Chiral phosphine ferrocene containing five-membered heterocyclic sulfydryl skeleton as well as synthesis method and application of chiral phosphine ferrocene

Abstract

The invention discloses chiral phosphine ferrocene containing a five-membered heterocyclic sulfydryl skeleton as well as a synthesis method and application of the chiral phosphine ferrocene. The preparation method comprises the following steps: in a nitrogen atmosphere, mixing and dissolving (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene as shown in a formula (I) and a sulfydryl five-membered heterocyclic derivative as shown in a formula (II) in an organic solvent, carrying out a reflux reaction, tracking a reaction process by TLC, and carrying out post-treatment after the reaction is finished, so as to obtain the chiral phosphine ferrocene containing the five-membered heterocyclic sulfydryl skeleton as shown in a formula (III), the compound can be used as a chiral ligand and forms a complex with metal to be used as a catalyst, and simple ketone is converted into chiral alcohol through asymmetric catalytic hydrogenation, or a good reaction environment is created for some simple nucleophilic reactions; # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of chiral phosphinoferrocene catalyst and asymmetric catalytic reaction, and in particular to a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton and a synthesis method and application thereof. Background Art

[0002] Asymmetric catalytic synthesis of chiral compounds is a direction with great application and research value. Asymmetric catalytic reactions have a chiral amplification effect. Only a small amount of chiral catalyst is needed to obtain a large amount of chiral products. It is a green, energy-efficient synthesis method. In the field of asymmetric catalytic reactions, the first thing is to develop an efficient chiral catalyst and ligand to efficiently chirally catalyze a type of reaction. Therefore, various chiral catalytic systems have emerged in recent years. Chiral ferrocene is one of the most widely used excellent chiral ligands. The ferrocene skeleton has the characteristics of strong stereochemistry, high stability, and low cost and easy availability. It is often used as a chiral ligand for metal catalysis and is widely used in various asymmetric catalytic reactions.

[0003] In 2001, Hayashi's research group pointed out that the material integrated with transition metal and ferrocene ligand can be complexed with metal palladium to catalyze the allylic alkylation of 1,3-diphenyl-2-propenyl acetate, achieving good results, but the reaction conditions are high and the reaction time is long. (Organometallics, 2001, 20, 3913-3917.)

[0004] In 2003, Knochel found that the use of N-type ferrocene ligands can be applied to asymmetric allylic alkylation reactions, which can achieve higher enantioselectivity, but the yield is not high. (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 has high selectivity and a good range of application, further expanding the types and uses of ferrocene ligands.

[0006] In 2017, Professor Zhang Xumu further modified the ferrocene skeleton group to develop a new PNN tridentate ligand Ir-f-Amphox system, and applied it to the asymmetric catalytic hydrogenation of ketones, which has high industrial application value. (Organic Letters, 2016, 18, 2938-2941.)

[0007] Although chiral ferrocenylphosphine ligands are a very important type of ligand in the field of asymmetric catalysis, most of the current development and research is based on nitrogen-phosphorus ligands. There is still a lot of room for development in the application of other atomic coordination. Summary of the invention

[0008] The invention provides a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton and a synthesis method thereof, as well as applications of the chiral phosphinoferrocene in asymmetric catalytic hydrogenation of simple ketones and asymmetric allyl substitution of amino groups.

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

[0010] A chiral phosphinoferrocene 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 dotted line indicates the connection with S.

[0015] The synthesis method of the chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton shown in formula (III) is:

[0016] Under a nitrogen atmosphere, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene represented by formula (I) and a thiol five-membered heterocyclic derivative represented by formula (II) are mixed and dissolved in an organic solvent, subjected to reflux reaction, and the reaction progress is tracked by TLC. After the reaction is completed, a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton represented by formula (III) is obtained by post-treatment;

[0017] The reaction formula is as follows:

[0018]

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

[0020] The molar ratio of (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene represented by formula (I) to the mercapto five-membered heterocyclic derivative represented by 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 the (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene shown in formula (I) is 5 to 20:1, mL / mmol.

