A method for preparing chiral amino alcohol compounds by using water as hydrogen source and nickel metal as catalyst

Abstract

The application discloses a method for preparing chiral amino alcohol compounds by using water as a hydrogen source and nickel metal as a catalyst. The method comprises the following steps: dissolving a nickel metal catalyst, zinc powder, an additive and a ligand in a dry organic solvent under an inert gas atmosphere; then adding an o-phthalimido ketone compound and water; and reacting at 40-70 DEG C to obtain a target product. The additive is one or more of silver iodide, cuprous bromide, cuprous iodide and cuprous chloride. The ligand is ( S, S p )- t‑ Bu-Phosferrox, S, S p )-Bn-Phosferrox, R, R p )-Ph-Phosferrox or R, R p )- i‑ Pr-Phosferrox. The application uses water as a hydrogen source and nickel metal as a catalyst to catalyze amino ketone compounds to obtain a series of chiral amino alcohol compounds. The method is simple, clean and environmentally friendly, and is suitable for the conventional preparation of chiral amino alcohol compounds.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing chiral amino alcohol compounds by nickel metal catalysis using water as a hydrogen source and amino ketones. Background Technology

[0002] Chiral amino alcohols are a very important class of organic compounds, widely found in natural products and drug molecules, and commonly used as ligands and chiral auxiliaries in catalytic reactions. Chiral amino alcohol structures are widely present in various amino acids required by the human body and in the structures of some hormones secreted by the body. Common amino acids such as serine and threonine contain chiral amino alcohol structures. Adrenaline and noradrenaline are two very important hormones in the human body, and their main structural unit is also a chiral amino alcohol. Furthermore, the main pharmacodynamic group of currently used adrenaline receptor agonists is a chiral amino alcohol structure. A representative drug is salbutamol, a short-acting β-2 adrenergic receptor agonist that effectively inhibits the release of histamine and other anaphylactic substances, prevents bronchospasm, and is suitable for bronchial asthma, wheezing bronchitis, bronchospasm, emphysema, and other conditions. Besides their medicinal uses, chiral amino alcohols often play an important role in catalytic reactions. For example, 1-amino-2,3-dihydro-1H-indan-2-ol (A) and 1-phenyl-2-(pyrrolidone-1-yl)prop-1-ol (B) are two very important chiral amino alcohol ligands. Using (A) in the catalytic synthesis of lactams and using (B) in the hydrogenation transfer between ketols and alcohols can both achieve excellent results.

[0003] Given the wide applications of chiral amino alcohols in daily life, research on their synthesis methods has always been a focus. Currently, there are several methods for synthesizing chiral amino alcohols via catalysis, such as amination reactions via CH bonds; addition reactions of imines, alkenes, carbonyl groups, and other unsaturated compounds; Mannich reactions; and ring-opening reactions of epoxides. However, the synthetic methods reported in the literature present a series of problems, including some reactions being difficult to operate, some requiring harsh reaction conditions, some exhibiting very poor atom economy, and others causing significant environmental pollution.

[0004] Therefore, it is essential to study a mild, low-cost, and efficient method for preparing chiral amino alcohols. Summary of the Invention

[0005] To address the above problems, the purpose of this invention is to provide a method for preparing chiral amino alcohol compounds from amino ketones using water as a hydrogen source and nickel metal catalysis.

[0006] The objective of this invention is achieved as follows: A method for preparing chiral amino alcohol compounds using water as a hydrogen source and nickel metal catalysis for amino ketones involves dissolving a nickel metal catalyst, zinc powder, additives, and ligands in a dry organic solvent under an inert gas atmosphere, then adding phthalimide ketone compounds and water, and reacting at 40–70°C to obtain the target product.

[0007] The structural formulas of phthalimide ketone reaction substrates are shown in Formula I or Formula II:

[0008]

[0009] Wherein: R is selected from any one of alkyl or heterocyclic compounds; R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen, alkyl, aryl, or halogen substitution; and n is 1 or 2.

[0010] The additive is one or more of silver iodide, cuprous bromide, cuprous iodide and cuprous chloride;

[0011] The ligand is (S,S) p )-t-Bu-Phosferrox、(S,S p )-Bn-Phosferrox、(R,R p )-Ph-Phosferrox or (R,R p )-i-Pr-Phosferrox.

