Asymmetric catalytic synthesis method of chiral secondary phosphorus oxide and chiral nitrogen-heteroarene-substituted tertiary phosphorus oxide and its application

Abstract

The present invention discloses an asymmetric catalytic synthesis method and application of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides. The method is characterized in that a racemic secondary phosphorus oxide (±)-I and 2-vinyl nitrogen-arene II are reacted in tert-butylbenzene and cyclohexane using a spirocyclic chiral phosphoric acid C1 or C2 as a chiral catalyst at 10-20°C to complete the reaction, followed by separation and purification to obtain a chiral nitrogen-arene-substituted tertiary phosphorus oxide III or a chiral secondary phosphorus oxide. R ‑I and chiral nitrogen-heteroarene-substituted tertiary phosphorus oxide III, wherein compound III can be reduced in one step to obtain chiral nitrogen-heteroarene-substituted tertiary phosphide IV, which can be used as a chiral nitrogen-phosphorus ligand to efficiently realize palladium-catalyzed asymmetric Tsuji‑Trost reaction.

Description

Technical Field

[0001] The present invention belongs to the field of asymmetric catalytic synthesis technology and application of chiral secondary phosphorus oxides and chiral nitrogen heteroaromatic hydrocarbon substituted tertiary phosphorus oxides, and specifically relates to an asymmetric catalytic synthesis method and application of chiral secondary phosphorus oxides and chiral nitrogen heteroaromatic hydrocarbon substituted tertiary phosphorus oxides. Background Art

[0002] Tertiary phosphorus and imine-containing nitrogen heteroarenes (such as pyridine) have been used as P and N donors in numerous metal-catalyzed asymmetric reactions, demonstrating their high efficiency and unique catalytic activity. Consequently, the development of chiral P and N ligands has attracted increasing attention from chemists in recent years. However, the structures of various chiral 1,5-hybridized phosphorus-nitrogen ligands are mostly limited to axial chirality, and the phosphide is generally directly attached to the aromatic ring. The synthesis of these C1-symmetric chiral ligands is not only expensive chiral raw materials and cumbersome preparation, but also inconvenient for adjusting the structure of either the phosphorus or the nitrogen heteroarene. Therefore, the discovery of new and easily prepared chiral P and N ligands remains an urgent task. In 2012, Mazet and colleagues developed a series of chiral phosphorus-pyridine ligands characterized by C- and P-stereocenters occluding an axially chiral binaphthyl skeleton. These chiral ligands exhibited considerable enantioselectivity control in asymmetric palladium-catalyzed reactions. Mechanistic studies revealed that the phosphorus configuration plays a significant role in enantioselectivity.

[0003] At the same time, with the successful application of racemic 2-pyridyl-ethylphosphine as a 1,5-hybrid P, N ligand in transition metal catalytic reactions, the synthesis of chiral 1,5-hybrid P, N ligands has become particularly important. This patent explores a method for the efficient and convenient synthesis of chiral nitrogen-heteroarene-substituted tertiary phosphorus oxides (TPOs). Chiral 1,5-hybrid P, N ligands can be obtained by one-step reduction and successfully used in palladium-catalyzed asymmetric Tsuji-Trost reactions. At the same time, through the kinetic resolution of racemic substrate secondary phosphorus oxides (SPOs), the catalytic asymmetric synthesis of chiral SPOs can also be achieved. Summary of the Invention

[0004] The present invention aims to overcome the shortcomings of the prior art by providing an asymmetric catalytic synthesis method for chiral secondary phosphorus oxides (SPOs) and chiral nitrogen-arene-substituted tertiary phosphorus oxides (TPOs). The chiral 1,5-hybrid P, N ligands are obtained by one-step reduction of the TPOs and successfully applied to the palladium-catalyzed asymmetric Tsuji-Trost reaction. This method utilizes simple and easily prepared substrates, operates under mild reaction conditions, is heavy metal-free, exhibits good atom economy, and produces high yields. This method provides two types of highly enantioselective phosphorus oxides (TPOs and SPOs) in a single step.

[0005] Specifically, the present invention adopts the following technical solutions:

[0006] In an air atmosphere, a racemic secondary phosphorus oxide (±)-I reacts with a 2-vinyl azaarene II in an organic solvent using a spirocyclic chiral phosphoric acid C1 or C2 as a chiral catalyst at -10 to -20°C, and after completion of the reaction, a chiral azaarene-substituted tertiary phosphorus oxide III is obtained by separation and purification, or a chiral secondary phosphorus oxide RI and a chiral azaarene-substituted tertiary phosphorus oxide III are obtained simultaneously.

[0007] In formula (±)-I, formula II, formula RI, and formula III, Ar 1 represents an aromatic compound; R is an alkyl or aryl group, Ar 2 represents an nitrogen heteroaryl group.

[0008] Preferably, R is isopropyl, cyclohexyl, phenyl or phenyl substituted with 1 to 3 F, Cl, Me or OMe. 1 for 2-thienyl, 4-methylphenyl, Naphthyl, R1 is H, F, Cl, Me, OMe, Ar 2 for

[0009] Specifically, the molar ratio of the racemic secondary phosphorus oxide (±)-I to the 2-vinylazaarene II is 2 to 3:1.

[0010] The addition amount of chiral phosphoric acid CPA is preferably 15% of the molar amount of 2-vinylazaarene II, the organic solvent is a mixed solvent consisting of tert-butylbenzene and cyclohexane in a volume ratio of 1:6, the temperature is -15°C, and the reaction time is 72-96 hours.

[0011] The chiral nitrogen-heteroarene substituted tertiary phosphorus oxide prepared by the above preparation method is used as a chiral nitrogen-phosphorus ligand in a palladium-catalyzed asymmetric Tsuji-Trost reaction, characterized in that the chiral nitrogen-heteroarene substituted tertiary phosphorus oxide III, tetraisopropoxytitanium and triethoxysilane are refluxed in toluene to obtain a chiral nitrogen-heteroarene substituted tertiary phosphide. Compound IV can be used as a chiral nitrogen-phosphorus ligand to realize palladium-catalyzed asymmetric Tsuji-Trost reaction.

[0012] The molar ratio of the chiral nitrogen-heteroarene-substituted tertiary phosphorus oxide III, tetraisopropoxytitanium and triethoxysilane is 1:1:6.

