Ferrocenyl biaryl chiral monophosphine ligand, preparation method and application

Abstract

The invention provides a ferrocenyl biaryl chiral monophosphine ligand as well as a preparation method and application thereof, provides a novel ferrocenyl structure chiral monophosphine ligand, and further provides a preparation method of the novel ferrocenyl structure chiral monophosphine ligand and a catalyst prepared from the novel ferrocenyl structure chiral monophosphine ligand. The novel chiral monophosphine ligand with the ferrocene structure can be applied to an organic synthesis catalytic reaction, particularly a C-H arylation coupling reaction of pyridine benzyl, pyridine benzyl aryl substituted compounds with a series of structures can be rapidly and diversity synthesized, and the chiral monophosphine ligand with the ferrocene structure has important significance on screening of new drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of metal organic catalysis, and in particular relates to a ferrocenyl biaryl chiral monophosphine ligand, a preparation method and application thereof. Background Art

[0002] In asymmetric catalytic reactions involving transition metals, transition metal catalysts play a vital role, and their activity and selectivity are directly affected by the electronic and stereo effects of the chiral ligands coordinated with them. The development of chiral phosphine ligands has made outstanding contributions to the development of asymmetric catalysis, especially in asymmetric hydrogenation reactions, where they play an indispensable role. Nowadays, chiral phosphine ligands are not only widely used in asymmetric hydrogenation reactions, but also promote the development of various types of transition metal-catalyzed asymmetric reactions, injecting important impetus into the basic and applied research of asymmetric catalysis. Compared with chiral diphosphine ligands, chiral monophosphine ligands have developed relatively slowly. They can catalyze various types of reactions when coordinated with metals, including allylic substitution reactions, dearomatization reactions, Heck reactions, cross-coupling reactions, C−H bond functionalization reactions, addition reactions, hydrogenation reactions, etc. According to literature research (V. Snieckus et al. Angew. Chem. Int. Ed. 2012, 51 ,5062-5085.), palladium-catalyzed coupling reactions are one of the most commonly used reactions in drug process synthesis, such as Suzuki-Miyaura coupling, Buchwald-Hartwig amination reaction, Sonogashira coupling, etc. These reactions are used in drug production almost every day.

[0003] Monophosphine ligands were among the first ligands used to explore asymmetric catalysis. In the early 1970s, Knowles (Knowles, WS et al. J. Chem. Soc., Chem. Commun. 1972, 10-11.) reported rhodium-catalyzed asymmetric hydrogenation of dehydrogenated amino acids, using the P-chiral monophosphine ligand CAMP to obtain up to 88% ee (enantiomeric excess). Morrison (Morrison, JD et al. J. Am. Chem. Soc. 1971, 93 , 1301-1303.) developed NMDPP (neomenthyldiphenylphosphine) monophosphine ligand, which is effective in rhodium metal-catalyzed ( E )- β -methylcinnamic acid hydrogenation reaction provides 61% ee. Professor Buchwald developed an axial chiral monophosphine ligand KenPhos with a binaphthyl skeleton (SL Buchwald et al. J. Am. Chem. Soc .2000, 122 ,12051.); Professor Feringa developed the axial chiral monophosphine ligand Monophos with a binaphthyl skeleton phosphoramidite structure (SE Reisman et al. Tetrahedron .2014, 70 , 3259-3265.); Professor Zhang Junliang developed the phosphine ligand Ming-phos with a tert-butylsulfenamide chiral auxiliary group (J. Zhang et al. Angew. Chem. Int. Ed .2021, 60 ,18542-18546.); Professor Tang Wenjun developed the sterically hindered electron-rich chiral monophosphine ligand BIDIME with a rigid structure of a benzophosphine oxide five-membered heterocyclic ring (W. Tang et al. Angew. Chem. Int. Ed .2010, 49 , 5879-5883.) They have played an important role in the development of asymmetric coupling reactions.

[0004] In summary, although chiral monophosphine ligands have developed rapidly in recent years, they are still extremely lacking compared to the rapid development of transition metal catalysis. The existing phosphine ligands still cannot meet the requirements of high reactivity and excellent selectivity of transition metal catalysis. Therefore, it is urgent to develop efficient chiral monophosphine ligands with novel structures, low cost and easy availability. Summary of the invention

[0005] The first object of the present invention is to provide a ferrocenyl biaryl chiral monophosphine ligand.

[0006] To this end, the above-mentioned purpose of the present invention is achieved through the following technical solutions: A ferrocenyl biaryl chiral monophosphine ligand, the structural formula of the ferrocenyl biaryl chiral monophosphine ligand is shown as follows: ;

[0007] Wherein, R1, R2, and R3 are each independently selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C4-C15 heteroaryl, C10-C30 aryl, and halogen, wherein the halogen is fluorine, chlorine, bromine, or iodine; R4 and R5 are each independently selected from a C1-C10 alkyl group, a C3-C8 cycloalkyl group, and a C4-C30 aryl group.

[0008] While adopting the above technical solutions, the present invention may also adopt or combine the following technical solutions: As a preferred technical solution of the present invention: the ferrocenyl biaryl chiral monophosphine ligand is selected from one of the following compounds: .

[0009] As a preferred technical solution of the present invention: the ferrocenyl biaryl chiral monophosphine ligand is prepared by reacting compound F with compound G: .

[0010] As a preferred technical solution of the present invention: Compound F is selected from one of the following compounds: .

[0011] As a preferred technical solution of the present invention: the compound G is selected from one of the following compounds: .

[0012] As a preferred technical solution of the present invention: the compound F is prepared by reacting the compound D with the compound E: .

[0013] As a preferred technical solution of the present invention: the compound E is selected from one of the following compounds: .

[0014] As a preferred technical solution of the present invention: the compound D is prepared by reacting the compound C with pinacol: .

[0015] As a preferred technical solution of the present invention: the compound C is prepared by reacting compound B with trimethyl borate: .

[0016] As a preferred technical solution of the present invention: the compound B is composed of compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate is prepared by reaction: .

[0017] The second object of the present invention is to provide a method for preparing the ferrocenyl biaryl chiral monophosphine ligand as described above, wherein the ferrocenyl biaryl chiral monophosphine ligand is prepared by reacting compound F with compound G: .

[0018] While adopting the above technical solutions, the present invention may also adopt or combine the following technical solutions: As a preferred technical solution of the present invention: the compound F is prepared by reacting the compound D with the compound E: .

[0019] As a preferred technical solution of the present invention: the compound D is prepared by reacting the compound C with pinacol: .

[0020] As a preferred technical solution of the present invention: the compound C is prepared by reacting compound B with trimethyl borate: .

[0021] As a preferred technical solution of the present invention: the compound B is composed of compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate is prepared by reaction: .

[0022] The third object of the present invention is to provide a catalyst, wherein the catalyst is prepared from the ferrocenyl biaryl chiral monophosphine ligand as described above.

[0023] Another object of the present invention is to provide the use of the ferrocenyl biaryl chiral monophosphine ligand as described above in organic synthesis catalysis.

[0024] While adopting the above technical solutions, the present invention may also adopt or combine the following technical solutions: As a preferred technical solution of the present invention: the organic synthesis catalytic reaction is a CH arylation coupling reaction at the benzyl position of pyridine.

