Chiral phosphine ferrocenes containing five-membered heterocyclic thiol skeleton, synthesis method and application thereof

Abstract

The application discloses a chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton and a synthesis method and application thereof; under a nitrogen atmosphere, (1R)-diphenyl phosphine-(2S)-acetoxyethyl ferrocene shown in formula (I) and a thiol five-membered heterocyclic derivative shown in formula (II) are mixed in an organic solvent, reflux reaction is carried out, a reaction process is tracked by TLC, after-treatment is carried out after the reaction is completed, and the chiral phosphine ferrocene containing the five-membered heterocyclic thiol skeleton shown in formula (III) is obtained; the compound can be used as a chiral ligand, forms a complex with a metal to be used as a catalyst, converts simple ketones into chiral alcohols through asymmetric catalytic hydrogenation, or creates a good reaction environment for some simple nucleophilic reactions.

Description

Technical Field

[0001] This invention relates to the fields of chiral phosphine ferrocene catalysts and asymmetric catalytic reaction technology, and particularly to a chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton, its synthesis method, and its applications. Background Technology

[0002] Asymmetric catalytic synthesis of chiral compounds is a field with immense application and research value. Asymmetric catalytic reactions exhibit a chiral scale-up effect, requiring only a small amount of chiral catalyst to yield a large quantity of chiral products. This makes it a green, efficient, and energy-saving synthetic method. In the field of asymmetric catalysis, the primary goal is to develop highly efficient chiral catalysts and ligands for the efficient chiral catalysis of a specific type of reaction. Therefore, various chiral catalytic systems have emerged in recent years. Chiral ferrocene is one such widely used and excellent chiral ligand. The ferrocene framework possesses strong stereochemistry, high stability, and is inexpensive and readily available, making it a common chiral ligand for metal catalysis in various asymmetric catalytic reactions.

[0003] In 2001, Hayashi's group pointed out that the substance integrated with transition metals and ferrocene ligands could be complexed with palladium to catalyze the allylic alkylation of 1,3-diphenyl-2-acetate with good results, but the reaction conditions were demanding and the reaction time was long. (Organometallics, 2001, 20, 3913-3917.)

[0004] In 2003, Knochel discovered that N-type ferrocene ligands could be used in asymmetric allylic alkylation reactions to achieve high enantioselectivity, but the yield was low. (Angew Chem International Edition, 2003, 42, 3941-3943.)

[0005] In 2016, Zhong Weihui disclosed a ferrocene catalyst with a thiophene structure in patent document CN104974192A and used it in asymmetric cycloaddition reactions. It exhibits high selectivity and a wide range of applications, further expanding the types and uses of ferrocene ligands.

[0006] In 2017, Professor Zhang Xumu developed a novel PNN tripentate ligand Ir-f-Amphox system by further modifying the ferrocene framework groups. This system was then applied to the asymmetric catalytic hydrogenation of ketones, demonstrating significant industrial application value. (Organic Letters, 2016, 18, 2938-2941.)

[0007] Although chiral ferrocene phosphine ligands are a very important class of ligands in the field of asymmetric catalysis, most of the current development and research are based on nitrogen and phosphorus ligands, and there is still a lot of room for development in the application of coordination with other atoms. Summary of the Invention

[0008] This invention provides a chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton and its synthesis method, as well as its application in the asymmetric catalytic hydrogenation of simple ketones and the asymmetric allyl substitution reaction of amino groups.

[0009] The technical solution of the present invention is as follows:

[0010] A chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton, as shown in formula (III):

[0011]

[0012] In formula (III), R is one of the following groups:

[0013]

[0014] The dashed line indicates the point where it connects to the S.

[0015] The method for synthesizing chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton, as shown in formula (III), is as follows:

[0016] Under a nitrogen atmosphere, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene as shown in formula (I) and the thiol five-membered heterocyclic derivative as shown in formula (II) were mixed in an organic solvent, and the reaction was carried out under reflux. The reaction process was monitored by TLC. After the reaction was completed, the chiral phosphinocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III) was obtained.