[0013] The specific process of compound IV as a chiral nitrogen-phosphorus ligand to realize palladium-catalyzed asymmetric Tsuji-Trost reaction is as follows: chiral nitrogen-arene-substituted tertiary phosphorus oxide III, allylpalladium (II) chloride dimer and lithium hydroxide monohydrate are dissolved in toluene under argon atmosphere, stirred for a period of time (0.5h to 1.5h), and then racemic (E)-1,3-diphenylallyl acetate is added and stirring is continued for 10 to 30 minutes. Subsequently, N,O-bistrimethylsilylacetamide and bis(3,5-bis(trifluoromethyl)phenyl)malonate are added, and the reaction is completed at -15°C to -25°C. After the reaction is completed, water is added to quench the reaction, and the organic layer is extracted with dichloromethane. After drying over anhydrous sodium sulfate, the organic layer is concentrated and separated by column chromatography to obtain bis(3,5-bis(trifluoromethyl)phenyl) (S,E)-2-(1,3-diphenylallyl)malonate.

[0014] Among them, the molar ratio of chiral nitrogen-substituted tertiary phosphorus oxide III, allylpalladium (II) chloride dimer, lithium hydroxide monohydrate, (E)-1,3-diphenylallyl acetate, N,O-bistrimethylsilylacetamide and bis(3,5-bis(trifluoromethyl)phenyl)malonate is: 0.05:0.02:0.2:1:3:3.

[0015] Compared with the prior art, the method of the present invention has the following beneficial effects:

[0016] In the present invention, chiral phosphoric acid is first used to convert the substrate secondary phosphorus oxides (SPOs) into tertiary phosphorus compounds, and then a conjugate addition-protonation reaction is performed on 2-vinyl azaarenes. Under the control of chiral phosphoric acid, asymmetric catalytic synthesis of chiral azaarenes substituted with tertiary phosphorus oxides (TPOs) is achieved. A one-step reduction of the chiral 1,5-hybrid P, N ligand is obtained, which is successfully applied to a palladium-catalyzed asymmetric Tsuji-Trost reaction. At the same time, the asymmetric catalytic synthesis of chiral SPOs can be achieved through the kinetic resolution of the racemic substrate secondary phosphorus oxides (SPOs). The reaction substrate is simple and easy to prepare, the conditions are mild, no heavy metals are involved, the atom economy is good, it is stable and efficient, the operation is simple, it is environmentally friendly, the substrate range is wide, the product conversion rate is high, and the enantioselectivity is good.

[0017] Compared with existing synthesis methods, the greatest feature of the method of the present invention is the asymmetric catalytic synthesis of chiral nitrogen-arenes substituted TPOs through direct enantioselective conjugated addition of 2-vinyl nitrogen-arenes to SPOs. The structures of the nitrogen-arenes and phosphides are easy to adjust, and chiral 1,5-hybrid P and N ligands can be synthesized in high yield and high enantioselectivity through a one-step reduction. These ligands can then be applied to palladium-catalyzed asymmetric Tsuji-Trost reactions. At the same time, asymmetric catalytic synthesis of chiral SPOs can also be achieved through kinetic resolution. The substrate is easy to adjust, the operation is simple, and the process is green and environmentally friendly, making the method highly valuable for promotion and application. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0019] In the following examples, chiral spirocyclic phosphate CPA was purchased from Daicel.

[0020] Example 1

[0021] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-isopropyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide are as follows:

[0022]

[0023] 50.4 mg (0.3 mmol) of racemic isopropyl(phenyl)phosphine oxide, 10.5 mg (0.1 mmol) of 2-vinylpyridine, and 10.4 mg (0.015 mmol) of chiral phosphoric acid C1 were added to a 10 mL reaction flask. 4.0 mL of a mixed solvent of tert-butylbenzene and cyclohexane (volume ratio 6:1) was then added. The reaction flask was placed in a -15°C thermostat and stirred for 72 hours. After the reaction was completed, column chromatography (n-hexane / ethyl acetate 30-3:1) was directly used to separate the product to obtain 21.3 mg of (S)-isopropyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide as a colorless oily liquid with a yield of 78% and an optical purity of 92% ee. Its NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.45(d,J=3.5Hz,1H),7.72–7.65(m,2H),7.53–7.39(m,4H),7.10–7.01(m,2H),3. 17–3.06(m,1H),2.87–2.76(m,1H),2.54–2.35(m,2H),2.08–1.94(m,1H),1.23–1.16(m,3H),1.06–0.96(m,3H).13 C NMR(151MHz,Chloroform-d)δ160.4(d,J=13.2Hz),149.2,136.6,131.5(d,J=2.5Hz),131.0(d,J=8.7Hz),130.6(d,J=89.9Hz),12 8.6(d,J=10.9Hz), 123.1, 121.5, 29.6(d,J=3.3Hz), 28.9(d,J=70.3Hz), 25.9(d,J=65.9Hz), 15.7(d,J=3.1Hz), 15.2(d,J=3.2Hz). 31 P NMR (243 MHz, Chloroform-d) δ 46.2. High resolution data: HRMS (ESI) m / z 274.1350 (M+H + ),calc.for C 16 H 21 NOP + 274.1355.

[0024] Example 2

[0025] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-cyclohexyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide are as follows:

[0026]

[0027] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 1 was replaced with racemic cyclohexyl (phenyl) phosphine oxide. The remaining steps were the same as in Example 1 to obtain 22.6 mg of (S)-cyclohexyl (phenyl) (2-(pyridin-2-yl)ethyl) phosphine oxide as a white solid in a 72% yield with an optical purity of 92% ee. Its melting point was 125.8-127.3°C, and its NMR data were: 1 H NMR(600MHz,Chloroform-d)δ8.45(d,J=4.2Hz,1H),7.71–7.62(m,2H),7.51–7.38(m,4H),7.07–7.00(m,2H),3. 16–3.04(m,1H),2.87–2.73(m,1H),2.54–2.34(m,2H),2.02–1.97(m,1H),1.83–1.56(m,5H),1.43–0.96(m,5H). 13C NMR(151MHz,Chloroform-d)δ160.4(d,J=13.2Hz),149.0,136.7,131.5(d,J=3.1Hz),131.0(d,J=8.5Hz),130.9(d,J=89.2Hz),128.5(d,J=11.1Hz),123 .2,121.5,39.1(d,J=69.5Hz),29.5(d,J=3.2Hz),26.3(d,J=3.2Hz),26.2(d ,J=2.6Hz),25.8(d,J=65.4Hz),25.8,25.3(d,J=2.8Hz),25.0(d,J=3.5Hz). 31 P NMR (243 MHz, Chloroform-d) δ 43.4. High resolution data: HRMS (ESI) m / z 314.1671 (M+Na + ),calc.for C 19 H 24 NOPNa + 314.1668.

