Strong coordination PNN tridentate chiral ligand based on antisteric effect and application of strong coordination PNN tridentate chiral ligand in free radical asymmetric functionalization and related reactions

Abstract

The invention discloses a strong-coordination PNN tridentate chiral ligand based on an anti-site effect and application of the strong-coordination PNN tridentate chiral ligand in free radical asymmetric functionalization and related reactions, and belongs to the technical field of organic chemistry. The strong-coordination PNN tridentate chiral ligand has unique structure and properties, can effectively solve the problem of poisoning of a catalyst by strong-coordination substrates such as heterocyclic compounds and the like, and remarkably improves the catalytic efficiency and enantioselectivity of the substrates in the reaction process. The strong-coordination PNN tridentate chiral ligand can be used for a free radical asymmetric functionalization reaction catalyzed by a cheap metal, and is especially suitable for an asymmetric azidation reaction. Meanwhile, the invention discloses a synthetic application of the strong coordination PNN tridentate chiral ligand in molecules of a vascular non-inflammatory protein-1 inhibitor (Vanin-1), onazolast, a natural product Connulothiazole A, a calcium ion channel antagonist TTA-A8 and the like. The invention further discloses a preparation method of the strong coordination PNN tridentate chiral ligand. The method has remarkable theoretical innovation and good practical application value.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemistry, and in particular to a strongly coordinated PNN tridentate chiral ligand based on anti-site effect and application thereof in asymmetric functionalization of free radicals and related reactions. Background Art

[0002] In recent years, free radical asymmetric functionalization catalyzed by cheap metals has attracted more and more attention. Free radical asymmetric functionalization reaction is an important means to construct many structurally rich chiral compounds, and plays a vital role in synthetic chemistry, drug discovery and materials science. The current bottleneck problem in this field is the lack of efficient asymmetric catalytic systems, and new chiral ligands are urgently needed to be developed.

[0003] Chiral tridentate ligands are widely used in transition metal catalysis. Such ligands are easy to modify in structure, and their stereo and electronic effects can be highly adjusted. Among them, chiral tridentate ligands containing weak coordination sites have shown excellent reactivity and enantioselectivity in free radical asymmetric functionalization reactions catalyzed by cheap metals, and thus have attracted attention. For example, the prior art, including the inventor's previous research results (CN118146274A), provides the following representative chiral tridentate ligands containing weak coordination sites:

[0004] The dialkylamine weak coordination site of the above type of ligand can form a metastable coordination with the metal, and the metastable coordination can stabilize the high-valent metal active intermediate and can dissociate to form an effective active reaction site. However, in the further research of the inventor, it was found that this type of ligand still has technical defects that need to be solved urgently. For substrates with strong coordination such as heterocycles, the strongly coordinated heteroatoms in the substrate can quickly replace the weak coordination sites of this type of tridentate ligand to form a stable metal intermediate coordinated by multiple substrates. The substrate coordinated in this type of metal intermediate is not easy to dissociate and cannot achieve catalytic cycle, thereby causing catalyst poisoning. Therefore, tridentate ligands containing metastable coordination are generally not suitable for asymmetric radical functionalization of strongly coordinated substrates.

[0005] In the application of related fields, chiral nitrogen heterocyclic compound fragments are commonly found in drugs, bioactive molecules and natural products. Chiral nitrogen heterocyclic compounds have significant pharmacological and biological activities, including antioxidant, antibacterial, anti-tuberculosis, analgesic, anti-inflammatory, antiviral, anticancer, anti-helminthic, etc. Among the 164 small molecule drugs approved by the US Food and Drug Administration (FDA) from 2010 to 2019, there were 144 nitrogen heterocyclic drugs, accounting for 87.8%. Among these 144 nitrogen heterocyclic drugs, pyridine drugs accounted for the largest proportion, 19.4%, followed by piperidines (15.2%), piperazines (10.4%), pyrimidines (6.9%), pyrazoles (6.9%), indoles (5.5%), etc. In addition, more than 30% of the top 200 drugs in terms of retail sales in 2019 contained chiral amine structures. Therefore, the synthesis of nitrogen-containing heterocyclic chiral amine compounds is of great significance.

[0006] However, due to the significant poisoning effect of nitrogen-containing heterocycles on catalysts, the tridentate chiral ligands reported so far are difficult to achieve asymmetric radical transformation of such substrates due to the above defects. Therefore, providing a strongly coordinated PNN tridentate chiral ligand to solve the existing shortcomings will have significant theoretical innovation and practical application value. Summary of the invention

[0007] In view of the above-mentioned defects of the prior art, in the first aspect of the present invention, there is provided a strongly coordinated PNN tridentate chiral ligand which can realize chiral control in the process of free radical functionalization, solve the poisoning of the catalyst by the strongly coordinated substrate, and has excellent reaction activity and enantioselectivity in the asymmetric free radical functionalization reaction of nitrogen-containing heterocyclic compounds, and has a structure as described in general formula I:

[0008] In the formula, the solid line on the left represents the structure of ferrocene or benzene ring; X is carbon or sulfur, and Y is carbon or oxygen; the solid line on the right represents that it forms a ring with nitrogen atom and Y atom; When X is a carbon element, the dotted line between X and oxygen represents the absence of such a bond, that is, the bridging group is a carbonyl group; when X is a sulfur element, the dotted line between X and oxygen represents the presence of such a bond, that is, the bridging group is a sulfonyl group; When Y is a carbon element, the representative structure of the solid line on the right side of the general formula includes pyridine and pyridine containing a substituent; when Y is an oxygen element, the representative structure of the solid line on the right side of the general formula includes oxazoline and oxazoline containing a substituent; R, R 1 , R 2Each is independently selected from an alkyl group or an aryl group; wherein the alkyl group includes one of a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a tert-butyl group, and a benzyl group; and the aryl group includes one of a phenyl group, a 2-methylphenyl group, a 2-methoxyphenyl group, a 2-trifluoromethylphenyl group, a 3-methylphenyl group, a 3-methoxyphenyl group, a 3-trifluoromethylphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenyl group, a 2,6-dimethylphenyl group, a 2,4,6-trimethylphenyl group, a 3,5-dimethylphenyl group, a 3,5-ditrifluoromethylphenyl group, a 3,5-di-tert-butylphenyl group, a 3,5-di-tert-butyl-4-methoxyphenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 1-anthracenyl group.

[0009] Preferably, the strongly coordinated PNN tridentate chiral ligand includes compounds of the following structural formulas L1 to L146: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , .

[0010] For the purpose of simplifying the compound structure, the above-mentioned substituted aryl group is represented by the common symbol Ar (aryl group) in the art, and its specific type is presented in the corresponding compound.

[0011] Based on the above technical scheme, the principle and design concept of the present invention is to propose a strongly coordinated tridentate PNN ligand based on the anti-position effect with the above structure. The ligand skeleton is a ferrocenium Ugi amine skeleton with superior face chirality and carbon center chirality and a simple chiral benzylamine skeleton. For the phosphorus atom coordination site in the ligand, the phosphine chirality can be precisely and controllably introduced through the chiral Ugi amine. The ligand contains a secondary amine coordination site that can be deprotonated, which can form an electron-rich σ coordination with the metal to enhance the reaction activity. The third strong coordination site in the ligand is pyridine or oxazoline, which can also be precisely and controllably introduced into a chiral environment. When the free radical acts on the central metal, the large steric hindered group of the free radical will avoid contact with the large steric hindered group in the coordination, thereby realizing chirality control in the free radical functionalization process.

[0012] The three coordination sites of the strongly coordinated tridentate PNN ligand are all strongly coordinated. When the strongly coordinated substrate is coordinated with the metal, the three strong coordination sites in the ligand form a stable chelate ring with the metal complex, and the substrate cannot replace the three strong coordination sites in the ligand. At this time, the strongly coordinated substrate can only coordinate at the anti-position of the bridging N atom in the ligand. The H atom on the bridging N atom in the ligand can be deprotonated under alkaline conditions to form a stable σ coordination with the metal. The bridging N atom that forms a σ coordination with the metal has a strong electron donor property, and the heteroatom of the strongly coordinated substrate in the anti-position also has a strong electron donor property. According to the anti-position effect principle, when both ligands in the anti-position are strong electron donors, one of the ligands is affected by the anti-position effect and is prone to dissociation. Therefore, the strongly coordinated substrate in the anti-position of the ligand bridging N atom can be affected by the anti-position effect and can dissociate, thereby realizing the catalytic cycle, and will not form a stable strong coordination complex to cause catalyst poisoning. In addition, since the three coordination sites of the tridentate PNN ligand in the present invention are all strongly coordinated, this type of ligand has a better stabilizing effect on high-valent active metal intermediates, and the strongly coordinated substrate is not easy to destroy the intrinsic structure of the complex formed by the ligand and the metal, so the corresponding catalyst has better stability during the catalytic process.

[0013] For the strongly coordinated tridentate PNN ligands L1~L4, L21~L56, the synthesis routes are as follows:

[0014] Wherein, rt represents room temperature; 1.5 h, 4 h, and 50 min represent reaction time, respectively; 0.25 M represents concentration, and the same applies to the subsequent reactions.

[0015] In the general structural formula of compounds 1, 2, 3, int-1 or products L1~L4, L21~L56 involved in the above synthetic route, R corresponds to the corresponding alkyl or aryl group, the alkyl group is selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, etc., and the aryl group is selected from phenyl, 2-methylphenyl, 4-methoxy-3,5-di-tert-butylphenyl, etc.; R' corresponds to the corresponding alkyl or aryl group, the alkyl group is selected from cyclohexyl, tert-butyl, etc., and the aryl group is phenyl, etc.; R 4Corresponding to the corresponding alkyl or aryl, the alkyl is selected from 2-methyl, 2-methoxy, 3-methyl, 3-ethyl, 3-isopropyl, 3-tert-butyl, 3-ethylphenyl, 3-methoxy, 3-trifluoromethyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-ethylphenyl, 4-methoxy, 4-trifluoromethyl, 5-methyl, etc., and the aryl is selected from 2-phenyl, 3-phenyl, 3-3,5-di-tert-butylphenyl, 3-1-naphthyl, 3-2-naphthyl, 3-1-anthryl, 4-phenyl, 4-3,5-di-tert-butylphenyl, 4-1-naphthyl, 4-2-naphthyl, 4-1-anthryl, 5-phenyl, etc. For the purpose of concise description, the introduction of a typical pyridine ring is used as an example for explanation in the pathway. For products containing quinoline or substituted quinoline structures, the corresponding structures of the substrates and products used in this part are quinoline or substituted quinoline.

[0016] Similarly, for the strongly coordinated tridentate PNN ligands L5~L13, the synthetic routes are as follows:

[0017] In the general structural formula of compounds 5, 6, int-2, or products L5~L13 involved in the above-mentioned synthetic route, Ar is the corresponding aromatic group, such as 3,5-di-tert-butylphenyl, 3,5-ditrifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 2-naphthyl, etc.

[0018] For the strongly coordinated tridentate PNN ligands L14~L20, the synthesis routes are as follows:

[0019] In the general structural formula of compounds 7, 8, int-3, or products L14 to L20 involved in the above synthetic route, R 1 Corresponding to the corresponding alkyl or aryl, the alkyl is selected from methyl, ethyl, ethylphenyl, isopropyl, tert-butyl, etc., and the aryl is selected from 4-methoxy-3,5-di-tert-butylphenyl, etc.

[0020] For the strongly coordinated tridentate PNN ligands L57~L63, the synthesis routes are as follows:

[0021] In the general structural formula of the compound int-1 or the products L57 to L63 involved in the above synthetic route, R 3 Corresponding to the corresponding 2-methyl, 2-phenyl; as mentioned above, for the products containing quinoline or substituted quinoline structure, the corresponding structures of the substrate and the product used are quinoline or substituted quinoline, etc.

[0022] For the strongly coordinated tridentate PNN ligands L64~L76, the synthesis routes are as follows:

[0023] In the above synthetic route, the heterocyclic structure is oxazoline and oxazoline containing a substituent.

