Strong coordination pnn tridentate chiral ligand based on counter effect and its application in radical asymmetric functionalization and related reactions

Abstract

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

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and in particular to a strongly coordinated PNN tridentate chiral ligand based on the antisite effect and its application in free radical asymmetric functionalization and related reactions. Background Technology

[0002] Radical asymmetric functionalization catalyzed by inexpensive metals has attracted increasing attention in recent years. Radical asymmetric functionalization reactions are an important means of constructing many structurally rich chiral compounds, playing a crucial role in synthetic chemistry, drug discovery, and materials science. The current bottleneck in this field is the lack of efficient asymmetric catalytic systems, and the development of novel chiral ligands is urgently needed.

[0003] Chiral tripentate ligands are widely used in transition metal catalysis. These ligands are structurally easy to modify, and their steric and electronic effects can be highly tunable. Among them, chiral tripentate ligands containing weak coordination sites have attracted attention due to their excellent reactivity and enantioselectivity in radical asymmetric functionalization reactions catalyzed by inexpensive metals. For example, existing technologies, including the inventor's previous research (CN118146274A), provide the following representative chiral tripentate ligands containing weak coordination sites:

[0004]

[0005] The dialkylamine weak coordination sites of the above-mentioned ligands can form metastable coordination with metals. These metastable coordination sites can stabilize high-valence metal active intermediates and simultaneously dissociate to form effective active reaction sites. However, further research by the inventors revealed that such ligands still have significant technical drawbacks that need to be addressed. For substrates with strong coordination, such as heterocycles, the strongly coordinating heteroatoms in the substrate can rapidly replace the weak coordination sites of these tripentate ligands, forming multiple stable metal intermediates with substrate coordination. The substrate coordinated in these metal intermediates is difficult to dissociate, preventing catalytic cycling and resulting in catalyst poisoning. Therefore, tripentate ligands with metastable coordination are generally unsuitable for the asymmetric radical functionalization of strongly coordinated substrates.

[0006] In related applications, chiral nitrogen heterocyclic compound fragments are ubiquitous in drugs, bioactive molecules, and natural products. Chiral nitrogen heterocyclic compounds possess significant pharmacological and biological activities, including antioxidant, antibacterial, antituberculosis, analgesic, anti-inflammatory, antiviral, anticancer, and anti-worm effects. Of the 164 small molecule drugs approved by the U.S. Food and Drug Administration (FDA) between 2010 and 2019, 144 (87.8%) were nitrogen-containing heterocyclic drugs. Among these 144 nitrogen-containing heterocyclic drugs, pyridines accounted for the largest proportion at 19.4%, followed by piperidines (15.2%), piperazines (10.4%), pyrimidines (6.9%), pyrazoles (6.9%), and indoles (5.5%). Furthermore, in 2019, over 30% of the top 200 drugs by retail sales contained chiral amine structures. Therefore, the synthesis of nitrogen-containing heterocyclic chiral amines is of great significance.

[0007] However, due to the significant poisoning effect of nitrogen-containing heterocycles on catalysts, the currently reported tridentate chiral ligands are unable to achieve asymmetric radical transformations of such substrates due to the aforementioned defects. Therefore, providing a strongly coordinated PNN tridentate chiral ligand to overcome the existing shortcomings would have significant theoretical innovation and practical application value. Summary of the Invention

[0008] In view of the above-mentioned deficiencies of the prior art, in a first aspect of the present invention, a strongly coordinated PNN tridentate chiral ligand is provided to achieve chiral control in the radical functionalization process, solve the poisoning of catalysts by strongly coordinated substrates, and exhibit excellent reactivity and enantioselectivity in the asymmetric radical functionalization reaction of nitrogen-containing heterocyclic compounds, having the structure as described in general formula I:

[0009]

[0010] In the formula, the solid line on the left represents a ferrocene or benzene ring structure; X is carbon or sulfur, and Y is carbon or oxygen; the solid line on the right represents a ring formed with nitrogen and Y atoms.

[0011] When X is carbon, the dashed line between X and oxygen represents the absence of this bond, meaning the bridging group is a carbonyl group; when X is sulfur, the dashed line between X and oxygen represents the presence of this bond, meaning the bridging group is a sulfonyl group.

[0012] When Y is carbon, the structures represented by the solid ring line on the right side of the general formula include pyridine and pyridine containing substituents; when Y is oxygen, the structures represented by the solid ring line on the right side of the general formula include oxazoline and oxazoline containing substituents.

[0013] R, R 1 R 2Each is independently selected from alkyl or aryl groups; wherein, alkyl groups include one of methyl, ethyl, isopropyl, cyclohexyl, tert-butyl, and benzyl; and aryl groups include one of phenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-di-tert-butylphenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 1-naphthyl, 2-naphthyl, and 1-anthrayl.

[0014] Preferably, the strongly coordinated PNN tridentate chiral ligand comprises compounds with the structural formulas shown in L1~L146 below:

[0015] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , .

[0016] For the purpose of simplifying the compound structure, the aforementioned substituted aryl groups are represented by the general notation Ar (arylgroup) in the art, and their specific types are shown in the corresponding compounds.

[0017] Based on the above technical solutions, the principle and design concept of this invention lies in proposing a strongly coordinated tridentate PNN ligand with the above structure based on the anti-site effect. The ligand skeleton is a ferrocene Ugiamine skeleton with superior facet chirality and carbon center chirality, as well as a simple chiral benzylamine skeleton. For the phosphorus atom coordination site in the ligand, phosphine chirality can be precisely and controllably introduced through the chiral Ugiamine. The ligand contains a secondary amine coordination site that can be deprotonated, which can form an electron-rich σ coordination with the metal, enhancing the reactivity. The third strong coordination site in the ligand is pyridine or oxazoline, which can also be precisely and controllably introduced into the chiral environment. When the free radical interacts with the central metal, the sterically hindered group of the free radical will avoid contact with the sterically hindered group in the coordination site, thereby achieving chiral control in the free radical functionalization process.

[0018] All three coordination sites of the strongly coordinated tripentate PNN ligand are strongly coordinated. When a strongly coordinated substrate coordinates with a metal, the substrate cannot replace these three strong coordination sites because a stable chelate ring is formed between the three strong coordination sites and the metal complex. In this case, 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 basic conditions, forming a stable σ-coordination with the metal. The bridging N atom forming the σ-coordination with the metal has strong electron-donating properties, and the heteroatom of the strongly coordinated substrate in the anti-position also has strong electron-donating properties. According to the anti-position principle, when both ligands in the anti-position are strong electron donors, one of the ligands is easily dissociated due to the anti-position effect. Therefore, the strongly coordinated substrate in the anti-position of the bridging N atom in the ligand can dissociate due to the anti-position effect, thus achieving catalytic cycling and preventing the formation of a stable strongly coordinated complex that would poison the catalyst. Furthermore, since all three coordination sites of the tridentate PNN ligand in this invention are strongly coordinated, this type of ligand has a better stabilizing effect on high-valence active metal intermediates. The strongly coordinated substrate is less likely to destroy the intrinsic structure of the complex formed by the ligand and the metal, thus the corresponding catalyst has better stability during the catalytic process.

[0019] The synthetic routes for the strongly coordinated tridentate PNN ligands L1~L4 and L21~L56 are as follows:

[0020]

[0021] Where rt represents room temperature; 1.5 h, 4 h, and 50 min represent reaction times; 0.25 M represents concentration, and the same applies thereafter.

[0022] In the above synthetic routes, the general structural formulas of compounds 1, 2, 3, int-1 or products L1~L4, L21~L56 include: R corresponding to the corresponding alkyl or aryl group; alkyl groups are selected from methyl, ethyl, isopropyl, tert-butyl, benzyl, etc.; aryl groups are selected from phenyl, 2-methylphenyl, 4-methoxy-3,5-di-tert-butylphenyl, etc.; R' corresponding to the corresponding alkyl or aryl group; alkyl groups are selected from cyclohexyl, tert-butyl, etc.; aryl groups are phenyl, etc.; R 4The corresponding alkyl or aryl groups are 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 groups are selected from 2-phenyl, 3-phenyl, 3-3,5-di-tert-butylphenyl, 3-1-naphthyl, 3-2-naphthyl, 3-1-anthrayl, 4-phenyl, 4-3,5-di-tert-butylphenyl, 4-1-naphthyl, 4-2-naphthyl, 4-1-anthrayl, 5-phenyl, etc. For the purpose of simplicity, the pathway is illustrated using a typical pyridine ring as an example. For products containing quinoline or substituted quinoline structures, the corresponding structures of the substrate and product used in this part are quinoline or substituted quinoline.