[0028] Example 3

[0029] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-isopropyl(4-methylphenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide are as follows:

[0030]

[0031] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 1 was replaced with racemic isopropyl (4-methylphenyl) phosphine oxide. The other steps were the same as in Example 1 to obtain 21.5 mg of (S)-isopropyl (4-methylphenyl) (2-(pyridin-2-yl)ethyl) phosphine oxide as a colorless oily liquid with a yield of 75% and an optical purity of 93% ee. Its NMR data are as follows: 1 HNMR(600MHz,Chloroform-d)δ8.47(s,1H),7.64–7.51(m,3H),7.25(d,J=7.5Hz,2H),7.17–7.05(m,2H),3.19–3.09(m,1 H),2.91–2.78(m,1H),2.52–2.42(m,2H),2.36(d,J=3.1Hz,3H),2.09–1.97(m,1H),1.23–1.16(m,3H),1.07–0.97(m,3H). 13C NMR(151MHz,Chloroform-d)δ160.3(d,J=13.2Hz),148.5,141.9(d,J=3.1Hz),137.2,131.1(d,J=8.7Hz),129.3(d,J=11.1Hz),127.2 (d,J=92.2Hz),123.5,121.7,29.4(d,J=3.1Hz),29.0(d,J=70.3Hz),26.0(d,J=65.2Hz),21.5,15.7(d,J=1.9Hz),15.2(d,J=3.2Hz). 31 P NMR (243 MHz, Chloroform-d) δ 45.9. High resolution data: HRMS (ESI) m / z 288.1507 (M+H + ),calc.forC 17 H 23 NOP + 288.1512.

[0032] Example 4

[0033] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-isopropyl(2-thienyl)(2-(pyridin-2-yl)ethyl)phosphine oxide are as follows:

[0034]

[0035] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 1 was replaced with racemic isopropyl (2-thienyl) phosphine oxide. The other steps were the same as in Example 1 to obtain 17.3 mg of (S)-isopropyl (2-thienyl) (2-(pyridin-2-yl)ethyl) phosphine oxide as a colorless oily liquid with a yield of 62% and an optical purity of 85% ee. Its NMR data are as follows: 1 HNMR(600MHz,Chloroform-d)δ8.5(d,J=5.6Hz,1H),7.7–7.7(m,1H),7.6–7.5(m,2H),7.2–7.2(m,1H),7.1(d,J=7.6Hz,1H),7.1–7.1 (m,1H),3.3–3.1(m,1H),3.0–2.9(m,1H),2.6–2.4(m,2H),2.2–2.0(m,1H),1.2(dd,J=16.6,7.1Hz,3H),1.1(dd,J=17.2,7.2Hz,3H). 13CNMR(151MHz,Chloroform-d)δ160.2(d,J=13.3Hz),149.1,136.7,135.4(d,J=7.7Hz),132.9(d,J=3.5Hz),131.1(d,J=93.6Hz),12 8.4(d,J=12.2Hz), 123.2, 121.6, 30.0(d,J=73.6Hz), 29.6(d,J=3.7Hz), 27.8(d,J=68.3Hz), 15.7(d,J=2.0Hz), 15.2(d,J=2.7Hz). 31 P NMR (243 MHz, Chloroform-d) δ 43.9. High resolution data: HRMS (ESI) m / z 280.0914 (M+H + ),calc.for C 14 H 19 NOPS + 280.0919.

[0036] Example 5

[0037] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-isopropyl(phenyl)(2-(4-cyanopyridin-2-yl)ethyl)phosphine oxide are as follows:

[0038]

[0039] In this example, 2-vinylpyridine in Example 1 was replaced with 2-vinyl-4-cyanopyridine. The remaining steps were the same as in Example 1 to obtain 21.5 mg of (S)-isopropyl(phenyl)(2-(4-cyanopyridin-2-yl)ethyl)phosphine oxide as a colorless oily liquid in a 72% yield with an optical purity of 90% ee. Its NMR data were as follows: 1 H NMR(600MHz,Chloroform-d)δ8.63(d,J=4.9Hz,1H),7.69–7.63(m,2H),7.52–7.47(m,1H),7.47–7.41(m,2H),7.29–7.23(m,2H),3.29–3.11(m ,1H),3.00–2.82(m,1H),2.62–2.48(m,1H),2.47–2.37(m,1H),2.13–1.99(m,1H),1.23(dd,J=15.8,7.1Hz,3H),1.05(dd,J=16.4,7.1Hz,3H). 13C NMR(151MHz,Chloroform-d)δ162.1(d,J=12.0Hz),150.2,131.7(d,J=1.4Hz),130.9(d,J=8.4Hz),130.5(d,J=90.1Hz),128 .6(d,J=10.4Hz),124.8,122.9,120.7,29.7(d,J=3.1Hz),29.0(d,J=69.9Hz),25.5(d,J=65.3Hz),15.6,15.1(d,J=2.7Hz). 31 P NMR (243 MHz, Chloroform-d) δ 45.4. High resolution data: HRMS (ESI) m / z 299.1306 (M+H + ),calc.forC 17 H 20 N2OP + 299.1308.

[0040] Example 6

[0041] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-isopropyl(phenyl)(2-(isoquinolin-2-yl)ethyl)phosphine oxide are as follows:

[0042]

[0043] In this example, 2-vinylpyridine in Example 1 was replaced with 2-vinyl-isoquinoline. The remaining steps were the same as in Example 1 to obtain 16.2 mg of (S)-isopropyl(phenyl)(2-(isoquinolin-2-yl)ethyl)phosphine oxide as a pale yellow oily liquid in a 50% yield with an optical purity of 90% ee. The NMR data were as follows: 1 H NMR(600MHz,Chloroform-d)δ8.39(d,J=5.8Hz,1H),8.13(d,J=8.5Hz,1H),7.80–7.73(m,3H),7.66(t,J=7.5Hz,1H),7.56(t,J=7.7Hz,1H),7.54–7 .43(m,4H),3.82–3.70(m,1H),3.39–3.23(m,1H),2.77–2.55(m,2H),2.28 –2.04(m,1H),1.26(dd,J=15.8,7.0Hz,3H),1.09(dd,J=16.4,7.2Hz,3H). 13CNMR(151MHz,Chloroform-d)δ159.9(d,J=13.2Hz),140.9,136.2,131.6(d,J=2.7Hz),131.1(d,J=7.9Hz),130.8(d,J=88.9Hz),130.4,12 8.6 (d, J = 11.0Hz), 127.6, 127.3, 126.8, 125.2, 120.0, 29.1 (d, J = 70.3Hz), 26.1, 24.8 (d, J = 65.9Hz), 15.8 (d, J = 3.0Hz), 15.3 (d, J = 3.2Hz). 31 P NMR (243 MHz, Chloroform-d) δ 46.3. High resolution data: HRMS (ESI) m / z 324.1514 (M+H + ),calc.for C 20 H 23 NOP + 324.1512.