[0025] The invention provides a ferrocenyl biaryl chiral monophosphine ligand, a preparation method and application thereof, and provides a novel ferrocenyl structure chiral monophosphine ligand. In addition, the invention also provides a preparation method of the novel ferrocenyl structure chiral monophosphine ligand, and a catalyst prepared by the novel ferrocenyl structure chiral monophosphine ligand. The novel ferrocenyl structure chiral monophosphine ligand can be applied to organic synthesis catalytic reactions, especially CH arylation coupling reactions at the pyridine benzyl position, and a series of structures of pyridine benzyl position aryl substituted compounds can be quickly and diversely synthesized, which is of great significance for new drug screening. DETAILED DESCRIPTION

[0026] The present invention provides a ferrocenyl biaryl chiral monophosphine ligand, which is selected from one of the following compounds: .

[0027] The ferrocenyl biaryl chiral monophosphine ligand is obtained by a nucleophilic substitution reaction between compound F and compound G in the presence of a tert-butyl lithium reagent.

[0028] Specifically, compound F is first subjected to a lithiation reaction, and then subjected to nucleophilic substitution with compound G, followed by borane protection and reduction to obtain a ferrocenyl biaryl chiral monophosphine ligand; Alternatively, the compound F is first subjected to a lithiation reaction, and then subjected to a nucleophilic substitution reaction with the compound G, followed by oxidation and reduction with hydrogen peroxide to obtain a ferrocenyl biaryl chiral monophosphine ligand.

[0029] Wherein: the lithiation reaction solvent is tetrahydrofuran; the lithiation reaction temperature is -78°C, and the reaction time is 15 minutes; The molar ratio of compound F and tert-butyl lithium reagent is 1:1.2; The solvent for the nucleophilic substitution reaction is tetrahydrofuran; the temperature for the nucleophilic substitution reaction is -78°C and the reaction is slowly restored to room temperature, and the reaction time is 1 hour at -78°C and then 2 hours at room temperature; The molar ratio of compound F to compound G is 1:1.5.

[0030] Compound F, that is, coupling compound F is selected from one of the following compounds: .

[0031] In compound G, R4 and R5 substituents are alkyl and aryl groups.

[0032] Compound G is selected from one of the following compounds: .

[0033] The reaction temperature with BH3·THF reagent is -78°C and slowly recovered to room temperature, the reaction time is -78°C for 0.5 hour, and then recovered to room temperature for 2 hours; the molar ratio of compound F and BH3·THF reagent is 1:3; the reduction reaction solvent is toluene; the reduction reaction temperature is 60°C, and the reaction time is 12 hours; The molar ratio of compound F to the base triethylenediamine reagent used in the reaction is 1:3 The reaction temperature with the hydrogen peroxide reagent is 0°C and slowly recovered to room temperature, the reaction time is 0°C for 0.5 hours, and then recovered to room temperature for 1 hour; the molar ratio of compound F to the hydrogen peroxide reagent is 1:4; the reduction reaction solvent is toluene; the reduction reaction temperature is 110°C, and the reaction time is 12 hours; the molar ratio of compound F to the reducing agent trichlorosilane reagent used in the reaction is 1:10, and the molar ratio of compound F to the base triethylamine reagent used in the reaction is 1:40.

[0034] Compound F is obtained by intermolecular coupling reaction of compound D and compound E in an organic solvent with transition metal palladium as a catalyst and the participation of a monophosphine ligand and a base.

[0035] Wherein: the solvent is tetrahydrofuran, N , N- At least one of dimethylformamide, 1,4-dioxane, dimethyl sulfoxide and toluene, preferably toluene; the reaction temperature is 110°C and the reaction time is 24 hours; The molar ratio of compound D to aryl iodide E is 1:1.5, the molar ratio of compound D to palladium catalyst is 1:0.04, the molar ratio of compound D to phosphine ligand is 1:0.04, and the molar ratio of compound D to alkaline reagent is 1:2; the palladium catalyst is palladium acetate; In the aryl iodide E, the R3 substituent is an alkyl group or an aryl group; The aryl iodide E is selected from one of the following compounds: .

[0036] The phosphine ligand is selected from one of the following compounds: .

[0037] The base is at least one of potassium phosphate, cesium fluoride, cesium carbonate, potassium hydroxide, and sodium hydroxide.

[0038] After the reaction is completed, the final product is separated by column chromatography, and the eluent of the column chromatography is a mixed solvent of ethyl acetate / dichloromethane, and the percentage of ethyl acetate is 8-20%.

[0039] Compound D is prepared by reacting compound C with pinacol.

[0040] Wherein: the reaction solvent is dichloromethane.

[0041] The reaction temperature was room temperature and the reaction time was 16 hours.

[0042] The molar ratio of compound C to the pinacol reagent is 1:4, and the molar ratio of compound C to the water absorbing agent anhydrous magnesium sulfate reagent used in the reaction is 1:10.

[0043] Compound C is obtained by a nucleophilic reaction of compound B and trimethyl borate in the presence of a lithium diisopropylamide reagent.

[0044] Specifically, compound B is first subjected to a lithiation reaction, and then subjected to a nucleophilic reaction to obtain compound C; Wherein: the reaction solvent is tetrahydrofuran.

[0045] The lithiation reaction temperature was -78°C and the reaction time was 0.5 hours.

[0046] The molar ratio of compound B to lithium diisopropylamide reagent is 1:2.

[0047] The nucleophilic substitution reaction temperature is -78°C and then slowly recovered to room temperature. The reaction time is 0.5 hour at -78°C and then 12 hours at room temperature.

[0048] The molar ratio of compound B to trimethyl borate reagent is 1:3.

[0049] Compound B is composed of compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate is obtained by a nucleophilic reaction in the presence of tert-butyl lithium reagent; Specifically, compound A is first subjected to a lithiation reaction, and then subjected to a nucleophilic reaction to obtain compound B; Wherein: the reaction solvent is tetrahydrofuran; The temperature of the lithiation reaction is from -78°C to room temperature, and the reaction procedure is to react at -78°C for 1.5 hours and then return to room temperature for 1 hour; The molar ratio of compound A to tert-butyl lithium reagent is 1:2, and the molar ratio of compound A to potassium tert-butoxide used as a base in the reaction is 1:0.12; The reaction temperature of the nucleophilic reaction was -55°C and the reaction time was 1 hour.

[0050] Compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate reagent has a molar ratio of 1:1.

[0051] The second aspect of the present invention is to provide a method for preparing the ferrocenyl biaryl chiral monophosphine ligand as described above, wherein the ferrocenyl biaryl chiral monophosphine ligand is obtained by a nucleophilic reaction of compound F and compound G in the presence of a tert-butyl lithium reagent.

[0052] Specifically, compound F is first subjected to a lithiation reaction, and then subjected to nucleophilic substitution with compound G, followed by borane protection and reduction to obtain a ferrocenyl biaryl chiral monophosphine ligand; Alternatively, the compound F is first subjected to a lithiation reaction, and then subjected to a nucleophilic substitution reaction with the compound G, followed by oxidation and reduction with hydrogen peroxide to obtain a ferrocenyl biaryl chiral monophosphine ligand.

[0053] Wherein: the lithiation reaction solvent is tetrahydrofuran; the lithiation reaction temperature is -78°C, and the reaction time is 15 minutes; The molar ratio of compound F and tert-butyl lithium reagent is 1:1.2; The solvent for the nucleophilic substitution reaction is tetrahydrofuran; The nucleophilic substitution reaction temperature is -78°C and slowly recovered to room temperature. The reaction time is -78°C for 1 hour and then recovered to room temperature for 2 hours. The molar ratio of compound F to compound G is 1:1.5; Compound F, that is, coupling compound F is selected from one of the following compounds: .

[0054] In compound G, R4 and R5 substituents are alkyl and aryl groups.

[0055] Compound G is selected from one of the following compounds: .

