A semi-active phosphoramide ligand and preparation method thereof

Abstract

A semi-active phosphoramide ligand and its preparation method, through catalytic amount of Ru3(CO) 12 for C–H activation of diaryl monophosphine and isocyanate, a modular strategy for constructing phosphoramide ligands in an ideal and economical way, thereby providing a series of phosphoramide ligands to promote transition metal-catalyzed reactions to obtain high reactivity and high regioselectivity.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a semi-active phosphoramidite ligand and a preparation method thereof. Background Art

[0002] Semi-active ligands have received extensive attention in recent decades due to the presence of substitutionally labile and inert donor atoms at the coordination terminus; bidentate semi-active P,N / O ligands with soft and hard nucleophilic centers within the molecule have achieved great success in a series of transition metal-catalyzed reactions, especially in asymmetric catalysis, and the demand has increased sharply; compared with bidentate phosphine ligands, these molecules will coordinate fully and dissociate the hard ligand component easily, thus providing a vacant site for binding to the substrate. However, the preparation of semi-active phosphine ligands usually requires multi-step synthesis, and the effective methods for their modular assembly may have a wide impact on ligand design.

[0003] The development of new reactions based on C-H bond activation and functionalization strategies is attractive to organic chemists because it can greatly simplify the process of synthesizing complex molecules from readily available starting materials. In the process of site-selective C-H bond activation, metal catalysts usually need to interact with O and / or N atoms of the guiding functional groups; during the catalytic process, due to the strong coordination effect, the increased steric hindrance of the formed product can promote the exchange of the ligand with the unreacted phosphine and promote the turnover of the catalyst. However, during the process of preparing bidentate ligands from monodentate phosphines, the enhanced coordination ability of the product may lead to catalyst poisoning.

[0004] Therefore, based on the self-characteristics of semi-active phosphine ligands, developing a class of highly active semi-active phosphine ligands and providing a single-step, safe and efficient synthesis method for them to promote the efficient development of transition metal-catalyzed reactions is an urgent problem to be solved in the field of organic synthesis. Summary of the Invention

[0005] The object of the present invention is to address the deficiencies in the prior art that semi-active ligands are widely used in transition metals and have a large demand, but currently there are defects such as cumbersome preparation steps and the enhanced coordination ability of the product during the process of preparing bidentate ligands from monodentate phosphines may lead to catalyst poisoning. The present invention provides a class of semi-active phosphoramidite ligands and a preparation method thereof, through catalytic amounts of Ru3(CO) 12 to carry out C-H activation on diaryl monophosphine and isocyanate, and a modular strategy for constructing phosphoramidite ligands in an ideal and economical way, thereby providing a series of phosphoramidite ligands to promote the high reactivity and high regioselectivity of transition metal-catalyzed reactions.

[0006] Technical Solution

[0007] To solve the above technical problems, the present invention provides a semi-active phosphoramidite ligand, which is characterized in that its chemical formula is:

[0008]

[0009] In the above chemical formulae:

[0010] Ar1 is an aryl group;

[0011] Ar2 is an aryl group, or an aryl group substituted by one or more R4;

[0012] R4 is one or more of an alkyl group, an alkoxy group, a halogen, a haloalkyl group, or an N-alkyl group;

[0013] R1 and R2 are the same or different and are one or more of an alkyl group, a cycloalkyl group, or an aryl group;

[0014] R3 is one or more of an alkyl group, an aryl group, or an alkyl group or an aryl group substituted by R5;

[0015] R5 is one or more of an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, an acyl group having 1 to 3 carbon atoms, an ester group having 1 to 3 carbon atoms, or a phenyl group.

[0016] Furthermore, Ar1 is one or more of a phenyl group, a naphthyl group, or an indolyl group;

[0017] Ar2 is one or more of a phenyl group, a naphthyl group, an indolyl group, a phenyl group substituted by one or more R4, a naphthyl group substituted by one or more R4, or an indolyl group substituted by one or more R4;

[0018] R4 is one or more of a methyl group, an ethyl group, an isopropyl group, a methoxy group, N,N-dimethyl, or fluorine;

[0019] R1 and R2 are the same or different and are one or more of a phenyl group or a cyclohexyl group;

[0020] When Ar2 is a phenyl group, R3 is a methyl group, an ethyl group, a phenyl group, or one or more of a methyl group, an ethyl group, or a phenyl group substituted by R5, and R5 is one or more of a methyl group, a methoxy group, fluorine, chlorine, bromine, a trifluoromethyl group, a trifluoromethoxy group, an acetyl group, an ethyl ester group, or a phenyl group.

[0021] Furthermore, when Ar2 is a naphthyl group, R3 is an ethyl group, or one or more of an ethyl group or a phenyl group substituted by R5, and R5 is one or more of fluorine, chlorine, bromine, a trifluoromethyl group, a trifluoromethoxy group, an acetyl group, an ethyl ester group, or a phenyl group, or a methyl group at the meta-position of the amide, or a methyl group at the para-position of the amide, or a methoxy group at the para-position of the amide.