[0023] Similarly, the synthetic routes for strongly coordinating tridentate PNN ligands L5~L13 are as follows:

[0024]

[0025] In the above synthetic routes, the general structural formulas of compounds 5, 6, int-2, or products L5~L13, Ar represents the corresponding aryl group, such as 3,5-di-tert-butylphenyl, 3,5-di-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 2-naphthyl, etc.

[0026] The synthetic routes for the strongly coordinated tridentate PNN ligands L14~L20 are as follows:

[0027]

[0028] In the above synthetic routes, the general structural formulas of compounds 7, 8, int-3, or products L14~L20, R 1 The corresponding alkyl or aryl group is selected from methyl, ethyl, ethylphenyl, isopropyl, tert-butyl, etc., and the aryl group is selected from 4-methoxy-3,5-di-tert-butylphenyl, etc.

[0029] The synthetic route for the strongly coordinated tridentate PNN ligands L57~L63 is as follows:

[0030]

[0031] In the general structural formulas of compounds int-1 or products L57~L63 involved in the above synthetic routes, R 3 Corresponding to the corresponding 2-methyl, 2-phenyl; as mentioned above, for products containing quinoline or substituted quinoline structures, the corresponding structures of the substrate and product are quinoline or substituted quinoline, etc.

[0032] The synthetic routes for the strongly coordinated tridentate PNN ligands L64~L76 are as follows:

[0033]

[0034] In the above synthetic route, the heterocyclic structures are oxazoline and oxazoline containing substituents.

[0035] The synthetic routes for the strongly coordinated tridentate PNN ligands L77~L115 and L123~L124 are as follows:

[0036]

[0037] In the above synthetic routes, the general structural formulas of compounds 9, int-4, or products L77~L115 and L123~L124 involve R. 4 Corresponding to the corresponding alkyl or aryl group, the alkyl group 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 group is selected from 2-phenyl, 3-phenyl, 3-3,5-di-tert-butylphenyl, 3-1-naphthyl, 3-2-naphthyl, 3-1-anthrayl, 4-phenyl, 4-3,5-di-tert-butylphenyl, 4-1-naphthyl, 4-2-naphthyl, 4-1-anthrayl, 5-phenyl, etc.; R 5 (representing R) 1 R 2 In cases where the group types are the same, R is used here. 5 (For explanation) Corresponding to the corresponding alkyl or aryl groups, the alkyl group is selected from cyclohexyl, etc., and the aryl group is selected from phenyl, 3,5-di-tert-butylphenyl, 3,5-di-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 4-methoxyphenyl, 2,4,6-trimethylphenyl, 1-naphthyl, 2-naphthyl, 2-methoxyphenyl, 4-methoxy-3,5-di-tert-butylphenyl, etc.

[0038] The synthetic route for the strongly coordinated tridentate PNN ligands L116~L122 is as follows:

[0039]

[0040] In the above synthetic routes, the general structural formulas of compounds 10, 11, 12, int-5 or products L116~L122 involve R corresponding to the corresponding alkyl or aryl groups. 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, dimethylphenyl, etc.

[0041] The synthetic route for the strongly coordinated tridentate PNN ligands L125~L131 is as follows:

[0042]

[0043] In the general structural formulas of the compound int-5 or products L125~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 structures, the corresponding structures of the substrates and products used in this part are quinoline or substituted quinoline, etc.

[0044] The synthetic route for the strongly coordinated tridentate PNN ligands L132~L146 is as follows:

[0045]

[0046] As mentioned above, for products containing quinoline or substituted quinoline structures, the corresponding structures of the substrate and the product are quinoline or substituted quinoline, etc.

[0047] The above synthetic route reflects the general synthetic route adopted by the inventors in this invention, which has the advantage of being simple to operate. Based on the structure of the corresponding product, those skilled in the art can also use other routes to synthesize the corresponding strongly coordinated tridentate PNN ligands.

[0048] In a second aspect of the invention, the application of the strongly coordinated PNN tridentate chiral ligand of the first aspect of the invention in radical asymmetric functionalization reactions and their derivative reactions is provided.

[0049] Preferably, the radical asymmetric functionalization reaction includes an asymmetric azidation reaction.

[0050] Preferably, the method of application includes the following steps: using the product formed by the complexation reaction of a strongly coordinated PNN tridentate chiral ligand with a metal compound as a catalyst for radical asymmetric functionalization reaction and its derivative reaction.

[0051] More 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.

[0052] Among the available metal atom types, copper is an inexpensive, readily available, and abundant metal, and copper compounds are diverse in type and valence state, offering a wide range of choices, making them particularly suitable for use as the metal compounds of this invention.

[0053] 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.

[0054] More preferably, the method of application specifically includes the following steps:

[0055] (1) Under an inert atmosphere, a metal compound, a strongly coordinated PNN tridentate chiral ligand, and a base are added to a solvent and mixed to carry out a complexation reaction to obtain a catalyst solution.

[0056] (2) Based on the expected product type of the free radical asymmetric functionalization reaction and its derivative reaction, alkyl halides, alkenes and TMSN3, or alkyl halides 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 crude product is purified to obtain the target product.

[0057] Furthermore, in 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]undec-7-ene (DBU), 2-tert-Butyl-1,1,3,3-tetramethylguanidine (BTMG), and (tert-butylimino)tris(pyrrolidin-1-yl)phosphoranylidene (BTPP).

[0058] 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.

[0059] Furthermore, in step (1), the complexation reaction is carried out at room temperature and the reaction time is ≤1 h.

[0060] Furthermore, in step (1), the molar ratio of the metal compound, the strongly coordinated PNN tridentate chiral ligand, and the base is 1:(1-1.5):(10-20).

[0061] Furthermore, in step (2), when the reaction substrate is an alkyl halide, an olefin, and TMSN3, the molar ratio of the alkyl halide, the olefin, and TMSN3 is 1:(1.1 ~ 2):(1.1 ~ 2); when the reaction substrate is an alkyl halide and TMSN3, the molar ratio of the alkyl halide to TMSN3 is 1:(1.1 ~ 2).

[0062] Furthermore, in step (2), the reaction temperature of the asymmetric azidation reaction is -20 to 50 °C, and the reaction time is 2 to 72 h.

[0063] The strongly coordinated tripentate PNN ligand developed in this invention innovatively solves the problem of catalyst poisoning by strongly coordinated substrates by utilizing the trans effect, thereby exhibiting excellent reactivity and enantioselectivity in asymmetric radical functionalization reactions of nitrogen-containing heterocyclic compounds. The strongly coordinated tripentate PNN ligand serves as a catalytically active material for radical asymmetric functionalization reactions and their derivatization reactions, especially in asymmetric azidation reactions. This invention has broad applicability in asymmetric azidation reactions; those skilled in the art can select suitable reaction substrates according to actual synthetic needs to complete asymmetric azidation reactions under the action of catalysts prepared with the strongly coordinated PNN tripentate chiral ligand. The following reaction equations concisely and clearly reflect the progress of representative asymmetric azidation reactions:

[0064]

[0065] 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~L146 of this invention, and R, R 1 R 2 R 3 The corresponding substituent is then the substrate. As presented in one or more embodiments of the present invention, the strongly coordinating tripentate PNN ligand is suitable for the efficient synthesis of a series of chiral nitrogen-containing heterocyclic compounds, such as vascular non-inflammatory molecule 1 (Vanin-1) inhibitors, ontazolast, the natural product Conulothiazole A, and the calcium ion channel antagonist TTA-A8, etc., and has good practical application value.

[0066] The intermediate synthesis route for Vanin-1 inhibitors is as follows:

[0067]

[0068] Wherein, 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, equivalence, time, etc., comply with the above-mentioned application limitations.

[0069] The synthetic route for the intermediates of ontazolast is as follows:

[0070]

[0071] Wherein, 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, equivalence, time, etc., comply with the above-mentioned application limitations.

[0072] The intermediate synthetic route for the natural product (Conulothiazole A) is as follows:

[0073]

[0074] Wherein, 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, equivalence, time, etc., comply with the above-mentioned application limitations.

[0075] The synthetic route for the intermediate of the bioactive molecule TTA-A8 is as follows:

[0076]

[0077] Wherein, 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, equivalence, time, etc., comply with the above-mentioned application limitations.

[0078] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0079] This invention provides a strongly coordinated PNN tridentate chiral ligand that achieves chiral control in the radical functionalization process. It utilizes the trans-site effect to solve the poisoning of the catalyst by the strongly coordinated substrate and exhibits excellent reactivity and enantioselectivity in the asymmetric radical functionalization reaction of nitrogen-containing heterocyclic compounds.

