A ferrocenyl biaryl chiral monophosphine ligand, preparation method and application

Abstract

The present invention provides a ferrocenyl biaryl chiral monophosphine ligand, a preparation method and an application thereof. A novel chiral monophosphine ligand with a ferrocene structure is provided. In addition, a preparation method of the novel chiral monophosphine ligand with a ferrocene structure is also provided, as well as a catalyst prepared from the novel chiral monophosphine ligand with a ferrocene structure. Moreover, the novel chiral monophosphine ligand with a ferrocene structure can be applied to organic synthesis catalytic reactions, especially in the C-H arylation coupling reaction at the benzylic position of pyridine, and a series of compounds with aryl substitution at the benzylic position of pyridine with diverse structures can be rapidly synthesized, which is of great significance for new drug screening.

Description

Technical Field

[0001] The present 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 an application thereof. Background Art

[0002] In asymmetric catalytic reactions involving transition metals, transition metal catalysts play a crucial role, and their activity and selectivity are directly affected by the electronic and steric effects of the chiral ligands coordinated with them. The development of chiral phosphine ligands has made outstanding contributions to the development of the field of asymmetric catalysis. Especially in asymmetric hydrogenation reactions, 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 bisphosphine ligands, the development of chiral monophosphine ligands is relatively slow. Their coordination with metals can catalyze various types of reactions including allylic substitution reactions, dearomative arylation 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 frequently used reactions in pharmaceutical process synthesis, such as Suzuki-Miyaura coupling, Buchwald-Hartwig amination reaction, Sonogashira coupling, etc. These reactions occur almost every day in pharmaceutical production.

[0003] Monophosphine ligands are one of the earliest ligands used to explore asymmetric catalysis. In the early 1970s, Knowles (Knowles, W. S. et al. J. Chem. Soc., Chem. Commun. 1972, 10-11.) reported the asymmetric hydrogenation of rhodium-catalyzed dehydroamino acids, and the use of the P-chiral monophosphine ligand CAMP could obtain up to 88% ee (enantiomeric excess). Morrison (Morrison, J. D. et al. J. Am. Chem. Soc. 1971, 93 , 1301-1303.) developed the NMDPP (neomenthyldiphenylphosphine) monophosphine ligand, and this monophosphine ligand provided 61% ee in the hydrogenation reaction of ( E )- β -methylcinnamic acid catalyzed by rhodium metal. The axially chiral monophosphine ligand KenPhos with a binaphthyl backbone developed by Professor Buchwald (S. L. Buchwald et al. J. Am. Chem. Soc.2000, 122 ,12051.); Professor Feringa developed the axially chiral monophosphine ligand Monophos with a binaphthyl backbone phosphonamide structure (S.E. Reisman et al. Tetrahedron .2014, 70 , 3259-3265.); Professor Junliang Zhang developed the phosphine ligand Ming-phos with a tert-butylsulfinamide chiral auxiliary (J. Zhang et al. Angew. Chem. Int. Ed .2021, 60 ,18542-18546.); Professor Wenjun Tang developed the sterically hindered electron-rich chiral monophosphine ligand BIDIME with a rigid structure of a benzophosphine oxide five-membered heterocycle (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-catalyzed reactions. These existing phosphine ligands still cannot meet the requirements of high reactivity and excellent selectivity in transition metal-catalyzed reactions. Therefore, it is urgently necessary to develop highly efficient chiral monophosphine ligands with novel structures that are cheap and easily available. 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 object of the present invention is achieved by the following technical solutions:

[0007] A ferrocenyl biaryl chiral monophosphine ligand, the structural formula of the ferrocenyl biaryl chiral monophosphine ligand is shown as follows:

[0008] ;

[0009] Wherein, R 1 , R 2 , R 3 are each independently selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C4-C15 heteroaryl, C10-C30 aryl, halogen, and the halogen is fluorine, chlorine, bromine, iodine;

[0010] R 4 , R 5 are each independently selected from C1-C10 alkyl, C3-C8 cycloalkyl, C4-C30 aryl.

[0011] While adopting the above technical solution, the present invention can also adopt or combine the following technical solutions:

[0012] As a preferred technical solution of the present invention: the ferrocenyl biaryl chiral monophosphine ligand is selected from one of the following compounds:

[0013] 。

[0014] As a preferred technical solution of the present invention: the ferrocenyl biaryl chiral monophosphine ligand is prepared by reacting compound F with compound G:

[0015] 。

[0016] As a preferred technical solution of the present invention: compound F is selected from one of the following compounds:

[0017] 。

[0018] As a preferred technical solution of the present invention: the compound G is selected from one of the following compounds:

[0019] 。

[0020] As a preferred technical solution of the present invention: the compound F is prepared by reacting compound D with compound E:

[0021] 。

[0022] As a preferred technical solution of the present invention: the compound E is selected from one of the following compounds:

[0023] 。

[0024] As a preferred technical solution of the present invention: the compound D is prepared by reacting compound C with pinacol:

[0025] 。

[0026] As a preferred technical solution of the present invention: the compound C is prepared by reacting compound B with trimethyl borate:

[0027] 。

[0028] As a preferred technical solution of the present invention: the compound B is prepared by reacting compound A with (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate:

[0029] 。

[0030] The second object of the present invention is to provide a preparation method of the ferrocenylbiaryl chiral monophosphine ligand as described above, and the ferrocenylbiaryl chiral monophosphine ligand is prepared by reacting compound F with compound G:

[0031] 。

[0032] While adopting the above technical solutions, the present invention can also adopt or combine the following technical solutions:

[0033] As a preferred technical solution of the present invention: Compound F is prepared by reacting compound D with compound E:

[0034] 。

[0035] As a preferred technical solution of the present invention: Compound D is prepared by reacting compound C with pinacol:

[0036] 。

[0037] As a preferred technical solution of the present invention: Compound C is prepared by reacting compound B with trimethyl borate:

[0038] 。

[0039] As a preferred technical solution of the present invention: Compound B is prepared by reacting compound A with (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate:

[0040] 。

[0041] The third object of the present invention is to provide a catalyst, and the catalyst is prepared from the ferrocenylbiaryl chiral monophosphine ligand as described above.