[0022] The present invention also provides a method for preparing a semi-active phosphoramide ligand, characterized in that the synthesis route is as follows:

[0023]

[0024] Specifically, it includes the following steps:

[0025] 1) In a dry reaction vessel, dissolve compound A, compound B, a catalyst, and a ligand in an organic solvent. Under the protection of an inert gas, raise the temperature and react for 1 to 24 h;

[0026] 2) After the reaction is completed, remove the solvent under reduced pressure, and purify the concentrate to obtain the target compound 1.

[0027] Further, the catalyst in step (1) is Ru3(CO) 12 .

[0028] Further, the ligand in step (1) is one or more of N-Boc-L-Ile-OH (L3) or N-Boc-L-Pro-OH (L4) or N-Boc-L-tLeu-OH (L5) or PivOH. Among them, the chemical formula of N-Boc-L-Ile-OH (L3) or N-Boc-L-Pro-OH (L4) or N-Boc-L-tLeu-OH (L5) or PivOH is:

[0029]

[0030] Further, the molar ratio of compound A to compound B, the catalyst, and the ligand in step (1) is: 1:(1 - 5):(0.005 - 0.1):(0.005 - 0.2).

[0031] Further, the molar ratio of compound A to compound B, the catalyst, and the ligand in step (1) is: 1:(2 - 5):0.02:0.18.

[0032] Further, the organic solvent in step (1) is one or more of toluene or xylene or hexane or cyclopentane or 1,4-dioxane.

[0033] Further, the mass-volume ratio of compound A to the organic solvent in step (1) is 1:(4 - 30) g / mL.

[0034] Further, the reaction temperature in step (1) is preferably 110 - 130 °C.

[0035] Further, the reaction time in step (1) is 16 h.

[0036] Beneficial effects

[0037] A semi-labile phosphonamide ligand provided by the present invention and its preparation method provide various phosphonamide ligands including related axially chiral compounds through ruthenium-catalyzed C-H activation of phosphine and phosphorus(III) atom-directed isocyanates; in the preparation method, the semi-labile phosphonamide ligand can be obtained through a one-step reaction with high reactivity, high regioselectivity, and more operability, simplicity, and safety; this transformation significantly expands the number of phosphonamide ligands, and some of these ligands exhibit excellent efficiency in asymmetric catalysis, with the ee value of the target product reaching up to 99%. More broadly, the present invention easily constructs semi-labile ligands directly from parent monodentate phosphines with ideal atom, step, and redox economy through C-H activation. Detailed Embodiments

[0038] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the described embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention. Unless otherwise defined, the technical terms or scientific terms used herein shall have the ordinary meaning as understood by those of ordinary skill in the art to which the present invention pertains.

[0039] In the prior art, the semi-labile ligands are widely used in transition metals, the preparation steps of such ligands are cumbersome, and in the process of preparing bidentate ligands from monodentate phosphines, the enhanced coordination ability of the products may lead to catalyst poisoning. To solve the above technical problems, this embodiment provides a semi-labile phosphonamide ligand, and its chemical formula is:

[0040]

[0041] In the above chemical formula:

[0042] Ar1 is an aryl group;

[0043] Ar2 is an aryl group or an aryl group substituted by one or more R4;

[0044] R4 is one or more of an alkyl group, an alkoxy group, a halogen, a haloalkyl group, or an N-alkyl group;

[0045] R1 and R2 are the same or different and are one or more of an alkyl group, a cycloalkyl group, or an aryl group;

[0046] R3 is an alkyl group or an aryl group, or one or more of an alkyl group or an aryl group substituted by R5;

[0047] R5 is one or more of an alkyl group, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, an acyl group having 1 to 3 carbon atoms, an ester group having 1 to 3 carbon atoms, or a phenyl group.

[0048] The preparation method of the above-mentioned semi-active phosphoramide ligand has the following synthetic route:

[0049]

[0050] Specifically, it includes the following steps:

[0051] In the first step, in a dry reaction vessel, compound A, compound B, a catalyst, and a ligand are dissolved in an organic solvent, and under the protection of an inert gas, the temperature is raised for reaction for 1 to 24 h;

[0052] In the second step, after the reaction is completed, the solvent is removed under reduced pressure, and the concentrate is purified to obtain the target compound 1.

[0053] The following further details the synthesis scheme of the present invention in combination with specific raw materials.

[0054] Example 1

[0055] Synthesis of 2'-(diphenylphosphino)-5-methyl-N-(p-tolyl)-[1,1'-biphenyl]-2-carboxamide (1a), and its synthetic route is as follows:

[0056]

[0057] In a dry reaction vessel, compound Aa (70.5 mg, 0.20 mmol), compound Ba (53.3 mg, 0.40 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol) and compound L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL), and under the protection of argon, the temperature was raised to 130 °C for reaction for 16 hours. After the reaction was completed, the solvent was removed under negative pressure, and then the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 88.2 mg of colorless oily 1a, with a yield of 91%.