[0012] This invention uses water as a hydrogen source and nickel metal as a catalyst to catalyze the preparation of a series of chiral amino alcohols from amino ketone compounds. The raw materials are inexpensive, readily available, clean, and environmentally friendly. The method is simple, easy to operate, and has mild reaction conditions. It also has high yield and enantioselectivity, making it suitable for the routine preparation of chiral amino alcohols. Attached Figure Description

[0013] Figure 1 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 1;

[0014] Figure 2 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 1;

[0015] Figure 3 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 2;

[0016] Figure 4 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 2;

[0017] Figure 5 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 3;

[0018] Figure 6 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 3;

[0019] Figure 7 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 4;

[0020] Figure 8 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 4;

[0021] Figure 9 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 5;

[0022] Figure 10 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 5;

[0023] Figure 11 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 6;

[0024] Figure 12 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 6;

[0025] Figure 13 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 7;

[0026] Figure 14 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 7;

[0027] Figure 15 This is the NMR F-spectrum of the chiral amino alcohol compound prepared in Example 7;

[0028] Figure 16 This is the C-NMR spectrum of the chiral amino alcohol compound prepared in Example 8;

[0029] Figure 17 This is the H-NMR spectrum of the chiral amino alcohol compound prepared in Example 8;

[0030] Figure 18 This is an HPLC chromatogram of the chiral amino alcohol compound prepared in Example 1;

[0031] Figure 19 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 2;

[0032] Figure 20 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 3;

[0033] Figure 21 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 4;

[0034] Figure 22 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 5;

[0035] Figure 23 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 6;

[0036] Figure 24 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 7;

[0037] Figure 25 This is the HPLC chromatogram of the chiral amino alcohol compound prepared in Example 8;

[0038] Figure 26 This is an HPLC chromatogram of the chiral amino alcohol compound prepared in Example 9. Detailed Implementation

[0039] The present invention will be further described below with reference to embodiments, but this is not intended to limit the present invention in any way. Any modifications or substitutions made based on the teachings of the present invention shall fall within the protection scope of the present invention.

[0040] This invention provides a method for preparing chiral amino alcohol compounds using water as a hydrogen source and nickel metal catalysis to amino ketones. The method involves dissolving a nickel metal catalyst, zinc powder, additives, and ligands in a dry organic solvent under an inert gas atmosphere, then adding phthalimide ketone compounds and water, and reacting at 40–70°C to obtain the target product.

[0041] The structural formulas of phthalimide ketone reaction substrates are shown in Formula I and Formula II below:

[0042]

[0043] Wherein: R is selected from any one of alkyl or heterocyclic compounds; R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen, alkyl, aryl, or halogen substitution; and n is 1 or 2.

[0044] The additive is one or more of silver iodide, cuprous bromide, cuprous iodide and cuprous chloride;

[0045] The ligand is (S,S) p )-t-Bu-Phosferrox、(S,S p )-Bn-Phosferrox、(R,R p )-Ph-Phosferrox or (R,R p)-i-Pr-Phosferrox.

[0046] The nickel metal catalyst is Ni(OAc)2·4H2O, NiBr2·DME, NiBF4·6H2O, NiCl2·DME, Ni(OTf)2, or NiNO3·6H2O.

[0047] The molar ratio of aminoketone compounds, nickel metal catalyst, zinc powder, water, additives and ligands is 1:0.025~0.05:3~4:5~30:0.05~0.2:0.05~0.12.

[0048] The dried organic solvent is one or more of dried toluene, dried dichloroethane, dried 2,2,2-trifluoroethanol, and dried 1,4-dioxane.

[0049] The inert gas is nitrogen or argon.

[0050] In this invention, NMR spectra were measured using a Brooker AV400 superconducting nuclear magnetic resonance spectrometer. The deuterated reagent was deuterated chloroform (CDCl3), the proton NMR spectrum used tetramethylsilane as an internal standard, and the carbon NMR spectrum used CDCl3 (δ = 77.0) as an internal standard.

[0051] The 200-300 mesh silica gel columns used for column chromatography were purchased from Beijing InnoCare Technology Co., Ltd.; the 0.2 mm thin-layer chromatography silica gel plates used for TLC were purchased from Yantai Chemical Industry Research Institute. Unless otherwise stated, all reagents and solvents used in this invention have been purified using standard methods (refer to the "Reagent Purification Handbook").