[0042] Another object of the present invention is to provide the application of the ferrocenylbiaryl chiral monophosphine ligand as described above in organic synthesis catalytic reactions.

[0043] While adopting the above technical solutions, the present invention can also adopt or combine the following technical solutions:

[0044] As a preferred technical solution of the present invention: The organic synthesis catalytic reaction is a C-H arylation coupling reaction at the benzylic position of pyridine.

[0045] The present invention provides a ferrocenyl biaryl chiral monophosphine ligand, a preparation method and an application thereof, providing a novel chiral monophosphine ligand with a ferrocene structure. In addition, a preparation method of the novel chiral monophosphine ligand with a ferrocene structure is also provided, as well as a catalyst prepared from the novel chiral monophosphine ligand with a ferrocene structure, and the novel chiral monophosphine ligand with a ferrocene structure can be applied to organic synthesis catalytic reactions, especially in the C-H arylation coupling reaction at the benzylic position of pyridine, and a series of compounds with aryl substitution at the benzylic position of pyridine with diverse structures can be rapidly synthesized, which is of great significance for new drug screening. Detailed implementation manners

[0046] The present invention provides a ferrocenyl biaryl chiral monophosphine ligand, which is selected from one of the following compounds:

[0047] 。

[0048] The ferrocenyl biaryl chiral monophosphine ligand is obtained by a nucleophilic substitution reaction of compound F and compound G in the presence of a tert-butyllithium reagent.

[0049] Specifically, compound F is first lithiated, then subjected to nucleophilic substitution with compound G, and then protected with borane and reduced to obtain the ferrocenyl biaryl chiral monophosphine ligand;

[0050] Or, compound F is first lithiated, then subjected to nucleophilic substitution with compound G, and then oxidized with hydrogen peroxide and reduced to obtain the ferrocenyl biaryl chiral monophosphine ligand.

[0051] Among them: the solvent for the lithiation reaction is tetrahydrofuran; the temperature of the lithiation reaction is -78 °C, and the reaction time is 15 minutes;

[0052] The molar ratio of compound F to the tert-butyllithium reagent is 1:1.2;

[0053] The solvent for the nucleophilic substitution reaction is tetrahydrofuran; the temperature of the nucleophilic substitution reaction is slowly restored from -78 °C to room temperature, the reaction time is 1 hour at -78 °C, and 2 hours at room temperature;

[0054] The molar ratio of compound F to compound G is 1:1.5.

[0055] Compound F, that is, the coupling compound F, is selected from one of the following compounds:

[0056] 。

[0057] In compound G, R 4 、R 5 The substituents are alkyl or aryl.

[0058] Compound G is selected from one of the following compounds:

[0059] .

[0060] React with BH 3 ·THF reagent at -78 °C and slowly warm to room temperature. The reaction time is 0.5 hour at -78 °C and 2 hours at room temperature after warming; the molar ratio of compound F to BH 3 ·THF reagent is 1:3; the solvent for the reduction reaction is toluene; the reduction reaction temperature is 60 °C and the reaction time is 12 hours;

[0061] The molar ratio of compound F to the base triethylenediamine reagent used in the reaction is 1:3

[0062] React with hydrogen peroxide reagent at 0 °C and slowly warm to room temperature. The reaction time is 0.5 hour at 0 °C and 1 hour at room temperature after warming; the molar ratio of compound F to hydrogen peroxide reagent is 1:4; the solvent for the reduction reaction 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.

[0063] Compound F is obtained by the intermolecular coupling reaction of compound D and compound E using transition metal palladium as a catalyst in the presence of a monophosphine ligand and a base in an organic solvent.

[0064] Among them: the solvent is at least one of tetrahydrofuran, N , N- dimethylformamide, 1,4-dioxane, dimethyl sulfoxide and toluene, preferably toluene; the reaction temperature is 110 °C and the reaction time is 24 hours;

[0065] 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 base reagent is 1:2; the palladium catalyst is palladium acetate;

[0066] In aryl iodide E, R 3 The substituent is alkyl or aryl;

[0067] Aryl iodide E is selected from one of the following compounds:

[0068] .

[0069] The phosphine ligand is selected from one of the following compounds:

[0070] .

[0071] The base is at least one of potassium phosphate, cesium fluoride, cesium carbonate, potassium hydroxide, and sodium hydroxide.

[0072] After the reaction is completed, the separation of the final product is achieved by column chromatography. The eluent for column chromatography is a mixed solvent of ethyl acetate / dichloromethane, and the percentage of ethyl acetate is 8 - 20%.

[0073] Compound D is prepared by reacting compound C with pinacol.

[0074] Among them: The reaction solvent is dichloromethane.

[0075] The reaction temperature is room temperature, and the reaction time is 16 hours.

[0076] The molar ratio of compound C to pinacol reagent is 1:4, and the molar ratio of compound C to the water absorbent anhydrous magnesium sulfate reagent used in the reaction is 1:10.

[0077] Compound C is obtained by subjecting compound B to a nucleophilic reaction with trimethyl borate in the presence of lithium diisopropylamide reagent.

[0078] Specifically, compound B is first lithiated and then subjected to a nucleophilic reaction to obtain compound C;

[0079] Among them: The reaction solvent is tetrahydrofuran.

[0080] The lithiation reaction temperature is -78 °C, and the reaction time is 0.5 hours.

[0081] The molar ratio of compound B to lithium diisopropylamide reagent is 1:2.

[0082] The nucleophilic substitution reaction temperature is slowly restored from -78 °C to room temperature. The reaction time is 0.5 hours at -78 °C and 12 hours at room temperature after restoration.

[0083] The molar ratio of compound B to trimethyl borate reagent is 1:3.

[0084] Compound B is obtained by subjecting compound A to a nucleophilic reaction with (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate in the presence of tert-butyllithium reagent;

[0085] Specifically, compound A is first lithiated and then subjected to a nucleophilic reaction to obtain compound B;

[0086] Among them: The reaction solvent is tetrahydrofuran;

[0087] The temperature of the lithiation reaction is from -78 °C to room temperature. The reaction procedure is to react at -78 °C for 1.5 hours and then resume to room temperature for 1 hour.