[0058] 1 H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 7.9 Hz, 1H), 7.42–7.35 (m, 3H), 7.35–7.29 (m, 5H), 7.27–7.25 (m, 1H), 7.25–7.23 (m, 1H), 7.22–7.18 (m, 3H), 7.15–7.09 (m, 3H), 7.03–6.97 (m, 4H), 6.49 (s, 1H), 2.27 (s, 3H), 2.07 (s, 3H).

[0059] 13 13C NMR (126 MHz, CDCl3) δ 166.4, 146.3 (d, J = 30.2 Hz), 139.8, 138.4 (d, J = 6.8 Hz), 137.2 (d, J = 12.6 Hz), 136.3 (d, J = 2.4 Hz), 136.2 (d, J = 3.3 Hz), 135.5, 134.4 (d, J = 20.2 Hz), 134.0, 133.9, 133.8, 133.8, 132.8 (d, J = 3.4 Hz), 132.4, 130.3 (d, J = 5.0 Hz), 129.4, 129.4, 129.3, 129.1, 128.9 (d, J = 11.0 Hz), 128.7 (d, J = 6.8 Hz), 128.6, 128.5 (d, J = 2.5 Hz), 120.1, 21.2, 21.0.

[0060] 31 31P NMR (202 MHz, CDCl3) δ -13.29.

[0061] ATR-FTIR (cm -1 ): 2988, 2912, 1651, 1512, 1448, 1322, 1120, 1023, 766.

[0062] HRMS (ESI) m / z calcd for C 33 H 29 NOP (M + H) + 486.1981, found 486.1972.

[0063] For further optimizing the reaction conditions, the following variables were investigated.

[0064] As shown in the following table, except for the exemplified variables, other reaction conditions were the same as those in Example 1, and the obtained reaction results are listed in Table 1.

[0065] Table 1 Influence of changing different conditions on the reaction

[0066]

[0067] [a] 31 31P NMR detection value; [b] Isolated yield.

[0068] The ligands used in the reaction are as follows:

[0069]

[0070] As can be seen from Table 1, in Comparative Examples 1 and 2, and Examples 2, 3, and 4, different ligands were used to replace L5 for the reaction on the basis of Example 1. When L3, L4, and PivOH were used in the reaction, the reaction yields all decreased. When L1 and L2 were used in the reaction, only a very small amount of the target product was obtained, and the catalytic effect was poor. Further, Comparative Example 3 shows that when the reaction was carried out without a ligand, the reaction became very slow and the yield was even lower. On the basis of Example 1, Comparative Examples 4 and 5 also tried to use the inorganic base K2CO3 and the organic base triethylenediamine (DABCO) to replace L5 for the reaction, but the reaction effect was not ideal. On the basis of Example 1, in Comparative Examples 6, 7, 8, and 9, different catalysts were used to catalyze the reaction, but no product was obtained. Catalysts with other ruthenium sources, such as [RuCl2(p-cymene)]2, and common C-H activation catalysts [RhCp*Cl2]2, [RhCp*Cl2]2, [RhCp*Cl2]2, also failed to obtain the target product, which reflects the uniqueness of the Ru cluster. In addition, when the reaction temperature was lowered from 130 °C in Example 1 to 110 °C in Example 5, the reaction yield also decreased significantly.

[0071] Example 6

[0072] Synthesis of 2'-(diphenylphosphino)-N-(4-methoxyphenyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide (1b)

[0073]

[0074] In a dry reaction vessel, compound Aa (70.5 mg, 0.20 mmol), compound Bb (59.7 mg, 0.40 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol), and compound L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the temperature was raised to 130 °C and the reaction was carried out for 16 hours. After the reaction was completed, the solvent was removed under negative pressure, and then the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 85.8 mg of colorless oily 1b with a yield of 85%.

[0075] 11H NMR (500 MHz, CDCl3) δ 7.83 (d, J = 6.4 Hz, 1H), 7.43–7.38 (m, 1H), 7.37–7.29 (m, 6H), 7.28–7.24 (m, 2H), 7.24–7.22 (m, 1H), 7.22–7.17 (m, 3H), 7.16–7.07 (m, 3H), 7.03–6.97 (m, 2H), 6.77–6.73 (m, 2H), 6.51 (s, 1H), 3.75 (s, 3H), 2.07 (s, 3H).

[0076] 13 13C NMR (126 MHz, CDCl3) δ 166.4, 156.4, 146.3 (d, J = 30.5 Hz), 139.8, 138.4 (d, J = 6.7 Hz), 137.2 (d, J = 12.4 Hz), 136.3 (d, J = 3.5 Hz), 136.2 (d, J = 4.6 Hz), 134.4 (d, J = 20.0 Hz), 134.0, 133.8 (d, J = 5.3 Hz), 132.8 (d, J = 3.4 Hz), 132.4, 131.2, 130.3 (d, J = 4.9 Hz), 129.4, 129.2, 129.1, 128.8 (d, J = 6.2 Hz), 128.7 (d, J = 6.8 Hz), 128.5, 128.5, 128.4, 121.8, 114.1, 55.6, 21.2.

[0077] 31 31P NMR (202 MHz, CDCl3) δ -13.32.