[0056] The reaction temperature with BH3·THF reagent is -78°C and slowly recovered to room temperature, the reaction time is -78°C for 0.5 hour, and then recovered to room temperature for 2 hours; the molar ratio of compound F and BH3·THF reagent is 1:3; the reduction reaction solvent is toluene; the reduction reaction temperature is 60°C, and the reaction time is 12 hours; The molar ratio of compound F to the base triethylenediamine reagent used in the reaction is 1:3.

[0057] The reaction temperature with the hydrogen peroxide reagent is 0°C and slowly recovered to room temperature, the reaction time is 0°C for 0.5 hours, and then recovered to room temperature for 1 hour; the molar ratio of compound F to the hydrogen peroxide reagent is 1:4; the reduction reaction solvent is toluene; the reduction reaction temperature is 110°C, and the reaction time is 12 hours; the molar ratio of compound F to the reducing agent trichlorosilane reagent used in the reaction is 1:10, and the molar ratio of compound F to the base triethylamine reagent used in the reaction is 1:40; Compound F is obtained by intermolecular coupling reaction of compound D and compound E in an organic solvent with transition metal palladium as a catalyst and the participation of a monophosphine ligand and a base.

[0058] Wherein: the solvent is tetrahydrofuran, N , N - at least one of dimethylformamide, 1,4-dioxane, dimethyl sulfoxide and toluene, preferably toluene; the reaction temperature is 110°C and the reaction time is 24 hours; The molar ratio of compound D to aryl iodide E is 1:1.5, the molar ratio of compound D to palladium catalyst is 1:0.04, the molar ratio of compound D to phosphine ligand is 1:0.04, and the molar ratio of compound D to alkaline agent is 1:2; In the aryl iodide E, the R3 substituent is an alkyl group or an aryl group; The aryl iodide E is selected from one of the following compounds: .

[0059] The phosphine ligand is selected from one of the following compounds: .

[0060] The palladium catalyst is palladium acetate; The base is at least one of potassium phosphate, cesium fluoride, cesium carbonate, potassium hydroxide, and sodium hydroxide.

[0061] After the reaction is completed, the final product is separated by column chromatography, and the eluent of the column chromatography is a mixed solvent of ethyl acetate / dichloromethane, and the percentage of ethyl acetate is 8-20%.

[0062] Compound D is prepared by reacting compound C with pinacol.

[0063] Wherein: the reaction solvent is dichloromethane.

[0064] The reaction temperature was room temperature and the reaction time was 16 hours.

[0065] The molar ratio of compound C to the pinacol reagent is 1:4, and the molar ratio of compound C to the water absorbing agent anhydrous magnesium sulfate reagent used in the reaction is 1:10.

[0066] Compound C is obtained by a nucleophilic reaction of compound B and trimethyl borate in the presence of a lithium diisopropylamide reagent.

[0067] Specifically, compound B is first subjected to a lithiation reaction, and then subjected to a nucleophilic reaction to obtain compound C; Wherein: the reaction solvent is tetrahydrofuran.

[0068] The lithiation reaction temperature was -78°C and the reaction time was 0.5 hours.

[0069] The molar ratio of compound B to lithium diisopropylamide reagent is 1:2.

[0070] The nucleophilic substitution reaction temperature is -78°C and then slowly recovered to room temperature. The reaction time is 0.5 hour at -78°C and then 12 hours at room temperature.

[0071] The molar ratio of compound B to trimethyl borate reagent is 1:3.

[0072] Compound B is composed of compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate is obtained by a nucleophilic reaction in the presence of tert-butyl lithium reagent; Specifically, compound A is first subjected to a lithiation reaction, and then subjected to a nucleophilic reaction to obtain compound B; Wherein: the reaction solvent is tetrahydrofuran; The temperature of the lithiation reaction is from -78°C to room temperature, and the reaction procedure is to react at -78°C for 1.5 hours and then return to room temperature for 1 hour; The molar ratio of compound A to tert-butyl lithium reagent is 1:2, and the molar ratio of compound A to potassium tert-butoxide used as a base in the reaction is 1:0.12; The reaction temperature of the nucleophilic reaction was -55°C and the reaction time was 1 hour.

[0073] Compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate reagent has a molar ratio of 1:1.

[0074] The third aspect of the present invention is to provide a catalyst, wherein the catalyst is prepared from the ferrocenyl biaryl chiral monophosphine ligand as described above.

[0075] Another aspect of the present invention is to provide the use of the ferrocenyl biaryl chiral monophosphine ligand as described above in an organic synthesis catalytic reaction.

[0076] Preferably, the organic synthesis catalytic reaction is an arylation coupling reaction at the benzyl position of pyridine. Specifically, in an inert gas atmosphere, pyridine derivative H and aryl bromide I are used as raw materials, Zn(TMP)2 is used as a base, 1,4-dioxane is used as a solvent, and transition metal palladium is used as a catalyst. Under the action of a phosphine ligand, a Negishi coupling intermolecular reaction occurs in an organic solvent to obtain compound J: .

[0077] Among them, R6~R 15 Each is independently selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C4-C15 heteroaryl, C10-C30 aryl, halogen, wherein the halogen is fluorine, chlorine, bromine, or iodine; The coupling compound J is selected from one of the following compounds: .

[0078] Wherein, the solvent is tetrahydrofuran, N , N - at least one of dimethylformamide, 1,4-dioxane, dimethyl sulfoxide and toluene, preferably 1,4-dioxane, the reaction temperature is 50°C, and the reaction time is 24 hours; The molar ratio of the pyridine derivative H to the aryl bromide I is 1:1, the molar ratio of the compound H to the palladium reagent is 1:0.04, the molar ratio of the compound H to the phosphine ligand is 1:0.04, and the molar ratio of the compound H to Zn(TMP)2 is 2:1.

[0079] The pyridine derivative H is preferably: .

[0080] The aryl bromide I is selected from one of the following compounds: .

[0081] The palladium catalyst is preferably palladium acetate.

[0082] The phosphine ligand is preferably: .

[0083] After the reaction is completed, the final product is separated by column chromatography, and the eluent of the column chromatography is a mixed solvent of ethyl acetate / dichloromethane, and the percentage of ethyl acetate is 8-20%.

[0084] The present invention is described in further detail with reference to specific examples.

[0085] Embodiments 1 to 8 Examples 1 to 8 In an inert gas atmosphere, ferrocene sulfoxide compound D and aryl iodide E-1 are used as raw materials, sodium hydroxide is used as a base, toluene is used as a solvent, and palladium acetate is used as a catalyst. Suzuki coupling reaction occurs under the action of different phosphine ligands. The reaction formula is as follows:

[0086] Under nitrogen atmosphere, D (0.1 mmol), E-1 (0.15 mmol), sodium hydroxide (0.2 mmol), palladium acetate (0.004 mmol), and phosphine ligand (0.004 mmol) were added to a 10 mL reaction tube, and solvent toluene (1 mL) was added. After stirring at 110 ° C for 24 hours, trimethoxybenzene (0.1 mmol) was added, and the solvent was directly distilled off under reduced pressure. The yield was calculated by nuclear magnetic resonance, and the results are shown in Table 1. In the table, the nuclear magnetic yield uses 1,3,5-trimethoxybenzene as an internal standard.