[0088] The molar ratio of compound A to the tert-butyllithium reagent is 1:2, and the molar ratio of compound A to the base potassium tert-butoxide used in the reaction is 1:0.12.

[0089] The reaction temperature of the nucleophilic reaction is -55 °C and the reaction time is 1 hour.

[0090] Compound A and (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate reagent have a molar ratio of 1:1.

[0091] The second aspect of the present invention lies in providing a preparation method of the ferrocenylbiaryl chiral monophosphine ligand as described above. The ferrocenylbiaryl chiral monophosphine ligand is obtained by subjecting compound F and compound G to a nucleophilic reaction in the presence of a tert-butyllithium reagent.

[0092] Specifically, first perform a lithiation reaction on compound F, then carry out a nucleophilic substitution with compound G, and then protect with borane and reduce to obtain the ferrocenylbiaryl chiral monophosphine ligand;

[0093] Or, first perform a lithiation reaction on compound F, then carry out a nucleophilic substitution with compound G, and then oxidize with hydrogen peroxide and reduce to obtain the ferrocenylbiaryl chiral monophosphine ligand.

[0094] Among them: The solvent for the lithiation reaction is tetrahydrofuran; the lithiation reaction temperature is -78 °C and the reaction time is 15 minutes;

[0095] The molar ratio of compound F to the tert-butyllithium reagent is 1:1.2;

[0096] The solvent for the nucleophilic substitution reaction is tetrahydrofuran;

[0097] The temperature of the nucleophilic substitution reaction is slowly restored from -78 °C to room temperature. The reaction time is 1 hour at -78 °C and 2 hours at room temperature after restoration;

[0098] The molar ratio of compound F to compound G is 1:1.5;

[0099] Compound F, that is, the coupling compound F, is selected from one of the following compounds:

[0100] .

[0101] In compound G, R 4 , R 5 The substituents are alkyl or aryl.

[0102] Compound G is selected from one of the following compounds:

[0103] 。

[0104] React with BH 3 ·THF reagent, the reaction temperature is slowly restored to room temperature from -78 °C, the reaction time is 0.5 hours at -78 °C and 2 hours at room temperature after restoration; the molar ratio of compound F and BH 3 ·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;

[0105] The molar ratio of compound F and the base triethylenediamine reagent used in the reaction is 1:3.

[0106] React with hydrogen peroxide reagent, the reaction temperature is slowly restored to room temperature from 0 °C, the reaction time is 0.5 hours at 0 °C and 1 hour at room temperature after restoration; the molar ratio of compound F and 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 and the reducing agent trichlorosilane reagent used in the reaction is 1:10, and the molar ratio of compound F and the base triethylamine reagent used in the reaction is 1:40;

[0107] Compound F is obtained by intermolecular coupling reaction of compound D and compound E in an organic solvent in the presence of a transition metal palladium catalyst, a monophosphine ligand and a base.

[0108] Among them: the solvent is at least one of tetrahydrofuran, N , N -dimethylformamide, 1,4-dioxane, dimethyl sulfoxide and toluene, preferably toluene; the reaction temperature is 110 °C and the reaction time is 24 hours;

[0109] The molar ratio of compound D and aryl iodide E is 1:1.5, the molar ratio of compound D and palladium catalyst is 1:0.04, the molar ratio of compound D and phosphine ligand is 1:0.04, and the molar ratio of compound D and base reagent is 1:2;

[0110] In aryl iodide E, R 3 The substituent is alkyl or aryl;

[0111] Aryl iodide E is selected from one of the following compounds:

[0112] 。

[0113] The phosphine ligand is selected from one of the following compounds:

[0114] 。

[0115] The palladium catalyst is palladium acetate;

[0116] The base is at least one of potassium phosphate, cesium fluoride, cesium carbonate, potassium hydroxide, and sodium hydroxide.

[0117] After the reaction is completed, the final product is separated by column chromatography. The eluent for column chromatography is a mixed solvent of ethyl acetate / dichloromethane, and the percentage of ethyl acetate is 8 - 20%.

[0118] Compound D is prepared by reacting compound C with pinacol.

[0119] Among them: The reaction solvent is dichloromethane.

[0120] The reaction temperature is room temperature, and the reaction time is 16 hours.

[0121] The molar ratio of compound C to pinacol reagent is 1:4, and the molar ratio of compound C to the water absorbent anhydrous magnesium sulfate reagent used in the reaction is 1:10.

[0122] Compound C is obtained by a nucleophilic reaction of compound B with trimethyl borate in the presence of lithium diisopropylamide reagent.

[0123] Specifically, compound B is first lithiated and then subjected to a nucleophilic reaction to obtain compound C;

[0124] Among them: The reaction solvent is tetrahydrofuran.

[0125] The lithiation reaction temperature is -78 °C, and the reaction time is 0.5 hours.

[0126] The molar ratio of compound B to lithium diisopropylamide reagent is 1:2.

[0127] The temperature of the nucleophilic substitution reaction is slowly restored from -78 °C to room temperature. The reaction time is 0.5 hours at -78 °C and 12 hours at room temperature after restoration.

[0128] The molar ratio of compound B to trimethyl borate reagent is 1:3.

[0129] Compound B is obtained by a nucleophilic reaction of compound A with (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate in the presence of tert-butyllithium reagent;

[0130] Specifically, compound A is first lithiated and then subjected to a nucleophilic reaction to obtain compound B;

[0131] Among them: The reaction solvent is tetrahydrofuran;

[0132] 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;

[0133] The molar ratio of compound A to the tert-butyllithium reagent is 1:2, and the molar ratio of compound A to the base potassium tert-butoxide used in the reaction is 1:0.12;

[0134] The reaction temperature of the nucleophilic reaction is -55 °C, and the reaction time is 1 hour.

[0135] Compound A and (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate reagent has a molar ratio of 1:1.

[0136] The third aspect of the present invention lies in providing a catalyst, which is prepared from the ferrocenylbiaryl chiral monophosphine ligand as described above.

[0137] Another aspect of the present invention lies in providing the application of the ferrocenylbiaryl chiral monophosphine ligand as described above in organic synthesis catalytic reactions.