[0052] The present invention will be further described below with reference to specific embodiments:

[0053] Example 1

[0054]

[0055] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. A solution of 3.8 mg of cuprous iodide (0.02 mmol), 39 mg of zinc powder (0.6 mmol), and 1.0 mL of 2,2,2-trifluoroethanol containing 53 mg of 2-(1-phenylacetophenone-2-yl)isoindoline-1,3-dione (0.2 mmol) was added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(1-phenylacetophenone-2-yl)isoindoline-1,3-dione was completely consumed. Among them, 2-(1-phenylethylone-2-yl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxy-2-phenylethyl)isoindoline-1,3-dione (51.4 mg, 96% yield, 95% ee). 1 H NMR(400MHz, CDCl3)δ7.84(dd,J=5.4,3.0Hz,2H),7.72(dd,J=5.5,3.0Hz,2H),7.48-7.42(m,2H),7.39-7.33(m,2H),7 .32-7.27(m,1H),5.09-5.04(m,1H),4.01(dd,J=14.3,8.6Hz,1H),3.93(dd,J=14.3,3.7Hz,1H),2.96(d,J=4.7Hz,1H); 13 C NMR (101MHz, CDCl3) δ168.78,141.06,134.16,131.88,128.62,128.13,125.89,123.48,72.65,45.76.

[0056] Example 2

[0057]

[0058] Under an argon atmosphere, NiBr2·DME (3.1 mg, 0.01 mmol), (S,S) pPhosferrox (6.3 mg, 0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes, and then silver iodide (4.7 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and a solution of 2-(2-oxo-2-(p-tolyl)ethyl)isoindoline-1,3-dione (56 mg, 0.2 mmol) in 2,2,2-trifluoroethanol (1.0 mL) were added to the mixture. After adding H₂O (18 μL, 1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-oxo-2-(p-tolyl)ethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-oxo-2-(p-tolyl)ethyl)isoindoline-1,3-dione, NiBr2·DME, (S,S) p The molar ratio of )-Bn-Phosferrox, silver iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxy-2-(p-tolyl)ethyl)isoindoline-1,3-dione (53.5 mg, 90% yield, 98% ee). 1 H NMR (400MHz, CDCl3) δ7.83 (dd, J=5.4, 3.1Hz, 2H), 7.75-7.69 (m, 2H), 7.36-7.30 (m, 2H), 7.16 (d, J=7.9Hz,2H),5.02(dt,J=8.7,4.1Hz,1H),4.05-3.82(m,2H),2.92(d,J=4.9Hz,1H),2.34(s,3H); 13 C NMR (101MHz, CDCl3) δ168.77,138.13,137.81,134.10,131.91,129.28,125.85,123.44,72.36,45.69,21.17.

[0059] Example 3

[0060]

[0061] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of dichloroethane were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. Silver iodide (0.02 mmol), zinc powder (0.6 mmol), and a solution of 2-(2-(4-ethylphenyl)-2-oxoethyl)isoindoline-1,3-dione (0.2 mmol) in dichloroethane (1.0 mL) were then added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-(4-ethylphenyl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-(4-ethylphenyl)-2-oxoethyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, silver iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-(4-ethylphenyl)-2-hydroxyethyl)isoindoline-1,3-dione (46.1 mg, 78% yield, 96% ee). 1 H NMR (400MHz, CDCl3) δ7.85 (dt, J=7.5, 3.7Hz, 2H), 7.73 (dd, J=5.5, 3.1Hz, 2H), 7.38 (d, J=7.7Hz, 2H), 7.21 (d, J=7.7Hz, 2H),5.04(dt,J=8.8,4.1Hz,1H),4.05-3.88(m,2H),2.80(d,J=4.9Hz,1H),2.64(q,J=7.6Hz,2H),1.23(t,J=7.6Hz,3H); 13 C NMR (101MHz, CDCl3) δ168.83,144.28,138.34,134.16,131.91,128.15,125.94,123.48,72.50,45.70,28.59,15.63.