[0087]

[0088] Table 1: Effect of phosphine ligand on the reaction

[0089] Embodiments 9 to 13 Examples 9 to 13: Using ferrocene sulfoxide compound D and aryl iodide E-1 as raw materials, sodium hydroxide as base, toluene as solvent, L8 as phosphine ligand, palladium acetate as catalyst, Suzuki coupling reaction occurred under the action of 5 different bases, and the reaction formula is as follows:

[0090] Table 2: Effect of base on reaction

[0091] Under nitrogen atmosphere, D (0.1 mmol), E-1 (0.15 mmol), base (0.2 mmol), palladium acetate (0.004 mmol), phosphine ligand (0.004 mmol) were added to a 10 mL reaction tube, and solvent toluene (1 mL) was added. After stirring at 110 ° C for 24 hours, trimethoxybenzene (0.1 mmol) was added, and the solvent was directly distilled off under reduced pressure. The yield was calculated by nuclear magnetic resonance, and the results are shown in Table 2. In the table, the nuclear magnetic yield uses 1,3,5-trimethoxybenzene as an internal standard.

[0092] Embodiments 14 to 18 In Examples 14 to 18, ferrocene sulfoxide compound D and aryl iodide E-1 were used as raw materials, sodium hydroxide was used as a base, L8 was used as a phosphine ligand, and palladium acetate was used as a catalyst. Suzuki coupling reaction occurred in the presence of 5 different solvents. The reaction formula is as follows:

[0093] Under nitrogen atmosphere, D (0.1 mmol), E-1 (0.15 mmol), sodium hydroxide (0.2 mmol), palladium acetate (0.004 mmol), and phosphine ligand (0.004 mmol) were added to a 10 mL reaction tube, and solvent (1 mL) was added. After stirring at 110 ° C for 24 hours, trimethoxybenzene (0.1 mmol) was added, and the solvent was directly distilled off under reduced pressure. The yield was calculated by nuclear magnetic resonance, and the results are shown in Table 3. In the table, the nuclear magnetic yield uses 1,3,5-trimethoxybenzene as an internal standard.

[0094] Table 3: Effect of solvent on reaction

[0095] Embodiment 19 Take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add A (40 mmol), potassium tert-butoxide (4.8 mmol) and 335 mL of distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After cooling the solution to -78°C with a dry ice ethanol bath, add tert-butyl lithium (80 mmol) dropwise through a syringe, stir for 30 minutes, remove the dry ice ethanol bath, slowly return to room temperature, and stir for 1 hour. Then cool the solution to -55°C with a dry ice methanol bath. Slowly (about 30 minutes) transfer the solution through a double-ended syringe to a container containing (1 R ,2 S ,5 R )-(-)-Menthol( S )-p-toluenesulfinate (40 mmol) was added to a cooled (-55°C) solution (205 mL of distilled tetrahydrofuran) and continued to stir for 1 hour, slowly returned to room temperature and stirred for 1 hour, and then quenched with 50 mL of saturated aqueous ammonium chloride solution. The reaction mixture was extracted three times with dichloromethane and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Compound B was obtained by separation and purification by silica gel column chromatography.

[0096]

[0097] Orange solid, 80% ee, 76% yield, (40 mmol, 9.9 g product), eluent: petroleum ether containing 10%-20% ethyl acetate.

[0098] Then, it was recrystallized twice in petroleum ether (25 ml), ethyl acetate (20 ml) and dichloromethane (15 ml) (-20°C) to obtain 9 g of crystals with 99.9% ee value and 90% yield. The NMR characterization data of the product are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.57 - 7.48 (m, 2H), 7.24 (s, 3H), 4.61 (dt, J = 2.7, 1.4 Hz, 1H), 4.45 - 4.23 (m, 8H), 2.37 (s, 3H).

[0099] HPLC conditions: Daicel Chiralpak OD-H column, hexane / i PrOH (90 / 10),0.5 mL / min, UV = 245 nm: t major = 26.7 min, t minor = 22.0 min.

[0100] Embodiment 20 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add compound B (44.7 mmol) and 520 mL of freshly distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, lithium diisopropylamide (53.6 mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, and then trimethyl borate (134 mmol) is slowly added through a syringe. After stirring at -78°C for 20 minutes, slowly return to room temperature and stir for 1 hour, then quench with 300 mL of saturated ammonium chloride aqueous solution. The reaction mixture is extracted with dichloromethane three times, the aqueous phase is combined, and the organic phase is dried over anhydrous sodium sulfate and filtered, and the solvent is removed by distillation under reduced pressure to obtain compound C.

[0101]

[0102] Yellow powder, 99% yield, (44.7 mmol, 16.5 g product), slurry purification to remove trace impurities (methyl tert-butyl ether: n-hexane = 3:1). The product NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl3)δ 7.39 (d, J = 7.9 Hz, 2H), 7.20 (d, J = 7.8Hz, 2H), 4.84 (d, J = 1.9 Hz, 1H), 4.68 (s, 1H), 4.61 (s, 1H), 4.46 (s, 5H),2.33 (s, 3H).

[0103] Embodiment 21 Take a reaction bottle and add a stirring bar to dry it. Add compound C (38 mmol), pinacol (152 mmol) and 420 mL of dry dichloromethane to the reaction bottle and stir to dissolve. Then add dried anhydrous magnesium sulfate (27.2 mmol) and stir to react for 16 hours. After the reaction is completed, add 300 mL of water to wash away the remaining pinacol. The mixture is extracted with dichloromethane three times, and the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation to obtain compound D.

[0104]

[0105] Yellow powder, 93% yield, (38 mmol, 14 g product), slurry purification (n-hexane: ethyl acetate = 10:1). The product NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl3). δ 8.16 (d,J = 7.8 Hz, 2H), 7.73 (d, J = 7.7 Hz,2H), 5.03 (d, J = 2.4 Hz, 1H), 4.81 (dd, J = 5.1, 2.7 Hz, 1H), 4.51 (s, 5H), 4.37(d, J = 2.5 Hz, 1H), 2.82 (s, 3H), 1.78 (s, 12H).

[0106] 13 C NMR (101 MHz, CDCl3). δ 141.2, 140.7, 129.2, 125.7, 99.2, 83.7,77.4, 77.4, 74.7, 72.7, 71.5, 70.8, 70.1, 24.9, 24.8, 24.8, 21.5.

[0107] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 451.1196, found: 451.1183.

[0108] Embodiment 22 Under nitrogen atmosphere, D (2.22 mmol), E-1 (3.33 mmol), sodium hydroxide (4.44 mmol), palladium acetate (0.09 mmol), phosphine ligand (0.09 mmol) were added to a 50 mL reaction tube, and solvent (22 mL) was added. After stirring at 110°C for 24 hours, the mixture was filtered through diatomaceous earth and washed with dichloromethane. The solvent was removed by distillation under reduced pressure from the filtrate, and the mixture was separated and purified by silica gel column chromatography to obtain compound F-1.

[0109]

[0110] Brown-yellow powder, 80% yield, (2.2 mmol, 817 mg product), eluent: dichloromethane containing 10% - 20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl3). δ 7.81 (d, J = 7.7 Hz, 2H), 7.38 (d, J = 7.7 Hz,2H), 7.28 (d, J= 8.3 Hz, 1H), 6.63 (d, J = 8.4 Hz, 2H), 4.74 (d, J = 2.7 Hz, 1H),4.35 (d, J = 2.8 Hz, 1H), 4.07 (d, J = 2.6 Hz, 1H), 4.03 (s, 5H), 3.87 (s, 6H), 2.47 (s, 3H).

[0111] 13 C NMR (101 MHz, CDCl3). δ 158.3, 141.5, 141.1, 129.1, 128.9, 125.5,111.5, 104.3, 94.6, 80.3, 74.4, 70.7, 68.1, 66.7, 55.6, 21.5.

[0112] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 461.0868, found: 461.0856.