[0017] The reaction formula is as follows:

[0018]

[0019] The definition of R in equation (II) is the same as that in equation (III);

[0020] The molar ratio of (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene shown in formula (I) to the mercapto five-membered heterocyclic derivative shown in formula (II) is 1:1.0 to 10.0, preferably 1:1.5 to 2.0;

[0021] The organic solvent is selected from one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, acetone, and methanol; the volume molar ratio of the organic solvent to (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene shown in formula (I) is 5 to 20:1, mL / mmol.

[0022] The preferred organic solvent is acetonitrile, and the reaction is preferably carried out under reflux at 82°C for 4–6 hours.

[0023] The specific post-processing method is as follows: After the reaction is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated under reduced pressure, and separated by column chromatography with 100-200 mesh silica gel. Gradient elution is performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1 as the eluent. The eluent containing the target compound is collected and evaporated to dryness under reduced pressure to obtain the chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III).

[0024] The chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton shown in formula (III) of this invention can be used for asymmetric catalytic hydrogenation of ketones, and also for asymmetric allyl substitution of amino groups.

[0025] A specific example of the asymmetric catalytic hydrogenation reaction of ketones is the catalytic hydrogenation of acetophenone to synthesize a chiral alcohol, and the operation method is as follows:

[0026] Under a nitrogen atmosphere, a chiral phosphine ferrocene (III) containing a five-membered heterocyclic thiol skeleton, 1,5-cyclooctadiene iridium chloride dimer, and isopropanol were mixed and stirred at room temperature for 1 h to serve as a pre-catalyst system. Then, acetophenone (IV), isopropanol, sodium tert-butoxide were mixed with the pre-catalyst system and stirred at room temperature under a H2 atmosphere for 12–48 h. The reaction solution was post-treated to obtain the product (R)-1-phenylethanol (V).

[0027] The reaction formula is as follows:

[0028]

[0029] In preferred chiral phosphine ferrocene (III) containing a five-membered heterocyclic thiol skeleton, R is...

[0030] Examples of asymmetric allyl substitution reactions of amino groups include:

[0031] Under a nitrogen atmosphere, a chiral phosphine ferrocene (III) containing a five-membered heterocyclic thiol skeleton, tris(dibenzylacetone)dipalladium, and dichloromethane were mixed and stirred at room temperature for 1 h as a pre-catalyst system. Then, (E)-1,3-diphenylallyl acetate (VI) and benzylamine were added, and the reaction was stirred at room temperature for 12–48 h. After post-treatment, the reaction solution yielded the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (VII).

[0032] The reaction formula is as follows:

[0033]

[0034] In preferred chiral phosphine ferrocene (III) containing a five-membered heterocyclic thiol skeleton, R is...

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] A chiral ferrophosphine containing a five-membered heterocyclic thiol skeleton was designed and synthesized for the first time, and its efficient application in simple ketone catalytic hydrogenation and chiral amino substitution reactions was demonstrated. This invention offers advantages such as high product yield, mild preparation conditions, a wide range of reaction substrates, and inexpensive and readily available reagents. The obtained chiral ferrophosphine containing a five-membered heterocyclic thiol skeleton has significant application value. Detailed Implementation

[0037] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0038] In the following embodiments,

[0039] Compound (I) can be synthesized with reference to the literature (Iridium Catalysts with f-Amphox Ligands: Asymmetric Hydrogenation of Simple Ketones.DOI:10.1021 / acs.orglett.6b01290).

[0040] Compounds II-a: Aladdin 25g CAS: 583-39-1 2-Mercaptobenzimidazole ≥98%; II-b: Aladdin 25g CAS: 2382-96-9 2-Mercaptobenzimidazole ≥98%; II-c: Aladdin 25g CAS: 149-30-4 2-Mercaptobenzimidazole ≥98%; II-d: Bid 25g CAS: 85916-84-3 1-Methyl-2-mercaptoimidazole 98%; II-e: Aladdin 25g CAS: 29490-19-5 2-Mercapto-5-methyl-1,3,4-thiadiazole ≥99%; II-f: Bid 100g CAS: 13183-79-4 5-Mercapto-1-methyltetrazole 98%.