[0022] The preferred organic solvent is acetonitrile, and the reaction is preferably refluxed at 82°C for 4 to 6 hours;

[0023] The specific post-treatment 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 using 100-200 mesh silica gel, and gradient elution is performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 20:1 as an eluent, and the eluate containing the target compound is collected and evaporated to dryness under reduced pressure to obtain a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III).

[0024] The chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton represented by formula (III) of the present invention can be used for the asymmetric catalytic hydrogenation reaction of ketones and can also be used for the asymmetric allyl substitution reaction of amino groups.

[0025] Asymmetric catalytic hydrogenation of ketones is specifically exemplified by the catalytic hydrogenation of acetophenone to synthesize chiral alcohols. The operation method is as follows:

[0026] In a nitrogen atmosphere, chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton, 1,5-cyclooctadiene iridium chloride dimer, and isopropanol are mixed and stirred at room temperature for 1 hour as a pre-catalyst system; then acetophenone (IV), isopropanol, sodium tert-butoxide and the pre-catalyst system are mixed, stirred at room temperature for 12 to 48 hours in a H2 atmosphere, and the reaction solution is post-treated to obtain the product (R)-1-phenylethanol (V);

[0027] The reaction formula is as follows:

[0028]

[0029] Preferably, in the chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton, R is

[0030] The specific examples of asymmetric allyl substitution reactions of amino groups are:

[0031] In a nitrogen atmosphere, chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton, tris(dibenzylideneacetone)dipalladium, and dichloromethane were mixed and stirred at room temperature for 1 hour as a pre-catalyst system, and then (E)-1,3-diphenylallyl acetate (VI) and benzylamine were added and stirred at room temperature for 12 to 48 hours. The reaction solution was post-treated to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (VII);

[0032] The reaction formula is as follows:

[0033]

[0034] Preferably, in the chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton, R is

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] For the first time, a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton is designed and synthesized, and is efficiently applied in the catalytic hydrogenation of simple ketones and chiral amino substitution reactions. The invention has the advantages of high product yield, mild preparation conditions, a wide range of reaction substrates, and cheap and readily available reaction reagents. The obtained chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton has good application value. DETAILED DESCRIPTION

[0037] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0038] In the following embodiments,

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

[0040] Compound II-a: Aladdin 25g CAS: 583-39-1 2-mercaptobenzimidazole ≥ 98%; II-b: Aladdin 25g CAS: 2382-96-9 2-mercaptobenzoxazole ≥ 98%; II-c: Aladdin 25g CAS: 149-30-4 2-mercaptobenzothiazole ≥ 98%; II-d: Bidane 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: Bidane 100g CAS: 13183-79-4 5-mercapto-1-methyltetrazole 98%.

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

[0042] Embodiment 1-a:

[0043] The reaction formula is:

[0044]

[0045] Under nitrogen protection, add (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene (0.2mmol, 91.2mg) and 2-mercaptobenzimidazole (0.4mmol, 60.0mg) shown in formula (I) to a dry 10ml pressure tube, and add acetonitrile (2.0mL) by syringe. Then stir at 82°C for 4h with a magnetic stirrer, and monitor the reaction progress with a TLC plate and liquid chromatography. After the reaction of compound (I) is completed, the reaction solution is extracted with dichloromethane, and the organic phase is concentrated and separated by column chromatography with 100-200 mesh silica gel. The eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 20:1 for gradient elution. The eluent containing the target compound is collected, the solvent is concentrated and dried to obtain a chiral phosphinoferrocene catalyst (98.3mg, yield: 90%) substituted with a five-membered heterocyclic thiol group shown in 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] Embodiment 1-b:

[0047] The reaction formula is:

[0048]

[0049] Under nitrogen protection, add (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene (0.2mmol, 91.2mg) and 2-mercaptobenzoxazole (0.4mmol, 60.4mg) shown in formula (I) to a dry 10ml pressure tube, and add acetonitrile (2.0mL) by syringe. Then stir at 82°C for 4h with a magnetic stirrer, and monitor the reaction progress with a TLC plate and liquid chromatography. After the reaction of compound (I) is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated, and then separated by column chromatography with 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 20:1 for gradient elution. The eluent containing the target compound is collected, the solvent is concentrated and dried to obtain a chiral phosphinoferrocene catalyst (103.9mg, yield: 95%) substituted with a five-membered heterocyclic thiol group shown in 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] Embodiment 1-c:

[0051] The reaction formula is:

[0052]

[0053] Under nitrogen protection, add (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene (0.2mmol, 91.2mg) and 2-mercaptobenzothiazole (0.4mmol, 66.8mg) shown in formula (I) to a dry 10ml pressure tube, and add acetonitrile (2.0mL) to the syringe. Then stir at 82°C for 4h with a magnetic stirrer, and monitor the reaction progress with a TLC plate and liquid chromatography. After the reaction of compound (I) is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated, and then separated by column chromatography with 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 20:1 for gradient elution. The eluent containing the target compound is collected, the solvent is concentrated and dried to obtain a chiral phosphinoferrocene catalyst (103.6mg, yield: 92%) substituted with a five-membered heterocyclic thiol group shown in 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] Embodiment 1-d:

[0055] The reaction formula is:

[0056]

[0057] Under nitrogen protection, add (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene (0.2mmol, 91.2mg) shown in formula (I) and 1-methyl-2-mercaptoimidazole (0.4mmol, 45.6mg) shown in formula (II)-d to a dry 10ml pressure tube, and add acetonitrile (2.0mL) by syringe. Then stir at 82°C for 4h with a magnetic stirrer, and monitor the reaction progress with a TLC plate and liquid chromatography. After the reaction of compound (I) is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated, and then separated by column chromatography with 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 20:1 for gradient elution. The eluent containing the target compound is collected, the solvent is concentrated and dried to obtain a chiral phosphinoferrocene catalyst (96.9mg, yield: 95%) substituted with a five-membered heterocyclic thiol group shown in 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] Embodiment 1-e:

[0059] The reaction formula is:

[0060]

[0061] Under nitrogen protection, add (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene (0.2mmol, 91.2mg) of formula (I) and 2-mercapto-5-methyl-1,3,4-thiadiazole (0.4mmol, 52.9mg) of formula (II)-e to a dry 10ml pressure tube, and add acetonitrile (2.0mL) by syringe. Then stir at 82℃ for 4h with a magnetic stirrer, and monitor the reaction progress with TLC plate and liquid chromatography. After the reaction of compound (I) is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated, and then separated by column chromatography using 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-20:1 for gradient elution. The eluate containing the target compound is collected, the solvent is concentrated and dried to obtain a chiral phosphinoferrocene catalyst substituted with a five-membered heterocyclic thiol group as shown in formula (III)-e (100.3 mg, yield: 95%). 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] Embodiment 1-f:

[0063] The reaction formula is:

[0064]

[0065] Under nitrogen protection, add (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene (0.2mmol, 91.2mg) shown in formula (I) and 5-mercapto-1-methyltetrazole (0.4mmol, 46.5mg) shown in formula (II)-f to a dry 10ml pressure tube, and add acetonitrile (2.0mL) by syringe. Then stir at 82°C for 4h with a magnetic stirrer, and monitor the reaction progress with a TLC plate and liquid chromatography. After the reaction of compound (I) is completed, the reaction solution is extracted with dichloromethane, the organic phase is concentrated, and then separated by column chromatography with 100-200 mesh silica gel, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 20:1 for gradient elution. Collect the eluent containing the target compound, concentrate the solvent and dry it to obtain a chiral phosphinoferrocene catalyst (90.1mg, yield: 88%) substituted with a five-membered heterocyclic thiol group shown in 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 are the use of chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton in the catalytic hydrogenation of acetophenone to chiral alcohol

[0067] Embodiment 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, and 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 inner liner of an autoclave. Then, a precatalyst solution in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was quickly purged with hydrogen three times 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 solution was purified by ethyl acetate silica gel column chromatography, the solvent was removed under reduced pressure, and compound (V) (R)-1-phenylethanol (1.10 g, yield 90%, 91% ee) was obtained after drying.