[0113] Embodiment 23 Under nitrogen atmosphere, D (2.22 mmol), E-2 (3.33 mmol), sodium hydroxide (4.44 mmol), palladium acetate (0.09 mmol), phosphine ligand (0.09 mmol) were added to a 50 mL reaction tube, and solvent (22 mL) was added. After stirring at 110°C for 24 hours, the mixture was filtered through diatomaceous earth and washed with dichloromethane. The solvent was removed by distillation under reduced pressure from the filtrate, and the mixture was separated and purified by silica gel column chromatography to obtain compound F-2.

[0114]

[0115] Brown-yellow powder, 58% yield, (2.2 mmol, 610 mg product), eluent: dichloromethane containing 10% - 20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl3). δ 7.80 (d, J = 7.9 Hz, 2H), 7.37 (d, J= 7.8 Hz, 2H), 6.46 (s, 2H), 4.73 (s, 1H), 4.33 (s, 1H), 4.03 (s, 6H), 3.85 (s, 6H), 2.47 (s, 3H), 2.38 (s, 3H).

[0116] 13 C NMR (101 MHz, CDCl3). δ 158.0, 141.5, 141.1, 139.3, 129.1, 125.5,108.4, 105.3, 94.2, 80.6, 74.5, 70.6, 68.0, 66.5, 55.6, 22.1, 21.5.

[0117] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 475.1025, found: 475.1017.

[0118] Embodiment 24 Under nitrogen atmosphere, D (2.22 mmol), E-3 (3.33 mmol), sodium hydroxide (4.44 mmol), palladium acetate (0.09 mmol), phosphine ligand (0.09 mmol) were added to a 50 mL reaction tube, and solvent (22 mL) was added. After stirring at 110°C for 24 hours, the mixture was filtered through diatomaceous earth and washed with dichloromethane. The solvent was removed by distillation under reduced pressure from the filtrate, and the mixture was separated and purified by silica gel column chromatography to obtain compound F-3.

[0119]

[0120] Brown-yellow powder, 46% yield, (2.2 mmol, 550 mg product), eluent: dichloromethane containing 10%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CDCl3). δ 7.82 (d, J = 7.7 Hz, 2H), 7.63 (d, J = 7.6 Hz,2H), 7.47 (d, J = 15.0 Hz, 2H), 7.39 (d, J= 7.7 Hz, 3H), 6.82 (s, 2H), 4.79 (s,1H), 4.38 (s, 1H), 4.07 (s, 6H), 3.94 (s, 6H), 2.48 (s, 3H).

[0121] 13 C NMR (101 MHz, CDCl3). δ 158.4, 142.3, 141.5, 141.3, 141.1, 129.2,128.8, 127.6, 127.2, 125.5, 110.6, 103.6, 94.6, 80.2, 74.5, 70.8, 68.2, 66.9,55.8, 21.6.

[0122] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 537.1181, found: 537.1171.

[0123] Embodiment 25 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add compound F-1 (1.1 mmol) and 22 mL of redistilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, tert-butyl lithium reagent (1.76 mmol) is added dropwise through a syringe and stirred for 30 minutes. Then compound G-2 (2.75mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, then slowly return to room temperature and stir for 2 hours. Then the reaction solution is cooled to 0°C with an ice water bath, hydrogen peroxide (4.4 mmol) is added dropwise through a syringe, and slowly returned to room temperature and stirred for 1 hour. Then quench with 30 mL of saturated sodium thiosulfate aqueous solution. The reaction mixture is extracted with dichloromethane three times, and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation. The oxidation product is separated and purified by silica gel column chromatography. Eluent: methanol containing 1%-3% ethyl acetate.

[0124] Then, take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add the oxidation product, triethylamine (44 mmol) and 22 mL of toluene to the Shrek bottle, and stir to dissolve. Then cool the reaction solution to 0°C with an ice-water bath, add trichlorosilane (11 mmol) dropwise through a syringe, heat to 110°C and stir for 12 hours. Then quench with 30 mL of saturated sodium carbonate aqueous solution at -30°C. The reaction mixture is extracted three times with dichloromethane and the organic phase is combined, dried over anhydrous sodium sulfate and filtered, the solvent is distilled off under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound (I)-1.

[0125]

[0126] Yellow powder, 45% yield, (1.1 mmol, 216 mg product), eluent: petroleum ether containing 10%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2). δ 7.21 (t, J = 8.3 Hz, 1H), 6.57 (s, 2H), 4.62(dq, J = 2.7, 1.3 Hz, 1H), 4.34 (t, J = 2.5 Hz, 1H), 4.31 - 4.28 (m, 1H), 4.14(d, J = 1.0 Hz, 5H), 3.88 (s, 3H), 3.66 (s, 3H), 2.24 (ddt, J = 14.1, 11.8, 6.9Hz, 1H), 1.61 (dt, J = 13.9, 6.9 Hz, 1H), 1.47 (ddd, J = 16.0, 7.4, 1.2 Hz, 3H),1.34 - 1.26 (m, 3H), 0.62 (ddd, J = 14.1, 7.0, 1.0 Hz, 3H), 0.47 (ddd, J = 10.6,6.9, 1.3 Hz, 3H).

[0127] 13C NMR (101 MHz, CD2Cl2). δ 127.8, 114.6, 103.9, 84.4, 80.5, 72.5,72.4, 70.2, 70.2, 69.8, 67.1, 24.8, 24.7, 24.6, 24.5, 22.6, 22.4, 20.1, 19.9,18.9, 18.9, 18.6, 18.5.

[0128] 31 P NMR (162 MHz, CD2Cl2)δ -3.73.

[0129] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 439.1484, found: 439.1467.

[0130] Embodiment 26 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add F-1 compound (0.65 mmol) and 13 mL of freshly distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, tert-butyl lithium reagent (1.04 mmol) is added dropwise through a syringe and stirred for 30 minutes. Compound G-3 (1.63 mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, then slowly return to room temperature and stir for 2 hours. Then the solution is cooled to -78°C with a dry ice ethanol bath, BH3·THF (1.95 mmol) is added dropwise through a syringe, slowly returned to room temperature and stirred for 2 hours. Then quench with 30 mL of saturated ammonium chloride aqueous solution. The reaction mixture is extracted with dichloromethane three times, and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation. The borane-protected product is obtained by separation and purification by silica gel column chromatography. Eluent: petroleum ether containing 5%-10% ethyl acetate.

[0131] Then, take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add borane protection product, triethylenediamine (1.95 mmol) and 2.5 mL toluene to the Shrek bottle, stir and dissolve. Heat to 60 ° C and stir for 12 hours. The reaction mixture is extracted with dichloromethane three times and the organic phase is combined, dried over anhydrous sodium sulfate and filtered, and the solvent is distilled off under reduced pressure. After separation and purification by silica gel column chromatography, compound (I)-2 is obtained.

[0132]

[0133] Yellow powder, 23% yield, (0.65 mmol, 70 mg product), eluent: methanol containing 1%-3% ethyl acetate. The NMR characterization data of the product are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 7.22 (td, J = 8.3, 2.2 Hz, 1H), 6.61 (dd, J =8.4, 2.0 Hz, 1H), 6.51 (dd, J = 8.1, 2.0 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.44 (q, J = 2.4, 1.9 Hz, 2H), 4.17 (d, J = 2.5 Hz, 5H), 3.89 (d, J = 2.1 Hz, 3H), 3.61 (d, J = 2.0 Hz, 3H), 1.51 (dd, J = 11.3, 2.8 Hz, 9H), 0.70 (dd, J = 10.7, 2.9 Hz, 9H).

[0134] 13 C NMR (101 MHz, CD2Cl2)δ 160.9, 159.3, 129.7, 116.4, 116.4, 105.3,105.2, 88.8, 88.4, 81.9, 81.6, 74.4, 74.4, 74.3, 74.3, 72.1, 69.7, 57.3,56.7, 34.5, 34.3, 33.9, 33.8, 33.3, 33.2, 31.6, 31.4.

