5.81(d,J=13.2Hz,1H),5.69(d,J=13.2Hz,1H),5.50(d,J=14.8Hz,1H),5.15(d,J=15.2Hz,1H),3.10(s,3H); 13 C NMR (101MHz, CDCl3) δ153.3,150.0,145.8,140.8,140.5,140.3,139.4,138.5,137.0,136.9,136. 7,136.4,134.5,133.5,133.0,132.9,132.4,131.8,131.4,130.9,130.4,130.1,129.9,129.6,129 .5,129.1,129.0,128.9,128.8,128.5,128.4,128.3(2C),127.8(2C),127.7,127.5(2C),127.4,12 7.3,127.1,127.0,126.4,126.0,125.0,123.3,121.6,120.6,60.9,49.7,48.3; HRMS(ESI-TOF)m / z Calcd.for C 59 H 44 N3O + [M-Br] + :810.3479;Found:810.3479.

[0123] Example 14:

[0124]

[0125] The preparation method is the same as in Example 10, yielding 7f of a yellow solid, 171mg, with a yield of 41%. 1 H NMR (400MHz, CDCl3) δ8.78(s,1H),8.55(d,J=4.0Hz,1H),8.27(d,J=6.8Hz,1H),8.11(d,J=8.4Hz,2H),8.06(s,1H),8.00–7.93(m, 4H),7.90(t,J=8.0Hz,4H),7.83(s,1H),7.77(d,J=8.4Hz,1H),7.72(d,J=7.2Hz,2H),7.61–7.56(m,2H),7.56–7.50(m,4H),7.49(d ,J=7.2Hz,1H),7.45(d,J=9.6Hz,1H),7.41(d,J=3.6Hz,1H),7.40–7.34(m,2H),7.34–7.30(m,2H),7.30–7.27(m,1H),7.04(d,J=8. 4Hz,1H),6.71(s,1H),5.59(d,J=13.6Hz,1H),5.44(d,J=15.2Hz,1H),5.33(d,J=13.6Hz,1H),5.18(d,J=14.8Hz,1H),3.07(s,3H); 13 C NMR (101MHz, CDCl3) δ153.5,149.9,146.0,139.9,137.2,136.9,136.8,136.5,135.7,135. 1,133.6,133.2,133.1,132.9,132.6,132.5,132.3,131.4,131.0,130.5,129.6,129.2,12 8.7,128.6,128.4,128.3(2C),128.1,128.0,127.9,127.6,127.3(2C),127.2,126.9,126. 5(2C),126.4(2C),126.1,125.0,123.4,121.5,120.6,61.0,49.9,47.9; HRMS(ESI-TOF)m / z Calcd.forC 55 H 40 N3O + [M-Br] + :758.3166; Found:758.3158.

[0126] Example 15:

[0127]

[0128] A dry 25 mL Schlenk tube was used. 5a (377.3 mg, 1.0 mmol, 2.0 equiv) and imidazole (34.0 mg, 0.5 mmol, 1.0 equiv) were dissolved in toluene (0.2 M) under a nitrogen atmosphere. The mixture was stirred at 120 °C for 72 hours, then cooled to room temperature. The crude product was purified by column chromatography (DCM / MeOH = 30 / 1-20 / 1) to give a white solid 8a, 267.0 mg, in 72% yield. 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 8.02 (d, J = 9.2Hz, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.90 (dd, J = 8 .4Hz,2H),7.71(d,J=7.8Hz,2H),7.61(d,J=8.4Hz,2H),7.49–7.45(m,3H),7.38–7.36(m,2H) ,7.26–7.22(m,2H),7.11(d,J=8.4Hz,2H),7.08–7.03(m,2H),7.02–6.97(m,2H),6.63(d,J=8 .4Hz,2H),6.58(d,J=2.0Hz,2H),5.20(d,J=14.0Hz,2H),4.66(d,J=14.0Hz,2H),3.69(s,6H). 13 C NMR (101MHz, CDCl3) δ154.3,146.1,137.3,135.0,133.9,132.9,131.6,130.0,129.5,128.5,128.3,128.2,127 .3,127.1,127.0,126.9,126.5,124.1,122.8,121.8,120.9,118.6,113.4,56.1,53.9,52.0; HRMS(ESI-TOF)m / z Calcd.for C 35 H 28 N3O + [M-Br] + Found: 661.2850; Found: 661.2849.