[0138] Preferably, the organic synthesis catalytic reaction is an arylation coupling reaction at the benzylic position of pyridine. Specifically, in an inert gas atmosphere, using a pyridine derivative H and an aryl bromide I as raw materials, Zn(TMP) 2 as the base, 1,4-dioxane as the solvent, a transition metal palladium as the catalyst, and under the action of a phosphine ligand, a Negishi intermolecular coupling reaction occurs in an organic solvent to obtain compound J:

[0139] .

[0140] Among them, R 6 ~R 15 each independently selected from hydrogen, C1-C10 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, C4-C15 heteroaryl, C10-C30 aryl, halogen, and the halogen is fluorine, chlorine, bromine, iodine;

[0141] The coupling compound J is selected from one of the following compounds:

[0142] .

[0143] Among them, the solvent is tetrahydrofuran, N , NAt least one of N,N-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;

[0144] The molar ratio of pyridine derivative H to aryl bromide I is 1:1, the molar ratio of compound H to palladium reagent is 1:0.04, the molar ratio of compound H to phosphine ligand is 1:0.04, and the molar ratio of compound H to Zn(TMP) 2 is 2:1.

[0145] Pyridine derivative H is preferably:

[0146] .

[0147] Aryl bromide I is selected from one of the following compounds:

[0148] .

[0149] The palladium catalyst is preferably palladium acetate.

[0150] The phosphine ligand is preferably:

[0151] .

[0152] After the reaction is completed, the final product is separated by column chromatography. The eluent for column chromatography is a mixed solvent of ethyl acetate / dichloromethane, and the percentage of ethyl acetate is 8-20%.

[0153] The present invention will be further described in detail with reference to specific examples.

[0154] Examples 1-8

[0155] In Examples 1-8, under an inert gas atmosphere, ferrocene sulfoxide compound D and aryl iodide E-1 are used as raw materials, sodium hydroxide is used as the base, toluene is used as the solvent, and palladium acetate is used as the catalyst. The Suzuki coupling reaction occurs under the action of different phosphine ligands. The reaction formula is as follows:

[0156]

[0157] Under a 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) are added to a 10 mL reaction tube, and the solvent toluene (1 mL) is added. After stirring at 110 °C for 24 hours, mesitylene (0.1 mmol) is added, and the solvent is directly distilled off under reduced pressure. The yield is calculated by NMR, and the results are shown in Table 1. In the table, the NMR yield uses 1,3,5-trimethoxybenzene as the internal standard.

[0158]

[0159] Table 1: Influence of Phosphine Ligands on the Reaction

[0160]

[0161] Examples 9 - 13

[0162] Examples 9 - 13 used ferrocene sulfoxide compound D and aryl iodide E - 1 as raw materials, sodium hydroxide as the base, toluene as the solvent, L8 as the phosphine ligand, and palladium acetate as the catalyst to carry out the Suzuki coupling reaction under the action of 5 different bases. The reaction formula is as follows:

[0163]

[0164] Table 2: Influence of Bases on the Reaction

[0165]

[0166] Under a nitrogen atmosphere, D (0.1 mmol), E - 1 (0.15 mmol), base (0.2 mmol), palladium acetate (0.004 mmol), and phosphine ligand (0.004 mmol) were added to a 10 mL reaction tube, and 1 mL of the solvent toluene was added. After stirring at 110°C for 24 hours, mesitylene (0.1 mmol) was added, and the solvent was directly removed by vacuum distillation. The yield was calculated by NMR, and the results are shown in Table 2. In the table, the NMR yield was determined using 1,3,5 - trimethoxybenzene as the internal standard.

[0167] Examples 14 - 18

[0168] Examples 14 - 18 used ferrocene sulfoxide compound D and aryl iodide E - 1 as raw materials, sodium hydroxide as the base, L8 as the phosphine ligand, and palladium acetate as the catalyst to carry out the Suzuki coupling reaction under the action of 5 different solvents. The reaction formula is as follows:

[0169]

[0170] Under a 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 1 mL of the solvent was added. After stirring at 110°C for 24 hours, mesitylene (0.1 mmol) was added, and the solvent was directly removed by vacuum distillation. The yield was calculated by NMR, and the results are shown in Table 3. In the table, the NMR yield was determined using 1,3,5 - trimethoxybenzene as the internal standard.

[0171] Table 3: Influence of Solvents on the Reaction

[0172]

[0173] Example 19

[0174] Take a Schlenk flask, add a magnetic stir bar and dry it. Evacuate and backfill with nitrogen three times. Add A (40 mmol), potassium tert-butoxide (4.8 mmol) and 335 mL of distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. Cool the solution to -78 °C in a dry ice-ethanol bath. Then, add tert-butyllithium (80 mmol) dropwise via syringe. Stir for 30 minutes, then remove the dry ice-ethanol bath and slowly warm the solution to room temperature. Stir for 1 hour. Then, cool the solution to -55 °C in a dry ice-methanol bath. Transfer the solution slowly (about 30 minutes) via a double-headed needle to a cooled (-55 °C) solution containing (1 R ,2 S ,5 R )-(-)-menthol( S )-p-toluenesulfonate (40 mmol) in 205 mL of distilled tetrahydrofuran, and continue to stir for 1 hour. Slowly warm the solution to room temperature and stir for 1 hour. Then, quench the reaction with 50 mL of saturated aqueous ammonium chloride. Extract the reaction mixture three times with dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography to obtain Compound B.

[0175]

[0176] Orange solid, 80% ee, 76% yield (40 mmol, 9.9 g of product), eluent: petroleum ether containing 10%-20% ethyl acetate.

[0177] Then, perform recrystallization twice (-20 °C) in petroleum ether (25 mL), ethyl acetate (20 mL) and dichloromethane (15 mL) to obtain 9 g of crystals, 99.9% ee, 90% yield. The NMR characterization data of the product are as follows:

[0178] 1 H NMR (400 MHz, CDCl 3 ) 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).

[0179] 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。

[0180] Example 20

[0181] Take a Schlenk flask, add a magnetic stir bar and dry it. Evacuate and backfill with nitrogen three times. Add compound B (44.7 mmol) and 520 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. Cool the solution to -78 °C in a dry ice-ethanol bath, then add lithium diisopropylamide (53.6 mmol) dropwise via syringe. Stir at -78 °C for 30 minutes, then slowly add trimethyl borate (134 mmol) via syringe. After stirring at -78 °C for 20 minutes, slowly warm to room temperature and stir for 1 hour, then quench with 300 mL of saturated aqueous ammonium chloride. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent by distillation under reduced pressure to obtain compound C.