[0070] Embodiment 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, and 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 inner liner of an autoclave. Then, a precatalyst solution in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was quickly purged with hydrogen three times 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 solution was purified by ethyl acetate silica gel column chromatography, the solvent was removed under reduced pressure, and compound (V) (R)-1-phenylethanol (0.92 g, yield 75%, 11% ee) was obtained after drying.

[0073] Embodiment 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, and 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 inner liner of an autoclave. Then, a precatalyst solution in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was quickly purged with hydrogen three times 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 solution was purified by ethyl acetate silica gel column chromatography, the solvent was removed under reduced pressure, and compound (V) (R)-1-phenylethanol (0.98 g, yield 80%, 26% ee) was obtained after drying.

[0076] Embodiment 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, and 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 inner liner of an autoclave. Then, a precatalyst solution in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was quickly purged with hydrogen three times and then pressurized to 80 bar H2. The reaction solution was stirred at room temperature for 12 h and the pressure was released carefully. The reaction mixture solution was purified by ethyl acetate silica gel column chromatography, the solvent was removed under reduced pressure, and compound (V) (R)-1-phenylethanol (1.10 g, yield 90%, 12% ee) was obtained after drying.

[0079] Embodiment 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, and 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 inner liner of an autoclave. Then, a precatalyst solution in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was quickly purged with hydrogen three times 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 solution was purified by ethyl acetate silica gel column chromatography, the solvent was removed under reduced pressure, and compound (V) (R)-1-phenylethanol (1.00 g, yield 82%, 21% ee) was obtained after drying.

[0082] Embodiment 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, and 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 inner liner of an autoclave. Then, a precatalyst solution in isopropanol (0.01% mmol, 200 μL) was added. The autoclave was quickly purged with hydrogen three times 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 solution was purified by ethyl acetate silica gel column chromatography, the solvent was removed under reduced pressure, and compound (V) (R)-1-phenylethanol (1.16 g, yield 95%, 1% ee) was obtained after drying.

[0085] Examples 3-a to 3-f are the use of chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton in catalyzing the asymmetric allylic substitution reaction of amino groups

[0086] Embodiment 3-a:

[0087] Ligand (III)-a (10.92 mg, 0.02 mmol) and catalyst tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen. The tube was evacuated with a high vacuum oil pump and then filled with nitrogen. This process was repeated 3 times. Then 3 ml of dichloromethane was added and 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. Stir at room temperature for 15 h. The reaction was monitored using TLC plates and liquid chromatography. 100-200 mesh silica gel was used for column chromatography separation, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 for gradient elution. The eluate 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] Embodiment 3-b:

[0089] Ligand (III)-b (10.94 mg, 0.02 mmol) and catalyst tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen. The tube was evacuated with a high vacuum oil pump and then filled with nitrogen. This process was repeated 3 times. Then 3 ml of dichloromethane was added and 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. Stir at room temperature for 15 h. The reaction was monitored using TLC plates and liquid chromatography. Column chromatography was performed on 100-200 mesh silica gel, and gradient elution was performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 10:1 as the eluent. The eluate containing the target compound was collected, and 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] Ligand (III)-c (11.26 mg, 0.02 mmol) and catalyst tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen. The tube was evacuated with a high vacuum oil pump and then filled with nitrogen. This process was repeated 3 times. Then 3 ml of dichloromethane was added and 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. Stir at room temperature for 15 h. The reaction was monitored using TLC plates and liquid chromatography. Column chromatography was performed on 100-200 mesh silica gel, and gradient elution was performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 10:1 as the eluent. The eluate containing the target compound was collected, and 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] Embodiment 3-d:

[0093] Ligand (III)-d (10.20 mg, 0.02 mmol) and catalyst tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen. The tube was evacuated with a high vacuum oil pump and then filled with nitrogen. This process was repeated 3 times. Then 3 ml of dichloromethane was added and 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. Stir at room temperature for 15 h. The reaction was monitored using TLC plates and liquid chromatography. 100-200 mesh silica gel was used for column chromatography separation, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 for gradient elution. The eluate 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] Embodiment 3-e:

[0095] Ligand (III)-e (10.56 mg, 0.02 mmol) and catalyst tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen. The tube was evacuated with a high vacuum oil pump and then filled with nitrogen. This process was repeated 3 times. Then 3 ml of dichloromethane was added and 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. Stir at room temperature for 15 h. The reaction was monitored using TLC plates and liquid chromatography. 100-200 mesh silica gel was used for column chromatography separation, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 1-10:1 for gradient elution. The eluate 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] Embodiment 3-f:

[0097] Ligand (III)-f (10.24 mg, 0.02 mmol) and catalyst tris(dibenzylideneacetone)dipalladium (9.16 mg, 0.01 mmol) were placed in a Schlenk tube under nitrogen. The tube was evacuated with a high vacuum oil pump and then filled with nitrogen. This process was repeated 3 times. Then 3 ml of dichloromethane was added and 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. Stir at room temperature for 15 h. The reaction was monitored using TLC plates and liquid chromatography. Column chromatography was performed on 100-200 mesh silica gel, and gradient elution was performed using a mixture of petroleum ether and ethyl acetate in a volume ratio of 1 to 10:1 as the eluent. The eluate containing the target compound was collected, and 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 phosphinoferrocene containing a five-membered heterocyclic thiol skeleton, as shown in formula (III): In formula (III), R is one of the following groups: The dotted line indicates the connection with S.

2. The method for synthesizing a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton represented by formula (III) as claimed in claim 1, characterized in that: The synthesis method is: Under a nitrogen atmosphere, (1R)-diphenylphosphino-(2S)-acetoxyethyl ferrocene represented by formula (I) and a thiol five-membered heterocyclic derivative represented by formula (II) are mixed and dissolved in an organic solvent, subjected to reflux reaction, and the reaction progress is tracked by TLC. After the reaction is completed, a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton represented by formula (III) is obtained by post-treatment; The reaction formula is as follows: In formula (II), R has the same meaning as in formula (III).

3. The synthesis method according to claim 2, characterized in that The molar ratio of (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene represented by formula (I) to the mercapto five-membered heterocyclic derivative represented by 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 according to claim 2, characterized in that The volume molar ratio of the organic solvent to the (1R)-diphenylphosphino-(2S)-acetoxyethylferrocene represented by the 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 refluxed at 82°C for 4 to 6 hours.

7. The synthesis method according to claim 2, characterized in that The post-treatment 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 column chromatography is performed with 100-200 mesh silica gel, and gradient elution is performed with a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 1-20:1 as an eluent, and the eluate containing the target compound is collected, and evaporated to dryness under reduced pressure to obtain a chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton as shown in formula (III).

8. Use of the chiral phosphinoferrocene containing a five-membered heterocyclic thiol skeleton represented by formula (III) as claimed in claim 1 in the asymmetric catalytic hydrogenation reaction of ketones and the asymmetric allylic substitution reaction of amino groups.

9. The use according to claim 8, characterized in that The asymmetric catalytic hydrogenation reaction of ketone is: catalytic hydrogenation of acetophenone to synthesize chiral alcohols. The operation method is as follows: In a nitrogen atmosphere, chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton, 1,5-cyclooctadiene iridium chloride dimer, and isopropanol are mixed and stirred at room temperature for 1 hour as a pre-catalyst system; then acetophenone (IV), isopropanol, sodium tert-butoxide and the pre-catalyst system are mixed, stirred at room temperature for 12 to 48 hours in a H2 atmosphere, and the reaction solution is post-treated to obtain the product (R)-1-phenylethanol (V); The reaction formula is as follows:

10. The use according to claim 8, characterized in that The asymmetric allyl substitution reaction of amino group is carried out as follows: In a nitrogen atmosphere, chiral phosphinoferrocene (III) containing a five-membered heterocyclic thiol skeleton, tris(dibenzylideneacetone)dipalladium, and dichloromethane were mixed and stirred at room temperature for 1 hour as a pre-catalyst system, and then (E)-1,3-diphenylallyl acetate (VI) and benzylamine were added and stirred at room temperature for 12 to 48 hours. The reaction solution was post-treated to obtain the product (R,E)-N-benzyl-1,3-diphenylprop-2-en-1-amine (VII); The reaction formula is as follows:

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