[0135] 31 P NMR (162 MHz, CD2Cl2)δ 20.98 (dt, J = 21.8, 11.1 Hz).

[0136] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 467.1797, found: 467.1789.

[0137] Embodiment 27 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add F-1 compound (0.65 mmol) and 13 mL of freshly distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, tert-butyl lithium reagent (1.04 mmol) is added dropwise through a syringe and stirred for 30 minutes. Compound G-4 (1.63 mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, then slowly return to room temperature and stir for 2 hours. Then the solution is cooled to -78°C with a dry ice ethanol bath, and BH3·THF (1.95 mmol) is added dropwise through a syringe, slowly returned to room temperature and stirred for 2 hours. Then quench with 30 mL of saturated ammonium chloride aqueous solution. The reaction mixture is extracted with dichloromethane three times, and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation. The borane-protected product is obtained by separation and purification by silica gel column chromatography. Eluent: petroleum ether containing 5%-10% ethyl acetate.

[0138] Then, take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add borane protection product, triethylenediamine (1.95 mmol) and 2.5 mL toluene to the Shrek bottle, stir and dissolve. Heat to 60 ° C and stir for 12 hours. The reaction mixture is extracted with dichloromethane three times and the organic phase is combined, dried over anhydrous sodium sulfate and filtered, and the solvent is distilled off under reduced pressure. After separation and purification by silica gel column chromatography, compound (I)-3 is obtained.

[0139]

[0140] Yellow powder, 49% yield, (0.65 mmol, 160 mg product), eluent: methanol containing 1%-3% ethyl acetate. The NMR characterization data of the product are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 7.63 (dq, J = 7.6, 3.0, 2.4 Hz, 2H), 7.43 -7.36 (m, 3H), 7.21 - 7.10 (m, 6H), 6.52 (d, J = 8.4 Hz, 2H), 4.62 (q, J = 2.0 Hz,1H), 4.46 (t, J = 2.6 Hz, 1H), 4.10 (t, J = 1.9 Hz, 1H), 3.93 (s, 5H), 3.63 (s, 7H).

[0141] 13C NMR (101 MHz, CD2Cl2)δ 158.3, 142.0, 140.3, 135.5, 135.2, 132.1,131.9, 128.8, 127.9, 127.9, 127.8, 127.6, 127.5, 126.8, 113.3, 103.5, 85.9,85.6, 76.4, 76.2, 74.2, 74.1, 71.2, 71.2, 70.1, 68.9, 55.1.

[0142] 31 P NMR (162 MHz, CD2Cl2)δ -18.17.

[0143] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 507.1171, found: 507.1165.

[0144] Embodiment 28 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add F-1 compound (0.65 mmol) and 13 mL of freshly distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, tert-butyl lithium reagent (1.04 mmol) is added dropwise through a syringe and stirred for 30 minutes. Then compound G-1 (1.63 mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, then slowly return to room temperature and stir for 2 hours. Then the reaction solution is cooled to 0°C with an ice water bath, hydrogen peroxide (2.6 mmol) is added dropwise through a syringe, and slowly returned to room temperature and stirred for 1 hour. Then quench with 30 mL of saturated sodium thiosulfate aqueous solution. The reaction mixture is extracted with dichloromethane three times, and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation. The oxidation product is separated and purified by silica gel column chromatography. Eluent: methanol containing 1%-5% ethyl acetate.

[0145] Then, take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add the oxidation product, triethylamine (26 mmol) and 13 mL of toluene to the Shrek bottle, and stir to dissolve. Then cool the reaction solution to 0°C with an ice-water bath, add trichlorosilane (6.5 mmol) dropwise through a syringe, heat to 110°C and stir for 12 hours. Then quench with 30 mL of saturated sodium carbonate aqueous solution at -30°C. The reaction mixture is extracted three times with dichloromethane and the organic phase is combined, dried over anhydrous sodium sulfate and filtered, the solvent is removed by distillation under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound (I)-4.

[0146]

[0147] Yellow powder, 47% yield, (0.65 mmol, 160 mg product), eluent: petroleum ether containing 10%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 7.22 (t, J = 8.3 Hz, 1H), 6.57 (d, J = 21.5 Hz,2H), 4.59 (q, J = 1.9 Hz, 1H), 4.34 (q, J = 2.9 Hz, 1H), 4.31 - 4.25 (m, 1H),4.15 (s, 5H), 3.90 (s, 3H), 3.64 (s, 3H), 2.35 (s, 1H), 2.23 - 2.04 (m, 2H),2.00 - 1.86 (m, 2H), 1.79 (d, J = 12.5 Hz, 1H), 1.64 (s, 1H), 1.46 (ddt, J =25.2, 12.8, 6.7 Hz, 9H), 1.08 (dd, J = 18.8, 6.4 Hz, 2H), 1.02 - 0.87 (m, 2H), 0.82 - 0.68 (m, 1H), 0.48 (d, J = 10.6 Hz, 1H).

[0148] 13C NMR (101 MHz, CD2Cl2)δ 127.8, 114.6, 103.9, 84.9, 84.6, 81.1,80.9, 72.2, 72.2, 70.7, 70.7, 69.7, 67.2, 55.9, 35.8, 35.7, 34.8, 34.7, 33.2,32.9, 30.9, 30.8, 29.1, 29.1, 29.0, 28.9, 28.3, 28.2, 27.7, 27.6, 27.2, 27.1,27.1, 26.8, 26.5.

[0149] 31 P NMR (162 MHz, CD2Cl2)δ -14.69.

[0150] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 519.2110, found: 519.2100.

[0151] Embodiment 29 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add F-2 compound (0.21 mmol) and 5 mL of freshly distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, tert-butyl lithium reagent (0.25 mmol) is added dropwise through a syringe and stirred for 30 minutes. Compound G-1 (0.32 mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, then slowly return to room temperature and stir for 2 hours. Then the solution is cooled to -78°C with a dry ice ethanol bath, and BH3·THF (0.63 mmol) is added dropwise through a syringe, slowly returned to room temperature and stirred for 2 hours. Then quench with 30 mL of saturated ammonium chloride aqueous solution. The reaction mixture is extracted with dichloromethane three times, and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation. The borane-protected product is obtained by separation and purification by silica gel column chromatography. Eluent: petroleum ether containing 5%-10% ethyl acetate.

[0152] Then, take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add borane protection product, triethylenediamine (0.63 mmol) and 3 mL toluene to the Shrek bottle, stir and dissolve. Heat to 60°C and stir for 12 hours. The reaction mixture is extracted with dichloromethane three times and the organic phase is combined, dried over anhydrous sodium sulfate and filtered, and the solvent is distilled off under reduced pressure. After separation and purification by silica gel column chromatography, compound (I)-5 is obtained.

[0153]

[0154] Yellow powder, 53% yield, (0.21 mmol, 60 mg product), eluent: methanol containing 1%-3% ethyl acetate. The NMR characterization data of the product are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 6.41 (s, 2H), 4.57 (s, 1H), 4.31 (d, J = 2.6Hz, 1H), 4.27 (d, J = 2.5 Hz, 1H), 4.14 (s, 5H), 3.88 (s, 3H), 3.62 (s, 3H), 2.36 (s, 3H), 2.21 - 2.15 (m, 1H), 2.10 (s, 1H), 1.92 (s, 2H), 1.79 (d, J =11.7 Hz, 2H), 1.47 (d, J = 12.6 Hz, 5H), 1.39 - 1.23 (m, 2H), 1.07 (t, J = 13.0Hz, 2H), 1.01 - 0.88 (m, 2H), 0.78 (dq, J = 12.7, 6.5, 4.0 Hz, 1H), 0.49 (d, J =11.1 Hz, 1H).