[0044] Example 7

[0045] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (S)-isopropyl(phenyl)(2-(benzo[d]thiazol-2-yl)ethyl)phosphine oxide are as follows:

[0046]

[0047] In this example, 2-vinylpyridine in Example 1 was replaced with 2-vinyl-benzo[d]thiazole, and chiral phosphoric acid C1 was replaced with C2. The remaining steps were the same as in Example 1 to obtain 16.5 mg of (S)-isopropyl(phenyl)(2-(benzo[d]thiazol-2-yl)ethyl)phosphine oxide as a colorless oily liquid in a 50% yield with an optical purity of 85% ee. Its NMR data were: 1HNMR(600MHz,Chloroform-d)δ7.93(d,J=8.2Hz,1H),7.79(d,J=8.0Hz,1H),7.7 4(t,J=8.7Hz,2H),7.54–7.45(m,3H),7.43(t,J=7.7Hz,1H),7.33(t,J=7.5Hz,1H ),3.55–3.38(m,1H),3.17–2.83(m,1H),2.76–2.65(m,1H),2.60(d,J=13.3Hz,1H ),2.17–2.00(m,1H),1.27(dd,J=15.7,7.0Hz,3H),1.09(dd,J=16.2,7.1Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ170.4(d,J=15.1Hz),153.1,135.2,131.8,131.0(d,J=7.5Hz),130.3(d,J=93.2H z), 128.7 (d, J = 9.9Hz), 126.1, 125.0, 122.5, 121.6, 29.0 (d, J = 69.3Hz), 26.3, 26.0 (d, J = 64.2Hz), 15.7, 15.2. 31 P NMR (243 MHz, Chloroform-d) δ 45.0. High resolution data: HRMS (ESI) m / z 352.0900 (M+Na + ),calc.for C 18 H 20 NOPSNa + 352.0895.

[0048] Example 8

[0049] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (R)-2,4,6-trimethylphenyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide are as follows:

[0050]

[0051] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 1 was replaced with racemic 2,4,6-trimethylphenyl (phenyl) phosphine oxide. The other steps were the same as in Example 1 to obtain 31.1 mg of (R)-2,4,6-trimethylphenyl (phenyl) (2-(pyridin-2-yl)ethyl) phosphine oxide as a white solid with an 89% yield and an optical purity of 94% ee. Its melting point was 106.8-108.5°C, and its NMR data were:1 H NMR(400MHz,Chloroform-d)δ8.46(d,J=5.3Hz,1H),7.66–7.56(m,2H),7.55–7.46(m,1H),7.46–7.39(m,1H),7.42–7.34(m,2H),7.14(d,J =7.8Hz,1H),7.09–7.01(m,1H),6.85(d,J=3.5Hz,2H),3.33–3.18(m,1H),3.08–2.94(m,1H),2.93–2.81(m,2H),2.43(s,6H),2.26(s,3H). 13 C NMR(151MHz,Chloroform-d)δ160.4(d,J=14.4Hz),148.8,143.2(d,J=10.0Hz ),141.6(d,J=3.1Hz),137.0,136.4(d,J=97.2Hz),131.4(d,J=2.9Hz),131.2( d,J=11.0Hz), 129.9(d,J=9.9Hz), 128.7(d,J=11.0Hz), 124.3(d,J=95.8Hz), 123.3, 121.6, 30.9 (d, J = 70.2Hz), 30.1 (d, J = 2.3Hz), 23.5 (d, J = 3.4Hz), 21.0. 31 P NMR (243 MHz, Chloroform-d) δ 38.2. High resolution data: HRMS (ESI) m / z 350.1675 (M+H + ),calc.for C 22 H 25 NOP + 350.1668.

[0052] Example 9

[0053] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is described, as shown in the following reaction formula. The specific preparation steps for (R)-2,4,6-trimethylphenyl(4-vinylphenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide are as follows:

[0054]

[0055] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 1 was replaced with racemic 2,4,6-trimethylphenyl (4-vinylphenyl) phosphine oxide, and the chiral phosphoric acid C1 was replaced with C2. The other steps were the same as in Example 1 to obtain 24.0 mg of (R)-2,4,6-trimethylphenyl (4-vinylphenyl) (2-(pyridin-2-yl)ethyl) phosphine oxide as a colorless oily liquid with a yield of 64% and an optical purity of 87% ee. Its NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.47(d,J=5.5Hz,1H),7.61–7.50(m,3H),7.41(dd,J= 8.3,2.4Hz,2H),7.15(d,J=7.8Hz,1H),7.07(dd,J=7.5,4.8Hz,1H),6.86(d,J=3.5Hz ,2H),6.69(dd,J=17.6,10.9Hz,1H),5.80(d,J=17.6Hz,1H),5.32(d,J=10.9Hz,1H) ,3.32–3.21(m,1H),3.08–2.98(m,1H),2.93–2.81(m,2H),2.44(s,6H),2.27(s,3H). 13 C NMR(151MHz,Chloroform-d)δ160.5(d,J=14.4Hz),148.9,143.2(d,J=10.0Hz),1 41.6(d,J=2.1Hz),140.4(d,J=1.8Hz),136.8,136.0,135.5(d,J=97.9Hz),131.2 (d,J=11.0Hz),130.3(d,J=10.1Hz),126.5(d,J=12.0Hz),124.4(d,J=95.8Hz),1 23.3,121.5,116.1,30.9(d,J=70.2Hz),30.3–29.8(m),23.6(d,J=3.9Hz),21.0. 31 P NMR (243 MHz, Chloroform-d) δ 37.8. High resolution data: HRMS (ESI) m / z 376.1829 (M+H + ),calc.for C 24 H 27 NOP + 376.1825.