[0024] For the strongly coordinated tridentate PNN ligands L77~L115, L123~L124, the synthesis routes are as follows:

[0025] In the general structural formula of compound 9, int-4 or products L77~L115 and L123~L124 involved in the above synthetic route, R 4 Corresponding to the corresponding alkyl or aryl, the alkyl is selected from 2-methyl, 2-methoxy, 3-methyl, 3-ethyl, 3-isopropyl, 3-tert-butyl, 3-ethylphenyl, 3-methoxy, 3-trifluoromethyl, 4-methyl, 4-ethyl, 4-isopropyl, 4-tert-butyl, 4-ethylphenyl, 4-methoxy, 4-trifluoromethyl, 5-methyl, and the aryl is selected from 2-phenyl, 3-phenyl, 3-3,5-di-tert-butylphenyl, 3-1-naphthyl, 3-2-naphthyl, 3-1-anthracenyl, 4-phenyl, 4-3,5-di-tert-butylphenyl, 4-1-naphthyl, 4-2-naphthyl, 4-1-anthracenyl, 5-phenyl, etc.; R 5 (represents R 1 , R 2 In case of the same group type, R 5 ) corresponds to the corresponding alkyl or aryl, the alkyl is selected from cyclohexyl, etc., and the aryl is selected from phenyl, 3,5-di-tert-butylphenyl, 3,5-ditrifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 2-naphthyl, 2-methoxyphenyl, 4-methoxy-3,5-di-tert-butylbenzene, etc.

[0026] For the strongly coordinated tridentate PNN ligands L116~L122, the synthetic routes are as follows:

[0027] In the general structural formula of compounds 10, 11, 12, int-5 or products L116~L122 involved in the above-mentioned synthetic route, R corresponds to the corresponding alkyl or aryl group, the alkyl group is selected from methyl, ethyl, isopropyl, tert-butyl, ethylphenyl, etc., and the aryl group is selected from phenyl, 4-methoxy-3,5-di-tert-butylphenyl, etc., dimethylphenyl, etc.

[0028] For the strongly coordinated tridentate PNN ligands L125~L131, the synthesis routes are as follows:

[0029] In the general structural formula of the compound int-5 or the products L125 to L131 involved in the above synthetic route, R 6 Selected from 2-methyl, 2-phenyl; as mentioned above, for products containing quinoline or substituted quinoline structure, the corresponding structures of the substrate and product used in this part are quinoline or substituted quinoline, etc.

[0030] For the strongly coordinated tridentate PNN ligands L132~L146, the synthesis routes are as follows:

[0031] As mentioned above, for products containing quinoline or substituted quinoline structures, the corresponding structures of the substrate and the product used are quinoline or substituted quinoline, etc.

[0032] The above synthetic route reflects the general synthetic route adopted by the inventors in the present invention, which has the advantage of being easy to operate. Based on the structure of the corresponding product, those skilled in the art can also adopt other routes to synthesize the corresponding strongly coordinated tridentate PNN ligand.

[0033] In the second aspect of the present invention, there is provided the use of the strongly coordinated PNN tridentate chiral ligand according to the first aspect of the present invention in a free radical asymmetric functionalization reaction and a derivatization reaction thereof.

[0034] Preferably, the free radical asymmetric functionalization reaction comprises an asymmetric azidation reaction.

[0035] Preferably, the application method comprises the following steps: using the product formed by the complexation reaction of the strongly coordinated PNN tridentate chiral ligand and the metal compound as a catalyst for free radical asymmetric functionalization reaction and its derivatization reaction.

[0036] Further preferably, the metal atoms in the metal compound include at least one of Cu, Fe, Zn, Mn, Cr, Co, Au, Ag, Ni, Ti, Pt, Pd, Rh, Ru, and Ir.

[0037] Among the optional metal atom types, copper is a cheap, easily available, abundant metal, and the types and valence states of copper in metal compounds are rich and the selection is wide, making it particularly suitable for use as the metal compound of the present invention.

[0038] Furthermore, the metal compound includes at least one of CuI, CuBr, CuCl, CuCN, Cu2O, Cu(CH3CN)4PF6, (CuOTf)2·PhH, (CuOTf)2·PhMe, Cu(OTf)2, Cu(NO3)2, Cu(OAc)2, Cu(OAc)2·H2O, Cu(acac)2, CuCl2, CuBr2, Cu(BF4)2, and CuSO4.

[0039] Further preferably, the application method specifically comprises the following steps: (1) Under an inert atmosphere, a metal compound, a strongly coordinated PNN tridentate chiral ligand, and a base are added to a solvent, mixed to carry out a complexation reaction, and a catalyst solution is obtained; (2) According to the expected product type of the free radical asymmetric functionalization reaction and its derivative reaction, an alkyl halide, an olefin and TMSN3, or an alkyl halide and TMSN3 are used as reaction substrates; a catalyst solution is added to the reaction substrate, the temperature is raised to the reaction temperature and an asymmetric azidation reaction is carried out under the action of the catalyst solution; after the reaction is completed, the obtained crude product is purified to obtain the target product.

[0040] Furthermore, in the step (1), the base includes at least one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, 1,8-diazabicyclo-bicyclo[5,4,0]-7-undecene (1,8-Diazabicyclo[5.4.0]undec-7-ene, DBU), 2-tert-Butyl-1,1,3,3-tetramethylguanidine (2-tert-Butyl-1,1,3,3-tetramethylguanidine, BTMG), and (tert-butylimino)tri(pyrrolidin-1-yl)phosphoranylidene)-propan-2-amine (BTPP).

[0041] Furthermore, in step (1), the solvent includes at least one of methanol, ethanol, isopropanol, tert-butanol, 1,4-dioxane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, and 2-methyl-tetrahydrofuran.

[0042] Furthermore, in the step (1), the temperature of the complexation reaction is room temperature, and the reaction time is ≤1 h.

[0043] Furthermore, in the step (1), the molar ratio of the metal compound, the strongly coordinating PNN tridentate chiral ligand, and the base is 1:(1-1.5):(10-20).

[0044] Furthermore, in the step (2), when the reaction substrates are alkyl halide, olefin and TMSN3, the molar ratio of the alkyl halide, olefin and TMSN3 is 1:(1.1 ~ 2):(1.1 ~ 2); when the reaction substrates are alkyl halide and TMSN3, the molar ratio of the alkyl halide to TMSN3 is 1:(1.1 ~ 2).

[0045] Furthermore, in the step (2), the reaction temperature of the asymmetric azidation reaction is -20 to 50 °C, and the reaction time is 2 to 72 h.

[0046] The strongly coordinated tridentate PNN ligand developed in the present invention utilizes the anti-position effect to innovatively solve the poisoning of the catalyst by the strongly coordinated substrate, thereby showing excellent reactivity and enantioselectivity in the asymmetric free radical functionalization reaction of nitrogen-containing heterocyclic compounds. The strongly coordinated tridentate PNN ligand is used as a catalytically active substance in free radical asymmetric functionalization reactions and their derivative reactions, especially in asymmetric azidation reactions. The present invention has a wide range of applicability in asymmetric azidation reactions. Those skilled in the art can select suitable reaction substrates according to actual synthesis requirements, and complete the asymmetric azidation reaction under the action of a catalyst prepared by a strongly coordinated PNN tridentate chiral ligand. The following reaction formula concisely and clearly reflects the process of a representative asymmetric azidation reaction:

[0047] In the formula, [Cu] represents a metal compound, L* represents a ligand, base represents a base, and solvent represents a solvent; wherein the ligand L* is selected from the strongly coordinated PNN tridentate chiral ligands L1 to L146 of the present invention, R, R 1 , R 2 , R 3 As shown in one or more embodiments of the present invention, the strongly coordinated tridentate PNN ligand can be applied to the efficient synthesis of a series of chiral nitrogen-containing heterocyclic compounds, such as vascular non-inflammatory molecule 1 (Vanin-1), Ontazolast, natural product Conulothiazole A, calcium channel antagonist TTA-A8, etc., and has good practical application value.

[0048] The intermediate synthesis route of vascular non-inflammatory protein-1 (Vanin-1) inhibitor is as follows:

[0049] Wherein, the ligand L* is any one of the PNN tridentate ligands, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. meet the requirements in the above application.

[0050] The intermediate synthesis route of Ontazolast is as follows:

[0051] Wherein, the ligand L* is any one of the PNN tridentate ligands, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. meet the requirements in the above application.

[0052] The intermediate synthesis route of the natural product (Conulothiazole A) is as follows:

[0053] Wherein, the ligand L* is any one of the PNN tridentate ligands, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. meet the requirements in the above application.

[0054] The intermediate synthesis route of the bioactive molecule TTA-A8 is as follows:

[0055] Wherein, the ligand L* is any one of the PNN tridentate ligands, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. meet the requirements in the above application.

[0056] Compared with the prior art, the present invention has the following advantages and beneficial effects: The present invention provides a strongly coordinated PNN tridentate chiral ligand, which realizes chirality control in the process of free radical functionalization, solves the poisoning of the catalyst by the strongly coordinated substrate by utilizing the anti-site effect, and has excellent reaction activity and enantioselectivity in the asymmetric free radical functionalization reaction of nitrogen-containing heterocyclic compounds.

[0057] The present invention provides an application of a strongly coordinated PNN tridentate chiral ligand, which has broad practical application prospects in free radical asymmetric functionalization reactions and derivative reactions thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 Schematic diagram of the advantages and disadvantages of representative chiral tridentate ligands containing weak coordination sites and the design principle of the strongly coordinated PNN tridentate chiral ligand of the present invention; Figure 2 This is a schematic diagram of the specific structural design of the strongly coordinated chiral tridentate PNN ligand and its corresponding effects. DETAILED DESCRIPTION

[0059] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0060] In the following embodiments: The preparation of precursor P1, the reaction process is as follows:

[0061] In a 250 mL round-bottom flask replaced with nitrogen atmosphere, S1 (( R )-2-dimethylamino-ethylferrocene, 12.86 g, 50 mmol, 1.0 equiv.) and anhydrous ether (100 mL, 0.50 M); 2.5 M n-butyllithium n-hexane solution (24 mL, 60 mmol, 1.2 equiv.) was added dropwise to the obtained solution at 0 °C, and the temperature was raised to room temperature for reaction for 1.5 h; after the reaction solution was cooled to 0 °C, diphenylphosphine chloride (16.50 g, 75 mmol, 1.5 equiv.) was added, and the obtained reaction solution was raised to room temperature for reaction for 4 h; after the reaction was completed, saturated ammonium chloride aqueous solution (30 mL) was added to the reaction solution, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (60 mL each time); the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure, the crude product was slurried with methanol for 4 h and filtered to obtain part of the product S2, the filtrate was purified by column chromatography to obtain another part of the product S2, and after mixing, a total of product S2 (10.25 g, i.e. 23.22 mmol, yield 47%); The product S2 of the previous step was transferred to a 100 mL round-bottom flask, acetic anhydride (17.6 mL, 185.76 mmol) was added, and the temperature was raised to 100 °C for reaction for 1 h. After the reaction was completed, a saturated sodium bicarbonate aqueous solution (20 mL) and sodium bicarbonate solid were added. The organic phase was separated after the reaction stopped bubbling, and the aqueous phase was extracted with ethyl acetate three times (40 mL each time); then the organic phase was washed with water and brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain product S3; then the obtained product S3 was transferred to an autoclave, and then acetonitrile and tetrahydrofuran were added in sequence at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of the product S3, wherein the concentration of S3 was 0.25 M, and then ammonia water (39 mL, 0.60 M) was added, and then the temperature was raised to 100 °C for reaction for 8 h, the reaction solution was concentrated and dried, water (20 mL) was added to the residual liquid, and the aqueous phase was extracted with ethyl acetate three times (40 mL); then the organic phase was washed with brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography to obtain the target product precursor P1 (7.44 g, yield 78%).