[0041] Examples 1-a to 1-f are the synthesis of chiral phosphine ferrocene(III) containing a five-membered heterocyclic thiol skeleton.

[0042] Example 1-a:

[0043] The reaction formula is:

[0044]

[0045] Under nitrogen protection, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene (0.2 mmol, 91.2 mg) of formula (I) and 2-mercaptobenzimidazole (0.4 mmol, 60.0 mg) of formula (II)-a were added to a dry 10 mL pressure-resistant tube, and acetonitrile (2.0 mL) was added to the tube. The mixture was then stirred at 82 °C for 4 h with a magnetic stirrer, and the reaction progress was monitored by TLC and liquid chromatography. After compound (I) had reacted completely, the reaction solution was extracted with dichloromethane, the organic phase was concentrated, and then separated by column chromatography using 100-200 mesh silica gel. The eluent was a gradient elution of a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the five-membered heterocyclic thiol-substituted chiral phosphinocene catalyst (98.3 mg, yield: 90%) of formula (III)-a. NMR(400MHz,Chloroform-d)δ10.88(s,1H),7.50-7.39(m,3H),7.31(dd,J=8.7,5 .2Hz,4H),7.07(d,J=8.1Hz,1H),7.01-6.89(m,4H),6.93-6.78(m,7H),6.78-6.72 (m,2H),6.66(t,J=7.4Hz,3H),4.89(s,1H),4.42(t,J=2.6Hz,1H),4.25(s,5H),3 .76(s,1H),1.84(d,J=6.9Hz,3H),1.44-1.19(m,3H).HRMS:m / z=547.1061[M+H]+.

[0046] Example 1-b:

[0047] The reaction formula is:

[0048]

[0049] Under nitrogen protection, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene (0.2 mmol, 91.2 mg) of formula (I) and 2-mercaptobenzoxazole (0.4 mmol, 60.4 mg) of formula (II)-b were added to a dry 10 mL pressure-resistant tube, and acetonitrile (2.0 mL) was added to the tube. The mixture was then stirred at 82 °C for 4 h with a magnetic stirrer, and the reaction progress was monitored by TLC and liquid chromatography. After compound (I) had reacted completely, the reaction solution was extracted with dichloromethane, the organic phase was concentrated, and then separated by column chromatography using 100-200 mesh silica gel. The eluent was a gradient elution of a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the five-membered heterocyclic thiol-substituted chiral phosphinocene catalyst (103.9 mg, yield: 95%) of formula (III)-b). NMR(400MHz,Chloroform-d)δ7.51-7.42(m,3H),7.37-7.26(m,4H),7.04-6.86(m,5H), 6.86-6.78(m,3H),6.69(t,J=7.5Hz,2H),6.53(s,1H),4.86(s,1H),4.44(t,J=2.6Hz,1H ),4.38-4.28(m,1H),4.23(s,5H),3.85-3.80(m,1H),1.85(d,J=7.0Hz,3H),1.63(d,J= 3.1Hz, 2H), 1.38 (d, J=15.4Hz, 1H), 1.29 (d, J=12.0Hz, 2H). HRMS: m / z=548.0859[M+H]+.

[0050] Example 1-c:

[0051] The reaction formula is:

[0052]

[0053] Under nitrogen protection, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene (0.2 mmol, 91.2 mg) of formula (I) and 2-mercaptobenzothiazole (0.4 mmol, 66.8 mg) of formula (II)-c were added to a dry 10 mL pressure-resistant tube, and acetonitrile (2.0 mL) was added to the tube. The mixture was then stirred at 82 °C for 4 h with a magnetic stirrer, and the reaction progress was monitored by TLC and liquid chromatography. After compound (I) had reacted completely, the reaction solution was extracted with dichloromethane, the organic phase was concentrated, and then separated by column chromatography using 100-200 mesh silica gel. The eluent was a gradient elution of a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the five-membered heterocyclic thiol-substituted chiral phosphinocene catalyst (103.6 mg, yield: 92%) of formula (III)-c. NMR(400MHz,Chloroform-d)δ7.48-7.20(m,9H),7.05(dtd,J=16.2,7.3,1.3Hz,3H),6.99-6.86(m,2H),6.81-6.63(m,4H),4.90(s,1H ),4.42(t,J=2.5Hz,1H),4.21(s,5H),3.79(s,1H),1.87(d,J=7.1Hz,3H),1.63(s,3H),1.42-1.24(m,4H).HRMS:m / z=564.0676[M+H]+.