[0062] Example 4

[0063]

[0064] Under an argon atmosphere, NiNO3·6H2O (2.9 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. Then, 1.0 mL of a solution of 2,2,2-trifluoroethanol containing cuprous iodide (3.8 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and 2-(2-(4-(tert-butyl)phenyl)-2-oxoethyl)isoindoline-1,3-dione (64 mg, 0.2 mmol) was added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-(4-(tert-butyl)phenyl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-(4-(tert-butyl)phenyl)-2-oxoethyl)isoindoline-1,3-dione, NiNO3·6H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-(4-(tert-butyl)phenyl)-2-hydroxyethyl)isoindoline-1,3-dione (56.8 mg, 88% yield, 97% ee). 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=5.4, 3.1Hz, 2H), 7.77-7.70 (m, 2H), 7.40 (s, 4H), 5.0 4(ddd,J=8.9,4.9,3.4Hz,1H),4.05-3.86(m,2H),2.77(d,J=4.9Hz,1H),1.32(s,9H); 13 C NMR (101MHz, CDCl3) δ168.85,151.19,138.10,134.16,131.95,125.68,125.60,123.48,72.50,45.69,34.61,31.35.

[0065] Example 5

[0066]

[0067] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (R,R) pPh-Phosferrox (6.1 mg, 0.012 mmol) and 1.0 mL of 1,4-dioxane were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes, and then cuprous iodide (3.8 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and a solution of 1,4-dioxane (64 mg, 0.2 mmol) in 2-(2-(4-(methylthio)phenyl)-2-oxoethyl)isoindoline-1,3-dione (1.0 mL) were added to the mixture. After adding H2O (18 μL, 1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-(4-(methylthio)phenyl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-(4-(methylthio)phenyl)-2-oxoethyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (R,R) p The molar ratio of )-Ph-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-(4-(methylthio)phenyl)-2-hydroxyethyl)isoindoline-1,3-dione (53.7 mg, 86% yield, 97% ee). 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=5.5, 3.1Hz, 2H), 7.74 (dd, J=5.5, 3.0Hz, 2H), 7.41-7.34 (m, 2H), 7. 29-7.21(m,2H),5.03(dt,J=8.2,3.8Hz,1H),4.04-3.88(m,2H),2.93(d,J=4.8Hz,1H),2.48(s,3H); 13 CNMR (101MHz, CDCl3) δ168.82,138.37,137.80,134.23,131.82,126.56,126.44,123.54,72.29,45.63,15.75.

[0068] Example 6

[0069]

[0070] Under an argon atmosphere, NiBF4·6H2O (1.7 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. A solution of 3.8 mg of cuprous iodide (0.02 mmol), 39 mg of zinc powder (0.6 mmol), and 1.0 mL of 2,2,2-trifluoroethanol containing 64 mg of 2-(2-(3-methoxyphenyl)-2-oxoethyl)isoindoline-1,3-dione (0.2 mmol) was added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-(3-methoxyphenyl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-(3-methoxyphenyl)-2-oxoethyl)isoindoline-1,3-dione, NiBF4·6H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxy-2-(3-methoxyphenyl)ethyl)isoindoline-1,3-dione (53.5 mg, 90% yield, 99% ee). 1 H NMR (400MHz, CDCl3) δ7.83 (dd, J=5.4, 3.0Hz, 2H), 7.71 (dd, J=5.4, 3.0Hz, 2H), 7.29-7.22 (m, 1H), 7.01 (dd, J=6.8, 1.5Hz,2H),6.86-6.79(m,1H),5.03(dt,J=8.1,3.6Hz,1H),4.04-3.87(m,2H),3.79(s,3H),3.06(d,J=4.7Hz,1H); 13 C NMR (101MHz, CDCl3) δ168.78,156.76,133.99,131.98,129.08,128.65,127.54,123.29,120.82,110.54,70.25,55.36,43.84.

[0071] Example 7

[0072]

[0073] Under an argon atmosphere, NiCl2·DME (2.2 mg, 0.01 mmol), (R,R) p)-i-Pr-Phosferrox (5.7 mg, 0.012 mmol) and 1.0 mL of toluene were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes, and then cuprous bromide (2.9 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and a toluene solution (1.0 mL) of 2-(2-(4-fluorophenyl)-2-oxoethyl)isoindoline-1,3-dione (57 mg, 0.2 mmol) were added to the mixture. After adding H2O (18 μL, 1 mmol), the mixture was stirred at 40 °C and monitored by TLC until 2-(2-(4-fluorophenyl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. 2-(2-(4-fluorophenyl)-2-oxoethyl)isoindoline-1,3-dione, NiCl2·DME, (R,R) p The molar ratio of (R)-i-Pr-Phosferrox, cuprous bromide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-(4-fluorophenyl)-2-hydroxyethyl)isoindoline-1,3-dione (51.1 mg, 89% yield, 98% ee). 1 HNMR(400MHz, CDCl3)δ7.84(dd,J=5.4,3.1Hz,2H),7.75-7.70(m,2H),7.44-7.38(m,2H), 7.08-7.00(m,2H),5.06(dt,J=7.9,3.6Hz,1H),4.04-3.87(m,2H),3.10(d,J=4.5Hz,1H); 13 C NMR (101MHz, CDCl3) δ168.78, 162.47 (d, J = 246.1Hz), 136.80 (d, J = 3.2Hz), 134.25, 131.77, 127.66, 127.58, 123.53, 115.60, 115.38, 72.00, 45.72; 19 F NMR (376MHz, CDCl3) δ-114.16.