[0062] The preparation of precursor P2, the reaction process is as follows:

[0063] In a 100 mL round-bottom flask replaced with nitrogen atmosphere, S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous ether (6.0 mL, 1.67 M) were added in sequence; 2.5 M n-butyl lithium n-hexane solution (4.8 mL, 12 mmol, 1.2 equiv.) was added dropwise to the obtained solution at 0 °C, and the temperature was raised to room temperature for reaction for 1.5 h; then the reaction solution was cooled to 0 °C, and dicyclohexylphosphine chloride (3.49 g, 15 mmol, 1.5 equiv.) was added, and the obtained reaction solution was heated to room temperature for reaction for 4 h; after the reaction was completed, saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate three times (40 mL each time). The obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure, and the crude product was purified by column chromatography to obtain product S4 (2.90 g, yield 64%); The product S4 of the previous step was transferred to a 100 mL round-bottom flask, acetic anhydride (6.0 mL, 64 mmol) was added, and the temperature was raised to 100 °C for reaction for 1 h. After the reaction, a saturated sodium bicarbonate aqueous solution (10 mL) and sodium bicarbonate solid were added. After the reaction stopped bubbling, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate three times (20 mL each time); then the organic phase was washed with water and brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain product S5; then the obtained product S5 was transferred to an autoclave, and then acetonitrile and tetrahydrofuran were added in sequence at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of the product S5, wherein the concentration of S5 was 0.25 M, and then ammonia water (39 mL, 0.60 M) was added, and then the temperature was raised to 100 °C for reaction for 8 h. After the reaction, the reaction solution was concentrated and dried, and water (20 mL) was added to the residual liquid, and the aqueous phase was extracted with ethyl acetate three times (40 mL); then the organic phase was washed with brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography to obtain the target product precursor P2 (567 mg, yield 21%).

[0064] The preparation of precursor P3, the reaction process is as follows:

[0065] In a 100 mL round-bottom flask replaced with nitrogen atmosphere, S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous ether (20 mL, 0.20 M) were added in sequence; 2.5 M n-butyllithium n-hexane solution (4.4 mL, 11 mmol, 1.1 equiv.) was added dropwise to the resulting solution at 0 °C, and the mixture was heated to room temperature for reaction for 1.5 h. After the reaction solution was cooled to -78 °C, phosphorus trichloride (1.58 g, 11.5 mmol, 1.15 equiv.) was added, and the resulting reaction solution was heated to room temperature for 4 h. After the reaction was completed, the reaction solution was cooled to -78 °C, and the previously prepared aryl-substituted Grignard reagent (1.0 M, 30 mL, 3.0 equiv.) was added, and the temperature was restored to room temperature for 12 h. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (40 mL each time). The resulting organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the first step product S6. The product S6 (800 mg, 1.20 mmol) of the first step was transferred to a 50 mL round-bottom flask, acetic anhydride (1.7 mL, 18 mmol) was added, and the temperature was raised to 100 °C for 50 min. After the reaction, saturated sodium bicarbonate aqueous solution (10 mL) and solid sodium bicarbonate were added. After the reaction stopped bubbling, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (20 mL each time). The organic phase was then washed with water and brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain product S7; the obtained product S7 was then transferred to an autoclave, and then acetonitrile and tetrahydrofuran were added in sequence at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of the product S7, wherein the concentration of S7 was 0.25 M, and then ammonia water (39 mL, 0.60 M) was added, and then the temperature was raised to 80 °C for reaction for 8 h. After the reaction was completed, the reaction solution was concentrated and dried, and water (10 mL) was added to the residual liquid, and the aqueous phase was extracted three times with ethyl acetate (20 mL each time); the organic phase was then washed with brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product, and the obtained crude product was purified by column chromatography to obtain the target product precursor P3 (1.39 g, yield 30%).

[0066] The preparation of precursor P4, the reaction process is as follows:

[0067] S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous ether (20 mL, 0.20 M) were added to a 100 mL round-bottom flask replaced with a nitrogen atmosphere. 2.5 M n-butyllithium n-hexane solution (4.4 mL, 11 mmol, 1.1 equiv.) was added dropwise to the resulting solution at 0 °C, and the mixture was heated to room temperature for reaction for 1.5 h. The reaction solution was cooled to -78 °C, and phosphorus trichloride (1.58 g, 11.5 mmol, 1.15 equiv.) was added, and the reaction solution was heated to room temperature for reaction for 4 h. After the reaction was completed, the reaction solution was cooled to -78 °C, and the previously prepared aryl-substituted Grignard reagent (1.0 M, 30 mL, 3.0 equiv.) was added, and the mixture was returned to room temperature for reaction for 12 h. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (40 mmol each time). mL); the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the first step product S8; The product S8 (650 mg, 1.20 mmol) of the first step was transferred to a 50 mL round-bottom flask, acetic anhydride (1.7 mL, 18 mmol) was added, the temperature was raised to 100 °C for reaction for 50 min, saturated sodium bicarbonate aqueous solution (10 mL) and sodium bicarbonate solid were added after the reaction was completed, the organic phase was separated after the reaction stopped bubbling, and the aqueous phase was extracted with ethyl acetate three times (20 mL each time); the organic phase was then washed with water and brine, the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain product S9; the obtained product S9 was then transferred to an autoclave, and then acetonitrile and tetrahydrofuran were added in sequence at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of the product S9, wherein the concentration of S9 was 0.25 M, and then ammonia water (39 mL, 0.60 M) was added, and then the temperature was raised to 80 °C for reaction for 8 h. After the reaction was completed, the reaction solution was concentrated and dried, water (10 mL) was added to the residual liquid, and the aqueous phase was extracted with ethyl acetate three times (20 mL); then the organic phase was washed with brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography to obtain the target product precursor P4 (1.0 g, yield 36%).

[0068] The preparation of precursor P5, the reaction process is as follows:

[0069] S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous ether (20 mL, 0.20 M) were added to a 100 mL round-bottom flask replaced with a nitrogen atmosphere. 2.5 M n-butyllithium n-hexane solution (4.4 mL, 11 mmol, 1.1 equiv.) was added dropwise to the resulting solution at 0 °C, and the mixture was heated to room temperature for reaction for 1.5 h. The reaction solution was cooled to -78 °C, and phosphorus trichloride (1.58 g, 11.5 mmol, 1.15 equiv.) was added, and the reaction solution was heated to room temperature for reaction for 4 h. After the reaction was completed, the reaction solution was cooled to -78 °C, and the previously prepared aryl-substituted Grignard reagent (1.0 M, 30 mL, 3.0 equiv.) was added, and the mixture was returned to room temperature for reaction for 12 h. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (40 mmol each time). mL); the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product, and the obtained crude product was purified by column chromatography to obtain the first step product S10; The product S10 (650 mg, 1.20 mmol) of the first step was transferred to a 50 mL round-bottom flask, acetic anhydride (1.7 mL, 18 mmol) was added, the temperature was raised to 100 °C for reaction for 50 min, saturated sodium bicarbonate aqueous solution (10 mL) and sodium bicarbonate solid were added after the reaction was completed, the organic phase was separated after the reaction stopped bubbling, and the aqueous phase was extracted with ethyl acetate three times (20 mL each time); the organic phase was then washed with water and brine, the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain the product S11; the obtained product S11 was then transferred to an autoclave, and then acetonitrile and tetrahydrofuran were added in sequence at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of the product S11, wherein the concentration of S11 was 0.25 M, and then ammonia water (39 mL, 0.60 M) was added, and then the temperature was raised to 80 °C for reaction for 8 h. After the reaction was completed, the reaction solution was concentrated and dried, and water (10 mL), the aqueous phase was extracted with ethyl acetate three times (20 mL each time); the organic phase was then washed with brine, the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the target product precursor P5 (1.0 g, yield 21%).

[0070] The preparation of precursor P6, the reaction process is as follows:

[0071] S1 (5.14 g, 20 mmol, 1.0 equiv.) and anhydrous ether (40 mL, 0.50 M) were added to a 100 mL round-bottom flask replaced with a nitrogen atmosphere. A 2.5 M n-butyllithium n-hexane solution (9.6 mL, 24 mmol, 1.2 equiv.) was added dropwise to the resulting solution at 0 °C, and the temperature was raised to room temperature for reaction for 1.5 h. After the reaction, the reaction solution was cooled to -78 °C, and dichlorophenylphosphine (3.58 g, 20 mmol, 1.0 equiv.) was added, and the temperature of the resulting reaction solution was slowly raised to room temperature for reaction for 1.5 h. After the reaction, the reaction solution was cooled to -78 °C, and methylmagnesium bromide (3.0 M, 8 mL, 1.2 equiv.) was added, and the temperature was slowly restored to room temperature for reaction for 12 h. After the reaction, a saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, the organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate (40 % each time). mL); the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the first step product S12 (3.1 g, yield 40%); The product S12 of the previous step was transferred to a 50 mL round-bottom flask, acetic anhydride (8.0 mL, 78.8 mmol) was added, and the temperature was raised to 100 °C for reaction for 50 min. After the reaction, a saturated sodium bicarbonate aqueous solution (10 mL) and sodium bicarbonate solid were added. The organic phase was separated after the reaction stopped bubbling, and the aqueous phase was extracted with ethyl acetate three times (20 mL each time); the organic phase was then washed with brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain product S13; the obtained product S13 was transferred to an autoclave, and then acetonitrile and tetrahydrofuran were added in sequence at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of the product S13, wherein the concentration of S13 was 0.25 M, and then ammonia water (11.3 mL, 0.7 M) was added, and then the temperature was raised to 80 °C for reaction for 12 h, the reaction solution was concentrated and dried, water (20 mL) was added to the residual liquid, and the aqueous phase was extracted with ethyl acetate three times (40 mL); then the organic phase was washed with brine, and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product. The obtained crude product was purified by column chromatography to obtain the target product precursor P6 (1.7 g, yield 61%).

[0072] The preparation of precursor S14, the reaction process is as follows:

[0073] In a 1000 mL round-bottom flask replaced with nitrogen atmosphere, S2 (10 g, 83 mmol, 1.0 equiv.) and anhydrous ether (83 mL, 1.0 M) were added in sequence; 2.5 M n-butyllithium n-hexane solution (83 mL, 83 mmol, 1.0 equiv.) was added dropwise to the resulting solution at -35 °C, stirred at -35 °C for 1 h, TMSCl (9.9 g, 91 mmol, 1.1 equiv.) was added dropwise to the reaction solution, the temperature was slowly raised to room temperature, and stirred for 1 h; the temperature was lowered to -35 °C, 2.5 M n-butyllithium n-hexane solution (249 mL, 249 mmol, 3.0 equiv.) was added dropwise to the resulting solution, stirred at -35 °C for 4 h, diphenylphosphine chloride (20.1 g, 83 mmol, 1.0 equiv.) was added dropwise to the reaction solution, the temperature was slowly raised to room temperature, and stirred for 7 h; quench with saturated ammonium chloride solution (83 mL), extract the aqueous phase with ethyl acetate three times (83 mL each time); then wash the organic phase with brine, dry the organic phase, and spin dry under reduced pressure, and purify by column chromatography to obtain S14.

[0074] Using a preparation method similar to that of precursor S14, the structure corresponding to the methyl group of S2 is replaced with ethyl, benzyl, and phenyl in sequence, and the corresponding precursors S15-S17 can be synthesized, and their structural formulas are as follows: , , .

[0075] Example 1 The strongly coordinated tridentate PNN ligand L1 was synthesized by the following method:

[0076] Precursor P1 (5.20 g, 12.6 mmol, 1.0 equiv.) of Example 1, 2-pyridinecarboxylic acid (1.70 g, 13.9 mmol, 1.1 equiv.), 4-dimethylaminopyridine (DMAP; 154 mg, 1.26 mmol, 0.10 equiv.), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI; 2.90 g, 15.1 mmol, 1.2 equiv.) were added to a 100 mL round-bottom flask in sequence, and after replacing the atmosphere with nitrogen, dichloromethane (DCM; 32 mL, 0.40 M) was added at 0 °C. The reaction was then returned to room temperature for 12 h. After the reaction was completed, water (20 mL) was added to quench the reaction, and the aqueous phase was extracted three times with dichloromethane (30 mL each time); the organic phase was then washed with brine, and the resulting organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain a crude product. The resulting crude product was purified by column chromatography to obtain the target product, a strongly coordinated tridentate PNN ligand L1 (6.40 g, yield 98%).