[0182]

[0183] Yellow powder, 99% yield, (44.7 mmol, 16.5 g of product), slurried and purified to remove trace impurities (methyl tert-butyl ether: n-hexane = 3:1). The NMR characterization data of the product are as follows:

[0184] 1 H NMR (400 MHz, CDCl 3 ) 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).

[0185] Example 21

[0186] Take a reaction flask, add a magnetic stir bar and dry it. Add compound C (38 mmol), pinacol (152 mmol) and 420 mL of dry dichloromethane to the reaction flask, and stir to dissolve. Then add dried anhydrous magnesium sulfate (27.2 mmol), stir and react for 16 hours. After the reaction is completed, add 300 mL of water to wash away the remaining pinacol. Extract the mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure to obtain compound D.

[0187]

[0188] Yellow powder, 93% yield, (38 mmol, 14 g of product), purified by trituration (n - hexane:ethyl acetate = 10:1). The NMR characterization data of the product are as follows:

[0189] 1 H NMR (400 MHz, CDCl 3 ). δ 8.16 (d, J J = 7.8 Hz, 2H), 7.73 (d, J J = 7.7 Hz,2H), 5.03 (d, J J = 2.4 Hz, 1H), 4.81 (dd, J J = 5.1, 2.7 Hz, 1H), 4.51 (s, 5H), 4.37(d, J J = 2.5 Hz, 1H), 2.82 (s, 3H), 1.78 (s, 12H).

[0190] 13 C NMR (101 MHz, CDCl 3 ). 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.

[0191] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 451.1196, found: 451.1183.

[0192] Example 22

[0193] Under a nitrogen atmosphere, D (2.22 mmol), E-1 (3.33 mmol), sodium hydroxide (4.44 mmol), palladium acetate (0.09 mmol), and a phosphine ligand (0.09 mmol) were added to a 50 mL reaction tube, and a solvent (22 mL) was added. After stirring at 110 °C for 24 hours, it was filtered through diatomaceous earth, washed with dichloromethane, the filtrate was distilled under reduced pressure to remove the solvent, and it was separated and purified by silica gel column chromatography to obtain compound F-1.

[0194]

[0195] Brown-yellow powder, 80% yield, (2.2 mmol, 817 mg of product), eluent: dichloromethane containing 10% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0196] 1 H NMR (400 MHz, CDCl 3 ). 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).

[0197] 13 C NMR (101 MHz, CDCl 3 ). 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.

[0198] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 461.0868, found: 461.0856.

[0199] Example 23

[0200] Under a nitrogen atmosphere, D (2.22 mmol), E-2 (3.33 mmol), sodium hydroxide (4.44 mmol), palladium acetate (0.09 mmol), and phosphine ligand (0.09 mmol) were added to a 50 mL reaction tube, and a solvent (22 mL) was added. After stirring at 110 °C for 24 hours, it was filtered through diatomaceous earth, washed with dichloromethane, the filtrate was distilled under reduced pressure to remove the solvent, and then separated and purified by silica gel column chromatography to obtain compound F-2.

[0201]

[0202] Yellowish-brown powder, 58% yield, (2.2 mmol, 610 mg of product), eluent: dichloromethane containing 10% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0203] 1 H NMR (400 MHz, CDCl 3 ). δ 7.80 (d, J J = 7.9 Hz, 2H), 7.37 (d, J 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).

[0204] 13 C NMR (101 MHz, CDCl 3 ). 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.

[0205] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 475.1025, found: 475.1017.

[0206] Example 24

[0207] Under a nitrogen atmosphere, D (2.22 mmol), E-3 (3.33 mmol), sodium hydroxide (4.44 mmol), palladium acetate (0.09 mmol), and phosphine ligand (0.09 mmol) were added to a 50 mL reaction tube, and a solvent (22 mL) was added. After stirring at 110 °C for 24 hours, it was filtered through diatomaceous earth, washed with dichloromethane, the filtrate was distilled under reduced pressure to remove the solvent, and purified by silica gel column chromatography to obtain compound F-3.

[0208]

[0209] Brown-yellow powder, 46% yield, (2.2 mmol, 550 mg of product), eluent: dichloromethane containing 10%-20% ethyl acetate. The NMR characterization data of the product are as follows:

[0210] 1 H NMR (400 MHz, CDCl 3 ). 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).

[0211] 13 C NMR (101 MHz, CDCl 3 ). 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.

[0212] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 537.1181, found: 537.1171.

[0213] Example 25

[0214] Take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add compound F-1 (1.1 mmol) and 22 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. Cool the solution to -78 °C in a dry ice-ethanol bath, then add tert-butyllithium reagent (1.76 mmol) dropwise via a syringe and stir for 30 minutes. Then add compound G-2 (2.75 mmol) dropwise via a syringe. Stir at -78 °C for 30 minutes, then slowly warm to room temperature and stir for 2 hours. Then cool the reaction mixture to 0 °C in an ice-water bath, add hydrogen peroxide (4.4 mmol) dropwise via a syringe, and slowly warm to room temperature and stir for 1 hour. Then quench with 30 mL of saturated aqueous sodium thiosulfate solution. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, distill off the solvent under reduced pressure, and purify by silica gel column chromatography to obtain the oxidation product. Eluent: methanol containing 1% - 3% ethyl acetate.

[0215] Then, take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add the oxidation product, triethylamine (44 mmol) and 22 mL of toluene to the Schlenk flask and stir to dissolve. Then cool the reaction mixture to 0 °C in an ice-water bath, add trichlorosilane (11 mmol) dropwise via a syringe, and heat to 110 °C and stir for 12 hours. Then quench at -30 °C with 30 mL of saturated aqueous sodium carbonate solution. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, distill off the solvent under reduced pressure, and purify by silica gel column chromatography to obtain compound (I)-1.