[0155] 13 C NMR (101 MHz, CD2Cl2)δ 138.0, 111.5, 104.9, 85.2, 84.9, 81.0,80.8, 72.3, 72.2, 70.7, 70.7, 69.7, 67.1, 36.0, 35.9, 34.8, 34.6, 33.2, 32.9,31.0, 30.8, 29.0, 29.0, 28.9, 28.3, 28.2, 27.7, 27.7, 27.2, 27.1, 27.1, 26.8,26.5, 21.8.

[0156] 31 P NMR (162 MHz, CD2Cl2)δ -11.40.

[0157] HRMS (ESI): calculated for C 23H 23 N [M + H] + 533.2266, found: 533.2254.

[0158] Embodiment 30 Take a Shrek bottle, add a stirrer and dry it, replace nitrogen three times, add F-3 compound (0.21 mmol) and 5 mL of freshly distilled tetrahydrofuran to the Shrek bottle, and stir to dissolve. After the solution is cooled to -78°C with a dry ice ethanol bath, tert-butyl lithium reagent (0.25 mmol) is added dropwise through a syringe and stirred for 30 minutes. Compound G-1 (0.32 mmol) is added dropwise through a syringe. Stir at -78°C for 30 minutes, then slowly return to room temperature and stir for 2 hours. Then the solution is cooled to -78°C with a dry ice ethanol bath, BH3·THF (0.63 mmol) is added dropwise through a syringe, slowly returned to room temperature and stirred for 2 hours. Then quench with 30 mL of saturated ammonium chloride aqueous solution. The reaction mixture is extracted with dichloromethane three times, and the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation. The borane-protected product is obtained by separation and purification by silica gel column chromatography. Eluent: petroleum ether containing 5%-10% ethyl acetate.

[0159] Then, take a Shrek bottle, add a stirring bar and dry it, replace nitrogen three times, add borane protection product, triethylenediamine (0.63 mmol) and 3 mL toluene to the Shrek bottle, stir and dissolve. Heat to 60 ° C and stir for 12 hours. The reaction mixture is extracted with dichloromethane three times and the organic phase is combined, dried over anhydrous sodium sulfate and filtered, and the solvent is distilled off under reduced pressure. After separation and purification by silica gel column chromatography, compound (I)-6 is obtained.

[0160]

[0161] Yellow powder, 22% yield, (0.21 mmol, 25 mg product), eluent: methanol containing 1%-3% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 7.71 - 7.61 (m, 2H), 7.46 (td, J = 8.2, 7.7,2.0 Hz, 2H), 7.37 (dd, J= 8.4, 6.4 Hz, 1H), 6.80 (s, 2H), 4.62 (s, 1H), 4.38 - 4.34 (m, 1H), 4.32 (s, 1H), 4.17 (s, 5H), 3.96 (s, 3H), 3.74 (s, 3H), 2.36(s, 1H), 2.19 (s, 1H), 2.12 (s, 1H), 1.92 (s, 2H), 1.79 (d, J = 12.6 Hz, 1H), 1.56 (s, 2H), 1.45 (d, J = 13.3 Hz, 7H), 1.09 (d, J = 12.7 Hz, 2H), 1.01 - 0.92(m, 2H), 0.90 - 0.83 (m, 1H), 0.79 (d, J = 12.8 Hz, 1H), 0.52 (d, J = 12.4 Hz, 1H).

[0162] 13 C NMR (101 MHz, CD2Cl2) δ 141.5, 140.9, 128.7, 127.4, 126.9, 103.0, 72.1, 70.9, 70.8, 69.7, 67.3, 36.0, 35.8, 34.8, 34.7, 33.2, 32.9, 31.0, 30.8, 29.7, 29.0, 28.9, 28.3, 28.2, 27.7, 27.6, 27.2, 27.1, 26.7, 26.5.

[0163] 31 P NMR (162 MHz, CD2Cl2) δ -11.31.

[0164] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 595.2423, found: 595.2394.

[0165] Example 31 Take two dry anhydrous vials and a magnet, mix ethylpyridine (0.2 mmol) and Zn(TMP)2 (0.1 mmol) in one vial under N2 atmosphere, add 1,4-dioxane (0.8 mL), heat to 50°C, and stir for 17 hours; then, mix tri(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (compound (I)-4) (0.08 mmol), 1,4-dioxane (1 mL) in another vial under N2 atmosphere, stir for 10 minutes, mix the reaction solutions in the two vials, add bromobenzene (0.2 mmol), heat to 40°C, and stir for 24 hours.

[0166] The reaction solution was quenched with saturated ammonium chloride solution; extracted with dichloromethane three times; absorbed with anhydrous sodium sulfate; filtered; concentrated under reduced pressure; purified by column chromatography using petroleum ether / ethyl acetate as eluent to obtain compound J-1.

[0167]

[0168] Yellow oily liquid, 75% yield, (0.2 mmol, 26 mg product), eluent: petroleum ether containing 8%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 8.59 - 8.53 (m, 1H), 7.57 (td, J = 7.7, 1.8Hz, 1H), 7.33 - 7.28 (m, 4H), 7.20 (ddd, J = 9.1, 4.0, 2.9 Hz, 1H), 7.14 -7.08 (m, 2H), 4.32 (q, J = 7.2 Hz, 1H), 1.71 (d, J = 7.2 Hz, 3H).

[0169] 13 C NMR (101 MHz, CDCl3) δ 165.00, 149.02, 145.03, 136.57, 128.50, 127.71, 126.35, 122.19, 121.27, 47.33, 20.75.

[0170] Embodiment 32 Take two dry anhydrous vials and a magnetic bar, mix ethylpyridine (0.2 mmol) and Zn(TMP)2 (0.1 mmol) in one vial under N2 atmosphere, add 1,4-dioxane (0.8 mL), heat to 50°C, and stir for 17 hours; then, mix tri(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (compound (I)-4) (0.08 mmol), 1,4-dioxane (1 mL) in another vial under N2 atmosphere, stir for 10 minutes, mix the reaction solutions in the two vials, and add 4-bromo- N , N -dimethylaniline (0.2 mmol), warm to 40 °C and stir for 24 hours.

[0171] The reaction solution was quenched with saturated ammonium chloride solution; extracted with dichloromethane three times; absorbed with anhydrous sodium sulfate; filtered; concentrated under reduced pressure; purified by column chromatography using petroleum ether / ethyl acetate as eluent to obtain compound J-2.

[0172]

[0173] Yellow oily liquid, 71% yield, (0.2 mmol, 32 mg product), eluent: petroleum ether containing 8%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 8.55 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.54(td, J = 7.7, 1.9 Hz, 1H), 7.21 - 7.15 (m, 2H), 7.14 - 7.04 (m, 2H), 6.75 -6.67 (m, 2H), 4.23 (q, J = 7.2 Hz, 1H), 2.91 (s, 6H), 1.68 (d, J = 7.2 Hz, 3H).

[0174] 13 C NMR (101 MHz, CDCl3)δ 165.91, 149.25, 148.87, 136.46, 133.16, 128.27, 122.06, 121.01, 112.90, 46.39, 40.79, 20.85.