[0080] This invention provides an application of a strongly coordinated PNN tridentate chiral ligand, which has broad practical application prospects in radical asymmetric functionalization reactions and their derivative reactions. Attached Figure Description

[0081] Figure 1 A schematic diagram illustrating 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.

[0082] Figure 2 A schematic diagram illustrating the specific structural design and corresponding effects of a strongly coordinating chiral tridentate PNN ligand. Detailed Implementation

[0083] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0084] In the following embodiments:

[0085] The preparation of precursor P1 follows the reaction process as follows:

[0086]

[0087] Add S1 (( R 12.86 g (50 mmol, 1.0 equiv.) and anhydrous diethyl ether (100 mL, 0.50 M) were added dropwise to the resulting solution at 0 °C. The solution was then heated to room temperature and reacted for 1.5 h. After cooling the reaction solution to 0 °C, diphenylphosphine chloride (16.50 g, 75 mmol, 1.5 equiv.) was added, and the reaction solution was heated to room temperature and reacted for 4 h. After the reaction was complete, 30 mL of saturated ammonium chloride aqueous solution 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 evaporated under reduced pressure. The crude product was slurried with methanol for 4 h and filtered to obtain a portion of product S2. The filtrate was purified by column chromatography to obtain another portion of product S2. After mixing, a total of product S2 (10.25 g) was obtained. g (i.e., 23.22 mmol, yield 47%).

[0088] Transfer all of product S2 from the previous step to a 100 mL round-bottom flask, add acetic anhydride (17.6 mL, 185.76 mmol), heat to 100 °C and react for 1 h. After the reaction is complete, add saturated sodium bicarbonate aqueous solution (20 mL) and solid sodium bicarbonate. After the reaction stops bubbling, separate the organic phase. Extract the aqueous phase three times with ethyl acetate (40 mL each time). Then wash the organic phase with water and brine. Dry the obtained organic phase with anhydrous sodium sulfate and then evaporate to dryness under reduced pressure to obtain product S3. Transfer all of product S3 to an autoclave. Then, add acetonitrile and tetrahydrofuran in a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of product S3, wherein the concentration of S3 is 0.25 M. Add ammonia water (39 mL, 0.60 M), then heat to 100 °C and react for 8 h. Concentrate the reaction solution to dryness under reduced pressure, add water (20 mL) to the residue, and extract the aqueous phase three times with ethyl acetate (40 mL each time). mL); then the organic phase was washed with brine, and the resulting organic phase was dried under reduced pressure with anhydrous sodium sulfate to obtain the crude product. The crude product was purified by column chromatography to obtain the target product precursor P1 (7.44 g, yield 78%).

[0089] The preparation of precursor P2 follows the reaction process as follows:

[0090]

[0091] In a 100 mL round-bottom flask under a nitrogen atmosphere, S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous diethyl ether (6.0 mL, 1.67 M) were added dropwise. A 2.5 M solution of n-butyllithium in n-hexane (4.8 mL, 12 mmol, 1.2 equiv.) was added dropwise to the resulting solution at 0 °C, and the mixture was heated to room temperature for 1.5 h. The reaction solution was then cooled to 0 °C, and dicyclohexylphosphine chloride (3.49 g, 15 mmol, 1.5 equiv.) was added. The resulting reaction solution was heated to room temperature for 4 h. After the reaction was complete, a saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (40 mL each time). The obtained organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The crude product was purified by column chromatography to obtain product S4 (2.90 g, yield 64%).

[0092] Transfer all of product S4 from the previous step to a 100 mL round-bottom flask, add acetic anhydride (6.0 mL, 64 mmol), heat to 100 °C and react for 1 h. After the reaction is complete, add saturated sodium bicarbonate aqueous solution (10 mL) and solid sodium bicarbonate. After the reaction stops bubbling, separate the organic phase. Extract the aqueous phase three times with ethyl acetate (20 mL each time). Then wash the organic phase with water and brine. Dry the obtained organic phase with anhydrous sodium sulfate and then evaporate to dryness under reduced pressure to obtain product S5. Transfer all of product S5 to an autoclave. Then, add acetonitrile and tetrahydrofuran in a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of product S5, wherein the concentration of S5 is 0.25 M. Add ammonia water (39 mL, 0.60 M), and then heat to 100 °C and react for 8 h. After the reaction is complete, concentrate the reaction solution and evaporate to dryness. Add water (20 mL) to the residue, and extract the aqueous phase three times with ethyl acetate (40 mL each time). mL); then the organic phase was washed with brine, and the resulting organic phase was dried with anhydrous sodium sulfate and then evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product precursor P2 (567 mg, yield 21%).

[0093] The preparation of precursor P3 follows the reaction process as follows:

[0094]

[0095] In a 100 mL round-bottom flask purged with nitrogen, S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous diethyl ether (20 mL, 0.20 M) were added sequentially. A 2.5 M solution of n-butyllithium in n-hexane (4.4 mL, 11 mmol, 1.1 equiv.) was added dropwise to the resulting solution at 0 °C, and the mixture was allowed to react at room temperature for 1.5 h. After cooling the reaction solution to -78 °C, phosphine trichloride (1.58 g, 11.5 mmol, 1.15 equiv.) was added, and the resulting reaction solution was heated to room temperature and reacted for 4 h. After the reaction was completed, the reaction solution was cooled to -78 °C, and a pre-prepared aryl-substituted Grignard reagent (1.0 M, 30 mL, 3.0 equiv.) was added, and the reaction was restored to room temperature and reacted for 12 h. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction solution, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (40 mL each time). The obtained organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the product S6 from the first step.

[0096] Take product S6 (800 mg, 1.20 mmol) from step one and transfer it to a 50 mL round-bottom flask. Add acetic anhydride (1.7 mL, 18 mmol), heat to 100 °C and react for 50 min. After the reaction is complete, add saturated sodium bicarbonate aqueous solution (10 mL) and sodium bicarbonate solid. After the reaction stops bubbling, separate the organic phase and extract the aqueous phase three times with ethyl acetate (20 mL each time). The organic phase was then washed with water and brine. The resulting organic phase was dried under reduced pressure after drying with anhydrous sodium sulfate to obtain product S7. All of product S7 was then transferred to an autoclave. Acetonitrile and tetrahydrofuran were added sequentially at a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of product S7, with a concentration of 0.25 M. Ammonia (39 mL, 0.60 M) was then added, and the mixture was heated to 80 °C and reacted for 8 h. After the reaction, the reaction solution was concentrated and evaporated to dryness. Water (10 mL) was added to the residue, and the aqueous phase was extracted three times with ethyl acetate (20 mL each time). The organic phase was then washed with brine. The resulting organic phase was dried under reduced pressure after drying with anhydrous sodium sulfate to obtain the crude product. The crude product was purified by column chromatography to obtain the target product precursor P3 (1.39 g, yield 30%).

[0097] The preparation of precursor P4 follows the reaction process as follows:

[0098]

[0099] In a 100 mL round-bottom flask under a nitrogen atmosphere, S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous diethyl ether (20 mL, 0.20 M) were added dropwise. A 2.5 M solution of n-butyllithium in n-hexane (4.4 mL, 11 mmol, 1.1 equiv.) was added dropwise to the resulting solution at 0 °C, and the reaction was allowed to proceed to room temperature for 1.5 h. The reaction solution was then cooled to -78 °C, and phosphine trichloride (1.58 g, 11.5 mmol, 1.15 equiv.) was added. The resulting reaction solution was allowed to proceed to room temperature for 4 h. After the reaction was complete, the reaction solution was cooled to -78 °C, and a pre-prepared aryl-substituted Grignard reagent (1.0 M, 30 mL, 3.0 equiv.) was added. The reaction was allowed to proceed to room temperature for 12 h. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (40 mL each time). The obtained organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the first step product S8.

[0100] Take product S8 (650 mg, 1.20 mmol) from the first step and transfer it to a 50 mL round-bottom flask. Add acetic anhydride (1.7 mL, 18 mmol), heat to 100 °C and react for 50 min. After the reaction is complete, add saturated sodium bicarbonate aqueous solution (10 mL) and solid sodium bicarbonate. After the reaction stops bubbling, separate the organic phase. Extract the aqueous phase three times with ethyl acetate (20 mL each time). Then wash the organic phase with water and brine. Dry the obtained organic phase with anhydrous sodium sulfate and then evaporate to dryness under reduced pressure to obtain product S9. Transfer all of product S9 to an autoclave. Then, add acetonitrile and tetrahydrofuran in a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of product S9, wherein the concentration of S9 is 0.25 M. Add ammonia water (39 mL, 0.60 M), and then heat to 80 °C and react for 8 h. After the reaction is complete, concentrate the reaction solution and evaporate to dryness. Add water (10 mL) to the residue and extract the aqueous phase three times with ethyl acetate (20 mL each time). The organic phase was then washed with brine, dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product precursor P4 (1.0 g, yield 36%).