[0216]

[0217] Yellow powder, 45% yield, (1.1 mmol, 216 mg of product), eluent: petroleum ether containing 10% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0218] 1 H NMR (400 MHz, CD 2 Cl 2 ). δ 7.21 (t, J J = 8.3 Hz, 1H), 6.57 (s, 2H), 4.62(dq, J J = 2.7, 1.3 Hz, 1H), 4.34 (t, J J = 2.5 Hz, 1H), 4.31 - 4.28 (m, 1H), 4.14(d, J J = 1.0 Hz, 5H), 3.88 (s, 3H), 3.66 (s, 3H), 2.24 (ddt,J = 14.1, 11.8, 6.9 Hz, 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).

[0219] 13 C NMR (101 MHz, CD 2 Cl 2 ). 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.

[0220] 31 P NMR (162 MHz, CD 2 Cl 2 ) δ -3.73.

[0221] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 439.1484, found: 439.1467.

[0222] Example 26

[0223] Take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add compound F-1 (0.65 mmol) and 13 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. After cooling the solution to -78 °C in a dry ice - ethanol bath, add tert - butyllithium reagent (1.04 mmol) dropwise via a syringe and stir for 30 minutes. Add compound G-3 (1.63 mmol) dropwise via a syringe. Stir at -78 °C for 30 minutes and then slowly warm to room temperature and stir for 2 hours. Then cool the solution to -78 °C in a dry ice - ethanol bath and add BH 3· THF (1.95 mmol), slowly warmed to room temperature and stirred for 2 h. Then it was quenched with 30 mL of saturated aqueous ammonium chloride. The reaction mixture was extracted with dichloromethane three times, the aqueous phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under reduced pressure, and the product was purified by silica gel column chromatography to obtain the borane-protected product. Eluent: petroleum ether containing 5% - 10% ethyl acetate.

[0224] Then, a Schlenk flask was taken, charged with a stir bar, dried, evacuated and backfilled with nitrogen three times. The borane-protected product, triethylenediamine (1.95 mmol) and 2.5 mL of toluene were added to the Schlenk flask and stirred until dissolved. The mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was extracted with dichloromethane three times, the aqueous phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under reduced pressure, and the product was purified by silica gel column chromatography to obtain compound (I)-2.

[0225]

[0226] Yellow powder, 23% yield, (0.65 mmol, 70 mg of product), eluent: methanol containing 1% - 3% ethyl acetate. The NMR characterization data of the product are as follows:

[0227] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 7.22 (td, J J = 8.3, 2.2 Hz, 1H), 6.61 (dd, J J = 8.4, 2.0 Hz, 1H), 6.51 (dd, J J = 8.1, 2.0 Hz, 1H), 4.70 - 4.60 (m, 1H), 4.44 (q, J J = 2.4, 1.9 Hz, 2H), 4.17 (d, J J = 2.5 Hz, 5H), 3.89 (d, J J = 2.1 Hz, 3H), 3.61 (d, J J = 2.0 Hz, 3H), 1.51 (dd, J J = 11.3, 2.8 Hz, 9H), 0.70 (dd, J J = 10.7, 2.9 Hz, 9H).

[0228] 13 C NMR (101 MHz, CD 2 Cl 2) 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。

[0229] 31 P NMR (162 MHz, CD 2 Cl 2 ) δ 20.98 (dt, J = 21.8, 11.1 Hz)。

[0230] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 467.1797, found: 467.1789。

[0231] Example 27

[0232] Take a Schlenk flask, add a magnetic stir bar and dry it. Evacuate and backfill with nitrogen three times. Add compound F-1 (0.65 mmol) and 13 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. After cooling the solution to -78 °C in a dry ice-ethanol bath, add tert-butyllithium reagent (1.04 mmol) dropwise via syringe and stir for 30 minutes. Add compound G-4 (1.63 mmol) dropwise via syringe. Stir at -78 °C for 30 minutes and then slowly warm to room temperature and stir for 2 hours. Then cool the solution to -78 °C in a dry ice-ethanol bath and add BH 3 ·THF (1.95 mmol) dropwise via syringe and slowly warm to room temperature and stir for 2 hours. Then quench with 30 mL of saturated aqueous ammonium chloride solution. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain the borane-protected product. Eluent: petroleum ether containing 5% - 10% ethyl acetate.

[0233] Then, take a Schlenk flask, add a magnetic stir bar and dry it. Evacuate and backfill with nitrogen three times. Add the borane-protected product, triethylenediamine (1.95 mmol) and 2.5 mL of toluene to the Schlenk flask and stir to dissolve. Heat to 60 °C and stir for 12 hours. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain compound (I)-3.

[0234]

[0235] Yellow powder, 49% yield, (0.65 mmol, 160 mg of product), eluent: methanol containing 1% - 3% ethyl acetate. The NMR characterization data of the product are as follows:

[0236] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 7.63 (dq, J 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 J = 8.4 Hz, 2H), 4.62 (q, J J = 2.0 Hz,1H), 4.46 (t, J J = 2.6 Hz, 1H), 4.10 (t, J J = 1.9 Hz, 1H), 3.93 (s, 5H), 3.63 (s,7H).

[0237] 13 C NMR (101 MHz, CD 2 Cl 2 ) 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.

[0238] 31 P NMR (162 MHz, CD 2 Cl 2 ) δ -18.17.

[0239] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 507.1171, found: 507.1165.

[0240] Example 28

[0241] Take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add compound F-1 (0.65 mmol) and 13 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. Cool the solution to -78 °C in a dry ice-ethanol bath, then add tert-butyllithium reagent (1.04 mmol) dropwise via a syringe and stir for 30 minutes. Then add compound G-1 (1.63 mmol) dropwise via a syringe. Stir at -78 °C for 30 minutes, then slowly warm to room temperature and stir for 2 hours. Then cool the reaction mixture to 0 °C in an ice-water bath, add hydrogen peroxide (2.6 mmol) dropwise via a syringe, and slowly warm to room temperature and stir for 1 hour. Then quench with 30 mL of saturated aqueous sodium thiosulfate. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation under reduced pressure, and purify by silica gel column chromatography to obtain the oxidation product. Eluent: methanol containing 1% - 5% ethyl acetate.