[0056] Example 10

[0057] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is disclosed, the reaction formula of which is shown below. The specific preparation steps for (R)-isopropyl(phenyl)phosphorus oxide and (S)-isopropyl(phenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphorus oxide are as follows:

[0058]

[0059] 50.4 mg (0.2 mmol) of racemic isopropyl (phenyl) phosphine oxide, 11.9 mg (0.1 mmol) of 2-vinyl-3-methylpyridine, and 10.4 mg (0.015 mmol) of chiral phosphoric acid C1 were added to a 10 mL reaction flask, followed by the addition of 4.0 mL of a mixed solvent of tert-butylbenzene and cyclohexane (volume ratio 6:1). The reaction flask was placed in a -15°C thermostat and stirred for 96 hours. After the reaction was completed, the mixture was directly separated by column chromatography (n-hexane / ethyl acetate 30 to 3:1) to obtain 17.8 mg of (R)-isopropyl (phenyl) phosphine oxide and 11.8 mg of (S)-isopropyl (phenyl) (2-(3-methylpyridin-2-yl)ethyl) phosphine oxide.

[0060] (R)-Isopropyl (phenyl) phosphine oxide is a colorless oily liquid with a yield of 53% and an optical purity of 90% ee. Its NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.66–7.58(m,2H),7.54–7.49(m,1H),7.48–7.4 2(m,2H),7.18(dd,J=457.2,2.5Hz,1H),2.13–2.04(m,1H),1.16–1.03(m,6H). 13 C NMR (151MHz, Chloroform-d) δ 132.4 (d, J = 2.3Hz), 130.3 (d, J = 10.7Hz), 129.7 (d, J = 93.0Hz), 128.8 (d, J = 12.1Hz), 28.7 (d, J = 69.2Hz), 15.1, 14.6. 31 P NMR (243 MHz, Chloroform-d) δ 39.4 (dd, J = 456.7, 16.0 Hz). High resolution data: HRMS (ESI) m / z 191.0597 (M + Na + ),calc.for C9H 13 OPNa + 191.0596.

[0061] (S)-Isopropyl(phenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphine oxide is a colorless oily liquid with a yield of 41% and an optical purity of 91% ee. Its NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.31(d,J=4.2Hz,1H),7.74–7.65(m,2H),7.49– 7.43(m,1H),7.45–7.39(m,2H),7.31(d,J=7.4Hz,1H),6.98(dd,J=7.5,4.8Hz ,1H),3.19–3.07(m,1H),2.84–2.69(m,1H),2.59–2.44(m,2H),2.17(s,3H),2 .11–2.00(m,1H),1.21(dd,J=15.7,7.1Hz,3H),1.04(dd,J=16.3,7.2Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ158.3(d,J=12.8Hz),146.3,137.6,131.5(d,J=2.6Hz),131.4,131.0(d,J=8.7Hz),130.8(d,J=89.1Hz) ,128.5(d,J=11.0Hz),121.5,29.0(d,J=69.5Hz),26.2(d,J=3.1Hz),24.3(d,J=66.1Hz),18.7,15.8(d,J=2.7Hz),15.2(d,J=3.2Hz). 31 P NMR (243 MHz, Chloroform-d) δ 46.5. High resolution data: HRMS (ESI) m / z 288.1507 (M+H + ),calc.for C 17 H 23 NOP + 288.1512.

[0062] Example 11

[0063] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is disclosed, the reaction formula of which is shown below. The specific preparation steps for (R)-isopropyl(1-naphthyl)phosphorus oxide and (S)-isopropyl(1-naphthyl)(2-(3-methylpyridin-2-yl)ethyl)phosphorus oxide are as follows:

[0064]

[0065] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 10 was replaced with racemic isopropyl (1-naphthyl) phosphine oxide, and the other steps were the same as in Example 10 to obtain 21.4 mg of (R)-isopropyl (phenyl) phosphine oxide and 31.0 mg of (S)-isopropyl (phenyl) (2-(3-methylpyridin-2-yl) ethyl) phosphine oxide.

[0066] (R)-Isopropyl (phenyl) phosphine oxide is a colorless oily liquid with a yield of 49% and an optical purity of 95% ee. Its NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.42(d,J=8.4Hz,1H),7.97(d,J=8.3Hz,1H),7.85(d,J=8.2Hz,1H),7.79(dd,J=17.5,6.6Hz,1H), 7.59–7.40(m,3H),7.49(dd,J=459.9,3.8Hz,1H),2.39–2.15(m,1H),1.19(dd,J=17.7,7.1Hz,3H),1.05(dd,J=19.6,7.1Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ133.6(d,J=8.7Hz),133.2(d,J=2.9Hz),133.0(d,J=8.8Hz),131.5(d,J=12.0Hz),129.1,127.6,1 26.7, 126.3 (d, J = 90.5Hz), 125.2 (d, J = 5.7Hz), 124.6 (d, J = 14.0Hz), 29.0 (d, J = 68.4Hz), 16.0 (d, J = 1.0Hz), 15.4 (d, J = 1.8Hz). 31 P NMR (243 MHz, Chloroform-d) δ 44.1 (dt, J = 460.3, 17.0 Hz). High resolution data: HRMS (ESI) m / z 241.0753 (M + Na + ),calc.for C 13 H 15 OPNa + 241.0753.

[0067] (S)-Isopropyl(phenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphine oxide is a white solid with a yield of 46% and an optical purity of 91% ee. Its NMR data are as follows: 1H NMR(600MHz,Chloroform-d)δ8.8(d,J=8.5Hz,1H),8.3(d,J=4.4Hz,1H),8.0–7.9(m ,2H),7.9(d,J=8.1Hz,1H),7.6–7.5(m,1H),7.6–7.5(m,2H),7.3(d,J=7.4Hz,1H),7 .0(dd,J=7.6,4.8Hz,1H),3.3–3.2(m,1H),2.9–2.8(m,2H),2.8–2.6(m,1H),2.4(h, J=7.2Hz,1H),2.1(s,3H),1.3(dd,J=16.0,7.1Hz,3H),1.1(dd,J=16.2,7.2Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ158.4(d,J=12.2Hz),146.3,137.5,134.0(d,J=7.9Hz) ),133.8(d,J=8.9Hz),132.6(d,J=3.2Hz),132.6(d,J=8.7Hz),131.4,129.1,127.3( d,J=84.5Hz),127.2,126.3,126.3,124.6(d,J=12.1Hz),121.4,29.8(d,J=69.3Hz) ,26.5(d,J=2.7Hz),25.4(d,J=66.5Hz),18.7,15.8(d,J=3.2Hz),15.8(d,J=3.3Hz). 31 P NMR (243 MHz, Chloroform-d) δ 49.5. High resolution data: HRMS (ESI) m / z 338.1669 (M+H + ),calc.for C 21 H 25 NOP + 338.1668.