[0101] The preparation of precursor P5 follows the reaction process as follows:

[0102]

[0103] In a 100 mL round-bottom flask under a nitrogen atmosphere, S1 (2.57 g, 10 mmol, 1.0 equiv.) and anhydrous diethyl ether (20 mL, 0.20 M) were added dropwise. A 2.5 M solution of n-butyllithium in n-hexane (4.4 mL, 11 mmol, 1.1 equiv.) was added dropwise to the resulting solution at 0 °C, and the reaction was allowed to proceed to room temperature for 1.5 h. The reaction solution was then cooled to -78 °C, and phosphine trichloride (1.58 g, 11.5 mmol, 1.15 equiv.) was added. The resulting reaction solution was allowed to proceed to room temperature for 4 h. After the reaction was complete, the reaction solution was cooled to -78 °C, and a pre-prepared aryl-substituted Grignard reagent (1.0 M, 30 mL, 3.0 equiv.) was added. The reaction was allowed to proceed to room temperature for 12 h. A saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (40 mL each time). The obtained organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the first step product S10.

[0104] Take product S10 (650 mg, 1.20 mmol) from the first step and transfer it to a 50 mL round-bottom flask. Add acetic anhydride (1.7 mL, 18 mmol), heat to 100 °C and react for 50 min. After the reaction is complete, add saturated sodium bicarbonate aqueous solution (10 mL) and solid sodium bicarbonate. After the reaction stops bubbling, separate the organic phase. Extract the aqueous phase three times with ethyl acetate (20 mL each time). Then wash the organic phase with water and brine. Dry the obtained organic phase with anhydrous sodium sulfate and then evaporate to dryness under reduced pressure to obtain product S11. Transfer all of the obtained product S11 to an autoclave. Then, add acetonitrile and tetrahydrofuran in a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of product S11, wherein the concentration of S11 is 0.25 M. Then add ammonia water (39 mL, 0.60 M), and then heat to 80 °C and react for 8 h. After the reaction is complete, concentrate the reaction solution and evaporate to dryness. Add water (10 mL) to the residue. The aqueous phase was extracted three times with ethyl acetate (20 mL each time); then the organic phase was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product precursor P5 (1.0 g, yield 21%).

[0105] The preparation of precursor P6 follows the reaction process as follows:

[0106]

[0107] In a 100 mL round-bottom flask under a nitrogen atmosphere, S1 (5.14 g, 20 mmol, 1.0 equiv.) and anhydrous diethyl ether (40 mL, 0.50 M) were added sequentially. A 2.5 M solution of n-butyllithium in n-hexane (9.6 mL, 24 mmol, 1.2 equiv.) was added dropwise to the resulting solution at 0 °C, and the mixture was heated to room temperature for 1.5 h. After the reaction, the solution was cooled to -78 °C, and dichlorophenylphosphine (3.58 g, 20 mmol, 1.0 equiv.) was added. The resulting solution was slowly heated to room temperature for 1.5 h. After the reaction, the solution was cooled to -78 °C, and methylmagnesium bromide (3.0 M, 8 mL, 1.2 equiv.) was added. The mixture was slowly restored to room temperature for 12 h. After the reaction, a saturated ammonium chloride aqueous solution (20 mL) was added to the solution, and the organic phase was separated. The aqueous phase was extracted three times with ethyl acetate (40 mL each time). The obtained organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the first step product S12 (3.1 g, yield 40%).

[0108] Transfer all of the product S12 from the previous step to a 50 mL round-bottom flask, add acetic anhydride (8.0 mL, 78.8 mmol), heat to 100 °C and react for 50 min. After the reaction is complete, add saturated sodium bicarbonate aqueous solution (10 mL) and solid sodium bicarbonate. After the reaction stops bubbling, separate the organic phase. Extract the aqueous phase three times with ethyl acetate (20 mL each time). Then wash the organic phase with brine, dry the obtained organic phase with anhydrous sodium sulfate, and then evaporate to dryness under reduced pressure to obtain product S13. Transfer all of the obtained product S13 to an autoclave. Then, add acetonitrile and tetrahydrofuran in a volume ratio of 2.5:1 to form an acetonitrile-tetrahydrofuran solution of product S13, wherein the concentration of S13 is 0.25 M. Then add ammonia water (11.3 mL, 0.7 M), and then heat to 80 °C and react for 12 h. Concentrate the reaction solution to dryness, add water (20 mL) to the residue, and extract the aqueous phase three times with ethyl acetate (40 mL each time). mL); then the organic phase was washed with brine, and the resulting organic phase was dried with anhydrous sodium sulfate and then evaporated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the target product precursor P6 (1.7 g, yield 61%).

[0109] The preparation of precursor S14 follows the reaction process as follows:

[0110]

[0111] In a 1000 mL round-bottom flask purged with nitrogen, S2 (10 g, 83 mmol, 1.0 equiv.) and anhydrous diethyl ether (83 mL, 1.0 M) were added dropwise. A 2.5 M solution of n-butyllithium in n-hexane (83 mL, 83 mmol, 1.0 equiv.) was added dropwise to the resulting solution at -35 °C, and the mixture was stirred at -35 °C for 1 h. TMSCl (9.9 g, 91 mmol, 1.1 equiv.) was added dropwise to the reaction solution, and the mixture was slowly heated to room temperature and stirred for 1 h. The mixture was then cooled to -35 °C, and a 2.5 M solution of n-butyllithium in n-hexane (249 mL, 249 mmol, 3.0 equiv.) was added dropwise to the resulting solution, and the mixture was stirred at -35 °C for 4 h. Diphenylphosphine chloride (20.1 g, 83 mmol, 1.0 equiv.) was added dropwise to the reaction solution, and the mixture was slowly heated to room temperature and stirred for 7 h. h; quench with saturated ammonium chloride solution (83 mL), extract three times with ethyl acetate in aqueous phase (83 mL each time); then wash the organic phase with brine, dry the organic phase under reduced pressure, and purify by column chromatography to obtain S14.

[0112] Using a similar preparation method as precursor S14, precursors S15-S17 can be synthesized by sequentially replacing the methyl structure in S2 with ethyl, benzyl, and phenyl groups, respectively, as shown below:

[0113] , , .

[0114] Example 1

[0115] The strongly coordinating tridentate PNN ligand L1 was synthesized using the following method:

[0116]

[0117] In a 100 mL round-bottom flask, precursor P1 (5.20 g, 12.6 mmol, 1.0 equiv.), 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.) from Example 1 were added sequentially. After replacing the atmosphere with nitrogen, dichloromethane (DCM; 32 mL, 0.40 M) was added at 0 °C. The reaction was then allowed to return to room temperature for 12 h. After the reaction was completed, water (20 mL) was added to quench the reaction. The aqueous phase was extracted three times with dichloromethane (30 mL each time). The organic phase was then washed with brine. The organic phase was dried under reduced pressure with anhydrous sodium sulfate to obtain the crude product. The crude product was purified by column chromatography to obtain the target product, strongly coordinated tripentate PNN ligand L1 (6.40 g, yield 98%).

[0118] 1H 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).

[0119] Example 2

[0120] The strongly coordinating tridentate PNN ligand L30 was synthesized using the following method:

[0121]

[0122] In a 50 mL round-bottom flask, precursor P1 (413 mg, 1.0 mmol, 1.0 equiv.), 5-phenylpyridinecarboxylic 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.) from Example 1 were added sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L30 (yellow solid, 553 mg, yield 93%), was obtained by column chromatography.

[0123] 1H 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).

[0124] Example 3

[0125] The strongly coordinating tridentate PNN ligand L31 was synthesized using the following method:

[0126]

[0127] In a 50 mL round-bottom flask, precursor P1 (413 mg, 1.0 mmol, 1.0 equiv.) and 5-(3,5-di-tert-butylphenyl)pyridinecarboxylic 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 sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L31 (yellow solid, 632 mg, 90% yield), was obtained by column chromatography.

[0128] 1H 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).