[0242] Then, take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add the oxidation product, triethylamine (26 mmol) and 13 mL of toluene to the Schlenk flask and stir to dissolve. Then cool the reaction mixture to 0 °C in an ice-water bath, add trichlorosilane (6.5 mmol) dropwise via a syringe, and heat to 110 °C and stir for 12 hours. Then quench at -30 °C with 30 mL of saturated aqueous sodium carbonate. Extract the reaction mixture with dichloromethane three times, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation under reduced pressure, and purify by silica gel column chromatography to obtain compound (I)-4.

[0243]

[0244] Yellow powder, 47% yield, (0.65 mmol, 160 mg of product), Eluent: petroleum ether containing 10% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0245] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 7.22 (t, J J = 8.3 Hz, 1H), 6.57 (d, J J = 21.5 Hz,2H), 4.59 (q, J 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).

[0246] 13 C NMR (101 MHz, CD 2 Cl 2 ) 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.

[0247] 31 P NMR (162 MHz, CD 2 Cl 2 ) δ -14.69.

[0248] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 519.2110, found: 519.2100.

[0249] Example 29

[0250] Take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add compound F-2 (0.21 mmol) and 5 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. Cool the solution to -78 °C in a dry ice-ethanol bath, then add tert-butyllithium reagent (0.25 mmol) dropwise via a syringe and stir for 30 minutes. Add compound G-1 (0.32 mmol) dropwise via a syringe. Stir at -78 °C for 30 minutes, then slowly warm to room temperature and stir for 2 hours. Then cool the solution to -78 °C in a dry ice-ethanol bath, and add BH 3 ·THF (0.63 mmol) dropwise via a syringe, and slowly warm to room temperature and stir for 2 hours. Then quench with 30 mL of saturated aqueous ammonium chloride solution. Extract the reaction mixture three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, distill off the solvent under reduced pressure, and purify by silica gel column chromatography to obtain the borane-protected product. Eluent: petroleum ether containing 5% - 10% ethyl acetate.

[0251] Then, take a Schlenk flask, add a magnetic stir bar and dry it. Flush with nitrogen three times. Add the borane-protected product, triethylenediamine (0.63 mmol) and 3 mL of toluene to the Schlenk flask and stir to dissolve. Heat to 60 °C and stir for 12 hours. Extract the reaction mixture three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, distill off the solvent under reduced pressure, and purify by silica gel column chromatography to obtain compound (I)-5.

[0252]

[0253] Yellow powder, 53% yield, (0.21 mmol, 60 mg of product), eluent: methanol containing 1% - 3% ethyl acetate. The NMR characterization data of the product are as follows:

[0254] 1 H NMR (400 MHz, CD 2 Cl 2 ) 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)。

[0255] 13 C NMR (101 MHz, CD 2 Cl 2 )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。

[0256] 31 P NMR (162 MHz, CD 2 Cl 2 )δ -11.40。

[0257] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 533.2266, found: 533.2254。

[0258] Example 30

[0259] Take a Schlenk flask, add a magnetic stir bar and dry it. Evacuate and backfill with nitrogen three times. Add compound F-3 (0.21 mmol) and 5 mL of freshly distilled tetrahydrofuran to the Schlenk flask and stir to dissolve. Cool the solution to -78 °C in a dry ice-ethanol bath, then add tert-butyllithium reagent (0.25 mmol) dropwise via syringe and stir for 30 minutes. Add compound G-1 (0.32 mmol) dropwise via syringe. Stir at -78 °C for 30 minutes, then slowly warm to room temperature and stir for 2 hours. Then cool the solution to -78 °C in a dry ice-ethanol bath, and add BH 3· THF (0.63 mmol), slowly warmed to room temperature and stirred for 2 h. Then it was quenched with 30 mL of saturated aqueous ammonium chloride solution. The reaction mixture was extracted with dichloromethane three times, the aqueous phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under reduced pressure, and purified by silica gel column chromatography to obtain the borane-protected product. Eluent: petroleum ether containing 5% - 10% ethyl acetate.

[0260] Then, take a Schlenk flask, add a stir bar and dry it, evacuate and backfill with nitrogen three times. Add the borane-protected product, triethylenediamine (0.63 mmol) and 3 mL of toluene to the Schlenk flask, stir to dissolve. Heat to 60 °C and stir for 12 h. The reaction mixture was extracted with dichloromethane three times, the aqueous phases were combined, the organic phase was dried over anhydrous sodium sulfate, filtered, the solvent was removed by distillation under reduced pressure, and purified by silica gel column chromatography to obtain compound (I)-6.

[0261]

[0262] Yellow powder, 22% yield, (0.21 mmol, 25 mg of product), eluent: methanol containing 1% - 3% ethyl acetate. The NMR characterization data of the product are as follows:

[0263] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 7.71 - 7.61 (m, 2H), 7.46 (td, J J = 8.2, 7.7, 2.0 Hz, 2H), 7.37 (dd, J 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 J = 12.6 Hz, 1H), 1.56 (s, 2H), 1.45 (d, J J = 13.3 Hz, 7H), 1.09 (d, J J = 12.7 Hz, 2H), 1.01 - 0.92 (m, 2H), 0.90 - 0.83 (m, 1H), 0.79 (d, J J = 12.8 Hz, 1H), 0.52 (d,J = 12.4 Hz, 1H).

[0264] 13 C NMR (101 MHz, CD 2 Cl 2 ) 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.

[0265] 31 P NMR (162 MHz, CD 2 Cl 2 ) δ -11.31.

[0266] HRMS (ESI): calculated for C 23 H 23 N [M + H] + 595.2423, found: 595.2394.

[0267] Example 31

[0268] Take two dry and anhydrous vials and magnetic stirrers. Under N 2 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 under N 2 atmosphere, mix tris(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (Compound (I)-4) (0.08 mmol), 1,4-dioxane (1 mL) in another vial, 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.

[0269] Quench the reaction solution with saturated ammonium chloride solution; extract three times with dichloromethane; absorb water with anhydrous sodium sulfate; filter; concentrate under reduced pressure; purify by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain Compound J-1.

[0270]

[0271] Yellow oily liquid, 75% yield, (0.2 mmol, 26 mg of product), eluent: petroleum ether containing 8% - 20% ethyl acetate. The NMR characterization data of the product is as follows:

[0272] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 8.59 - 8.53 (m, 1H), 7.57 (td, J = 7.7, 1.8 Hz, 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).