[0068] Example 12

[0069] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is disclosed, the reaction formula of which is shown below. The specific preparation steps for (S)-2,4,6-trimethylphenyl(phenyl)phosphorus oxide and (R)-2,4,6-trimethylphenyl(phenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphorus oxide are as follows:

[0070]

[0071] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 10 was replaced with racemic 2,4,6-trimethylphenyl (phenyl) phosphine oxide, and the other steps were the same as in Example 10 to obtain 25.9 mg of (S)-2,4,6-trimethylphenyl (phenyl) phosphine oxide and 29.8 mg of (R)-2,4,6-trimethylphenyl (phenyl) (2-(3-methylpyridin-2-yl)ethyl) phosphine oxide.

[0072] (S)-2,4,6-Trimethylphenyl (phenyl)phosphine oxide is a colorless oily liquid with a yield of 53% and an optical purity of 96% ee. Its NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.54(d,J=482.5Hz,1H),7.61(dd,J=13.4,7.5Hz,2H),7. 50(t,J=7.4Hz,1H),7.46–7.40(m,2H),6.89(d,J=3.9Hz,2H),2.44(s,6H),2.29(s,3H). 13 C NMR (151MHz, Chloroform-d) δ142.8 (d, J = 2.5Hz), 142.1 (d, J = 10.0Hz), 132.4 (d, J = 99.0Hz), 131.9 (d, J = 3.2 Hz), 130.5 (d, J = 11.0Hz), 130.3 (d, J = 10.9Hz), 128.8 (d, J = 12.2Hz), 124.4 (d, J = 103.0Hz), 21.5, 21.4, 21.3. 31 P NMR (243 MHz, Chloroform-d) δ 9.8 (d, J = 481.5 Hz). High resolution data: HRMS (ESI) m / z 267.0901 (M + Na + ),calc.for C 15 H 17 OPNa + 267.0909.

[0073] (R)-2,4,6-Trimethylphenyl(phenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphine oxide is a colorless oily liquid with a yield of 41% and an optical purity of 91% ee. Its NMR data are as follows: 1H NMR(600MHz,Chloroform-d)δ8.3(d,J=3.9Hz,1H),7.7–7.6(m,2H),7.5–7.4(m,1H),7.4–7.4(m,2H),7.4(d,J=7.5Hz,1H),7.0( dd,J=7.6,4.8Hz,1H),6.9(d,J=3.5Hz,2H),3.3–3.2(m,1H),3.1–3.0(m,1H),2.9–2.8(m,2H),2.5(s,6H),2.3(d,J=10.8Hz,6H). 13 C NMR(151MHz,Chloroform-d)δ158.6(d,J=14.3Hz),146.5,143.2(d,J=10.0Hz),141.5(d,J=3.1Hz),137.5,136.5(d,J=96.8Hz),131.3(d,J=1.9Hz),131 .3,131.2(d,J=11.3Hz),130.0(d,J=9.9Hz),128.7(d,J=11.0Hz),124.7(d, J=95.6Hz), 121.4, 29.5 (d, J=70.4Hz), 27.0, 23.6 (d, J=3.4Hz), 21.0, 18.7. 31 P NMR (243 MHz, Chloroform-d) δ 38.8. High resolution data: HRMS (ESI) m / z 364.1819 (M+H + ),calc.for C 23 H 27 NOP + 364.1825.

[0074] Example 13

[0075] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is disclosed, the reaction formula of which is shown below. The specific preparation steps for (S)-2,4,6-trimethylphenyl(4-fluorophenyl)phosphorus oxide and (R)-2,4,6-trimethylphenyl(4-fluorophenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphorus oxide are as follows:

[0076]

[0077] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 10 was replaced with racemic 2,4,6-trimethylphenyl (4-fluorophenyl) phosphine oxide, and the other steps were the same as in Example 10 to obtain 27.8 mg of (S)-2,4,6-trimethylphenyl (4-fluorophenyl) phosphine oxide and 32.8 mg of (R)-2,4,6-trimethylphenyl (4-fluorophenyl) (2-(3-methylpyridin-2-yl) ethyl) phosphine oxide.

[0078] (S)-2,4,6-Trimethylphenyl (4-fluorophenyl)phosphine oxide is a colorless oily liquid with a yield of 43% and an optical purity of 93% ee. Its NMR data are as follows: 1 H NMR (600MHz, Chloroform-d) δ8.53(d,J=485.3Hz,1H),7.69–7.47(m,2H),7.14(td,J=8.7,2.0Hz,2H),6.90(d,J=4.0Hz,2H),2.44(s,6H),2.30(s,3H). 13 C NMR(151MHz,Chloroform-d)δ165.1(dd,J=253.0,4.0Hz),143.1(d,J=2.1Hz),142.1(d,J=9.9Hz),133.1(d,J=8.9Hz),133.0(d,J=8.8H z), 130.4 (d, J = 11.0Hz), 128.2 (dd, J = 101.2, 3.3Hz), 124.1 (d, J = 103.5Hz), 116.3 (d, J = 7.6Hz), 116.3 (d, J = 35.2Hz), 21.4, 21.4, 21.3. 31 P NMR (243MHz, Chloroform-d) δ8.8 (d, J=484.4Hz). 19 F NMR (565MHz, Chloroform-d) δ-106.7. High resolution data: HRMS (ESI) m / z 285.0806 (M+Na + ),calc.for C 15 H 16 FOPNa + 285.0815.