[0054] Example 1-d:

[0055] The reaction formula is:

[0056]

[0057] Under nitrogen protection, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene (0.2 mmol, 91.2 mg) of formula (I) and 1-methyl-2-mercaptoimidazole (0.4 mmol, 45.6 mg) of formula (II)-d were added to a dry 10 mL pressure-resistant tube, and acetonitrile (2.0 mL) was added to the tube. The mixture was then stirred at 82 °C for 4 h with a magnetic stirrer, and the reaction progress was monitored by TLC and liquid chromatography. After compound (I) had reacted completely, the reaction solution was extracted with dichloromethane, and the organic phase was concentrated and separated by column chromatography using 100-200 mesh silica gel. The eluent was a gradient elution of a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the five-membered heterocyclic thiol-substituted chiral phosphinocene catalyst (96.9 mg, yield: 95%) of formula (III)-d. NMR(400MHz,Chloroform-d)δ7.53-7.44(m,2H),7.40-7.26(m,4H),7.12-7.00(m,5H), 6.29-6.19(m,1H),6.05(d,J=2.4Hz,1H),5.89(d,J=2.4Hz,1H),4.62(d,J=1.9Hz,1H), 4.38(t,J=2.7Hz,1H),4.15(s,5H),3.86-3.78(m,1H),3.08(s,2H),1.68(d,J=6.8Hz,3 H),1.37(s,1H),1.27(d,J=10.2Hz,3H),0.91-0.81(m,1H).HRMS:m / z=511.1055[M+H]+.

[0058] Example 1-e:

[0059] The reaction formula is:

[0060]

[0061] Under nitrogen protection, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene (0.2 mmol, 91.2 mg) as shown in formula (I) and 2-mercapto-5-methyl-1,3,4-thiadiazole (0.4 mmol, 52.9 mg) as shown in formula (II)-e were added to a dry 10 mL pressure-resistant tube, and acetonitrile (2.0 mL) was added to the tube using a syringe. The mixture was then stirred at 82 °C for 4 h with a magnetic stirrer, and the reaction progress was monitored using TLC and liquid chromatography. After compound (I) has reacted completely, the reaction solution is extracted with dichloromethane. The organic phase is concentrated and then separated by column chromatography using 100-200 mesh silica gel. The eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1 for gradient elution. The eluent containing the target compound is collected, the solvent is concentrated and dried to obtain the five-membered heterocyclic thiol-substituted chiral phosphine ferrocene catalyst (100.3 mg, yield: 95%) represented by formula (III)-e. NMR(400MHz,Chloroform-d)δ7.47(pd,J=5.3,4.7,2.9Hz,2H),7.35(dqd,J=4.8,3.6,1.4Hz,3H ),7.24-7.11(m,3H),7.06(tt,J=7.0,1.5Hz,2H),6.57(qd,J=6.8,2.4Hz,1H),4.71(dt,J=2.8, 1.5Hz,1H),4.40(t,J=2.6Hz,1H),4.16(s,4H),3.76(dt,J=2.3,1.1Hz,1H),2.10(s,3H),1.78( d,J=6.8Hz,3H),1.33-1.24(m,3H),0.91-0.86(m,1H),0.09(s,3H).HRMS:m / z=529.0619[M+H]+.