[0078] ATR-FTIR (cm -1 ): 3007, 2943, 1475, 1408, 1277, 1119, 1022, 767.

[0079] HRMS (ESI) m / z calcd for C 33 H 29 NO2P (M + H) + 502.1930, found 502.1925.

[0080] Example 7

[0081] Synthesis of 2'-(Diphenylphosphino)-N-(2-fluorophenyl)-5-methyl-[1,1'-biphenyl]-2-carboxamide (1c)

[0082]

[0083] In a dry reaction vessel, compound Aa (70.5 mg, 0.20 mmol), compound Bc (54.8 mg, 0.40 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol) and compound L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the mixture was heated to 130 °C and reacted for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 86.7 mg of colorless oil 1c with a yield of 89%.

[0084] 1 1H NMR (500 MHz, CDCl3) δ 8.32–8.26 (m, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.42–7.37 (m, 1H), 7.36–7.27 (m, 5H), 7.24–7.16 (m, 6H), 7.15–7.09 (m, 3H), 7.09–7.04 (m, 1H), 7.00–6.90 (m, 2H), 6.53 (s, 1H), 2.08 (s, 3H).

[0085] 13 13C NMR (126 MHz, CDCl3) δ 166.6, 152.4 (d, J = 245.7 Hz), 145.8 (d, J = 30.3 Hz), 140.3, 138.9 (d, J = 6.9 Hz), 137.0 (d, J = 13.2 Hz), 136.9 (d, J = 9.8 Hz), 136.3 (d, J = 10.4 Hz), 134.4 (d, J = 20.3 Hz), 134.2, 133.9 (d, J = 19.7 Hz), 133.1 (d, J = 3.0 Hz), 132.0 (d, J = 1.9 Hz), 130.1 (d, J = 5.0 Hz), 129.3 (d, J = 2.9 Hz), 128.9, 128.8, 128.6, 128.5 (d, J = 2.3 Hz), 128.5, 128.5, 126.7 (d, J = 10.1 Hz), 124.5 (d, J = 3.5 Hz), 124.1 (d, J = 7.5 Hz), 121.9, 114.7 (d, J = 19.1 Hz), 21.2.

[0086] 31 31P NMR (202 MHz, CDCl3) δ -13.58 (d, J = 4.9 Hz).

[0087] 1919F NMR (471 MHz, CDCl3) δ -130.48 (d, J = 4.8 Hz).

[0088] ATR-FTIR (cm -1 ): 2985, 2944, 2912, 1448, 1275, 1114, 1023, 737.

[0089] HRMS (ESI) m / z calcd for C 32 H 26 FNOP (M + H) + 490.1731, found 490.1728.

[0090] Example 8

[0091] Synthesis of N-benzyl-2'-(diphenylphosphino)-5-methyl-[1,1'-biphenyl]-2-carboxamide (1d)

[0092]

[0093] In a dry reaction vessel, compound Aa (70.5 mg, 0.20 mmol), compound Bd (53.3 mg, 0.40 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol) and compound L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the mixture was heated to 130 °C and reacted for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 80.2 mg of 1d as a yellow oil, with a yield of 83%.

[0094] 1 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 1H), 7.42–7.32 (m, 5H), 7.31–7.26 (m, 3H), 7.25–7.22 (m, 2H), 7.21–7.12 (m, 5H), 7.01 (ddd, J = 7.8, 3.9, 1.3 Hz, 1H), 6.81 (d, J = 6.9 Hz, 2H), 6.75 (t, J = 7.4 Hz, 2H), 6.37 (s, 1H), 6.02 (s, 1H), 4.50 (dd, J = 14.6, 6.4 Hz, 1H), 4.19 (dd, J = 14.6, 4.5 Hz, 1H), 2.01 (s, 3H).

[0095] 1313C NMR (126 MHz, CDCl3) δ 169.0, 146.5 (d, J = 30.6 Hz), 139.0, 138.0 (d, J = 6.9 Hz), 137.7, 136.6 (d, J = 11.6 Hz), 136.3 (d, J = 8.6 Hz), 136.2 (d, J = 9.5 Hz), 134.6 (d, J = 20.2 Hz), 133.8, 133.7, 133.7, 133.0 (d, J = 3.7 Hz), 132.5, 130.2 (d, J = 5.2 Hz), 129.2, 128.7 (d, J = 2.3 Hz), 128.6, 128.6, 128.6, 128.6, 128.5, 128.1, 128.0, 127.4, 44.2, 21.1.

[0096] 31 31P NMR (202 MHz, CDCl3) δ -13.06.

[0097] ATR-FTIR (cm -1 ): 3007, 2988, 2912, 1641, 1476, 1277, 1026, 767.

[0098] HRMS (ESI) m / z calcd for C 33 H 29 NOP (M + H) + 486.1981, found 486.1975.

[0099] Example 9

[0100] Synthesis of 2'-(Diphenylphosphino)-4,5-dimethoxy-N-(p-tolyl)-[1,1'-biphenyl]-2-carboxamide (1e)

[0101]

[0102] In a dry reaction vessel, compound Ae (79.7 mg, 0.20 mmol), compound Ba (53.3 mg, 0.40 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol) and compound L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the mixture was heated to 130 °C and reacted for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 94.2 mg of 1e as a colorless oil, with a yield of 88%.