[0129] Example 4

[0130] The strongly coordinating tridentate PNN ligand L32 was synthesized using the following method:

[0131]

[0132] In a 25 mL round-bottom flask, precursor P1 (300 mg, 0.73 mmol, 1.0 equiv.) and 5-(naphthyl-2-yl)pyridinecarboxylic 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 sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and the reaction was allowed to proceed to room temperature for 12 h. After the reaction was completed, water (5 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (10 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L32 (yellow solid, 306 mg, yield 65%), was obtained by column chromatography.

[0133] 1H 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).

[0134] Example 5

[0135] The strongly coordinating tridentate PNN ligand L28 was synthesized using the following method:

[0136]

[0137] In a 25 mL round-bottom flask, precursor P1 (413 mg, 1.0 mmol, 1.0 equiv.) and 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 sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, and the reaction was allowed to proceed to room temperature for 12 h. After the reaction was completed, water (5 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (10 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L28 (yellow solid, 492 mg, yield 84%), was obtained by column chromatography.

[0138] 1H 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).

[0139] Example 6

[0140] The strongly coordinating tridentate PNN ligand L3 was synthesized using the following method:

[0141]

[0142] In a 50 mL round-bottom flask, precursor P2 (2.30 g, 5.4 mmol, 1.0 equiv.) and 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 sequentially. After purging with nitrogen, DCM (12 mL, 0.27 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L3 (yellow solid, 3.1 g, yield 80%), was obtained by column chromatography.

[0143] 1H 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).

[0144] Example 7

[0145] The strongly coordinating tridentate PNN ligand L7 was synthesized using the following method:

[0146]

[0147] In a 50 mL round-bottom flask, precursor P3 (460 mg, 0.84 mmol, 1.0 equiv.) and 2-pyridinecarboxylic 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 sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L7 (yellow solid, 516 mg, yield 94%), was obtained by column chromatography.

[0148] 1H 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).

[0149] Example 8

[0150] The strongly coordinating tridentate PNN ligand L12 was synthesized using the following method:

[0151]

[0152] In a 50 mL round-bottom flask, precursor P4 (257 mg, 0.50 mmol, 1.0 equiv.) and 2-pyridinecarboxylic 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 sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L12 (yellow solid, 269 mg, yield 87%), was obtained by column chromatography.

[0153] 1H 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).

[0154] Example 9

[0155] The strongly coordinating tridentate PNN ligand L10 was synthesized using the following method:

[0156]

[0157] In a 50 mL round-bottom flask, 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.), and EDCI (146 mg, 0.76 mmol, 1.2 equiv.) were added sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L10 (yellow solid, 181 mg, yield 37%), was obtained by column chromatography.

[0158] 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).

[0159] Example 10

[0160] The strongly coordinating tridentate PNN ligand L15 was synthesized using the following method:

[0161]

[0162] In a 50 mL round-bottom flask, 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 sequentially. After purging with nitrogen, DCM (3.5 mL, 0.30 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L15 (yellow solid, 800 mg, yield 62%), was obtained by column chromatography.

[0163] 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).

[0164] Example 11

[0165] The strongly coordinating tridentate PNN ligand L77 was synthesized using the following method:

[0166]

[0167] In a 100 mL round-bottom flask, precursor S14 (4.7 g, 15.4 mmol, 1.0 equiv.) and 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 sequentially. After purging with nitrogen, DCM (38.5 mL, 0.40 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (40 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L77 (white solid, 5.69 g, 90% yield), was obtained by column chromatography.

[0168] 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).

[0169] Example 12

[0170] The strongly coordinating tridentate PNN ligand L146 was synthesized using the following method:

[0171]

[0172] In a 50 mL round-bottom flask, the following substances were added sequentially: precursor S14 (915 mg, 3.0 mmol, 1.0 equiv.), (3aS,8aR)-3a,8a-dihydro-8H-indeno[1,2-d]oxazol-2-carboxylate sodium (1.01 g, 4.5 mmol, 1.5 equiv.), N,N-diisopropylethylamine (DIPEA; 1.75 g, 13.5 mmol, 4.5 equiv.), and 1-hydroxybenzotriazole (HOBT; 689 mg, 5.1 mmol, 1.7 equiv.). The reaction mixture was prepared by replacing the nitrogen atmosphere with N,N-dimethylformamide (DMF; 15 mL, 0.20 M), 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.), and then adding N,N-dimethylformamide (DMF; 15 mL, 0.20 M) at 0 °C. The reaction was then brought back to room temperature and reacted for 12 h. After the reaction was completed, water (20 mL) was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product ligand L146 (white solid, 536 mg, yield 36%) was obtained by column chromatography.

[0173] 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).

[0174] Example 13

[0175] The strongly coordinating tridentate PNN ligand L145 was synthesized using the following method:

[0176]

[0177] In a 10 mL round-bottom flask, precursor S14 (153 mg, 0.5 mmol, 1.0 equiv.), sodium (S)-4-tert-butyl-4,5-dihydrooxazol-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 sequentially. The mixture was then purged under a nitrogen atmosphere, and DMF (2.5 mL, 0.20 M) was added at 0 °C. The reaction was then allowed to return to room temperature for 12 h. After the reaction was complete, water (5 mL) was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (5 mL each time). The organic phase was then washed with brine, dried, and evaporated to dryness under reduced pressure. The purified product, ligand L145 (white solid, 66.4 g / mL), was obtained by column chromatography. mg, yield 29%).

[0178] 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).

[0179] Example 14

[0180] The strongly coordinating tridentate PNN ligand L132 was synthesized using the following method:

[0181]

[0182] In a 10 mL round-bottom flask, precursor S14 (153 mg, 0.5 mmol, 1.0 equiv.), sodium (S)-4-phenyl-4,5-dihydrooxazol-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 sequentially. The mixture was then purged under a nitrogen atmosphere, and DMF (2.5 mL, 0.20 M) was added at 0 °C. The reaction was then allowed to return to room temperature for 12 h. After the reaction was complete, water (5 mL) was added to quench the reaction. The aqueous phase was extracted three times with ethyl acetate (5 mL each time). The organic phase was then washed with brine, dried, and evaporated to dryness under reduced pressure. The purified product, ligand L132 (white solid, 78.5 μL), was obtained by column chromatography. mg, yield 33%).

[0183] 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).

[0184] Example 15

[0185] The strongly coordinating tridentate PNN ligand L116 was synthesized using the following method:

[0186]

[0187] In a 50 mL round-bottom flask, precursor S15 (958 mg, 3.0 mmol, 1.0 equiv.) and pyridinecarboxylic 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 sequentially. After purging with nitrogen, DCM (15 mL, 0.20 M) was added at 0 °C, and the reaction was allowed to proceed to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L116 (white solid, 751 mg, yield 59%), was obtained by column chromatography.

[0188] 1H 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).

[0189] Example 16

[0190] The strongly coordinating tridentate PNN ligand L119 was synthesized using the following method:

[0191]

[0192] In a 50 mL round-bottom flask, precursor S16 (396 mg, 1.0 mmol, 1.0 equiv.) and pyridinecarboxylic 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 sequentially. After purging to a nitrogen atmosphere, DCM (5 mL, 0.20 M) was added at 0 °C, followed by a reaction at room temperature for 12 h. After the reaction was complete, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L119 (white solid, 399 mg, yield 82%), was obtained by column chromatography.

[0193] 1H 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).

[0194] Example 17

[0195] The strongly coordinating tridentate PNN ligand L120 was synthesized using the following method:

[0196]

[0197] In a 50 mL round-bottom flask, precursor S17 (588 mg, 1.6 mmol, 1.0 equiv.) and pyridinecarboxylic 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 sequentially. After purging with nitrogen, DCM (8 mL, 0.20 M) was added at 0 °C, and the reaction was allowed to proceed to room temperature for 12 h. After the reaction was completed, water (10 mL) was added to quench the reaction. The aqueous phase was extracted three times with DCM (20 mL each time). The organic phase was then washed with brine, dried, and evaporated under reduced pressure. The purified product, ligand L120 (white solid, 387 mg, 99% yield), was obtained by column chromatography.

[0198] 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).

[0199] Example 18

[0200] The reaction process of the strongly coordinating tripentate PNN ligand L125 is as follows:

[0201]

[0202] In a 50 mL round-bottom flask, triethylamine (810 mg, 8.0 mmol, 4.0 equiv.) and 2-pyridinesulfonic acid (710 mg, 4.0 mmol, 2.0 equiv.) were added sequentially. After replacing the atmosphere with nitrogen, dichloromethane (20 mL, 0.10 M) was added at 0 °C. The mixture was stirred for 15 min, and then trifluoromethanesulfonic anhydride (1.13 g, 4.0 mmol, 2.0 equiv.) was slowly added dropwise at 0 °C. After stirring for another 2 h at 0 °C, precursor S14 (242 mg, 2.0 mmol, 1.0 equiv.) was added. The mixture was then allowed to return to room temperature and reacted for 17 h. The organic phase was dried and then evaporated under reduced pressure. The product ligand L125 (white solid, 387 mg, yield 69%) was purified by column chromatography.