[0062] Example 1-f:

[0063] The reaction formula is:

[0064]

[0065] Under nitrogen protection, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene (0.2 mmol, 91.2 mg) of formula (I) and 5-mercapto-1-methyltetraazole (0.4 mmol, 46.5 mg) of formula (II)-f were added to a dry 10 mL pressure-resistant tube, and acetonitrile (2.0 mL) was added to the tube. The mixture was then stirred at 82 °C for 4 h with a magnetic stirrer, and the reaction progress was monitored by TLC and liquid chromatography. After compound (I) had reacted completely, the reaction solution was extracted with dichloromethane, the organic phase was concentrated, and then separated by column chromatography using 100-200 mesh silica gel. The eluent was a gradient elution of a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the five-membered heterocyclic thiol-substituted chiral phosphinocene catalyst (90.1 mg, yield: 88%) of formula (III)-f. NMR (400MHz, Chloroform-d) δ7.45(d,J=8.1Hz,2H),7.36(d,J=5.4Hz,3H),7.14(q,J=7.6,6.8Hz,3H),6.95(t,J=7.1Hz,2H),6.26(dd,J=7. 1,2.9Hz,1H),4.83(s,1H),4.46(d,J=2.5Hz,1H),4.20(s,5H),3.77(s,1H),3.31(s,3H),1.88(d,J=6.8Hz,3H).HRMS:m / z=513.0979[M+H]+.

[0066] Examples 2-a to 2-f illustrate the application of chiral phosphine ferrocene(III) containing a five-membered heterocyclic thiol skeleton in the catalytic hydrogenation of acetophenone to a chiral alcohol.

[0067] Example 2-a:

[0068] Under nitrogen protection, catalyst 1,5-cyclooctadiene iridium chloride dimer (6.71 mg, 0.01 mmol) and ligand (III)-a (10.92 mg, 0.02 mmol) were added to 2.0 mL of anhydrous isopropanol in a 10.0 mL vial. The mixture was stirred at 25 °C for 1 h.

[0069] Acetophenone (1.2 g, 10 mmol), isopropanol (2 mL), and sodium tert-butoxide (48 mg, 0.5 mmol) were added to a 10 mL liner of an autoclave. Then, a solution of the pre-catalyst in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was rapidly purged three times with hydrogen and then pressurized to 80 bar H2. The reaction solution was stirred at room temperature for 12 h, and the pressure was carefully released. The reaction mixture was purified by silica gel column chromatography with ethyl acetate, the solvent was removed under reduced pressure, and the solution was dried to give compound (V)(R)-1-phenylethanol (1.10 g, 90% yield, 91% ee).

[0070] Example 2-b:

[0071] Under nitrogen protection, catalyst 1,5-cyclooctadiene iridium chloride dimer (6.71 mg, 0.01 mmol) and ligand (III)-b (10.94 mg, 0.02 mmol) were added to 2.0 mL of anhydrous isopropanol in a 10.0 mL vial. The mixture was stirred at 25 °C for 1 h.

[0072] Acetophenone (1.2 g, 10 mmol), isopropanol (2 mL), and sodium tert-butoxide (48 mg, 0.5 mmol) were added to a 10 mL liner of an autoclave. Then, a solution of the pre-catalyst in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was rapidly purged three times with hydrogen and then pressurized to 80 bar H2. The reaction solution was stirred at room temperature for 12 h, and the pressure was carefully released. The reaction mixture was purified by silica gel column chromatography with ethyl acetate. The solvent was removed under reduced pressure, and the solution was dried to give compound (V)(R)-1-phenylethanol (0.92 g, 75% yield, 11% ee).

[0073] Example 2-c:

[0074] Under nitrogen protection, catalyst 1,5-cyclooctadiene iridium chloride dimer (6.71 mg, 0.01 mmol) and ligand (III)-c (11.26 mg, 0.02 mmol) were added to 2.0 mL of anhydrous isopropanol in a 10.0 mL vial. The mixture was stirred at 25 °C for 1 h.

[0075] Acetophenone (1.2 g, 10 mmol), isopropanol (2 mL), and sodium tert-butoxide (48 mg, 0.5 mmol) were added to a 10 mL liner of an autoclave. Then, a solution of the pre-catalyst in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was rapidly purged three times with hydrogen and then pressurized to 80 bar H2. The reaction solution was stirred at room temperature for 12 h, and the pressure was carefully released. The reaction mixture was purified by silica gel column chromatography with ethyl acetate, the solvent was removed under reduced pressure, and the solution was dried to give compound (V)(R)-1-phenylethanol (0.98 g, 80% yield, 26% ee).