[0103] 11H NMR (500 MHz, CDCl3) δ 7.59 (s, 1H), 7.44–7.32 (m, 7H), 7.31–7.26 (m, 3H), 7.25–7.21 (m, 2H), 7.15–7.12 (m, 1H), 7.12–7.07 (m, 2H), 7.03–6.99 (m, 2H), 6.97–6.93 (m, 2H), 6.17 (s, 1H), 3.97 (s, 3H), 3.23 (s, 3H), 2.27 (s, 3H).

[0104] 13 13C NMR (126 MHz, CDCl3) δ 165.7, 149.5, 148.5, 146.2 (d, J = 30.7 Hz), 137.2 (d, J = 12.2 Hz), 136.5 (d, J = 2.8 Hz), 136.4 (d, J = 3.3 Hz), 135.5, 134.4, 134.1 (d, J = 25.1 Hz), 133.8 (d, J = 7.4 Hz), 131.9 (d, J = 6.9 Hz), 130.8 (d, J = 4.8 Hz), 129.7, 129.7, 129.4, 129.2, 129.0, 128.8 (d, J = 2.3 Hz), 128.8, 128.8 (d, J = 1.8 Hz), 127.0, 119.9, 114.4 (d, J = 3.5 Hz), 112.2, 56.1, 55.4, 21.0.

[0105] 31 31P NMR (202 MHz, CDCl3) δ -13.99.

[0106] ATR-FTIR (cm -1 ): 3007, 2988, 2913, 1475, 1277, 1117, 1025, 767.

[0107] HRMS (ESI) m / z calcd for C 34 H 31 NO3P (M + H) + 532.2036, found 532.2033.

[0108] Example 10

[0109] Synthesis of 2-(2-(Dicyclohexylphosphino)phenyl)-1-methyl-N-(p-tolyl)-1H-indole-3-carboxamide (1f)

[0110]

[0111] In a dry reaction vessel, compound Af (80.7 mg, 0.20 mmol), compound Ba (53.3 mg, 0.40 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol) and compound L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the mixture was heated to 130 °C and reacted for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 90.0 mg of white solid 1f with a yield of 84%.

[0112] 1 1H NMR (500 MHz, CDCl3) δ 8.53–8.47 (m, 1H), 7.79–7.75 (m, 1H), 7.68–7.63 (m, 1H), 7.63–7.58 (m, 1H), 7.56–7.52 (m, 1H), 7.40–7.35 (m, 1H), 7.35–7.27 (m, 2H), 7.09–7.01 (m, 3H), 7.01–6.95 (m, 2H), 3.49 (s, 3H), 2.23 (s, 3H), 2.11–2.02 (m, 1H), 1.79–1.66 (m, 4H), 1.61–1.48 (m, 4H), 1.44–1.37 (m, 2H), 1.37–1.24 (m, 3H), 1.23–1.12 (m, 2H), 1.12–1.03 (m, 1H), 1.02–0.88 (m, 3H), 0.87–0.75 (m, 1H), 0.74–0.62 (m, 1H).

[0113] 1313C NMR (126 MHz, CDCl3) δ 163.0, 141.8 (d, J = 5.2 Hz), 139.9 (d, J = 23.9 Hz), 139.0 (d, J = 32.8 Hz), 136.4, 136.2, 134.3 (d, J = 3.3 Hz), 132.5, 131.7 (d, J = 5.8 Hz), 129.8, 129.5, 129.3, 127.3, 123.0, 122.4, 121.9, 118.8, 110.4 (d, J = 2.2 Hz), 109.7, 35.2 (d, J = 15.6 Hz), 33.1 (d, J = 13.3 Hz), 31.3 (d, J = 5.3 Hz), 30.4 (d, J = 13.0 Hz), 30.1 (d, J = 17.8 Hz), 29.9 (d, J = 8.4 Hz), 29.5 (d, J = 12.1 Hz), 27.5 (d, J = 8.2 Hz), 27.4 (d, J = 10.9 Hz), 27.2 (d, J = 9.5 Hz), 27.0 (d, J = 11.4 Hz), 26.5, 26.1, 20.9.

[0114] 31 31P NMR (202 MHz, CDCl3) δ -8.31.

[0115] ATR-FTIR (cm -1 ): 3007, 2988, 2912, 1474, 1277, 1114, 1024, 767.

[0116] HRMS (ESI) m / z calcd for C 35 H 42 N2OP (M + H) + 537.3029, found 537.3027.

[0117] Example 11

[0118] Synthesis of 2'-(diphenylphosphino)-N-(p-tolyl)-[1,1'-biphenyl-2-carboxamide] (1 g)

[0119]

[0120] In a dry reaction vessel, Ag (87.7 mg, 0.20 mmol), Ba (133.2 mg, 1.0 mmol), Ru3(CO) 12(2.6 mg, 0.004 mmol) and L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the mixture was heated to 130 °C and reacted for 16 h. After the reaction was completed, the solvent was removed under reduced pressure, and then the concentrate was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 88.2 mg of yellow solid 1g, with a yield of 74% and ee > 99%.