[0203] 1 H 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).

[0204] Example 19

[0205] This embodiment applies some of the different strongly coordinated chiral tridentate PNN ligands prepared above to copper-catalyzed radical asymmetric functionalization reactions, including olefin three-component radical asymmetric azidation and alkyl halide radical asymmetric azidation. The reaction processes are shown below:

[0206]

[0207] In the three-component radical asymmetric azidation reaction of olefins, the copper source used was Cu(CH3CN)4PF6 (10 mol%), the molar ratio of strongly coordinated tripentate PNN ligand to Cu(CH3CN)4PF6 was 1.2:1, the base was K3PO4 (1.5 equiv.), the additive was KOAc (1.5 equiv.), and the solvent was a mixture of 1,4-dioxane and tetrahydrofuran (v / v=1:1, 0.050 M). The reaction temperature was 0 °C, and the reaction time was 72 h. The nuclear magnetic resonance (NMR) spectra of the products are as follows:

[0208] 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).

[0209] 13 C 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).

[0210] 19 F NMR (377 MHz, CDCl3) δ -94.58 (ddd, J = 86.8, 20.8, 13.5 Hz).

[0211] In the asymmetric azidation reaction of alkyl halide radicals, the copper source used was Cu(CH3CN)4PF6 (10.0 mol%), the molar ratio of strongly coordinated tripentate PNN ligand to Cu(CH3CN)4PF6 was 1.2:1, the base was K3PO4 (1.5 equiv.), the reaction solvent was 1,4-dioxane (0.050 M), the reaction temperature was 25 °C, and the reaction time was 12 h. The NMR spectrum of the target product is as follows:

[0212] 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).

[0213] 13 C NMR (101 MHz, CDCl3) δ 160.06, 149.45, 137.03, 122.87, 120.57,61.60, 20.12.

[0214] The analysis was performed using high performance liquid chromatography (HPLC) to determine the enantiomeric excess (ee value). The reaction results are shown in Tables 1 and 2.

[0215]

[0216] The reaction results in Table 1 show that the strongly coordinated tripentate PNN ligand exhibits excellent reaction yields and enantioselectivity in the three-component radical asymmetric azidation reaction of pyridine-containing olefins (Table 1, entries 1-2, 12-14); while the previously reported tripentate ligands containing weak coordination sites (Table 1, entries 3-5) show no reactivity, possibly due to pyridine poisoning of the catalyst. This result indicates that the strongly coordinated tripentate PNN ligand disclosed in this invention effectively solves the problem of substrate poisoning of the catalyst, demonstrating a significant advantage over previously reported known tripentate PNN ligands. Furthermore, the previously reported bisoxazoline ligand (Table 1, entry 6) and chiral bidentate phosphine ligand (Table 1, entry 7) suitable for radical asymmetric azidation reactions also show no reactivity in the three-component radical azidation reaction of pyridine-containing olefins. Replacing the amide in ligand L77 with a sulfonamide (Table 1, entry 8) or replacing the pyridine with a quinoline (Table 1, entry 9) resulted in no reactivity of the corresponding ligands, indicating that a strict structural match is required between the substrate and the ligand. Furthermore, introducing a substituent at the ortho position of the pyridine unit in ligand L77 also led to ligand deactivation, possibly because the presence of the ortho substituent affected the coordination of pyridine with Cu.

[0217] Meanwhile, the strongly coordinated tripentate PNN ligands in this invention are also well-suited for copper-catalyzed radical asymmetric azidation reactions of alkyl halides (Table 2). Strongly coordinated tripentate PNN ligands based on chiral phenethylamine and chiral Ugiamine skeletons exhibit excellent reactivity and enantioselectivity. The pyridine coordination unit in the tripentate ligand can also be replaced with an oxazoline (Table 2, entry 4), but when the substituent on the phosphine in the ligand is changed from aryl to alkyl, the enantioselectivity decreases significantly (Table 2, entries 14-15). Furthermore, for the pyridine coordination unit on the ligand, introducing a substituent at the meta or para position of the N atom does not significantly change the reactivity and enantioselectivity (Table 2, entries 6-9).

[0218] Example 20

[0219] In this embodiment, L77 was used as the ligand to investigate the asymmetric radical azidation of a series of pyridine-containing alkyl halides catalyzed by a strongly coordinated tripentate PNN ligand. The reaction process is shown below:

[0220]

[0221] In the formula, R 10 R 11 The corresponding substituents of the products are respectively.

[0222] The specific steps of the reaction were as follows: In a nitrogen-filled glove box, Cu(CH3CN)4PF6 (18.6 mg, 0.050 mmol, 0.10 equiv.), strongly coordinating tripentate PNN 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 flask containing a magnetic stir bar. 1,4-Dioxane (10 mL, 0.050 M) was then added, and the mixture was stirred to form a complex for 30 min. Azide-trimethylsilane (86.4 mg, 0.75 mmol, 1.5 equiv.) and an alkyl bromide (0.50 mmol, 1.0 equiv.) were then added. The reaction flask was removed from the glove box and reacted at 25 °C for 24-48 h (48 h for 3aa, 3ab, and 3ac, and 24 h for the remaining products). The target product was then purified by column chromatography. After NMR identification, the ee value of the purified product was determined by HPLC analysis. The product test results are as follows:

[0223] (1) Product structure: Yield: 94%; ee value: 96%; NMR spectrum information:

[0224] 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).

[0225] 13 C NMR (101 MHz, CDCl3) δ 159.23, 149.51, 136.85, 122.85, 121.26, 68.07, 28.04, 10.47.

[0226] (2) Product structure: Yield: 91%; ee value: 96%; NMR spectrum information:

[0227] 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).

[0228] 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.

[0229] (3) Product structure: Yield: 93%; ee value: 96%; NMR spectrum information:

[0230] 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).

[0231] 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.

[0232] (4) Product structure: Yield: 99%; ee value: 99%; NMR spectrum information:

[0233] 1H 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).

[0234] 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.

[0235] (5) Product structure: Yield: 98%; ee value: 96%; NMR spectrum information:

[0236] 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).

[0237] 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.

[0238] (6) Product structure: Yield: 95%; ee value: 96%; NMR spectrum information:

[0239] 1H 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).

[0240] 13 C 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.

[0241] (7) Product structure: Yield: 95%; ee value: 93%; NMR spectrum information:

[0242] 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).

[0243] 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.

[0244] (8) Product structure: Yield: 97%; ee value: 97%; NMR spectrum information:

[0245] 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).

[0246] 13 C 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.

[0247] (9) Product structure: Yield: 80%; ee value: 94%; NMR spectrum information:

[0248] 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).

[0249] 13C 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.

[0250] (10) Product structure: Yield: 93%; ee value: 98%; NMR spectrum information:

[0251] 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).

[0252] 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.

[0253] (11) Product structure: Yield: 93%; ee value: 93%; NMR spectrum information:

[0254] 1H 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).

[0255] 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.

[0256] (12) Product structure: Yield: 95%; ee value: 95%; NMR spectrum information:

[0257] 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).

[0258] 13 C NMR (101 MHz, CDCl3) δ 158.65, 149.55, 136.90, 133.39, 122.98,121.38, 118.51, 65.89, 39.12.

[0259] (13) Product structure: Yield: 92%; ee value: 95%; NMR spectrum information:

[0260] 1H 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).

[0261] 13 C NMR (101 MHz, CDCl3) δ 157.90, 148.72, 136.13, 122.78 (d, J = 11.3Hz), 36.11, 26.50.

[0262] (14) Product structure: Yield: 96%; ee value: 95%; NMR spectrum information:

[0263] 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).

[0264] 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.

[0265] (15) Product structure: Yield: 81%; ee value: 98%; NMR spectrum information:

[0266] 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).

[0267] 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).

[0268] (16) Product structure: Yield: 95%; ee value: 92%; NMR spectrum information:

[0269] 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).

[0270] 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.

[0271] (17) Product structure: Yield: 87%; ee value: 94%; NMR spectrum information:

[0272] 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).

[0273] 13 C NMR (101 MHz, CDCl3) δ 197.11, 161.75, 150.65, 143.92, 120.51,118.19, 61.39, 26.77, 20.10.

[0274] (18) Product structure: Yield: 98%; ee value: 91%; NMR spectrum information:

[0275] 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).