[0074] Example 8

[0075]

[0076] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. A solution of 1.0 mL of 2,2,2-trifluoroethanol containing 3.8 mg of cuprous iodide (0.02 mmol), 39 mg of zinc powder (0.6 mmol), and 65 mg of methyl 4-(2-(1,3-dioxoisoindoline-2-yl)acetyl)benzoate was then added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 50 °C and monitored by TLC until methyl 4-(2-(1,3-dioxoisoindoline-2-yl)acetyl)benzoate was completely consumed. Methyl 4-(2-(1,3-dioxoisoindolin-2-yl)acetyl)benzoate, Ni(OAc)2·4H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-4-(2-(1,3-dioxoisoindoline-2-yl)-1-hydroxyethyl)benzoate (49 mg, 75% yield, 94% ee). 1 HNMR (400MHz, CDCl3) δ8.04-7.99(m,2H),7.84(dd,J=5.5,3.1Hz,2H),7.73(dd,J=5.5,3.0Hz,2H),7.58-7.49(m ,2H),5.14(dt,J=8.4,4.1Hz,1H),4.02(d,J=8.1Hz,1H),4.00-3.93(m,1H),3.91(s,3H),3.31(d,J=4.2Hz,1H); 13 C NMR (101MHz, CDCl3) δ168.77,166.85,146.07,134.30,131.71,129.90,129.79,125.87,123.58,72.35,52.18,45.59.

[0077] Example 9

[0078]

[0079] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (R,R) p5.7 mg of i-Pr-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. A solution of cuprous iodide (3.8 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and 2-(2-(naphthyl-2-yl)-2-oxoethyl)isoindoline-1,3-dione (63 mg, 0.2 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-(naphthyl-2-yl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-(naphthyl-2-yl)-2-oxoethyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (R,R) p The molar ratio of (R)-i-Pr-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxy-2-(naphthyl-2-yl)ethyl)isoindoline-1,3-dione (55.7 mg, 88% yield, 98% ee). 1 H NMR(400MHz, CDCl3) δ7.93(d,J=1.7Hz,1H),7.89-7.80(m,5H),7.72(dd,J=5.5,3.0Hz,2H),7.58(dd,J=8 .5,1.8Hz,1H),7.51-7.45(m,2H),5.24(dt,J=8.5,4.1Hz,1H),4.16-3.98(m,2H),3.09(d,J=4.9Hz,1H); 13 C NMR (101MHz, CDCl3) δ168.86,138.43,134.20,133.25,133.16,131.86,128. 49,128.07,127.74,126.29,126.11,124.92,123.77,123.53,72.83,45.70.

[0080] Example 10

[0081]

[0082] Under an argon atmosphere, Ni(OTf)₂ (3.6 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. Cuprous chloride (1.98 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and a solution of 2-(2-oxo-2-(thiophen-2-yl)ethyl)isoindoline-1,3-dione (54 mg, 0.2 mmol) in 2,2,2-trifluoroethanol (1.0 mL) were then added to the mixture. After adding H₂O (18 μL, 1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-oxo-2-(thiophen-2-yl)ethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-oxo-2-(thiophen-2-yl)ethyl)isoindoline-1,3-dione, Ni(OTf)2, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous chloride, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxy-2-(thiophen-2-yl)ethyl)isoindoline-1,3-dione (48.3 mg, 88% yield, 98% ee). 1 H NMR (400MHz, CDCl3) δ7.90-7.82(m,2H),7.78-7.71(m,2H),7.30-*7.25(m,1H),7.07(dt,J=3.5,1.1Hz, 1H), 6.99 (dd, J=5.0, 3.5Hz, 1H), 5.32 (dt, J=8.7, 4.6Hz, 1H), 4.18-3.99 (m, 2H), 3.11 (d, J=5.6Hz, 1H); 13 C NMR (101MHz, CDCl3) δ168.73,144.69,134.27,131.82,127.00,125.22,124.25,123.59,68.81,45.57.