[0076] Example 2-d:

[0077] Under nitrogen protection, catalyst 1,5-cyclooctadiene iridium chloride dimer (6.71 mg, 0.01 mmol) and ligand (III)-d (10.20 mg, 0.02 mmol) were added to 2.0 mL of anhydrous isopropanol in a 10.0 mL vial. The mixture was stirred at 25 °C for 1 h.

[0078] Acetophenone (1.2 g, 10 mmol), isopropanol (2 mL), and sodium tert-butoxide (48 mg, 0.5 mmol) were added to a 10 mL liner of an autoclave. Then, a solution of the pre-catalyst in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was rapidly purged three times with hydrogen and then pressurized to 80 bar H₂. The reaction solution was stirred at room temperature for 12 h, and the pressure was carefully released. The reaction mixture was purified by silica gel column chromatography with ethyl acetate, the solvent was removed under reduced pressure, and the solution was dried to give compound (V)(R)-1-phenylethanol (1.10 g, 90% yield, 12% ee).

[0079] Example 2-e:

[0080] Under nitrogen protection, catalyst 1,5-cyclooctadiene iridium chloride dimer (6.71 mg, 0.01 mmol) and ligand (III)-e (10.56 mg, 0.02 mmol) were added to 2.0 mL of anhydrous isopropanol in a 10.0 mL vial. The mixture was stirred at 25 °C for 1 h.

[0081] Acetophenone (1.2 g, 10 mmol), isopropanol (2 mL), and sodium tert-butoxide (48 mg, 0.5 mmol) were added to a 10 mL liner of an autoclave. Then, a solution of the pre-catalyst in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was rapidly purged three times with hydrogen and then pressurized to 80 bar H2. The reaction solution was stirred at room temperature for 12 h, and the pressure was carefully released. The reaction mixture was purified by silica gel column chromatography with ethyl acetate, the solvent was removed under reduced pressure, and the solution was dried to give compound (V)(R)-1-phenylethanol (1.00 g, 82% yield, 21% ee).

[0082] Example 2-f:

[0083] Under nitrogen protection, catalyst 1,5-cyclooctadiene iridium chloride dimer (6.71 mg, 0.01 mmol) and ligand (III)-f (10.24 mg, 0.02 mmol) were added to 2.0 mL of anhydrous isopropanol in a 10.0 mL vial. The mixture was stirred at 25 °C for 1 h.

[0084] Acetophenone (1.2 g, 10 mmol), isopropanol (2 mL), and sodium tert-butoxide (48 mg, 0.5 mmol) were added to a 10 mL liner of an autoclave. Then, a solution of the pre-catalyst in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was rapidly purged three times with hydrogen and then pressurized to 80 bar H2. The reaction solution was stirred at room temperature for 12 h, and the pressure was carefully released. The reaction mixture was purified by silica gel column chromatography with ethyl acetate, the solvent was removed under reduced pressure, and the solution was dried to give compound (V)(R)-1-phenylethanol (1.16 g, 95% yield, 1% ee).

[0085] Examples 3-a to 3-f illustrate the application of chiral phosphine ferrocene(III) containing a five-membered heterocyclic thiol skeleton in catalyzing asymmetric allyl substitution reactions of amino groups.

[0086] Example 3-a:

[0087] The ligand (III)-a (10.92 mg, 0.02 mmol) and the catalyst tris(dibenzylacetone)palladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen atmosphere. The tube was evacuated using a high-vacuum oil pump and then filled with nitrogen. This process was repeated three times. Then, 3 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 h. Then, (0.25 g, 1 mmol) (E)-1,3-diphenylallyl acetate (VI) and benzylamine (0.128 g, 1.2 mmol) were added. The mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC and liquid chromatography. Separation was performed by column chromatography using 100-200 mesh silica gel. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (0.275 g, yield 92%, 12% ee) as shown in (VII). 1H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,2H),7.52–7.40(m,9H),7.40–7.32(m,4H),7.31(d,J=7.2H z,1H),6.71(d,J=15.8Hz,1H),6.45(dd,J=15.8,7.5Hz,1H),4.52(d,J=7.5Hz,1H),3.97–3.85(m,2H).