[0276] 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.

[0277] (19) Product structure: Yield: 94%; ee value: 84%; NMR spectrum information:

[0278] 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).

[0279] 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.

[0280] (20) Product structure: Yield: 94%; ee value: 84%; NMR spectrum information:

[0281] 1 H 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).

[0282] 13 C NMR (101 MHz, CDCl3) δ 157.1, 149.8, 137.5, 132.4, 120.1, 61.4,20.1, 18.1.

[0283] (21) Product structure: Yield: 91%; ee value: 87%; NMR spectrum information:

[0284] 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).

[0285] 13 C NMR (101 MHz, CDCl3) δ 155.1, 151.9, 137.0, 121.2, 121.0, 61.1,55.6, 20.0.

[0286] (22) Product structure: Yield: 99%; ee value: 96%; NMR spectrum information:

[0287] 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).

[0288] 13C 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.

[0289] (23) Product structure: Yield: 88%; ee value: 93%; NMR spectrum information:

[0290] 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).

[0291] 13 C NMR (101 MHz, CDCl3) δ 167.6, 160.5, 149.6, 142.8, 121.2, 61.5,61.4, 20.0.

[0292] (24) Product structure: Yield: 87%; ee value: 94%; NMR spectrum information:

[0293] 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).

[0294] 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.

[0295] The above results demonstrate that the strongly coordinated tripentate PNN ligands of this invention have broad substrate applicability in the asymmetric radical azidation of pyridine alkyl halogenated compounds.

[0296] Example 21

[0297] This embodiment leverages the excellent reactivity and enantioselectivity of strongly coordinated chiral tripentate PNN ligands in the radical asymmetric azidation of heterocyclic substrates. The strongly coordinated chiral tripentate PNN ligand L77 was applied to the synthesis of Vanin-1, and the reaction pathway is as follows:

[0298]

[0299] The specific steps for synthesis are as follows:

[0300] In a nitrogen-filled glove box, Cu(CH3CN)4PF6 (37.2 mg, 0.050 mmol, 0.10 equiv.), the 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 flask containing a magnetic stir bar. 1,4-Dioxane (20 mL, 0.050 M) was then added, and the mixture was stirred to form a complex for 30 min. Azide-trimethylsilane (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 flask was removed from the glove box, and the mixture was reacted at -10 °C for 72 h. The resulting product, B2 (138.7 mg), was purified by column chromatography. mg, 93% yield, 92% ee);

[0301] 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).

[0302] 13 C NMR (101 MHz, CDCl3) δ 155.41, 144.15, 144.03, 142.74, 59.18,19.54.

[0303] Add B2 (138.7 mg, 0.50 mmol, 1.0 equiv.), Pd / C (13.9 mg, 10 wt.%), and MeOH (5 mL, 0.10 M) to a 10 mL reaction flask containing a magnetic magnet. Replace the air in the reaction flask with hydrogen and stir at room temperature for 8 h in a hydrogen atmosphere at 15 psi. Filter the mixture through diatomaceous earth and concentrate the filtrate to obtain B3 (49.1 mg, 80% yield, 92% ee).

[0304] 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).

[0305] 13 C NMR (101 MHz, CDCl3) δ 160.72, 143.88, 143.05, 142.60, 50.39, 24.24.

[0306] 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]decene, and 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).

[0307] Example 22

[0308] This embodiment leverages the excellent reactivity and enantioselectivity of strongly coordinated chiral tripentate PNN ligands in the radical asymmetric azidation of heterocyclic substrates, applying these ligands to the synthesis of Ontazolasts. The reaction pathway is as follows:

[0309]

[0310] The specific steps for synthesis are as follows:

[0311] Using the aforementioned 3f as a 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 flask containing a magnetic ball. The air in the reaction flask was replaced with hydrogen, and the mixture was stirred at room temperature for 8 h in a hydrogen atmosphere at 15 psi. The mixture was then filtered through diatomaceous earth, and the filtrate was concentrated to obtain B6 (78.8 mg, 96% yield, 96% ee).

[0312] 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).

[0313] 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.

[0314] 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.

[0315] Example 23

[0316] This embodiment leverages the excellent reactivity and enantioselectivity of strongly coordinated chiral tripentate PNN ligands in the radical asymmetric azidation of heterocyclic substrates. The strongly coordinated chiral tripentate PNN ligand L77 was applied to the synthesis of Conulothiazole A, and the reaction pathway is as follows:

[0317]

[0318] The specific steps for synthesis are as follows:

[0319] In a nitrogen-filled glove box, 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 flask containing a magnetic stir bar. 1,4-Dioxane (10 mL, 0.050 M) was then added, and the mixture was stirred to form a complex for 30 min. Azide-trimethylsilane (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 flask was removed from the glove box, and the reaction was carried out at 25 °C for 24 h. The mixture was then purified by column chromatography to obtain B10 (69.4 mg). mg, 90% yield, 94% ee);

[0320] 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).

[0321] 13 C NMR (101 MHz, CDCl3) δ 170.30, 142.93, 119.56, 58.10, 20.41.

[0322] 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 flask containing a magnetic ball. The mixture was stirred at 50 °C for 2 h, and then 25 wt.% NH3·H2O (0.83 mL, 0.36 M) was added. The mixture was stirred at 50 °C for another 2 h, and then B11 (31.5 mg, 82% yield, 94% ee) was obtained by column chromatography.

[0323] 1H 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.

[0324] According to the procedure 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 give the final product B12, namely Conulothiazole A, which is a natural product.

[0325] Example 24

[0326] This embodiment leverages the excellent reactivity and enantioselectivity of strongly coordinated chiral tripentate PNN ligands in the radical asymmetric azidation of heterocyclic substrates. The strongly coordinated chiral tripentate PNN ligand L77 was applied to the synthesis of TTA-A8, and the reaction pathway is as follows:

[0327]

[0328] The specific steps for synthesis are as follows:

[0329] In a nitrogen-filled glove box, Cu(CH3CN)4PF6 (3.7 mg, 0.010 mmol, 0.10 equiv.), the 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 flask containing a magnetic stir bar. 1,4-Dioxane (1 mL) and dichloromethane (1 mL) were also added, and the mixture was stirred to complex for 30 min. Then, 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 flask was then removed from the glove box and incubated at -25°C. After reacting at ℃ for 72 h, B14 (17.2 mg, 70% yield, 91% ee) was purified by column chromatography.

[0330] 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).

[0331] 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).

[0332] 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 flask containing a magnetic magnet. The mixture was stirred at 50 °C for 2 h, and then 25 wt.% NH3·H2O (0.19 mL, 0.36 M) was added. The mixture was stirred at 50 °C for another 2 h. The reaction was then quenched with 0.5 mL of hydrochloric acid and impurities were extracted with 1 mL of ethyl acetate. The aqueous phase was adjusted to pH > 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (1 mL × 3). The organic phases were combined and dried over anhydrous Na2SO4. The resulting product was obtained by rotary evaporation under reduced pressure to yield B15 (12.9 mg, 84% yield, 91% ee).

[0333] 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).

[0334] 13C 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).

[0335] According to the steps in the patent (WO2009 / 54984, 2009, A1), B15 is condensed with 4-(carboxymethyl)phenylboronic acid pinacol ester to generate B16; B16 is then reacted with 2-chloro-3-methylpyrazine to finally give product B17, namely TTA-A8, which is a calcium ion channel antagonist.

[0336] In summary, Figure 1 This paper presents 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 this invention. For example... Figure 1 As shown in Figure A, the weak coordination sites of dialkylamines containing representative chiral tripenteric ligands with weak coordination sites can form metastable coordination with metals. These metastable coordination sites can stabilize high-valence metal reactive intermediates while simultaneously dissociating to form effective reactive sites. However, as... Figure 1 As shown in Figure B, for strongly coordinated substrates such as heterocycles, the strongly coordinated heteroatoms in the substrate can rapidly replace the weak coordination sites of these tripentate ligands, forming stable metal intermediates with multiple substrate coordination sites. Substrates coordinated in these metal intermediates are difficult to dissociate and cannot achieve catalytic cycling, thus causing catalyst poisoning. Therefore, tripentate ligands with metastable coordination are generally unsuitable for the asymmetric radical functionalization of strongly coordinated substrates. To address this problem, this invention proposes the development of strongly coordinated tripentate PNN ligands based on the anti-site effect. All three coordination sites of these ligands are strongly coordinated. When a strongly coordinated substrate coordinates with a metal, because the three strongly coordinated sites in the ligand form a stable chelate ring with the metal complex, the substrate cannot replace the three strongly coordinated sites in the ligand. In this case, the strongly coordinated substrate can only coordinate at the anti-site of the bridging N atom in the ligand. For example... Figure 1As shown in Figure C, the H atom on the bridging N atom in the ligand can be deprotonated under basic conditions, forming a stable σ coordination with the metal. The bridging N atom forming a σ coordination with the metal has strong electron-donating properties, while the heteroatom of the strongly coordinated substrate in the anti-position also has strong electron-donating properties. According to the anti-position principle, when both ligands in the anti-position are strong electron donors, one of the ligands is easily dissociated due to the anti-position effect. Therefore, the strongly coordinated substrate in the anti-position of the ligand-bridging N atom can dissociate due to the anti-position effect, thereby achieving catalytic cycling and preventing the formation of a stable strongly coordinated complex that would poison the catalyst. Furthermore, since all three coordination sites of the tridentate PNN ligand in this invention are strongly coordinated, this type of ligand has a better stabilizing effect on high-valence active metal intermediates. The strongly coordinated substrate is less likely to disrupt the intrinsic structure of the complex formed between the ligand and the metal, thus the corresponding catalyst has better stability during the catalytic process.