[0129] Example 16: Optimization of Synthetic Conditions for N-Fused Heterocyclic Compounds (Screening of Palladium Salts)

[0130]

[0131]

[0132] Unless otherwise stated, the reaction is carried out in 1 mL of 1,4-dioxane solvent at a scale of 0.1 mmol.

[0133] Example 17: Optimization of Synthetic Conditions for N-Fused Heterocyclic Compounds (Solvent Screening)

[0134]

[0135]

[0136]

[0137] Unless otherwise stated, the reaction is carried out in 1 mL of solvent on a 0.1 mmol scale.

[0138] Example 18: Optimization of Synthetic Conditions for N-Fused Heterocyclic Compounds (Base Screening)

[0139]

[0140]

[0141] Unless otherwise stated, the reaction was carried out in 1 mL of 1,4-dioxane solvent at a scale of 0.1 mmol. Example 19: Optimization of Synthetic Conditions for N-Fused Heterocyclic Compounds (Ligand Screening)

[0142]

[0143]

[0144]

[0145] Unless otherwise stated, the reaction is carried out in 1 mL of 1,4-dioxane solvent at a scale of 0.1 mmol.

[0146] Example 20: Application of axially chiral nitrogen heterocyclic carbene in the asymmetric catalytic synthesis of N-fused heterocyclic compounds.

[0147]

[0148] A dry 25 mL Schlenk tube was used. Palladium acetate (10 mol%), ligand (20 mol%), and K₂CO₃ (2.0 equiv) were added sequentially. The gas was purged three times under nitrogen protection. Then, 1 mL of ultra-dry 1,4-dioxane solvent was added. The reaction was stirred in a 70°C oil bath for 30 minutes. Substrate 9 or 11 (0.1 mmol) was then added, followed by the addition of an oxygen bulb (1 atm). The reaction was then stirred in a 70°C oil bath for 48 hours. After the reaction was completed, the reaction solvent was removed under reduced pressure. The residue was purified by column chromatography, and the enantiomeric ratio (er) of the product was analyzed by high performance liquid chromatography. The experimental results of the obtained N-fused heterocyclic compounds with various substituents are shown in the table below.

[0149]

[0150]

[0151]

[0152] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. An axially chiral nitrogen heterocyclic carbene ligand, characterized in that, The axially chiral nitrogen heterocyclic carbene ligand has the following general formula (Ⅰ): In the general formula (Ⅰ): Chirality marked with * indicates R configuration or S configuration; The anion X portion of the axially chiral nitrogen heterocyclic carbene ligand is selected from any one of chloride, bromine, iodine, tetrafluoroborate, or hexafluorophosphate. The axially chiral portion A of the axially chiral nitrogen heterocyclic carbene ligand is either A-1 or A-2; The B portion of the axially chiral nitrogen heterocyclic carbene ligand is either B-1 or B-2 or the same as A; R 1 It is selected from any one of alkyl, alkoxy, hydroxy, phenyl, and substituted phenyl groups; R 2 Each is independently selected from hydrogen, alkyl, phenyl, or substituted phenyl; R 3 Each of the following is independently selected from hydrogen, halogen, alkyl, alkoxy, phenyl, substituted phenyl, naphthyl, anthraceneyl, phenanthryl, and heteroaryl; R 4 -R 8 Each of the following is independently selected from hydrogen, halogen, and alkyl groups.

2. The axially chiral nitrogen heterocyclic carbene 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 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 2 When R is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, or tert-butyl; 2 When the substituted phenyl group is used, the substituted phenyl group is a methyl-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 3 When R 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; 3 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy, isobutyloxy, or tert-butyloxy; when the 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 3 When the heteroaryl group is a furanyl, thiophene, indolyl, or pyridinyl group; When the R 4 -R 8 When the alkyl group is an alkyl group, the alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; When the R 4 -R 8 When the halogen is halogen, the halogen is fluorine, chlorine, or bromine.

3. A method for preparing the axially chiral nitrogen heterocyclic carbene ligand as described in claim 1, characterized by comprising: The following steps are required: (1) Compound 2 is prepared by reacting compound 1 with glyoxal and paraformaldehyde in an acid under the presence of nitrogen or an inert gas in an organic solvent. (2) Compound 4 is prepared by reacting compound 3, triethyl orthoformate and ammonium salt in an organic solvent under nitrogen or inert gas. (3) Compound 5 and compound 6 are reacted in an organic solvent under nitrogen or inert gas to prepare compound 7 by the action of ammonium salt; (4) Compound 5 is prepared by reacting imidazole with an ammonium salt in an organic solvent under nitrogen or an inert gas atmosphere.