[0121] 1 H NMR (500 MHz, CDCl3) δ 8.01–7.97 (m, 2H), 7.86–7.83 (m, 1H), 7.59–7.54 (m, 1H), 7.52–7.46 (m, 3H), 7.45–7.29 (m, 3H), 7.23–7.18 (m, 2H), 7.15–6.98 (m, 15H), 2.32 (s, 3H).

[0122] 13 C NMR (126 MHz, CDCl3) δ 166.0, 153.7, 143.0 (d, J = 34.1 Hz), 140.0, 136.7 (d, J = 11.1 Hz), 136.5 (d, J = 12.1 Hz), 136.3 (d, J = 12.6 Hz), 135.2, 135.2 (d, J = 3.0 Hz), 134.8, 134.1 (d, J = 2.8 Hz), 134.1, 134.1, 134.0, 133.7 (d, J = 20.7 Hz), 133.6, 133.5, 133.2 (d, J = 19.0 Hz), 133.1 (d, J = 7.0 Hz), 132.9 (d, J = 2.2 Hz), 131.1, 130.6 (d, J = 2.0 Hz), 129.5, 129.0 (d, J = 6.3 Hz), 128.8, 128.6, 128.5 (d, J = 6.3 Hz), 128.4, 128.3 (d, J = 3.2 Hz), 128.2, 128.0, 127.6 (d, J = 6.7 Hz), 127.5, 127.0, 126.5, 126.4 (d, J = 3.0 Hz), 125.6, 120.7, 119.5, 20.8.

[0123] 31 P NMR (202 MHz, CDCl3) δ -14.91.

[0124] ATR-FTIR (cm -1 ): 3054, 3007, 2987, 1277, 1260, 896, 767, 703.

[0125] HRMS(ESI) m / z calcd for C 40 H 31 NOP(M + H) + 572.2138, found 572.2138.

[0126] [α] D 25 = 41.7 (c = 0.99, CHCl3).

[0127] The ee value was determined by chiral HPLC analysis.

[0128] The analysis conditions were as follows:

[0129] hexane / isopropanol = 80 / 20, flow rate = 1.0 mL / min, column temperature = 25 °C, uv-vis detection at λ = 220 nm, t R1 = 8.5 min (minor), t R2 = 19.0 min (major).

[0130] Example 12

[0131] Synthesis of 2'-(diphenylphosphino)-N-(4-fluorophenyl)-[1,1'-biphenyl-2-carboxamide] (1h)

[0132]

[0133] In a dry reaction vessel, Ag (87.7 mg, 0.20 mmol), Bh (137.1 mg, 1.0 mmol), Ru3(CO) 12 (2.6 mg, 0.004 mmol) and L5 (0.036 mmol, 8.3 mg) were dissolved in toluene (0.5 mL). Under argon protection, the mixture was heated to 130 °C and reacted for 16 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then the concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 56.3 mg of yellow solid 1h, with a yield of 48% and ee > 99%.

[0134] 11H NMR (500 MHz, CDCl3) δ 8.10–8.05 (m, 2H), 7.97–7.89 (m, 3H), 7.56–7.51 (m, 1H), 7.49–7.45 (m, 1H), 7.45–7.40 (m, 1H), 7.37–7.33 (m, 1H), 7.32–7.26 (m, 2H), 7.21–7.15 (m, 2H), 7.13–7.06 (m, 6H), 7.05–7.01 (m, 1H), 7.01–6.96 (m, 2H), 6.89–6.85 (m, 1H), 6.79–6.73 (m, 2H), 6.71–6.66 (m, 2H).

[0135] 13 13C NMR (126 MHz, CDCl3) δ 166.2, 159.2 (d, J = 243.2 Hz), 143.1 (d, J = 34.2 Hz), 136.6 (d, J = 11.8 Hz), 136.4 (d, J = 12.3 Hz), 135.5 (d, J = 8.6 Hz), 134.3, 133.9 (d, J = 2.8 Hz), 133.8 (d, J = 3.8 Hz), 133.6 (d, J = 5.2 Hz), 133.4, 133.3, 133.1 (d, J = 7.0 Hz), 133.0 (d, J = 2.3 Hz), 130.7, 129.2, 129.0, 128.7, 128.6, 128.6, 128.5 (d, J = 4.1 Hz), 128.4, 128.3, 128.1, 127.8, 127.7, 127.3, 126.7, 126.5 (d, J = 2.7 Hz), 125.6, 121.2 (d, J = 8.0 Hz), 115.3 (d, J = 22.5 Hz).

[0136] 31 31P NMR (202 MHz, CDCl3) δ -15.07.

[0137] 19 19F NMR (471 MHz, CDCl3) δ -118.49.

[0138] ATR-FTIR (cm -1 ): 3054, 3007, 2988, 1277, 1260, 1216, 896, 767.