[0077] 1 H NMR (400 MHz, CDCl3) δ 8.37 - 8.35 (m, 1H), 8.29 - 8.26 (m, 1H), 8.02 - 7.99 (m, 1H), 7.73 - 7.69 (m, 1H), 7.58 - 7.52 (m, 2H), 7.38 - 7.33 (m,3H), 7.32 - 7.28 (m, 1H), 7.10 - 7.05 (m, 2H), 6.94 - 6.89 (m, 2H), 6.86 -6.82 (m, 1H), 5.46 - 5.38 (m, 1H), 4.56 - 4.54 (m, 1H), 4.32 (t, J = 2.4 Hz,1H), 4.02 (s, 5H), 3.84 - 3.82 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H). Example 2 The strongly coordinated tridentate PNN ligand L30 was synthesized by the following method:

[0078] In a 50 mL round-bottom flask, the precursor P1 (413 mg, 1.0 mmol, 1.0 equiv.) of Example 1, 5-phenylpicolinic acid (219 mg, 1.1 mmol, 1.1 equiv.), 4-dimethylaminopyridine (12 mg, 0.10 mmol, 0.10 equiv.), and EDCI (230 mg, 1.2 mmol, 1.2 equiv.) were added in sequence, and after replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and then returned to room temperature to react for 12 h; after the reaction was completed, water (10 mL) was added to quench, and the aqueous phase was extracted with DCM three times (20 mL each time); then the organic phase was washed with brine, dried, and then dried under reduced pressure, and purified by column chromatography to obtain the target product ligand L30 (yellow solid, 553 mg, yield 93%).

[0079] 1 H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 2.3 Hz, 1H), 8.04 (dd, J = 8.1,2.3 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.69 - 7.67 (m, 2H), 7.56 - 7.52 (m,4H), 7.49 - 7.46 (m, 1H), 7.39 - 7.37 (m, 3H), 7.06 - 7.01 (m, 2H), 6.93 -6.89 (m, J = 7.5, 1.6 Hz, 2H), 6.81 (t, J = 7.4 Hz, 1H), 5.49 - 5.41 (m, 1H),4.70 - 4.69 (m, 1H), 4.44 (t, J = 2.5 Hz, 1H), 4.07 (s, 5H), 3.87 - 3.86 (m,1H), 1.62 (d, J = 6.8 Hz, 3H). Example 3 The strongly coordinated tridentate PNN ligand L31 was synthesized by the following method:

[0080] Precursor P1 (413 mg, 1.0 mmol, 1.0 equiv.), 5-(3,5-di-tert-butylphenyl)picolinic acid (342 mg, 1.1 mmol, 1.1 equiv.), 4-dimethylaminopyridine (12 mg, 0.10 mmol, 0.10 equiv.), and EDCI (230 mg, 1.2 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and then returned to room temperature to react for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L31 (yellow solid, 632 mg, yield 90%).

[0081] 1 H NMR (400 MHz, CD3OD) δ 8.27 (d, J = 2.4 Hz, 1H), 7.72 - 7.69 (m,1H), 7.59 (d, J = 8.4 Hz, 1H), 7.28 - 7.22 (m, 3H), 7.17 (d, J = 1.6 Hz, 2H),7.10 - 7.06 (m, 3H), 6.74 (t, J = 7.2 Hz, 2H), 6.66 - 6.61 (m, 2H), 6.54 (t,J = 7.2 Hz, 1H), 5.18 - 5.13 (m, 1H), 4.41 - 4.40 (m, 1H), 4.14 (t, J = 2.8Hz, 1H), 3.77 (s, 5H), 3.57 - 3.56 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H), 1.12(s, 18H). Example 4 The strongly coordinated tridentate PNN ligand L32 was synthesized by the following method:

[0082] Precursor P1 (300 mg, 0.73 mmol, 1.0 equiv.) and 5-(naphthalene-2-yl)picolinic acid (330 mg, 0.80 mmol, 1.1 equiv.), 4-dimethylaminopyridine (14 mg, 0.073 mmol, 0.10 equiv.), and EDCI (270 mg, 0.88 mmol, 1.2 equiv.) were added to a 25 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and then returned to room temperature for reaction for 12 h. After the reaction was completed, water (5 mL) was added to quench, and the aqueous phase was extracted with DCM three times (10 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L32 (yellow solid, 306 mg, yield 65%).

[0083] 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 1.6 Hz, 1H), 8.31 (dd, J = 8.8,2.8 Hz, 1H), 8.12 (dd, J = 8.0, 0.8 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 8.03(dd, J = 8.0, 2.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.97 - 7.90 (m, 2H),7.72 (dd, J = 8.4, 2.0 Hz, 1H), 7.59 - 7.53 (m, 4H), 7.37 - 7.35 (m, 3H),7.13 - 7.08 (m, 2H), 6.98 - 6.94 (m, 2H), 6.89 -6.85 (m, 1H), 5.50 - 5.42 (m,1H), 4.59 - 4.57 (m, 1H), 4.34 (t, J = 2.8 Hz, 1H), 4.04 (s, 5H), 3.86 - 3.85(m, 1H), 1.60 (d, J = 6.8 Hz, 3H). Example 5 The strongly coordinated tridentate PNN ligand L28 was synthesized by the following method:

[0084] Precursor P1 (413 mg, 1.0 mmol, 1.0 equiv.), 5-trifluoromethylpyridine-2-carboxylic acid (210 mg, 1.10 mmol, 1.1 equiv.), 4-dimethylaminopyridine (12 mg, 0.10 mmol, 0.10 equiv.), and EDCI (230 mg, 1.20 mmol, 1.2 equiv.) were added to a 25 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and then returned to room temperature for 12 h. After the reaction was completed, water (5 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (10 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L28 (yellow solid, 492 mg, yield 84%).

[0085] 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.93 (dd, J = 8.4, 2.0 Hz, 1H), 7.53 - 7.48 (m, 2H),7.36 - 7.34 (m, 3H), 7.05 - 7.01 (m, 2H), 6.90 - 6.85 (m, 2H), 6.82 - 6.79(m, 1H), 5.52 - 5.44 (m, 1H), 4.58 - 4.57 (m, 1H), 4.34 (t, J = 2.8 Hz, 1H), 4.04 (s, 5H), 3.84 - 3.83 (m, 1H), 1.59 (d, J = 6.4 Hz, 3H). Example 6 The strongly coordinated tridentate PNN ligand L3 was synthesized by the following method:

[0086] Precursor P2 (2.30 g, 5.4 mmol, 1.0 equiv.), 5-(3,5-di-tert-butylphenyl)pyridine-2-carboxylic acid (1.83 mg, 5.9 mmol, 1.1 equiv.), 4-dimethylaminopyridine (66 mg, mmol, 0.10 equiv.), and EDCI (1.24 mg, 6.5 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (12 mL, 0.27 M) was added at 0 °C, and then the reaction was restored to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L3 (yellow solid, 3.1 g, yield 80%).

[0087] 1 H NMR (400 MHz, CDCl3) δ 9.15 (s, 1H), 8.77 (dd, J = 2.4, 0.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 8.4, 2.4 Hz, 1H), 7.52 (t, J =1.6 Hz, 1H), 7.42 (d, J = 1.6 Hz, 2H), 5.22 - 5.15 (m, 1H), 4.43 (s, 1H), 4.31 (s, 1H), 4.16 (s, 5H), 2.43 - 2.18 (m, 3H), 1.92 - 1.73 (m, 6H), 1.57 -1.42 (m, 7H), 1.39 (s, 18H), 1.29 - 1.24 (m, 4H), 1.16 - 0.98 (m, 5H). Example 7 The strongly coordinated tridentate PNN ligand L7 was synthesized by the following method:

[0088] Precursor P3 (460 mg, 0.84 mmol, 1.0 equiv.), 2-picolinic acid (115 mg, 0.92 mmol, 1.1 equiv.), 4-dimethylaminopyridine (10 mg, 0.084 mmol, 0.10 equiv.), and EDCI (211 mg, 1.1 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and then the reaction was restored to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L7 (yellow solid, 516 mg, yield 94%).

[0089] 1 H NMR (400 MHz, CD3OD) δ 7.99 - 7.98 (m, 1H), 7.43 - 7.36 (m, 6H), 7.05 - 7.02 (m, 1H), 6.86 - 6.81 (m, 5H), 5.21 - 5.15 (m, 1H), 4.47 - 4.46(m, 1H), 4.18 (t, J = 2.6 Hz, 1H), 3.79 (s, 5H), 3.51 - 3.49 (m, 1H), 1.33(d, J = 6.8 Hz, 3H). Example 8 The strongly coordinated tridentate PNN ligand L12 was synthesized by the following method:

[0090] Precursor P4 (257 mg, 0.50 mmol, 1.0 equiv.), 2-picolinic acid (57 mg, 0.55 mmol, 1.1 equiv.), 4-dimethylaminopyridine (6 mg, 0.050 mmol, 0.10 equiv.), and EDCI (115 mg, 0.60 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and then the temperature was restored to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L12 (yellow solid, 269 mg, yield 87%).

[0091] 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.3 Hz, 1H), 7.94 (d, J = 8.6Hz, 1H), 7.84 - 7.72 (m, 5H), 7.56 - 7.43 (m, 6H), 7.41 - 7.30 (m, 4H), 7.21(q, J = 7.0 Hz, 1H), 6.89 - 6.83 (m, 1H), 5.57 (t, J = 7.6 Hz, 1H), 4.64 -4.61 (m, 1H), 4.37 - 4.34 (m, 1H), 4.07 (s, 5H), 3.91 (s, 1H), 1.65 (d, J =6.6 Hz, 3H). Example 9 The strongly coordinated tridentate PNN ligand L10 was synthesized by the following method:

[0092] Precursor P5 (300 mg, 0.63 mmol, 1.0 equiv.) and 5-(3,5-di-tert-butylphenyl)pyridine-2-carboxylic acid ((220 mg, 0.69 mmol, 1.1 equiv.), 4-dimethylaminopyridine (8 mg, 0.063 mmol, 0.10 equiv.), EDCI (146 mg, 0.76 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0°C, and then the reaction was restored to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L10 (yellow solid, 181 mg, yield 37%).

[0093] 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 9.2,2.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.89 (dd, J = 8.0, 2.0 Hz, 1H), 7.51(t, J = 2.0 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.41 (d, J = 1.6 Hz, 2H), 7.03 (dd,J = 8.4, 6.8 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.48 - 6.46 (m, 2H), 5.48 -5.40 (m, 1H), 4.54 - 4.53 (m, 1H), 4.30 (t, J = 2.8 Hz, 1H), 4.06 (s, 5H), 3.81 - 3.80 (m, 4H), 3.40 (s, 3H), 1.58 (d, J = 6.8 Hz, 3H), 1.40 (s, 18H). Example 10 The strongly coordinated tridentate PNN ligand L15 was synthesized by the following method:

[0094] Precursor P6 (700 mg, 2.0 mmol, 1.0 equiv.) and 5-(3,5-di-tert-butylphenyl)pyridine-2-carboxylic acid (680 mg, 2.2 mmol, 1.1 equiv.), 4-dimethylaminopyridine (24 mg, 0.020 mmol, 0.10 equiv.), and EDCI (460 mg, 2.4 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0°C, and then the reaction was restored to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L15 (yellow solid, 800 mg, yield 62%).

[0095] 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 1.6 Hz, 1H), 8.09 (dd, J = 8.0,0.8 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.0, 2.4 Hz, 1H), 7.52(t, J = 1.6 Hz, 1H), 7.38 (d, J = 2.0 Hz, 2H), 7.19 - 7.15 (m, 2H), 6.89 -6.82 (m, 3H), 5.43 - 5.35 (m, 1H), 4.55 - 4.54 (m, 1H), 4.42 - 4.40 (m, 2H),4.23 (s, 5H), 1.57 - 1.55 (m, 6H), 1.40 (s, 18H). Embodiment 11 The strongly coordinated tridentate PNN ligand L77 was synthesized by the following method:

[0096] Precursor S14 (4.7 g, 15.4 mmol, 1.0 equiv.), pyridine-2-carboxylic acid (2.08 g, 16.9 mmol, 1.1 equiv.), 4-dimethylaminopyridine (188 mg, 1.54 mmol, 0.10 equiv.), and EDCI (3.54 g, 18.5 mmol, 1.2 equiv.) were added to a 100 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (38.5 mL, 0.40 M) was added at 0 °C, and then the reaction was restored to room temperature for 12 h. After the reaction was completed, water (40 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L77 (white solid, 5.69 g, yield 90%).