[0079] (R)-2,4,6-Trimethylphenyl(4-fluorophenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphine oxide is a colorless oily liquid with a yield of 41% and an optical purity of 91% ee. Its NMR data are as follows: 1H NMR(600MHz,Chloroform-d)δ8.31(d,J=4.2Hz,1H),7.70–7.59(m,2H),7.36(d,J=7.4Hz,1H),7.09(td,J=8.7,2.0Hz,2H),7.01(dd,J =7.6,4.8Hz,1H),6.87(d,J=3.5Hz,2H),3.29–3.18(m,1H),3.05–2.95(m,1H),2.94–2.84(m,2H),2.45(s,6H),2.26(d,J=10.8Hz,6H). 13 C NMR(151MHz,Chloroform-d)δ165.4(d,J=2.4Hz),163.7(d,J=3.2Hz),158.4(d,J=13.6 Hz),146.5,143.1(d,J=9.9Hz),141.6(d,J=3.1Hz),137.5,132.7(dd,J=98.4,3.7Hz),1 32.5(d,J=2.7Hz),132.5(d,J=19.8Hz),131.3,131.3(d,J=11.1Hz),124.5(d,J=95.9Hz ),121.5,116.0(dd,J=21.4,12.7Hz),29.7(d,J=71.4Hz),27.0,23.6,23.6,21.0,18.7. 31 P NMR(243MHz,Chloroform-d)δ37.8. 19 F NMR (565MHz, Chloroform-d) δ-107.7. High resolution data: HRMS (ESI) m / z 382.1730 (M+H + ),calc.for C 23 H 26 FNOP + 382.1731.

[0080] Example 14

[0081] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is disclosed, the reaction formula of which is shown below. The specific preparation steps for (S)-2,4,6-trimethylphenyl(3-methoxyphenyl)phosphorus oxide and (R)-2,4,6-trimethylphenyl(3-methoxyphenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphorus oxide are as follows:

[0082]

[0083] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 10 was replaced with racemic 2,4,6-trimethylphenyl (3-methoxyphenyl) phosphine oxide, and the other steps were the same as in Example 10 to obtain 31.8 mg of (S)-2,4,6-trimethylphenyl (3-methoxyphenyl) phosphine oxide and 27.5 mg of (R)-2,4,6-trimethylphenyl (3-methoxyphenyl) (2-(3-methylpyridin-2-yl)ethyl) phosphine oxide.

[0084] (S)-2,4,6-Trimethylphenyl (3-methoxyphenyl)phosphine oxide is a colorless oily liquid with a yield of 58% and an optical purity of 92% ee. Its NMR data are as follows: 1 H NMR (600MHz, Chloroform-d) δ8.51 (d, J=483.5Hz, 1H), 7.32 (td, J=7.8, 3.7Hz, 1H), 7.28–7. 20(m,1H),7.10–6.98(m,2H),6.88(d,J=3.9Hz,2H),3.80(s,3H),2.45(s,6H),2.29(s,3H). 13 C NMR(151MHz,Chloroform-d)δ159.9(d,J=15.1Hz),142.8(d,J=2.1Hz),142.1(d,J=9.9Hz),133.8(d,J=98.0Hz),130.3(d,J=10.8Hz),1 30.1 (d, J = 15.3Hz), 124.3 (d, J = 102.7Hz), 122.4 (d, J = 11.2Hz), 118.0 (d, J = 3.2Hz), 115.5 (d, J = 11.9Hz), 55.5, 21.5 (d, J = 8.7Hz), 21.3. 31 P NMR (243 MHz, Chloroform-d) δ 9.7 (d, J = 483.6 Hz). High resolution data: HRMS (ESI) m / z 275.1186 (M + H + ),calc.forC 16 H 20 O2P + 275.1195.

[0085] (R)-2,4,6-Trimethylphenyl(3-methoxyphenyl)(2-(3-methylpyridin-2-yl)ethyl)phosphine oxide is a colorless oily liquid with a yield of 35% and an optical purity of 92%ee. Its NMR data are as follows: 1H NMR(600MHz,Chloroform-d)δ8.31(d,J=4.3Hz,1H),7.35(d,J=7.6Hz,1H),7.31(td,J=8.0,3.6Hz,1H),7.23–7.16(m,2H),7.03–6.92( m,2H),6.86(d,J=3.5Hz,2H),3.77(s,3H),3.29–3.16(m,1H),3.07–2.95(m,1H),2.92–2.77(m,2H),2.46(s,6H),2.26(d,J=8.3Hz,6H). 13 C NMR (151MHz, Chloroform-d) δ159.7 (d, J = 14.3Hz), 158.6 (d, J = 14.3Hz), 146.5, 143. 2(d,J=10.0Hz),141.4(d,J=2.9Hz),138.2,137.5,131.3,131.2(d,J=11.1Hz),130. 0(d,J=13.3Hz),124.7(d,J=95.7Hz),122.2(d,J=9.9Hz),121.4,117.0(d,J=3.0Hz) ,115.3(d,J=10.6Hz),55.4,29.7(d,J=70.4Hz),27.1,23.6(d,J=3.3Hz),21.0,18.7. 31 P NMR (243 MHz, Chloroform-d) δ 38.9. High resolution data: HRMS (ESI) m / z 394.1928 (M+H + ),calc.for C 24 H 29 NO2P + 394.1930.

[0086] Example 15

[0087] A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides is disclosed, the reaction formula of which is shown below. The specific preparation steps for (S)-2,4,6-trimethylphenyl(2-naphthyl)phosphorus oxide and (R)-2,4,6-trimethylphenyl(2-naphthyl)(2-(3-methylpyridin-2-yl)ethyl)phosphorus oxide are as follows:

[0088]

[0089] In this example, the racemic isopropyl (phenyl) phosphine oxide in Example 10 was replaced with 2,4,6-trimethylphenyl (2-naphthyl) phosphine oxide, and the other steps were the same as in Example 10 to obtain 33.0 mg of (S)-2,4,6-trimethylphenyl (2-naphthyl) phosphine oxide and 32.3 mg of (R)-2,4,6-trimethylphenyl (2-naphthyl) (2-(3-methylpyridin-2-yl) ethyl) phosphine oxide.

[0090] (S)-2,4,6-Trimethylphenyl(2-naphthyl)phosphine oxide is a light yellow oily liquid with a yield of 56% and an optical purity of 90% ee. Its NMR data are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.68(d,J=482.9Hz,1H),8.31(d,J=15.0Hz,1H),7.9 8–7.78(m,3H),7.66–7.42(m,3H),6.93(d,J=4.0Hz,2H),2.49(s,6H),2.32(s,3H). 13 C NMR(151MHz,Chloroform-d)δ142.9(d,J=2.0Hz),142.2(d,J=10.7Hz),134.8(d,J=2.1Hz),132.7(d,J=13.6Hz),132.7(d,J=9.8Hz),130 .4,130.4,129.4(d,J=99.0Hz),128.8,128.7(d,J=12.3Hz),128.2,127.9,127.0,125.1,125.0,124.5(d,J=103.3Hz),21.6,21.5,21.4. 31 P NMR (243 MHz, Chloroform-d) δ 9.6 (d, J = 483.6 Hz). High resolution data: HRMS (ESI) m / z 295.1236 (M+H + ),calc.for C 19 H 20 OP + 295.1246.