[0139] HRMS (ESI) m / z calcd for C 39 H 28 FNOP (M + H) + 576.1887, found 576.1887.

[0140] [α] D 25 = 64.2 (c = 0.70, CHCl3).

[0141] The ee value was determined by chiral HPLC analysis.

[0142] The analysis conditions were as follows:

[0143] hexane / isopropanol = 80 / 20, flow rate = 1.0 mL / min, column temperature = 25 °C, uv-vis detection at λ = 220 nm, t R1 = 6.5 min (minor), t R2 = 12.2 min (major).

[0144] It should be noted that according to the preparation method provided by the present invention, referring to Example 1, phosphoramide ligand compounds as shown in Table 2 below can be prepared according to different starting compounds:

[0145] Table 2

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] Similarly, according to the preparation method provided by the present invention, referring to Example 11, phosphoramide ligand compounds as shown in Table 3 below can be prepared according to different starting compounds:

[0154] Table 3

[0155]

[0156]

[0157] This example also provides the applications of the phosphoramide ligand as follows:

[0158] Application Example 1: Synthesis of (S)-1-Benzyl-3-hydroxy-3-phenylindolin-2-one (4a)

[0159]

[0160] A solution of [RhCl(C2H4)2]2 (1.9 mg, 9.8 μmol Rh) and 1 g (20 μmol) in THF (1.0 mL) was stirred at room temperature for 10 minutes. KOH (0.10 mL, 30 μmol; 0.3 M aqueous solution), 4a (0.20 mmol), and 5a (0.40 mmol) were added successively, and an additional THF (1.0 mL) was added. The resulting mixture was stirred at 40 °C for 48 hours and then passed directly through a silica gel pad with Et2O. After removing the solvent under vacuum, the residue was purified by column chromatography on silica gel (petroleum ether∶ethyl acetate = 3∶1) to give 50.5 mg (80%) of 11aa, 96% ee, as a white solid.

[0161] 1 1H NMR (500 MHz, CDCl3) δ 7.43–7.37 (m, 2H), 7.36–7.25 (m, 9H), 7.21 (td, J = 7.8, 1.3 Hz, 1H), 7.03 (td, J = 7.6, 1.0 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 5.04 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6 Hz, 1H), 3.59 (s, 1H).

[0162] 13 13C NMR (126 MHz, CDCl3) δ 177.7, 142.7, 140.2, 135.4, 131.7, 129.8, 128.9, 128.7, 128.4, 127.8, 127.3, 125.4, 125.0, 123.6, 109.8, 78.0, 44.1.

[0163] The ee value was determined by chiral HPLC analysis.

[0164] The analysis conditions were as follows:

[0165] hexane / isopropanol = 50 / 50, flow rate = 5.0 mL / min, column temperature = 25 °C, uv-vis detection at λ = 220 nm, t R1 = 20.0 min (minor), t R2 = 31.3 min (major).

[0166] Comparison of Ligand Activities:

[0167] Table 4 Comparison of Ligand Activities

[0168]

[0169]

[0170] As can be seen from Table 4, when the self-made ligands 1g - 1j were used to catalyze the reaction, although the reaction yields were comparable to those obtained using the existing ligands L6 and MeO-MOP, the ee value of 6a was significantly improved compared to the reaction results using the existing ligands.

[0171] Application Example 2:

[0172] Synthesis of (S)-1-benzyl-5-chloro-3-hydroxy-3-phenylindolin-2-one (6b)

[0173]

[0174] A solution of [RhCl(C2H4)2]2 (1.9 mg, 9.8 μmol Rh) and 1g (20 μmol) in THF (1.0 mL) was stirred at room temperature for 10 minutes. KOH (0.10 mL, 30 μmol; 0.3 M aqueous solution), 4b (0.20 mmol), and 5a (0.40 mmol) were added sequentially, and an additional THF (1.0 mL) was added. The resulting mixture was stirred at 40 °C for 48 hours and then passed directly through a silica gel pad with Et2O. After removing the solvent under vacuum, the residue was purified by column chromatography on silica gel (petroleum ether∶ethyl acetate = 3∶1) to give 54.4 mg (80.1%) of 6a, 97% ee, as a white solid.

[0175] 1 H NMR (500 MHz, CDCl3) δ 7.38–7.22 (m, 11H), 7.19–7.11 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.00 (d, J = 15.7 Hz, 1H), 4.79 (d, J = 15.7 Hz, 1H), 4.00 (s, 1H).

[0176] 13 C NMR (126 MHz, CDCl3) δ 177.5, 141.1, 139.6, 135.0, 133.4, 129.7, 129.1, 129.0, 128.8, 128.6, 128.0, 127.3, 125.6, 125.2, 110.9, 78.0, 44.2.

[0177] The ee value was determined by chiral HPLC analysis.

[0178] The analysis conditions are as follows:

[0179] hexane / isopropanol = 50 / 50, flow rate = 0.5 mL / min, column temperature = 25 °C, uv-vis detection at λ = 220 nm, t R1 = 12.8 min (minor), t R2 = 24.1 min (major). Ligand activity comparison:

[0180] Table 5 Ligand activity comparison

[0181]

[0182] As can be seen from Table 5, when the self-made ligands 1g - 1j were used to catalyze the reaction, although the reaction yields were comparable to those obtained using the existing ligands L6 and MeO-MOP, the ee value of 6b was significantly improved compared with the reaction results using the existing ligands.