[0097] 1H NMR (400 MHz, CDCl3) δ 8.43 - 8.40 (m, 1H), 8.30 (d, J = 7.2 Hz,1H), 8.07 - 8.04 (m, 1H), 7.78 - 7.73 (m, 1H), 7.57 - 7.53 (m, 1H), 7.41 -7.32 (m, 2H), 7.30 - 7.12 (m, 11H), 7.01 - 6.98 (m, 1H), 6.00 - 5.93 (m, 1H), 1.56 (d, J = 7.0 Hz, 3H). Example 12 The strongly coordinated tridentate PNN ligand L146 was synthesized by the following method:

[0098] In a 50 mL round-bottom flask, precursor S14 (915 mg, 3.0 mmol, 1.0 equiv.), sodium (3aS, 8aR)-3a, 8a-dihydro-8H-indeno[1,2-d]oxazole-2-carboxylate (1.01 g, 4.5 mmol, 1.5 equiv.), N,N-diisopropylethylamine (DIPEA; 1.75 g, 13.5 mmol, 4.5 equiv.), 1-hydroxybenzotriazole (HOBT; 689 mg, 5.1 mmol, 1.7 equiv.), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, TBTU; 1.54 g, 4.8 mmol, 1.6 equiv.), after replacing with nitrogen atmosphere, N,N-dimethylformamide (DMF; 15 mL, 0.20M) was added at 0 ℃, and then the temperature was restored to room temperature for 12 h; after the reaction was completed, water (20 mL) was added to quench, and the aqueous phase was extracted with ethyl acetate three times (20 mL each time); then the organic phase was washed with brine, dried and dried under reduced pressure, and purified by column chromatography to obtain the target product ligand L146 (white solid, 536 mg, yield 36%).

[0099] 1H NMR (400 MHz, CDCl3) δ 7.46 - 7.40 (m, 2H), 7.38 - 7.27 (m, 6H), 7.24 - 7.14 (m, 6H), 7.12 - 7.06 (m, 2H), 7.01 - 6.91 (m, 2H), 5.81 - 5.73(m, 1H), 5.61 (d, J = 8.0 Hz, 1H), 5.44 - 5.38 (m, 1H), 3.44 - 3.28 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H). Embodiment 13 The strongly coordinated tridentate PNN ligand L145 was synthesized by the following method:

[0100] Precursor S14 (153 mg, 0.5 mmol, 1.0 equiv.), sodium (S)-4-tert-butyl-4,5-dihydrooxazole-2-carboxylate (145 mg, 0.75 mmol, 1.5 equiv.), DIPEA (291 mg, 2.25 mmol, 4.5 equiv.), HOBT (115 mg, 0.85 mmol, 1.7 equiv.), and TBTU (257 mg, 0.8 mmol, 1.6 equiv.) were added to a 10 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DMF (2.5 mL, 0.20 M) was added at 0 °C, and then the mixture was returned to room temperature for 12 h. After the reaction was completed, water (5 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate three times (5 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. The target product ligand L145 (white solid, 66.4 mg, yield 29%).

[0101] 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 1H), 7.50 - 7.37 (m,3H), 7.36 - 7.27 (m, 8H), 7.22 - 7.15 (m, 1H), 7.01 - 6.93 (m, 1H), 5.86 -5.74 (m, 1H), 3.83 (dd, J = 11.3, 3.2 Hz, 1H), 3.74 - 3.65 (m, 1H), 3.56 (dd,J = 11.6, 8.0 Hz, 1H), 1.41 (d, J = 6.8 Hz, 3H), 0.95 (s, 9H). Embodiment 14 The strongly coordinated tridentate PNN ligand L132 was synthesized by the following method:

[0102] Precursor S14 (153 mg, 0.5 mmol, 1.0 equiv.), sodium (S)-4-phenyl-4,5-dihydrooxazole-2-carboxylate (160 mg, 0.75 mmol, 1.5 equiv.), DIPEA (291 mg, 2.25 mmol, 4.5 equiv.), HOBT (115 mg, 0.85 mmol, 1.7 equiv.), and TBTU (257 mg, 0.8 mmol, 1.6 equiv.) were added to a 10 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DMF (2.5 mL, 0.20 M) was added at 0 °C, and then the temperature was restored to room temperature to react for 12 h. After the reaction was completed, water (5 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate three times (5 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. The target product ligand L132 (white solid, 78.5 mg, yield 33%).

[0103] 1H NMR (400 MHz, CDCl3) δ 7.50 - 7.42 (m, 2H), 7.40 - 7.27 (m, 12H), 7.23 - 7.16 (m, 4H), 7.01 (dd, J = 8.0, 4.0 Hz, 1H), 5.91 - 5.80 (m, 1H), 5.28 (t, J = 10.0 Hz, 1H), 4.75 (t, J = 8.8 Hz, 1H), 4.20 (t, J = 8.8 Hz, 1H), 1.51 (d, J = 6.8 Hz, 3H). Embodiment 15 The strongly coordinated tridentate PNN ligand L116 was synthesized by the following method:

[0104] Precursor S15 (958 mg, 3.0 mmol, 1.0 equiv.), picolinic acid (406 mg, 3.3 mmol, 1.1 equiv.), DMAP (37 mg, 0.30 mmol, 0.10 equiv.), and EDCI (690 mg, 3.6 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (15 mL, 0.20 M) was added at 0 °C, and then returned to room temperature to react for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L116 (white solid, 751 mg, yield 59%).

[0105] 1 H NMR (400 MHz, CDCl3) δ 8.53 - 8.43 (m, 2H), 8.05 (dt, J = 8.0, 1.2Hz, 1H), 7.75 (td, J = 7.6, 1.6 Hz, 1H), 7.51 - 7.48 (m, 1H), 7.38 - 7.33 (m,2H), 7.28 - 7.27 (m, 1H), 7.26 - 7.14 (m, 10H), 7.04 - 7.01 (m, 1H), 5.75 -5.68 (m, 1H), 2.07 - 1.99 (m, 1H), 1.95 - 1.85 (m, 1H), 0.88 (t, J = 7.2 Hz,3H). Example 16 The strongly coordinated tridentate PNN ligand L119 was synthesized by the following method:

[0106] Precursor S16 (396 mg, 1.0 mmol, 1.0 equiv.), picolinic acid (135 mg, 1.1 mmol, 1.1 equiv.), DMAP (12 mg, 0.10 mmol, 0.10 equiv.), and EDCI (230 mg, 1.2 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (5 mL, 0.20 M) was added at 0 °C, and then returned to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L119 (white solid, 399 mg, yield 82%).

[0107] 1 H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 4.4Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.41 (m, 1H),7.34 - 7.20 (m, 12H), 7.19 - 7.06 (m, 6H), 7.04 - 7.00 (m, 1H), 6.21 - 6.00(m, 1H), 3.44 - 2.95 (m, 2H). Embodiment 17 The strongly coordinated tridentate PNN ligand L120 was synthesized by the following method:

[0108] Precursor S17 (588 mg, 1.6 mmol, 1.0 equiv.), picolinic acid (222 mg, 1.8 mmol, 1.1 equiv.), DMAP (20 mg, 0.16 mmol, 0.10 equiv.), and EDCI (364 mg, 1.9 mmol, 1.2 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, DCM (8 mL, 0.20 M) was added at 0 °C, and then returned to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and the aqueous phase was extracted with DCM three times (20 mL each time). The organic phase was then washed with brine, dried, and then dried under reduced pressure. Purification by column chromatography gave the target product ligand L120 (white solid, 387 mg, yield 99%).

[0109] 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.0 Hz, 1H), 8.48 - 8.35 (m,1H), 8.09 (dt, J = 8.0, 1.2 Hz, 1H), 7.78 (td, J = 8.0, 1.6 Hz, 1H), 7.40 -7.33 (m, 3H), 7.24 - 7.06 (m, 18H). Embodiment 18 The reaction process of the strongly coordinated tridentate PNN ligand L125 is as follows:

[0110] Triethylamine (810 mg, 8.0 mmol, 4.0 equiv.) and 2-pyridinesulfonic acid (710 mg, 4.0 mmol, 2.0 equiv.) were added to a 50 mL round-bottom flask in sequence. After replacing the atmosphere with nitrogen, dichloromethane (20 mL, 0.10 M) was added at 0 °C. After stirring for 15 min, trifluoromethanesulfonic anhydride (1.13 g, 4.0 mmol, 2.0 equiv.) was slowly added dropwise at 0 °C. After stirring at 0 °C for 2 h, precursor S14 (242 mg, 2.0 mmol, 1.0 equiv.) was added, and then the mixture was returned to room temperature for reaction for 17 h. The organic phase was dried and evaporated to dryness under reduced pressure. The target product ligand L125 (white solid, 387 mg, yield 69%) was obtained by column chromatography purification.

[0111] 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.01 (s, 1H), 7.71 - 7.51 (m,9H), 7.48-7.40 (m, 4H), 7.36 - 7.28 (m, 1H), 7.22 - 7.19 (m, 1H), 7.06 - 7.02(m, 1H), 6.90 - 6.85 (m, 1H), 5.18 -5.11 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H). Embodiment 19 In this example, some of the above-prepared different strongly coordinated chiral tridentate PNN ligands were applied to copper-catalyzed free radical asymmetric functionalization reactions, including three-component free radical asymmetric azidation of olefins and free radical asymmetric azidation of alkyl halides. The reaction processes are shown below:

[0112] The copper source selected in the three-component free radical asymmetric azidation reaction of olefins is Cu(CH3CN)4PF6 (10 mol%), the molar ratio of the strongly coordinated tridentate PNN ligand to Cu(CH3CN)4PF6 is 1.2:1, the base is K3PO4 (1.5 equiv.), the additive is KOAc (1.5 equiv.), the solvent is a mixture of 1,4-dioxane and tetrahydrofuran (v / v=1:1, 0.050 M), the reaction temperature is 0 ℃, the reaction time is 72 h, and the nuclear magnetic resonance (NMR) spectrum information of the product is as follows: 1 H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 4.8, 2.0 Hz, 1H), 7.71 - 7.67 (td, J = 7.7, 1.8 Hz, 1H), 7.50 (dd, J = 6.4, 2.8 Hz, 2H), 7.42 (q, J = 3.6,2.8 Hz, 3H), 7.30 (d, J = 7.6 Hz, 1H), 7.23 (dd, J = 7.6, 4.8 Hz, 1H), 4.71(dd, J = 8.0, 5.2 Hz, 1H), 3.04 - 2.88 (m, 1H), 2.84 - 2.67 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 157.89, 149.73, 137.07, 136.61 (t, J = 26.2Hz), 130.03 (t, J = 1.9 Hz), 128.57, 124.92 (t, J = 6.4 Hz), 123.23, 121.74,121.66 (t, J = 245 Hz), 60.83 (t, J = 3.23 Hz), 43.26 (t, J = 27.6 Hz). 19 F NMR (377 MHz, CDCl3) δ -94.58 (ddd, J = 86.8, 20.8, 13.5 Hz). The copper source selected in the asymmetric azidation reaction of alkyl halide free radicals is Cu(CH3CN)4PF6 (10.0mol%), the molar ratio of the strongly coordinated tridentate PNN ligand to Cu(CH3CN)4PF6 is 1.2:1, the base is K3PO4 (1.5 equiv.), the reaction solvent is 1,4-dioxane (0.050 M), the reaction temperature is 25 °C, the reaction time is 12 h, and the NMR spectrum information of the target product is: 1 H NMR (400 MHz, CDCl3) δ 8.58 (dd, J = 4.9, 1.6 Hz, 1H), 7.73 - 7.68(m, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.24 - 7.20 (m, 1H), 4.67 (q, J = 6.8 Hz,1H), 1.60 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.06, 149.45, 137.03, 122.87, 120.57,61.60, 20.12. The enantiomeric excess (ee value) was determined by high performance liquid chromatography (HPLC). The reaction results are shown in Tables 1 and 2 respectively.