[0175] Embodiment 33 Take two dry anhydrous vials and a magnet, mix ethylpyridine (0.2 mmol) and Zn(TMP)2 (0.1 mmol) in one vial under N2 atmosphere, add 1,4-dioxane (0.8 mL), heat to 50°C, and stir for 17 hours; then, mix tri(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (compound (I)-4) (0.08 mmol), 1,4-dioxane (1 mL) in another vial under N2 atmosphere, stir for 10 minutes, mix the reaction solutions in the two vials, add 2-bromonaphthalene (0.2 mmol), heat to 40°C, and stir for 24 hours.

[0176] The reaction solution was quenched with saturated ammonium chloride solution; extracted with dichloromethane three times; absorbed with anhydrous sodium sulfate; filtered; concentrated under reduced pressure; purified by column chromatography using petroleum ether / ethyl acetate as eluent to obtain compound J-3.

[0177]

[0178] Yellow oily liquid, 72% yield, (0.2 mmol, 33 mg product), eluent: petroleum ether containing 8%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 8.63 - 8.57 (m, 1H), 7.79 (q, J = 8.9, 7.9 Hz,4H), 7.57 (td, J = 7.7, 1.7 Hz, 1H), 7.51 - 7.38 (m, 3H), 7.18 - 7.07 (m, 2H), 4.49 (q, J = 7.2 Hz, 1H), 1.81 (d, J = 7.2 Hz, 3H).

[0179] 13 C NMR (101 MHz, CDCl3)δ 164.91, 149.09, 142.48, 136.60, 133.59,132.27, 128.11, 127.81, 127.60, 126.60, 125.99, 125.74, 125.50, 122.35,121.35, 47.45, 20.66.

[0180] Embodiment 34 Take two dry anhydrous vials and a magnet, mix ethylpyridine (0.2 mmol) and Zn(TMP)2 (0.1 mmol) in one vial under N2 atmosphere, add 1,4-dioxane (0.8 mL), heat to 50°C, and stir for 17 hours; then, mix tri(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (compound (I)-4) (0.08 mmol), 1,4-dioxane (1 mL) in another vial under N2 atmosphere, stir for 10 minutes, mix the reaction solutions in the two vials, add 4-bromophenylbutyl ether (0.2 mmol), heat to 40°C, and stir for 24 hours.

[0181] The reaction solution was quenched with saturated ammonium chloride solution; extracted with dichloromethane three times; absorbed with anhydrous sodium sulfate; filtered; concentrated under reduced pressure; purified by column chromatography using petroleum ether / ethyl acetate as eluent to obtain compound J-4.

[0182]

[0183] Yellow oily liquid, 70% yield, (0.2 mmol, 36 mg product), eluent: petroleum ether containing 8%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 8.48 (dt, J = 4.5, 1.6 Hz, 1H), 7.50 (td, J= 7.7, 1.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.06 - 6.98 (m, 2H), 6.88 - 6.76 (m,2H), 4.20 (q, J = 7.2 Hz, 1H), 1.61 (d, J = 7.3 Hz, 3H), 1.24 (s, 9H).

[0184] 13 C NMR (101 MHz, CDCl3)δ 165.29, 153.70, 148.93, 139.70, 136.60, 128.00, 124.08, 122.15, 121.23, 78.23, 46.63, 28.85, 20.92.

[0185] Embodiment 35 Prepare two dry anhydrous vials and a magnet. In a N2 atmosphere, mix ethylpyridine (0.2 mmol) and Zn(TMP)2 (0.1 mmol) in one vial, add 1,4-dioxane (0.8 mL), heat to 50°C, and stir for 17 hours. Then, in a N2 atmosphere, mix tri(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (compound (I)-4) (0.08 mmol), and 1,4-dioxane (1 mL) in another vial, stir for 10 minutes, mix the reaction solutions in the two vials, and add 1-bromo-4-((1 R , 2 S , 5 R )-2-isopropyl-5-methylcyclohexyl)oxy)benzene (0.2 mmol), the temperature was raised to 40°C, and the mixture was stirred for 24 hours.

[0186] The reaction solution was quenched with saturated ammonium chloride solution; extracted with dichloromethane three times; absorbed with anhydrous sodium sulfate; filtered; concentrated under reduced pressure; purified by column chromatography using petroleum ether / ethyl acetate as eluent to obtain compound J-5.

[0187]

[0188] White solid, 74% yield, (0.2 mmol, 50 mg product), eluent: petroleum ether containing 8%-20% ethyl acetate. The product NMR characterization data are as follows: 1 H NMR (400 MHz, CD2Cl2)δ 8.58 - 8.43 (m, 1H), 7.53 (td, J = 7.7, 1.5Hz, 1H), 7.22 (dd, J = 8.0, 6.6 Hz, 4H), 7.18 - 7.12 (m, 2H), 7.12 - 7.04 (m,5H), 7.01 (d, J = 7.8 Hz, 1H), 5.65 (s, 1H).

[0189] 13 C NMR (101 MHz, CDCl3)δ 163.1, 149.4, 142.6, 136.6, 129.4, 128.4,126.5, 123.8, 121.5, 59.2.

[0190] The above-mentioned specific implementation methods are used to explain the present invention and are only preferred embodiments of the present invention, rather than limiting the present invention. Any modifications, equivalent substitutions, improvements, etc. made to the present invention within the spirit of the present invention and the protection scope of the claims shall fall within the protection scope of the present invention.

Claims

1. A ferrocenyl biaryl chiral monophosphine ligand, characterized in that: The structural formula of the ferrocenyl biaryl chiral monophosphine ligand is shown below: ； Wherein, R1, R2, and R3 are each independently selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C4-C15 heteroaryl, C10-C30 aryl, and halogen, wherein the halogen is fluorine, chlorine, bromine, or iodine; R4 and R5 are each independently selected from C1~C10 alkyl, C3~C8 cycloalkyl, and C4~C30 aryl.

2. The ferrocenyl biaryl chiral monophosphine ligand according to claim 1, characterized in that: The ferrocenyl biaryl chiral monophosphine ligand is prepared by reacting compound F with compound G: 。 3. The ferrocenyl biaryl chiral monophosphine ligand according to claim 2, characterized in that: The compound F is prepared by reacting compound D with compound E: 。 4. The ferrocenyl biaryl chiral monophosphine ligand according to claim 3, characterized in that: The compound D is prepared by reacting compound C with pinacol: 。 5. The ferrocenyl biaryl chiral monophosphine ligand according to claim 4, characterized in that: The compound C is prepared by reacting compound B with trimethyl borate: 。 6. The ferrocenyl biaryl chiral monophosphine ligand according to claim 5, characterized in that: The compound B is composed of compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate is prepared by reaction: 。 7. The method for preparing a ferrocenyl biaryl chiral monophosphine ligand according to any one of claims 1 to 6, characterized in that: The ferrocenyl biaryl chiral monophosphine ligand is prepared by reacting compound F with compound G: 。 8. The preparation method according to claim 7, characterized in that: The compound F is prepared by reacting compound D with compound E: 。 9. The preparation method according to claim 7, characterized in that: The compound D is prepared by reacting compound C with pinacol: 。 10. The preparation method according to claim 7, characterized in that: The compound C is prepared by reacting compound B with trimethyl borate: 。 11. The preparation method according to claim 7, characterized in that: The compound B is composed of compound A and (1 R ,2 S ,5 R )-(-)-Menthol( S )-toluenesulfinate is prepared by reaction: 。 12. A catalyst, characterized in that: The catalyst is prepared from the ferrocenyl biaryl chiral monophosphine ligand as claimed in any one of claims 1 to 6.

13. Use of the ferrocenyl biaryl chiral monophosphine ligand according to any one of claims 1 to 6 in organic synthesis catalysis.

14. The use according to claim 13, characterized in that: The organic synthesis catalytic reaction is a CH arylation reaction at the benzyl position of pyridine.

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