[0088] Example 3-b:

[0089] The ligand (III)-b (10.94 mg, 0.02 mmol) and the catalyst tris(dibenzylacetone)palladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen atmosphere. The tube was evacuated using a high-vacuum oil pump and then filled with nitrogen. This process was repeated three times. Then, 3 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 h. Then, (0.25 g, 1 mmol) (E)-1,3-diphenylallyl acetate (VI) and benzylamine (0.128 g, 1.2 mmol) were added. The mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC and liquid chromatography. Separation was performed by column chromatography using 100-200 mesh silica gel. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (0.287 g, yield 96%, 55% ee) as shown in (VII). 1H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,2H),7.52–7.40(m,9H),7.40–7.32(m,4H),7.31(d,J=7.2H z,1H),6.71(d,J=15.8Hz,1H),6.45(dd,J=15.8,7.5Hz,1H),4.52(d,J=7.5Hz,1H),3.97–3.85(m,2H).

[0090] Example 3-c:

[0091] The ligand (III)-c (11.26 mg, 0.02 mmol) and the catalyst tris(dibenzylacetone)palladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen atmosphere. The tube was evacuated using a high-vacuum oil pump and then filled with nitrogen. This process was repeated three times. Then, 3 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 h. Then, (0.25 g, 1 mmol) (E)-1,3-diphenylallyl acetate (VI) and benzylamine (0.128 g, 1.2 mmol) were added. The mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC and liquid chromatography. Separation was performed by column chromatography using 100-200 mesh silica gel. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (0.284 g, yield 95%, 82% ee) as shown in (VII). 1H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,2H),7.52–7.40(m,9H),7.40–7.32(m,4H),7.31(d,J=7.2H z,1H),6.71(d,J=15.8Hz,1H),6.45(dd,J=15.8,7.5Hz,1H),4.52(d,J=7.5Hz,1H),3.97–3.85(m,2H).

[0092] Example 3-d:

[0093] The ligand (III)-d (10.20 mg, 0.02 mmol) and the catalyst tris(dibenzylacetone)palladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen atmosphere. The tube was evacuated using a high-vacuum oil pump and then filled with nitrogen. This process was repeated three times. Then, 3 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 h. Then, (0.25 g, 1 mmol) (E)-1,3-diphenylallyl acetate (VI) and benzylamine (0.128 g, 1.2 mmol) were added. The mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC and liquid chromatography. Separation was performed by column chromatography using 100-200 mesh silica gel. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (0.284 g, yield 95%, 12% ee) as shown in (VII). 1H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,2H),7.52–7.40(m,9H),7.40–7.32(m,4H),7.31(d,J=7.2H z,1H),6.71(d,J=15.8Hz,1H),6.45(dd,J=15.8,7.5Hz,1H),4.52(d,J=7.5Hz,1H),3.97–3.85(m,2H).

[0094] Example 3-e:

[0095] The ligand (III)-e (10.56 mg, 0.02 mmol) and the catalyst tris(dibenzylacetone)palladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen atmosphere. The tube was evacuated using a high-vacuum oil pump and then filled with nitrogen. This process was repeated three times. Then, 3 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 h. Then, (0.25 g, 1 mmol) (E)-1,3-diphenylallyl acetate (VI) and benzylamine (0.128 g, 1.2 mmol) were added. The mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC and liquid chromatography. Separation was performed by column chromatography using 100-200 mesh silica gel. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (0.275 g, yield 92%, 33% ee) as shown in (VII). 1H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,2H),7.52–7.40(m,9H),7.40–7.32(m,4H),7.31(d,J=7.2H z,1H),6.71(d,J=15.8Hz,1H),6.45(dd,J=15.8,7.5Hz,1H),4.52(d,J=7.5Hz,1H),3.97–3.85(m,2H).