[0091] (R)-2,4,6-Trimethylphenyl(2-naphthyl)(2-(3-methylpyridin-2-yl)ethyl)phosphine oxide is a white solid with a yield of 39% and an optical purity of 90% ee. Its melting point is 132.8-134.7°C and its NMR data are: 1H NMR(600MHz,Chloroform-d)δ8.3(d,J=3.9Hz,1H),8.2(d,J=13.3Hz,1H),7.9–7.8(m,3H),7.7–7.6(m,1H),7.6–7.5(m,2H),7.4(d ,J=7.4Hz,1H),7.0(dd,J=7.5,4.8Hz,1H),6.9(d,J=3.4Hz,2H),3.3–3.2(m,1H),3.1–2.9(m,3H),2.5(s,6H),2.3(d,J=8.5Hz,6H). 13 C NMR(151MHz,Chloroform-d)δ158.5(d,J=14.2Hz),146.3,143.2(d,J=10.0Hz),141.5(d,J=1 .9Hz),137.7,134.5(d,J=2.0Hz),133.7(d,J=96.8Hz),132.7,132.6,131.5,131.2(d,J=11.1 Hz), 131.2 (d, J = 9.0Hz), 128.9, 128.6 (d, J = 11.7Hz), 127.8 (d, J = 4.0Hz), 126.8, 125.6 (d, J = 1 0.1Hz), 124.8 (d, J = 95.8Hz), 121.5, 29.6 (d, J = 70.4Hz), 27.0, 23.7 (d, J = 4.2Hz), 21.0, 18.7. 31 P NMR (243 MHz, Chloroform-d) δ 38.8. High resolution data: HRMS (ESI) m / z 414.1982 (M+H + ),calc.for C 27 H 29 NOP + 414.1981.

[0092] Synthetic Applications

[0093]

[0094] 0.94 g (3.0 mmol) of (S)-cyclohexyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphine oxide with an optical purity of 92% ee was added to a 25 mL reaction flask, and the nitrogen atmosphere was evacuated three times. Under a nitrogen atmosphere, 1.0 mL of toluene solvent, 3.3 mL (18.0 mmol) of triethoxysilane, and 0.89 mL (3.0 mmol) of tetraisopropoxytitanium were added in sequence. The reaction was then placed in an oil bath at 100°C for overnight reaction. After completion of the reaction, the reaction was monitored by TLC and directly separated by column chromatography (n-hexane / ethyl acetate 20-10:1) to obtain 0.75 g of (S)-cyclohexyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphide with a yield of 84% and an optical purity of 92% ee. The product was recrystallized from n-hexane and ethyl acetate to obtain (S)-cyclohexyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphide with an optical purity of 99% ee.

[0095]

[0096] (S)-Cyclohexyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphide (optically pure, 99% ee) can be used as a chiral ligand in the palladium-catalyzed Tsuji-Trost reaction of racemic (E)-1,3-diphenylallyl acetate and bis(3,5-bis(trifluoromethyl)phenyl)malonate.

[0097] The specific operation is as follows: (S)-cyclohexyl(phenyl)(2-(pyridin-2-yl)ethyl)phosphide (optically pure 99% ee, 5.0% eq), allylpalladium(II) chloride dimer (2.0% eq) and lithium hydroxide monohydrate (20.0% eq) were dissolved in 2.0 mL of toluene solvent under argon atmosphere. After stirring for 1 hour, racemic (E)-1,3-diphenylallyl acetate (0.1 mmol, 1.0 eq) was added and stirring was continued for 20 minutes. Then, N,O-bis(trimethylsilyl)acetamide (0.0 mmol, 1.0 eq) was added. The reaction mixture was stirred for 2 hours at room temperature for 12 hours. The reaction mixture was stirred for 2 hours at room temperature for 3 hours. The reaction mixture was stirred for 2 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours. The reaction mixture was stirred for 2 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours. The reaction mixture was stirred for 2 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours. The reaction mixture was stirred for 3 hours at room temperature for 3 hours.

Claims

1. A method for the asymmetric catalytic synthesis of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides, characterized in that: In an air atmosphere, a racemic secondary phosphorus oxide (±)-I reacts with a 2-vinyl azaarene II in an organic solvent using a spirocyclic chiral phosphoric acid C1 or C2 as a chiral catalyst at -10 to -20°C, and after completion of the reaction, a chiral azaarene-substituted tertiary phosphorus oxide III is obtained by separation and purification, or a chiral secondary phosphorus oxide RI and a chiral azaarene-substituted tertiary phosphorus oxide III are obtained simultaneously. In formula (±)-I, formula II, formula RI, and formula III, R is isopropyl, cyclohexyl, phenyl, or phenyl substituted with 1 to 3 F, Cl, Me, or OMe, and Ar is 1 for 2-thienyl, 4-methylphenyl, Naphthyl, R1 is H, F, Cl, Me, OMe, Ar 2 for 2. The asymmetric catalytic synthesis method of chiral secondary phosphorus oxides and chiral nitrogen-substituted tertiary phosphorus oxides according to claim 1, characterized in that: The molar ratio of the racemic secondary phosphorus oxide compound (±)-I to the 2-vinyl azaarene II is 2 to 3:

1.

3. The asymmetric catalytic synthesis method of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides according to claim 1 or 2, characterized in that: The amount of the chiral catalyst added is 15% of the molar amount of 2-vinylazaarene II.

4. The asymmetric catalytic synthesis method of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides according to claim 1, characterized in that: The organic solvent is a mixed solvent of tert-butylbenzene and cyclohexane in a volume ratio of 1:

6.

5. The asymmetric catalytic synthesis method of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides according to claim 4, characterized in that: The reaction temperature is -15°C.

6. The asymmetric catalytic synthesis method of chiral secondary phosphorus oxides and chiral nitrogen-arene-substituted tertiary phosphorus oxides according to claim 5, characterized in that: The reaction time is 72-96 hours.

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