[0273] 13 C NMR (101 MHz, CDCl 3 ) δ 165.00, 149.02, 145.03, 136.57, 128.50, 127.71, 126.35, 122.19, 121.27, 47.33, 20.75.

[0274] Example 32

[0275] Take two dry and anhydrous vials and magnetic stirrers. Under N 2 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 under N 2 atmosphere, mix tris(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (Compound (I) - 4) (0.08 mmol), 1,4 - dioxane (1 mL) in another vial, stir for 10 minutes, mix the reaction solutions in the two vials, add 4 - bromo - N , N - dimethylaniline (0.2 mmol), heat to 40 °C, and stir for 24 hours.

[0276] Quench the reaction solution with saturated ammonium chloride solution; extract with dichloromethane three times; absorb water with anhydrous sodium sulfate; filter; concentrate under reduced pressure; purify by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain Compound J - 2.

[0277]

[0278] Yellow oily liquid, yield 71% (0.2 mmol, 32 mg of product), eluent: petroleum ether containing 8% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0279] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 8.55 (ddd, J J = 4.9, 1.9, 0.9 Hz, 1H), 7.54 (td, J 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 J = 7.2 Hz, 1H), 2.91 (s, 6H), 1.68 (d, J J = 7.2 Hz, 3H).

[0280] 13 C NMR (101 MHz, CDCl 3 ) 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.

[0281] Example 33

[0282] Take two dry and anhydrous vials and magnetic stirrers. Under N 2 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 under N 2 atmosphere, mix tris(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (Compound (I) - 4) (0.08 mmol), 1,4 - dioxane (1 mL) in another vial, 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.

[0283] Quench the reaction solution with saturated ammonium chloride solution; extract three times with dichloromethane; absorb water with anhydrous sodium sulfate; filter; concentrate under reduced pressure; purify by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain Compound J - 3.

[0284]

[0285] Yellow oily liquid, yield 72% (0.2 mmol, 33 mg of product). Eluent: Petroleum ether containing 8% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0286] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 8.63 - 8.57 (m, 1H), 7.79 (q, J J = 8.9, 7.9 Hz, 4H), 7.57 (td, J J = 7.7, 1.7 Hz, 1H), 7.51 - 7.38 (m, 3H), 7.18 - 7.07 (m, 2H), 4.49 (q, J J = 7.2 Hz, 1H), 1.81 (d, J J = 7.2 Hz, 3H).

[0287] 13 C NMR (101 MHz, CDCl 3 ) 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.

[0288] Example 34

[0289] Take two dry and anhydrous vials and magnetic stirrers. Under N 2 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 under N 2 atmosphere, mix tris(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (Compound (I) - 4) (0.08 mmol), 1,4 - dioxane (1 mL) in another vial, stir for 10 minutes, mix the reaction solutions in the two vials, add 4 - bromophenetole (0.2 mmol), heat to 40 °C, and stir for 24 hours.

[0290] The reaction solution was quenched with saturated ammonium chloride solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain compound J-4.

[0291]

[0292] Yellow oily liquid, yield 70% (0.2 mmol, 36 mg of product), eluent: petroleum ether containing 8% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0293] 1 H NMR (400 MHz, CD 2 Cl 2 ) 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).

[0294] 13 C NMR (101 MHz, CDCl 3 ) 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.

[0295] Example 35

[0296] Prepare two dry and anhydrous vials and magnetic stirrers. Under N 2 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, under N 2 atmosphere, mix tris(dibenzylideneacetone)dipalladium (0.04 mmol) and ligand (compound (I)-4) (0.08 mmol), 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-methylcyclohexyloxy)benzene (0.2 mmol), heated to 40 °C and stirred for 24 hours.

[0297] The reaction mixture was quenched with saturated ammonium chloride solution; extracted three times with dichloromethane; dried over anhydrous sodium sulfate; filtered; concentrated under reduced pressure; purified by column chromatography using petroleum ether / ethyl acetate as the eluent to obtain Compound J-5.

[0298]

[0299] White solid, 74% yield, (0.2 mmol, 50 mg of product), eluent: petroleum ether containing 8% - 20% ethyl acetate. The NMR characterization data of the product are as follows:

[0300] 1 H NMR (400 MHz, CD 2 Cl 2 ) δ 8.58 - 8.43 (m, 1H), 7.53 (td, J J = 7.7, 1.5Hz, 1H), 7.22 (dd, J J = 8.0, 6.6 Hz, 4H), 7.18 - 7.12 (m, 2H), 7.12 - 7.04 (m,5H), 7.01 (d, J J = 7.8 Hz, 1H), 5.65 (s, 1H).

[0301] 13 C NMR (101 MHz, CDCl 3 ) δ 163.1, 149.4, 142.6, 136.6, 129.4, 128.4,126.5, 123.8, 121.5, 59.2.

[0302] The above specific embodiments are used to explain the present invention, which are only the preferred embodiments of the present invention, rather than limiting the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and scope of the claims of the present invention 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 is hydrogen; R2 is hydrogen; R3 is selected from hydrogen, C1-C10 alkyl, C10-C30 aryl; R4 and R5 are each independently selected from C1-C10 alkyl and C3-C8 cycloalkyl.

2. The method for preparing a 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 preparation method according to claim 2, characterized in that: The compound F is prepared by reacting compound D with compound E:

4. The preparation method according to claim 3, characterized in that: The compound D is prepared by reacting compound C with pinacol:

5. The preparation method according to claim 4, characterized in that: The compound C is prepared by reacting compound B with trimethyl borate:

6. The preparation method according to claim 5, characterized in that: The compound B is prepared by reacting compound A with (1R, 2S, 5R)-(-)-menthol (S)-p-toluenesulfinate:

7. Use of the ferrocenyl biaryl chiral monophosphine ligand according to claim 1 in an organic synthesis catalytic reaction, wherein the organic synthesis catalytic reaction is a CH arylation reaction at the benzyl position of pyridine.

8. A ferrocenyl biaryl chiral monophosphine ligand, characterized in that: The structural formula of the ferrocenyl biaryl chiral monophosphine ligand is shown below:

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