[0096] Example 3-f:

[0097] The ligand (III)-f (10.24 mg, 0.02 mmol) and the catalyst tris(dibenzylacetone)palladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen atmosphere. The tube was evacuated using a high-vacuum oil pump and then filled with nitrogen. This process was repeated three times. Then, 3 mL of dichloromethane was added, and the mixture was stirred at room temperature for 1 h. Then, (0.25 g, 1 mmol) (E)-1,3-diphenylallyl acetate (VI) and benzylamine (0.128 g, 1.2 mmol) were added. The mixture was stirred at room temperature for 15 h. The reaction was monitored by TLC and liquid chromatography. Separation was performed by column chromatography using 100-200 mesh silica gel. The eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1. The eluent containing the target compound was collected, the solvent was concentrated and dried to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (0.275 g, yield 92%, 25% ee) as shown in (VII). 1H NMR(400MHz,Chloroform-d)δ7.60–7.52(m,2H),7.52–7.40(m,9H),7.40–7.32(m,4H),7.31(d,J=7.2H z,1H),6.71(d,J=15.8Hz,1H),6.45(dd,J=15.8,7.5Hz,1H),4.52(d,J=7.5Hz,1H),3.97–3.85(m,2H).

Claims

1. A chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton, as shown in formula (III): In formula (III), R is one of the following groups: The dashed line indicates the point where it connects to the S.

2. The method for synthesizing chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III) of claim 1, characterized in that, The synthesis method is as follows: Under a nitrogen atmosphere, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene as shown in formula (I) and the thiol five-membered heterocyclic derivative as shown in formula (II) were mixed in an organic solvent, and the reaction was carried out under reflux. The reaction process was monitored by TLC. After the reaction was completed, the chiral phosphinocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III) was obtained. The reaction formula is as follows: The definition of R in equation (II) is the same as that in equation (III).

3. The synthesis method as described in claim 2, characterized in that, The molar ratio of (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene shown in formula (I) to the mercapto five-membered heterocyclic derivative shown in formula (II) is 1:1.0 to 10.

0.

4. The synthesis method according to claim 2, characterized in that, The organic solvent is selected from one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, acetone, and methanol.

5. The synthesis method as described in claim 2, characterized in that, The volume molar ratio of the organic solvent to (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene as shown in formula (I) is 5 to 20:1, mL / mmol.

6. The synthesis method according to claim 2, characterized in that, The organic solvent is acetonitrile, and the reaction is carried out under reflux at 82°C for 4–6 hours.

7. The synthesis method according to claim 2, characterized in that, The post-processing method is as follows: After the reaction is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated under reduced pressure, and separated by column chromatography with 100-200 mesh silica gel. Gradient elution is performed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1 as the eluent. The eluent containing the target compound is collected and evaporated to dryness under reduced pressure to obtain the chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III).

8. The application of chiral phosphine ferrocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III) of claim 1 in the asymmetric catalytic hydrogenation of ketones and the asymmetric allyl substitution of amino groups.

9. The application as described in claim 8, characterized in that, The asymmetric catalytic hydrogenation reaction of ketones is as follows: Acetophenone is catalytically hydrogenated to synthesize chiral alcohols. The procedure is as follows: Under a nitrogen atmosphere, a chiral phosphine ferrocene (III) containing a five-membered heterocyclic thiol skeleton, 1,5-cyclooctadiene iridium chloride dimer, and isopropanol were mixed and stirred at room temperature for 1 h to serve as a pre-catalyst system. Then, acetophenone (IV), isopropanol, sodium tert-butoxide were mixed with the pre-catalyst system and stirred at room temperature under a H2 atmosphere for 12–48 h. The reaction solution was post-treated to obtain the product (R)-1-phenylethanol (V). The reaction formula is as follows:

10. The application as described in claim 8, characterized in that, The procedure for the asymmetric allyl substitution reaction of amino groups is as follows: Under a nitrogen atmosphere, a chiral phosphine ferrocene (III) containing a five-membered heterocyclic thiol skeleton, tris(dibenzylacetone)dipalladium, and dichloromethane were mixed and stirred at room temperature for 1 h as a pre-catalyst system. Then, (E)-1,3-diphenylallyl acetate (VI) and benzylamine were added, and the reaction was stirred at room temperature for 12–48 h. After post-treatment, the reaction solution yielded the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (VII). The reaction formula is as follows:

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