[0113]

[0114] The reaction results in Table 1 show that the strongly coordinated tridentate PNN ligand exhibits good reaction yield and enantioselectivity in the three-component free radical asymmetric azidation reaction of pyridine-containing alkenes (Table 1, entries 1-2, 12-14); while the previously reported tridentate ligands containing weak coordination sites (Table 1, entries 3-5) do not have any reaction activity, which may be caused by the poisoning of the catalyst by pyridine. This result shows that the strongly coordinated tridentate PNN ligand disclosed in the present invention can well solve the problem of substrate poisoning of the catalyst, and has obvious advantages over the previously reported known tridentate PNN ligands. In addition, the bisoxazoline ligands (Table 1, entry 6) and chiral bidentate phosphine ligands (Table 1, entry 7) previously reported in the literature for free radical asymmetric azidation reactions also do not have any reaction activity in the three-component free radical azidation reaction of pyridine-containing alkenes. When the amide in ligand L77 was replaced by sulfonamide (Table 1, entry 8), or pyridine was replaced by quinoline (Table 1, entry 9), the corresponding ligands also showed no reactivity, indicating that the substrate needs to have a strict structural match with the ligand. In addition, the introduction of substituents at the ortho position of the pyridine unit in ligand L77 will also lead to ligand inactivation, which may be due to the presence of ortho substituents affecting the coordination of pyridine to Cu.

[0115] At the same time, the strongly coordinated tridentate PNN ligands of the present invention are also well suited for the copper-catalyzed free radical asymmetric azidation reaction of alkyl halides (Table 2). The strongly coordinated tridentate PNN ligands based on chiral phenylethylamine and chiral Ugi amine skeletons have good reactivity and enantioselectivity. The pyridine coordination unit in the tridentate ligand can also be replaced with oxazoline (Table 2, entry 4), but when the substituent on the phosphine in the ligand is changed from aromatic to alkyl, the enantioselectivity is significantly reduced (Table 2, entries 14-15); in addition, for the pyridine coordination unit on the ligand, when a substituent is introduced at the meta or para position of the N atom, the reactivity and enantioselectivity do not change significantly (Table 2, entries 6-9).

[0116] Embodiment 20 In this example, L77 was used as a ligand to investigate the copper-catalyzed asymmetric radical azidation of a series of alkyl halides containing pyridine units using a strongly coordinated tridentate PNN ligand. The reaction process is shown below:

[0117] In the formula, R 10 , R 11 They correspond to the corresponding substituents of the products respectively.

[0118] The specific reaction steps are as follows: in a glove box filled with nitrogen, add Cu(CH3CN)4PF6 (18.6 mg, 0.050 mmol, 0.10 equiv.), strongly coordinated tridentate PNN ligand L77 (24.6 mg, 0.060 mmol, 0.12 equiv.) and K3PO4 (159.2 mg, 0.75 mmol, 1.5 equiv.) to a 20 mL reaction bottle with a magnet, add 1,4-dioxane (10 mL, 0.050 M), stir and complex for 30 min. Add trimethylsilyl azide (86.4 mg, 0.75 mmol, 1.5 equiv.) and alkyl bromide (0.50 mmol, 1.0 equiv.). The reaction bottle was removed from the glove box and reacted at 25 °C for 24-48 h (3aa, 3ab, 3ac for 48 h, and the other products for 24 h), and then purified by column chromatography to obtain the target product. After nuclear magnetic resonance identification, the purified product was analyzed by HPLC to determine its ee value. The product test results are as follows: (1) Product structure: ; Yield: 94%; ee value: 96%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.59 -8.57 (m, 1H), 7.71 - 7.67 (m, 1H), 7.31 -7.28 (m, 1H), 7.22 - 7.19 (m, 1H), 4.42 (t, J = 7 Hz, 1H), 2.02 - 1.86(m, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.23, 149.51, 136.85, 122.85, 121.26, 68.07, 28.04, 10.47. (2) Product structure: ; Yield: 91%; ee value: 96%; NMR spectrum information: 1H NMR (400 MHz, CDCl3) δ 8.61 - 8.59 (m, 1H), 7.73 - 7.68 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 - 7.21 (m, 1H), 4.25 (d, J = 7.6 Hz, 1H), 2.3- 2.18 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 158.87, 149.44, 136.65, 122.78, 121.86, 73.27, 33.22, 19.65, 18.43. (3) Product structure: ; Yield: 93%; ee value: 96%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.61 - 8.59 (m, 1H), 7.73 - 7.69 (m, 1H), 7.31 (d, J = 8.0, 1H), 7.24 - 7.21 (m, 1H), 4.47 (t, J = 7.2 Hz, 1H), 1.95 -1.85 (m, 2H), 1.44 - 1.25 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.51, 149.53, 136.91, 122.86, 121.21, 66.75, 34.62, 28.22, 22.39, 13.95. (4) Product structure: ; Yield: 99%; ee value: 99%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.49 - 8.47 (m, 1H), 7.45 - 7.43 (m, 1H), 7.16 (dd, J = 7.6, 4.8 Hz, 1H), 4.70 (t, J = 4.4 Hz, 1H), 2.86 - 2.69 (m,2H), 2.09 - 1.76 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 153.69, 147.52, 137.44, 132.70, 123.12, 60.24, 29.01, 28.15, 18.38. (5) Product structure: ; Yield: 98%; ee value: 96%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.54 - 8.52 (m, 1H), 7.66 - 7.62 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.20 - 7.15 (m, 1H), 4.50 (dd, J = 9.2, 6.0 Hz,1H), 1.79 - 1.56 (m, 8H), 1.40 - 1.29 (m, 1H), 1.15 - 1.08 (m, 2H), 0.95 -0.86 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 159.84, 149.55, 136.97, 122.90, 121.21, 64.23, 42.39, 34.39, 33.61, 32.64, 26.46, 26.21, 26.07. (6) Product structure: ; Yield: 95%; ee value: 96%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 4.8 Hz, 1H), 7.76 - 7.71 (m,1H), 7.40 (d, J = 8.0 Hz, 1H), 7.29 - 7.24 (m, 1H), 5.00 (dd, J = 8.8, 5.6Hz, 1H), 4.22 - 4.15 (m, 2H), 3.08 (dd, J = 16.4, 5.2 Hz, 1H), 2.93 - 2.85(m, 1H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.41, 157.57, 149.63, 137.06, 123.23,121.67, 62.35, 60.95, 39.39, 14.12. (7) Product structure: ; Yield: 95%; ee value: 93%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.4 Hz, 1H), 8.20 (d, J = 8.0Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 3.6Hz, 1H), 7.19 - 7.16 (m, 2H), 7.03 - 6.99 (m, 1H), 5.22 (t, J = 7.2 Hz, 1H), 4.16 - 4.04 (m, 2H), 3.31 - 3.16 (m, 3H), 3.06 - 2.98 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 167.74, 157.76, 149.70, 142.72, 137.10,131.18, 127.54, 124.58, 123.89, 123.27, 122.64, 117.13, 62.17, 48.06, 40.26,27.98. (8) Product structure: ; Yield: 97%; ee value: 97%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.57 - 8.56 (m, 1H), 7.69 - 7.65 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.20 - 7.17 (m, 1H), 4.99 (t, J = 7.6 Hz, 1H), 3.51(t, J = 6.8 Hz, 2H), 2.37 - 2.22 (m, 2H), 1.86 - 1.75 (m, 2H), 1.72 - 1.61(m, 1H), 1.51 - 1.40 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 160.00, 149.43, 137.04, 123.08, 122.21, 54.76, 44.59, 37.34, 31.85, 25.39. (9) Product structure: ; Yield: 80%; ee value: 94%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.2 Hz, 1H), 7.66 (t, J = 7.6Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 - 7.16 (m,1H), 5.49 (t, J = 7.2 Hz,1H), 3.76 - 3.69 (m, 1H), 3.55 - 3.48 (m, 1H), 2.60 - 2.53 (m, 1H), 1.91 -1.80 (m, 2H), 1.75 - 1.76 - 1.65 (m, 2H), 1.61 - 1.42 (m, 8H). 13 C NMR (101 MHz, CDCl3) δ 210.58, 159.00, 149.43, 136.97, 123.13,123.05, 52.55, 47.81, 47.33, 29.44, 29.39, 28.27, 26.60, 26.58. (10) Product structure: ; Yield: 93%; ee value: 98%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.60 - 8.58 (m, 1H), 7.68 (td, J = 7.8, 2.0Hz, 1H), 7.38 - 7.28 (m, 6H), 7.22 - 7.19 (m, 1H), 5.11 (s, 2H), 4.75 (d, J =9.2 Hz, 1H), 4.28 - 4.11 (m, 2H), 2.77 (d, J = 42.4 Hz, 2H), 2.44 - 2.34 (m,1H), 2.27 - 2.21 (m, 1H), 1.40 - 1.33 (m, 2H), 1.15 (qd, J = 12.4, 4.4 Hz,1H). 13 C NMR (101 MHz, CDCl3) δ 158.92, 155.14, 149.63, 136.95, 136.82,128.49, 127.98, 127.85, 123.04, 122.94, 67.06, 60.47, 43.96, 43.56, 42.23. (11) Product structure: ; Yield: 93%; ee value: 93%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.8 Hz, 1H), 7.70 - 7.66 (m,1H), 7.29 - 7.19 (m, 2H), 4.449 (d, J = 8.8 Hz, 1H), 2.94 - 2.84 (m, 1H), 2.19 - 2.10 (m, 1H), 2.06 - 1.99 (m, 1H), 1.87 - 1.83 (m, 4H). 13 C NMR (101 MHz, CDCl3) δ 158.21, 149.46, 136.73, 122.89, 121.43,71.08, 39.60, 25.68, 25.07, 17.96. (12) Product structure: ; Yield: 95%; ee value: 95%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.7 Hz, 1H), 7.71 (t, J = 7.7Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.24 (dd, J = 7.6, 4.9 Hz, 1H), 5.78 (ddt,J = 16.9, 9.7, 6.9 Hz, 1H), 5.31 - 4.92 (m, 2H), 4.57 (t, J = 7.0 Hz, 1H), 2.71 (qt, J = 14.5, 7.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 158.65, 149.55, 136.90, 133.39, 122.98,121.38, 118.51, 65.89, 39.12. (13) Product structure: ; Yield: 92%; ee value: 95%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 7.70 (td, J= 7.7, 1.8 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.23 (dd, J = 7.5, 4.9 Hz, 1H), 4.43 (s, 1H), 0.96 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 157.90, 148.72, 136.13, 122.78 (d, J = 11.3Hz), 36.11, 26.50. (14) Product structure: ; Yield: 96%; ee value: 95%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.69 - 8.50 (m, 1H), 7.65 (td, J = 7.7, 1.8Hz, 1H), 7.31 - 7.19 (m, 8H), 7.19 - 7.14 (m, 3H), 4.72 (dd, J = 8.6, 5.7 Hz, 1H), 3.30 (dd, J = 13.8, 5.7 Hz, 1H), 3.14 (dd, J = 13.8, 8.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 158.58, 149.63, 137.26, 136.87, 129.44, 128.48, 126.82, 123.06, 121.65, 67.78, 41.30. (15) Product structure: ; Yield: 81%; ee value: 98%; NMR spectrum information: 1H NMR (400 MHz, CDCl3) δ 8.60 - 8.58 (m, 1H), 7.73 (td, J = 8.0, 1.6Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.30 (ddd, J = 7.8, 4.8, 1.2 Hz, 1H), 4.96(q, J = 7.0 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ 150.86, 149.73, 137.27, 124.61, 122.97,123.61 (q, J = 283.6 Hz), 66.06 (q, J = 30.7 Hz). (16) Product structure: ; Yield: 95%; ee value: 92%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 2H), 4.70 (q, J = 6.8 Hz, 1H), 1.66 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.93 (d, J = 22 Hz), 164.90, 158.25,155.61, 145.22 (d, J = 80 Hz), 60.81 (d, J = 8.4 Hz), 19.06. (17) Product structure: ; Yield: 87%; ee value: 94%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.78 (dd, J = 5.2, 0.8 Hz, 1H), 7.79 (t, J =1.2 Hz, 1H), 7.67 (dd, J = 5.2, 1.6 Hz, 1H), 4.77 (q, J = 6.8 Hz, 1H), 2.65(s, 3H), 1.65 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 197.11, 161.75, 150.65, 143.92, 120.51,118.19, 61.39, 26.77, 20.10. (18) Product structure: ; Yield: 98%; ee value: 91%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.74 (dd, J = 5.2, 0.8 Hz, 1H), 7.91 -7.90(m, 1H), 7.79 (dd, J = 5.2, 1.6 Hz, 1H), 4.75 (q, J = 6.8 Hz, 1H), 3.98 (s,3H), 1.64 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.4, 161.4, 150.3, 138.4, 122.1, 119.9, 61.4, 52.8, 20.1. (19) Product structure: ; Yield: 94%; ee value: 84%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.74 (dd, J = 5.2, 0.8 Hz, 1H), 7.91 -7.90(m, 1H), 7.79 (dd, J = 5.2, 1.6 Hz, 1H), 4.75 (q, J = 6.8 Hz, 1H), 3.98 (s,3H), 1.64 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.4, 161.4, 150.3, 138.4, 122.1, 119.9, 61.4, 52.8, 20.1. (20) Product structure: ; Yield: 94%; ee value: 84%; NMR spectrum information: 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.53 - 7.49 (m,1H), 7.27 -6.93 (m, 1H), 4.68 - 4.61 (m, 1H), 2.43 - 2.12 (m, 3H), 1.60 - 1.56 (m, 3H). 13 C NMR (101 MHz, CDCl3) δ 157.1, 149.8, 137.5, 132.4, 120.1, 61.4,20.1, 18.1. (21) Product structure: ; Yield: 91%; ee value: 87%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.29 - 8.26 (m, 1H), 7.29 - 7.23 (m, 1H), 7.23 - 7.17 (m, 1H), 4.71 - 4.54 (m, 1H), 3.88 - 3.80 (m, 3H), 1.63 - 1.49(m, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.1, 151.9, 137.0, 121.2, 121.0, 61.1,55.6, 20.0. (22) Product structure: ; Yield: 99%; ee value: 96%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 5.6 Hz, 1H), 7.40 (d, J = 2.0Hz, 1H), 7.22 (dd, J = 5.6, 2.4 Hz, 1H), 6.92 (s, 1H), 4.62 (q, J = 6.8 Hz,1H), 1.57 (d, J = 6.8 Hz, 3H), 1.52 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 161.2, 151.9, 150.2, 146.6, 111.5, 109.1,81.9, 61.6, 28.2, 20.1. (23) Product structure: ; Yield: 88%; ee value: 93%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.67 (dd, J = 5.2, 0.8 Hz, 1H), 7.57 (s,1H), 7.45 (dd, J = 5.2, 0.8 Hz, 1H), 4.72 (q, J = 6.8 Hz, 1H), 3.55 (s, 3H), 3.37 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.6, 160.5, 149.6, 142.8, 121.2, 61.5,61.4, 20.0. (24) Product structure: ; Yield: 87%; ee value: 94%; NMR spectrum information: 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.0,2.4 Hz, 1H), 7.38 (d, 8.0 Hz, 1H), 6.71 (s, 2H), 5.03 (s, 2H), 4.70 (q, J =6.8 Hz, 1H), 2.35 (s, 6H), 1.62 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 159.94, 156.14, 148.57, 137.36, 136.35,131.70, 126.99, 120.46, 114.76, 67.40, 61.40, 21.00, 20.13. The above results indicate that the strongly coordinated tridentate PNN ligands of the present invention have a wide range of substrate applicability in the asymmetric radical azidation reaction of pyridine alkyl halide compounds.