[0183] Application Example 3:

[0184]

[0185] At room temperature and under an argon atmosphere, N,O-bis(trimethylsilyl)acetamide (BSA, 122.1 mg, 0.6 mmol) and allyl ester 7a (50.4 mg, 0.2 mmol) were added to a mixture of chiral ligand 1g (9.2 mg, 0.016 mmol), [Pd(η 3 -C3H5)Cl]2 (2.9 mg, 0.008 mmol) and LiOAc (1.1 mg, 0.016 mmol) in diethyl ether (1 mL). After 30 minutes, diethyl malonate 8a (96.0 mg, 0.6 mmol) was added. After 10 hours, the reaction mixture was diluted with diethyl ether and water. The organic layer was washed with saturated brine and dried over Na2SO4. The filtrate was concentrated and purified by column chromatography (petroleum ether∶ethyl acetate = 5∶1) to obtain 9a (63.4 mg, 90% yield, 97% ee).

[0186] 11H NMR (500 MHz, CDCl3) δ 7.33–7.16 (m, 10H), 6.47 (d, J = 15.7 Hz, 1H), 6.34 (ddd, J = 15.7, 8.6, 1.4 Hz, 1H), 4.30–4.23 (m, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.97 (tt, J = 7.0, 3.7 Hz, 2H), 3.93–3.90 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H).

[0187] 13 13C NMR (126 MHz, CDCl3) δ 168.0, 167.5, 140.4, 137.0, 131.8, 129.5, 128.8, 128.6, 128.1, 127.6, 127.2, 126.5, 61.7, 61.5, 57.9, 49.3, 14.3, 13.9. The ee value was determined by chiral HPLC analysis.

[0188] The analysis conditions were as follows:

[0189] hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min, column temperature = 25 °C, uv-vis detection at λ = 220 nm, t R1 = 9.7 min (major), t R2 = 12.2 min (minor).

[0190] As can be seen from Application Examples 1, 2, and 3, the ligand prepared by the present invention exhibits excellent catalytic activity in asymmetric catalytic reactions.

Claims

1. A preparation method of a semi-active phosphoramide ligand, characterized in that its chemical formula is: In the above chemical formula: The Ar1 is one or more of phenyl, naphthyl or indolyl; The Ar2 is one or more of phenyl or naphthyl; The R4 is one or more of methyl, ethyl, isopropyl, methoxy, N,N-dimethyl or fluorine; The R1 and R2 are the same or different and are one or more of phenyl or cyclohexyl; When the Ar2 is phenyl, the R3 is methyl, ethyl or phenyl, or one or more of methyl, ethyl, phenyl substituted by R5, and the R5 is one or more of methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, acetyl, ethyl ester or phenyl; When the Ar2 is naphthyl, the R3 is ethyl or one or more of ethyl, phenyl substituted by R5, and the R5 is fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, acetyl, ethyl ester or phenyl, or methyl at the meta position of the amide, or methyl at the para position of the amide, or methoxy at the para position of the amide; Its synthesis route is as follows: The Ru(cat) is Ru3(CO)12; The L is one or more of N-Boc-L-Ile-OH (L3), N-Boc-L-Pro-OH (L4), N-Boc-L-tLeu-OH (L5) or PivOH.

2. The preparation method of a semi-active phosphoramide ligand according to claim 1, characterized in that, It includes the following steps: (1) In a dry reaction vessel, dissolve compound A, compound B, catalyst and ligand in an organic solvent, and under the protection of an inert gas, raise the temperature and react for 1 to 24 h; 2) After the reaction is completed, remove the solvent under reduced pressure, and the concentrate is purified to obtain the target compound 1.

3. The preparation method of a semi-active phosphoramide ligand according to claim 2, characterized in that, The molar ratio of compound A, compound B, catalyst and ligand in step (1) is: 1:(1 - 5):(0.005 - 0.1):(0.005 - 0.2).

4. The preparation method of a semi-active phosphoramide ligand according to claim 3, characterized in that, The molar ratio of compound A, compound B, catalyst and ligand in step (1) is: 1:(2 - 5):0.02:0.

18.

5. The preparation method of a semi-active phosphoramide ligand according to claim 2, characterized in that, The organic solvent in step (1) is one or more of toluene, xylene, hexane, cyclopentane or 1,4-dioxane.

6. The preparation method of a semi-active phosphoramide ligand as described in claim 2, characterized in that, The mass-volume ratio of compound A to the organic solvent in step (1) is 1:(4 - 30) g / mL.

7. The preparation method of a semi-active phosphoramide ligand as claimed in claim 2, wherein, The reaction temperature in step (1) is preferably 110 - 130 °C.

8. The preparation method of a semi-active phosphoramide ligand according to claim 2, characterized in that, The reaction time in step (1) is 16 h.

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