4. The method for preparing an axially chiral nitrogen heterocyclic carbene ligand according to claim 3, characterized in that, The organic solvents mentioned in steps (1), (2), (3) and (4) 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 mentioned in steps (1), (2), (3) and (4) includes one or more of argon, helium, neon and krypton; The acid mentioned in steps (1), (2), (3) and (4) is selected from one of formic acid, acetic acid, tetrafluoroboric acid, hydrochloric acid, hydrogen bromide or hexafluorophosphoric acid; The ammonium salts mentioned in steps (1), (2), (3) and (4) are selected from one of ammonium chloride, ammonium sulfate, ammonium tetrafluoroborate or ammonium bromide; The preparation method of the axial chiral nitrogen heterocyclic carbene ligand, wherein the reaction temperature of the synthesis steps (1), (2), (3) and (4) is 25 to 120 °C; The preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the reaction time of the synthesis steps (1), (2), (3) and (4) is 8-72 hours; In the preparation method of the axially chiral nitrogen heterocyclic carbene ligand, the feeding ratio of compound 1, glyoxal and paraformaldehyde in step (1) is 2:1:0.5 to 3:1:0.5 molar ratio; In the preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the molar ratio of compound 3 to triethyl orthoformate in step (2) is 1:10 to 1:

20. In the preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the molar ratio of compound 5 to compound 6 in step (3) is 1:1 to 1:

2. In the preparation method of the axial chiral nitrogen heterocyclic carbene ligand, the molar ratio of compound 5 to imidazole in step (4) is 2:1 to 2.5:

1.

5. A complex formed by the complexation of an axially chiral nitrogen heterocyclic carbene ligand as described in claim 1 and a transition metal compound, characterized in that, The complex is formed in situ by the complexation of an axially chiral nitrogen heterocyclic carbene 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 hexafluorophosphate tetraacetonitrile, nickel iodide, nickel chloride, nickel trifluoromethanesulfonate, ferric chloride, ferric bromide, ferrous trifluoromethanesulfonate, tetra(triphenylphosphine)palladium, tri(dibenzylacetone)dipalladium, palladium acetate, palladium chloride, palladium acetylacetonate, nickel chloride, nickel acetate, bis(1,5-cyclooctadiene)nickel, or bis(1,5-cyclooctadiene)iridium.

6. A method for synthesizing chiral N-fused heterocyclic compounds, characterized in that, The method for synthesizing chiral N-fused heterocyclic compounds includes the following steps: Under a reaction gas, the axially chiral nitrogen heterocyclic carbene ligand as described in claim 1 is complexed with a palladium salt and a base in an organic solvent, and compound 9 or 11 is reacted according to the following formula to obtain compound 10 or 12; Among them, R 9 -R 10 Selected from alkyl, alkoxy, phenyl, substituted phenyl, or halogen; R 11 Selected from alkyl, phenyl, or substituted phenyl groups; R 12 -R 17 Selected from alkyl, alkoxy, phenyl, substituted phenyl, or halogen; The chirality marked with * indicates S configuration, R configuration, or racemic chirality.

7. The method for synthesizing chiral N-fused heterocyclic compounds according to claim 6, characterized in that, When R 9 -R 10 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 9 -R 10 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; when the R 9 -R 10 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, or a bromine-substituted phenyl group; when R 9 -R 10 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine; When R 11 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 11 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, or a bromine-substituted phenyl group. When R 12 -R 17 When R is an alkyl group, the alkyl group is methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, or cyclohexyl; 12 -R 17 When the alkoxy group is alkoxy, the alkoxy group is methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy; when the R 12 -R 17 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, or a bromine-substituted phenyl group; when R 12 -R 17 When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine; 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. The palladium salt is selected from at least one of palladium chloride, palladium bromide, palladium acetate, palladium acetylacetonate, palladium trifluoroacetate, tetra(triphenylphosphine)palladium, di(triphenylphosphine)palladium chloride, tri(dibenzylacetone)palladium, or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; 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 9 in the organic solvent is 0.01–1.0 M; The molar concentration of compound 11 in the organic solvent is 0.01–1.0 M; The molar ratio of the palladium salt to the base is 1:1 to 1:30; The molar ratio of the palladium salt to the axially chiral nitrogen heterocyclic carbene ligand is 1:1 to 1:3.

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