[0337] The specific structural design of the strongly coordinating chiral tridentate PNN ligand developed in this invention is as follows: Figure 2 As shown, the ligand skeleton consists of a ferrocene Ugiamine skeleton with superior facet chirality and carbon center chirality, and a simple chiral benzylamine skeleton. For the phosphorus atom coordination site in the ligand, phosphine chirality can be precisely and controllably introduced through chiral Ugiamine. The ligand contains deprotonable secondary amine coordination sites, which can form electron-rich σ coordination sites with metals, enhancing reactivity. The third strong coordination site in the ligand is pyridine or oxazoline, which can also be precisely and controllably introduced into a chiral environment. Figure 2 It can be seen that when a free radical interacts with a central metal, the sterically hindered group of the free radical will avoid contact with the sterically hindered R group in the coordination, thereby achieving chiral control in the free radical functionalization process.

[0338] The novel strongly coordinated chiral tripentate PNN ligand developed in this invention innovatively solves the problem of catalyst poisoning by strongly coordinated substrates by utilizing the trans effect. It exhibits excellent reactivity and enantioselectivity in the asymmetric radical functionalization reactions of nitrogen-containing heterocyclic compounds. Furthermore, the novel strongly coordinated tripentate PNN ligand developed in this invention is applicable to the efficient synthesis of a series of chiral nitrogen-containing heterocyclic compounds, such as the vascular non-inflammatory protein-1 inhibitor (Vanin-1), ontazolast, the natural product Conulothiazole A, and the calcium channel antagonist TTA-A8, demonstrating significant theoretical innovation and practical application value.

[0339] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A strongly coordinated PNN tridentate chiral ligand, characterized in that, It has the structure described in general formula I: In the formula, the solid line on the left represents a ferrocene or benzene ring structure; X is carbon, and Y is carbon or oxygen; the solid line on the right represents a ring formed with nitrogen and Y atoms. When X is carbon, the dashed line between X and oxygen represents the absence of this bond, meaning that the bridging group is a carbonyl group. When Y is carbon, the structure represented by the solid ring line on the right side of the general formula is pyridine or pyridine containing substituents. In pyridine containing substituents, the substituent is one of the substitutions at the 3, 4, and 5 positions, and the substituent type is one of 3,5-di-tert-butylphenyl, methyl, isopropyl, tert-butyl, benzyl, trifluoromethyl, methoxy, phenyl, 1-naphthyl, 2-naphthyl, 9-anthrayl, and 10-anthrayl. When Y is oxygen, the structure represented by the solid ring line on the right side of the general formula is (3aS,8aR)-3a,8a-dihydro-8H-indole[1,2-d]oxazole. R, R 1 R 2 Each component is independently selected from alkyl or aryl groups; wherein the alkyl group is selected from methyl, ethyl, isopropyl, cyclohexyl, tert-butyl, and benzyl; and the aryl group is selected from phenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl, 3,5-di-tert-butylphenyl, 3,5-di-tert-butyl-4-methoxy-phenyl, 1-naphthyl, 2-naphthyl, and 1-anthrayl.

2. The strongly coordinated PNN tridentate chiral ligand according to claim 1, characterized in that, Strongly coordinated PNN tridentate chiral ligands are compounds with the following structural formula: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The application of the strongly coordinated PNN tridentate chiral ligand according to claim 1 in radical asymmetric functionalization reactions, characterized in that, The application method is as follows: the product formed by the complexation reaction of a strongly coordinated PNN tridentate chiral ligand with a metal compound is used as a catalyst for the radical asymmetric functionalization reaction; the metal atom in the metal compound is at least one of Cu, Fe, Zn, Mn, Cr, Co, Au, Ag, Ni, Ti, Pt, Pd, Rh, Ru, and Ir.

4. The application of the strongly coordinated PNN tridentate chiral ligand according to claim 3 in radical asymmetric functionalization reactions, characterized in that: The metal compound is 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.

5. The application of the strongly coordinated PNN tridentate chiral ligand according to claim 3 in radical asymmetric functionalization reactions, characterized in that, The application method involves 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 and mixed to carry out a complexation reaction to obtain a catalyst solution. (2) Based on the expected product type of the free radical asymmetric functionalization reaction, alkyl halides, alkenes and TMSN3, or alkyl halides 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 crude product is purified to obtain the target product.

6. The application of the strongly coordinated PNN tridentate chiral ligand according to claim 5 in radical asymmetric functionalization reactions, characterized in that: In step (1), the base is 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)tris(pyrrolidine)phosphine; the solvent is at least one of methanol, ethanol, isopropanol, tert-butanol, 1,4-dioxane, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, toluene, and 2-methyltetrahydrofuran.

7. The application of the strongly coordinated PNN tridentate chiral ligand according to claim 5 in radical asymmetric functionalization reactions, characterized in that: In step (1), the molar ratio of the metal compound, the strongly coordinated PNN tridentate chiral ligand, and the base is 1:(1~1.5):(10~20); in step (2), when the reaction substrate is an alkyl halide, an alkene, and TMSN3, the molar ratio of the alkyl halide, the alkene, and TMSN3 is 1:(1.1~2):(1.1~2); when the reaction substrate is an alkyl halide and TMSN3, the molar ratio of the alkyl halide to TMSN3 is 1:(1.1~2).

8. The application of the strongly coordinated PNN tridentate chiral ligand according to claim 5 in radical asymmetric functionalization reactions, characterized in that: In step (1), the complexation reaction is carried out at room temperature and the reaction time is ≤1 h; in step (2), the asymmetric azidation reaction is carried out at a temperature of -20 ~ 50 ℃ and the reaction time is 2 ~ 72 h.

9. The application of the strongly coordinated PNN tridentate chiral ligand according to any one of claims 5 to 8 in radical asymmetric functionalization reactions, characterized in that, The steps using alkyl halides and TMSN3 as reaction substrates are as follows, which constitute the intermediate synthetic route for preparing an vascular non-inflammatory protein-1 inhibitor: Wherein, the alkyl halide is 2-(1-bromoethyl)pyrazine, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, and X is a halogen.

10. The application of the strongly coordinated PNN tridentate chiral ligand according to any one of claims 5 to 8 in radical asymmetric functionalization reactions, characterized in that, The steps using alkyl halides and TMSN3 as reaction substrates are as follows, which constitute the synthetic route for preparing the intermediate of onzolast: Wherein, the alkyl halide is 2-(1-chloro-2-cyclohexylethyl)pyridine, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, and X is a halogen.

11. The application of the strongly coordinated PNN tridentate chiral ligand according to any one of claims 5 to 8 in radical asymmetric functionalization reactions, characterized in that, The steps using alkyl halides and TMSN3 as reaction substrates are as follows, which constitute the intermediate synthetic route for preparing the natural product Conulothiazole A: Wherein, the alkyl halide is 2-(1-bromoethyl)-1,3-thiazole, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, and X is a halogen.

12. The application of the strongly coordinated PNN tridentate chiral ligand according to any one of claims 5 to 8 in radical asymmetric functionalization reactions, characterized in that, The steps using alkyl halides and TMSN3 as reaction substrates are as follows, which constitute the intermediate synthetic route for the bioactive molecule TTA-A8: Wherein, the alkyl halide is 2-(1-2-(1-bromoethyl)-5-(2,2,2-trifluoroethoxy)pyridine, the ligand L* is any one of the PNN tridentate ligands described in claim 1 or 2, [Cu] is a metal compound, and X is a halogen.

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