[0119] Embodiment 21 In this example, based on the excellent reactivity and enantioselectivity of strongly coordinated chiral tridentate PNN ligands in the free radical asymmetric azidation reaction of heterocyclic substrates, the strongly coordinated chiral tridentate PNN ligand L77 was applied to the synthesis of Vanin-1, and the reaction pathway is as follows:

[0120] The specific steps of the synthesis are as follows: In a glove box filled with nitrogen, Cu(CH3CN)4PF6 (37.2 mg, 0.050 mmol, 0.10 equiv.), strongly coordinating chiral tridentate PNN ligand L77 (49.2 mg, 0.060 mmol, 0.12 equiv.) and K3PO4 (318.4 mg, 0.75 mmol, 1.5 equiv.) were added to a 20 mL reaction bottle containing a magnet. 1,4-dioxane (20 mL, 0.050 M) was added and stirred for 30 min. Azidotrimethylsilane (172.8 mg, 0.75 mmol, 1.5 equiv.) and 2-(1-bromoethyl)pyrazine (187.0 mg, 1.0 mmol, 1.0 equiv.) were added. The reaction bottle was removed from the glove box and reacted at -10 °C for 72 h. B2 (138.7 mg, 93% yield, 92% ee); 1 H NMR (400 MHz, CDCl3) δ 8.66 – 8.59 (m, 1H), 8.56 – 8.46 (m, 2H), 4.67 (q, J = 6.9 Hz, 1H), 1.63 (d, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 155.41, 144.15, 144.03, 142.74, 59.18,19.54. To a 10 mL reaction bottle containing a magnetic bar, B2 (138.7 mg, 0.50 mmol, 1.0 equiv.), Pd / C (13.9 mg, 10 wt.%), and MeOH (5 mL, 0.10 M) were added. The air in the reaction bottle was replaced with hydrogen, and the reaction bottle was stirred at room temperature for 8 h in a hydrogen atmosphere at 15 psi. The mixture was filtered through celite, and the filtrate was concentrated to obtain B3 (49.1 mg, 80% yield, 92% ee).

[0121] 1 H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.48 – 8.42 (m, 1H), 8.39 (d,J = 2.5 Hz, 1H), 4.16 (q, J = 6.8 Hz, 1H), 2.06 (s, 2H), 1.40 (d, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.72, 143.88, 143.05, 142.60, 50.39, 24.24. According to the literature (Org. Process Res. Dev. 2024, 28, 2226-2236.), B3 was refluxed with ethyl 2-chloropyrimidine-5-carboxylate, DIPEA, and isopropan-2-ol (IPA) for 1 h to obtain B4; then B4, 8-oxa-2-azaspiro[4.5]decane, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (1,5,7-Triazabicyclo[4.4.0]dec-5-ene, TBD) were heated to 90 °C and stirred for 4 h to obtain the final product B5; B5 is the vascular non-inflammatory protein-1 inhibitor (Vanin-1).

[0122] Embodiment 22 In this example, based on the excellent reactivity and enantioselectivity of the strongly coordinated chiral tridentate PNN ligand in the free radical asymmetric azidation reaction of heterocyclic substrates, the strongly coordinated chiral tridentate PNN ligand was applied to the synthesis of Ontazolast, and the reaction pathway is as follows:

[0123] The specific steps of the synthesis are as follows: Using the above 3f as the raw material, 3f (92.1 mg, 0.40 mmol, 1.0 equiv.), Pd / C (9.2 mg, 10 wt.%), and MeOH (4 mL, 0.10 M) were added to a 10 mL reaction bottle containing a magnetic electron. The air in the reaction bottle was replaced with hydrogen, and the reaction bottle was stirred at room temperature for 8 h under a 15 psi hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain B6 (78.8 mg, 96% yield, 96% ee). 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 4.7 Hz, 1H), 7.64 – 7.60 (m,1H), 7.24 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 7.5, 4.8 Hz, 1H), 4.05 (t, J =7.2 Hz, 1H), 2.23 (s, 2H), 1.80 – 1.52 (m, 7H), 1.3 – 1.26 (m, 1H), 1.24 –1.11 (m, 3H), 1.02 – 0.84 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 165.30, 149.19, 136.43, 121.77, 120.88,54.38, 46.42, 34.40, 33.78, 32.92, 26.51, 26.22, 26.11. According to the procedure in the literature (J. Med. Chem. 1994, 37, 913-923.), B6 ​​reacts with 2-chloro-5-methyl-1,3-benzoxazole B7 to generate drug B8, which is Ontazolast.

[0124] Embodiment 23 In this example, based on the excellent reactivity and enantioselectivity of the strongly coordinated chiral tridentate PNN ligand in the free radical asymmetric azidation reaction of heterocyclic substrates, the strongly coordinated chiral tridentate PNN ligand L77 was applied to the synthesis of Conulothiazole A, and the reaction pathway is as follows:

[0125] The specific steps of the synthesis are as follows: In a glove box filled with nitrogen, Cu(CH3CN)4PF6 (18.6 mg, 0.050 mmol, 0.10 equiv.), PNN tridentate ligand L77 (24.6 mg, 0.060 mmol, 0.12 equiv.) and K3PO4 (159.2 mg, 0.75 mmol, 1.5 equiv.) were added to a 20 mL reaction bottle with a magnetic pole. 1,4-Dioxane (10 mL, 0.050 M) was added and stirred for 30 min. Azidotrimethylsilane (86.4 mg, 0.75 mmol, 1.5 equiv.) and 2-(1-bromoethyl)-1,3-thiazole (96 mg, 0.50 mmol, 1.0 equiv.) were added. The reaction bottle was removed from the glove box and reacted at 25 °C for 24 h. B10 (69.4 mg, 90% yield, 94% ee); 1 H NMR (400 MHz, CDCl3) δ 7.80 – 7.70 (m, 1H), 7.31 (t, J = 2.6 Hz, 1H), 4.91 (q, J = 6.5 Hz, 1H), 1.69 (dd, J = 6.8, 2.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.30, 142.93, 119.56, 58.10, 20.41. B10 (46.3 mg, 0.30 mmol, 1.0 equiv.), triphenylphosphine (94.4 mg, 0.36 mmol, 1.2 equiv.), and tetrahydrofuran (0.60 mL, 0.50 M) were added to a 10 mL reaction bottle with a magnetic bar, and stirred at 50 °C for 2 h. Then, 25 wt.% NH3·H2O (0.83 mL, 0.36 M) was added, and stirring at 50 °C was continued for 2 h. Then, B11 (31.5 mg, 82% yield, 94% ee) was separated by column chromatography. 1 H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 3.3, 1.3 Hz, 1H), 7.18 (dd, J= 3.3, 1.3 Hz, 1H), 4.39 – 4.34 (m, 1H), 2.10 (s, 2H), 1.48 (d, J = 6.7 Hz,3H). 13 C NMR (101 MHz, CDCl3) δ 178.39, 142.40, 118.37, 49.68, 24.70. According to the steps in the literature (Org. Lett. 2019, 21, 4318-4321), B11 reacts with (2E,7E)-7-phenyl-8-chloro-2-methyloctane-2,7-dienoic acid to obtain the final product B12, namely Conulothiazole A, which is a natural product.

[0126] Embodiment 24 In this example, based on the excellent reactivity and enantioselectivity of strongly coordinated chiral tridentate PNN ligands in the free radical asymmetric azidation reaction of heterocyclic substrates, the strongly coordinated chiral tridentate PNN ligand L77 was applied to the synthesis of TTA-A8, and the reaction pathway is as follows:

[0127] The specific steps of the synthesis are as follows: In a nitrogen-filled glove box, Cu(CH3CN)4PF6 (3.7 mg, 0.010 mmol, 0.10 equiv.), strongly coordinating chiral tridentate PNN ligand L77 (4.9 mg, 0.012 mmol, 0.12 equiv.) and K3PO4 (31.8 mg, 0.15 mmol, 1.5 equiv.) were added to a 4 mL reaction bottle containing a magnet. 1,4-dioxane (1 mL) and dichloromethane (1 mL) were added and stirred for 30 min. Azidotrimethylsilane (17.3 mg, 0.15 mmol, 1.5 equiv.) and 2-(1-2-(1-bromoethyl)-5-(2, 2, 2-trifluoroethoxy)pyridine (28.4 mg, 0.10 mmol, 1.0 equiv.) were added. The reaction bottle was removed from the glove box and heated at -25 °C for 30 min. After reaction at ℃ for 72 h, B14 (17.2 mg, 70% yield, 91% ee) was obtained by column chromatography purification; 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.8 Hz, 1H), 7.35 – 7.27 (m,2H), 4.66 (q, J = 6.8 Hz, 1H), 4.41 (q, J = 8.0 Hz, 2H), 1.59 (dd, J = 6.8,0.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 154.24, 153.08, 137.60, 122.82, 123.01 (J =278.76 Hz), 121.24, 66.20 (q, J = 36.2 Hz), 60.98, 20.06. 19 F NMR (377 MHz, CDCl3) δ -73.92 (t, J = 8.0 Hz). B14 (17.2 mg, 0.070 mmol, 1.0 equiv.), triphenylphosphine (22.0 mg, 0.084 mmol, 1.2 equiv.), and tetrahydrofuran (0.14 mL, 0.50 M) were added to a 4 mL reaction bottle with a magnetic rod, and stirred at 50 °C for 2 h. Then, 25 wt.% NH3·H2O (0.19 mL, 0.36 M) was added and stirred at 50 °C for 2 h. The reaction was quenched with 0.5 mL of hydrochloric acid and the impurities were extracted with 1 mL of ethyl acetate. The pH of the aqueous phase was adjusted to >7 with saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (1 mL×3). The organic phases were combined and dried over anhydrous Na2SO4, and then vacuum evaporated to obtain B15 (12.9 mg, 84% yield, 91% ee). 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 8.5Hz, 1H), 7.15 (dd, J = 8.6, 2.8 Hz, 1H), 4.31 (q, J = 8.0 Hz, 2H), 4.05 (q, J= 6.7 Hz, 1H), 1.77 (s, 2H), 1.31 (d, J = 6.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 160.04, 152.35, 137.12, 122.70, 123.03 (q,J = 279.1 Hz), 120.42, 66.21 (q,J = 36.4 Hz), 51.76, 24.44. 19 F NMR (377 MHz, CDCl3) δ -74.08 (t, J = 8.0 Hz). According to the patent (WO2009 / 54984, 2009, A1) steps, B15 is condensed with 4-(carboxymethyl)phenylboronic acid pinacol ester to generate B16; B16 is finally reacted with 2-chloro-3-methylpyrazine to obtain product B17, namely TTA-A8, which is a calcium channel antagonist.

[0128] In summary, Figure 1 The advantages and disadvantages of representative chiral tridentate ligands with weak coordination sites and the design principle of the strongly coordinated PNN tridentate chiral ligand of the present invention are presented. Figure 1As shown in Figure .A, the dialkylamine weak coordination site of the representative chiral tridentate ligand containing a weak coordination site can form a metastable coordination with the metal, which can stabilize the high-valent metal active intermediate and dissociate to form an effective active reaction site. Figure 1 As shown in .B, for substrates with strong coordination such as heterocycles, the strongly coordinated heteroatoms in the substrate can quickly replace the weak coordination sites of this type of tridentate ligand to form a stable metal intermediate coordinated by multiple substrates. The substrate coordinated in this type of metal intermediate is not easy to dissociate and cannot achieve the catalytic cycle, thus causing catalyst poisoning. Therefore, tridentate ligands containing metastable coordination are generally not suitable for asymmetric radical functionalization of strongly coordinated substrates. In response to this problem, the present invention proposes to develop strongly coordinated tridentate PNN ligands based on the trans-site effect. The three coordination sites of this type of ligand are all strongly coordinated. When the strongly coordinated substrate is coordinated to the metal, the three strong coordination sites in the ligand form a stable chelate ring with the metal complex, and the substrate cannot replace the three strong coordination sites in the ligand. At this time, the strongly coordinated substrate can only be coordinated to the trans-site of the bridging N atom in the ligand. As Figure 1 .C, the H atom on the bridging N atom in the ligand can be deprotonated under alkaline conditions to form a stable σ coordination with the metal. The bridging N atom that forms a σ coordination with the metal has a strong electron donor property, and the heteroatom of the strong coordination substrate in the anti-position also has a strong electron donor property. According to the principle of the anti-position effect, when the two ligands in the anti-position are both strong electron donors, one of the ligands is affected by the anti-position effect and is prone to dissociation. Therefore, the strong coordination substrate in the anti-position of the ligand-bridging N atom is affected by the anti-position effect and can dissociate, thereby realizing the catalytic cycle, and will not form a stable strong coordination complex to cause catalyst poisoning. In addition, since the three coordination sites of the tridentate PNN ligand in the present invention are all strongly coordinated, this type of ligand has a better stabilizing effect on high-valent active metal intermediates, and the strong coordination substrate is not easy to destroy the intrinsic structure of the complex formed by the ligand and the metal, so the corresponding catalyst has better stability during the catalytic process.

[0129] The specific structural design of the strongly coordinated chiral tridentate PNN ligand developed in the present invention is as follows: Figure 2 As shown in the figure, the ligand skeleton is a ferrocene Ugi amine skeleton with superior face chirality and carbon center chirality and a simple chiral benzylamine skeleton; for the phosphorus atom coordination site in the ligand, the chiral phosphine can be precisely and controllably introduced through the chiral Ugi amine; the ligand contains a secondary amine coordination site that can be deprotonated, which can form an electron-rich σ coordination with the metal and enhance the reaction activity; the third strong coordination site in the ligand is pyridine or oxazoline, which can also precisely and controllably introduce a chiral environment. Figure 2 It can be seen that when the free radical reacts with the central metal, the large steric hindered group of the free radical will avoid contact with the large steric hindered R group in the coordination, thereby achieving chirality control in the free radical functionalization process.

[0130] The novel strongly coordinated chiral tridentate PNN ligand developed in the present invention utilizes the anti-position effect to innovatively solve the poisoning of the catalyst by the strongly coordinated substrate, and exhibits excellent reactivity and enantioselectivity in the asymmetric free radical functionalization reaction of nitrogen-containing heterocyclic compounds. At the same time, the novel strongly coordinated tridentate PNN ligand developed in the present invention can be applied to the efficient synthesis of a series of chiral nitrogen-containing heterocyclic compounds, such as vascular non-inflammatory protein-1 inhibitor (Vanin-1), Ontazolast, natural product Conulothiazole A, calcium channel antagonist TTA-A8, etc., with significant theoretical innovation and practical application value.

[0131] The preferred specific embodiments of the present invention are described in detail above. It should be understood that a person skilled in the art can make many modifications and changes based on the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by a person skilled in the art through logical analysis, reasoning or limited experiments based on the concept of the present invention on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A strongly coordinated PNN tridentate chiral ligand, characterized in that: Having the structure as described in general formula I: In the formula, the solid line on the left represents the structure of ferrocene or benzene ring; X is carbon or sulfur, and Y is carbon or oxygen; the solid line on the right represents that it forms a ring with nitrogen atom and Y atom; When X is a carbon element, the dotted line between X and oxygen represents the absence of such a bond, that is, the bridging group is a carbonyl group; when X is a sulfur element, the dotted line between X and oxygen represents the presence of such a bond, that is, the bridging group is a sulfonyl group; When Y is a carbon element, the representative structure of the solid line on the right side of the general formula includes pyridine and pyridine containing a substituent; when Y is an oxygen element, the representative structure of the solid line on the right side of the general formula includes oxazoline and oxazoline containing a substituent; R, R 1 , R 2 Each is independently selected from an alkyl group or an aryl group; wherein the alkyl group includes one of a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a tert-butyl group, and a benzyl group; and the aryl group includes one of a phenyl group, a 2-methylphenyl group, a 2-methoxyphenyl group, a 2-trifluoromethylphenyl group, a 3-methylphenyl group, a 3-methoxyphenyl group, a 3-trifluoromethylphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenyl group, a 2,6-dimethylphenyl group, a 2,4,6-trimethylphenyl group, a 3,5-dimethylphenyl group, a 3,5-ditrifluoromethylphenyl group, a 3,5-di-tert-butylphenyl group, a 3,5-di-tert-butyl-4-methoxyphenyl group, a 1-naphthyl group, a 2-naphthyl group, and a 1-anthracenyl group.

2. The strongly coordinated PNN tridentate chiral ligand according to claim 1, characterized in that: Strongly coordinated PNN tridentate chiral ligands include compounds of the following structural formulas L1 to L146: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. An application of the strongly coordinated PNN tridentate chiral ligand as claimed in claim 1 or 2 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: The free radical asymmetric functionalization reaction includes an asymmetric azidation reaction.

4. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 1 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: The application method comprises the following steps: using the product formed by the complexation reaction of the strongly coordinated PNN tridentate chiral ligand and the metal compound as a catalyst for the free radical asymmetric functionalization reaction and its derivative reaction.

5. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 4 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: The metal atoms in the metal compound include at least one of Cu, Fe, Zn, Mn, Cr, Co, Au, Ag, Ni, Ti, Pt, Pd, Rh, Ru, and Ir.

6. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 5 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: The metal compound includes at least one of CuI, CuBr, CuCl, CuCN, Cu2O, Cu(CH3CN)4PF6, (CuOTf)2·PhH, (CuOTf)2·PhMe, Cu(OTf)2, Cu(NO3)2, Cu(OAc)2, Cu(OAc)2·H2O, Cu(acac)2, CuCl2, CuBr2, Cu(BF4)2, and CuSO4.

7. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 4 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: The application method specifically includes the following steps: (1) Under an inert atmosphere, a metal compound, a strongly coordinated PNN tridentate chiral ligand, and a base are added to a solvent, mixed to carry out a complexation reaction, and a catalyst solution is obtained; (2) According to the expected product type of the free radical asymmetric functionalization reaction and its derivative reaction, an alkyl halide, an olefin and TMSN3, or an alkyl halide and TMSN3 are used as reaction substrates; a catalyst solution is added to the reaction substrate, the temperature is raised to the reaction temperature and an asymmetric azidation reaction is carried out under the action of the catalyst solution; after the reaction is completed, the obtained crude product is purified to obtain the target product.

8. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 7 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: In the step (1), the base includes at least one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, 1,8-diazabicyclo-bicyclo[5,4,0]-7-undecene, 2-tert-butyl-1,1,3,3-tetramethylguanidine, and (tert-butylimino)tri(pyrrolidine)phosphine; and the solvent includes at least one of methanol, ethanol, isopropanol, tert-butanol, 1,4-dioxane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, and 2-methyl-tetrahydrofuran.

9. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 7 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: In the step (1), the molar ratio of the metal compound, the strongly coordinated PNN tridentate chiral ligand, and the base is 1:(1 to 1.5):(10 to 20); in the step (2), when the reaction substrates are alkyl halide, olefin, and TMSN3, the molar ratio of the alkyl halide, olefin, and TMSN3 is 1:(1.1 to 2):(1.1 to 2); when the reaction substrates are alkyl halide and TMSN3, the molar ratio of the alkyl halide to TMSN3 is 1:(1.1 to 2).

10. The use of the strongly coordinated PNN tridentate chiral ligand according to claim 7 in a free radical asymmetric functionalization reaction and its derivatization reaction, characterized in that: In the step (1), the temperature of the complexation reaction is room temperature, and the reaction time is ≤1h; in the step (2), the reaction temperature of the asymmetric azidation reaction is -20 ~ 50 °C, and the reaction time is 2 ~ 72 h.

11. Use of the strongly coordinating PNN tridentate ligand according to claim 1 or 2 and a heterocyclic chiral amine fragment in a new synthesis route for intermediates of drugs, bioactive molecules and natural products.

12. The use according to claim 11, characterized in that: The invention includes an intermediate synthesis route for preparing a vascular non-inflammatory protein-1 (Vanin-1) inhibitor, which is as follows: Wherein, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. comply with claims 5 to 10.

13. The use according to claim 12, characterized in that: The invention includes an intermediate synthesis route for preparing Ontazolast, which is as follows: Wherein, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. comply with claims 5 to 10.

14. The use according to claim 11, characterized in that: The invention includes an intermediate synthesis route for preparing a natural product (Conulothiazole A), as follows: Wherein, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. comply with claims 5 to 10.

15. The use according to claim 11, characterized in that: The invention includes an intermediate synthesis route for the biologically active molecule TTA-A8, as follows: Wherein, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, X is a halogen, and the reaction steps, metal compound, base, reaction temperature, equivalent, time, etc. comply with claims 5 to 10.

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