[0083] Example 11

[0084]

[0085] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. Cuprous chloride (1.98 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and a solution of 2-(2-(furan-2-yl)-2-oxoethyl)isoindoline-1,3-dione (51 mg, 0.2 mmol) in 2,2,2-trifluoroethanol (1.0 mL) were then added to the mixture. After adding H₂O (18 μL, 1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-(furan-2-yl)-2-oxoethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-(furan-2-yl)-2-oxoethyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous chloride, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-(furan-2-yl)-2-hydroxyethyl)isoindoline-1,3-dione (36 mg, 70% yield, 97% ee). 1 HNMR(400MHz, CDCl3) δ7.86(dd,J=5.4,3.0Hz,2H),7.74(dd,J=5.5,3.0Hz,2H),7.41(t,J=1.3Hz,1 H),6.39-6.31(m,2H),5.06(ddd,J=8.4,6.7,4.1Hz,1H),4.21-4.03(m,2H),2.82(d,J=6.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ168.66,153.33,142.63,134.22,131.86,123.54,110.37,107.20,66.30,42.81.

[0086] Example 12

[0087]

[0088] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. A solution of 3.8 mg of cuprous iodide (0.02 mmol), 39 mg of zinc powder (0.6 mmol), and 49 mg of isoindoline-1,3-dione (0.2 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was then added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2,2,2-(3,3-dimethyl-2-oxobutyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(3,3-dimethyl-2-oxobutyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (S,S p The molar ratio of )-t-Bu-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxy-3,3-dimethylbutyl)isoindoline-1,3-dione (45.5 mg, 92% yield, 97% ee). 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=5.4, 3.1Hz, 2H), 7.77-7.70 (m, 2H), 7.40 (s, 4H), 5.0 4(ddd,J=8.9,4.9,3.4Hz,1H),4.05-3.86(m,2H),2.77(d,J=4.9Hz,1H),1.32(s,9H); 13 C NMR (101MHz, CDCl3) δ169.09, 134.09, 132.01, 123.39, 78.25, 40.93, 34.62, 25.59.

[0089] Example 13

[0090]

[0091] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p)-t-Bu-Phosferrox (5.9 mg, 0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes, and then silver iodide (4.7 mg, 0.02 mmol), zinc powder (39 mg, 0.6 mmol), and a 2,2,2-trifluoroethanol solution (1.0 mL) of 2-(2-oxobutyl)isoindoline-1,3-dione (43 mg, 0.2 mmol) were added to the mixture. After adding H2O (18 μL, 1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(2-oxobutyl)isoindoline-1,3-dione was completely consumed. The 2-(2-oxobutyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, and (S,S) were added. p The molar ratio of (R)-t-Bu-Phosferrox, silver iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-hydroxybutyl)isoindoline-1,3-dione (34.7 mg, 80% yield, 98% ee). 1 H NMR (400MHz, CDCl3) δ7.86 (tt, J=5.1, 2.5Hz, 2H), 7.74 (dd, J=5.4, 3.1Hz, 2H), 3.8 8-*3.72(m,3H),2.34(d,J=5.5Hz,1H),1.62-*1.46(m,2H),1.03(t,J=7.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ169.07,134.17,131.93,123.46,71.97,44.10,28.07,9.83.

[0092] Example 14

[0093]

[0094] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. Silver iodide (0.02 mmol), zinc powder (0.6 mmol), and a solution of 2-(3-oxo-3-phenylpropyl)isoindoline-1,3-dione (0.2 mmol) in 1.0 mL of 2,2,2-trifluoroethanol were then added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2-(3-oxo-3-phenylpropyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(3-oxo-3-phenylpropyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, silver iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(3-hydroxy-3-phenylpropyl)isoindoline-1,3-dione (33.7 mg, 60% yield, 93% ee). 1 H NMR (400MHz, CDCl3) δ7.82 (dd, J=5.5, 3.1Hz, 2H), 7.71 (dd, J=5.5, 3.1Hz, 2H), 7.37-7.24 (m, 4H), 7.23-7.1 5(m,1H),4.68(ddd,J=7.6,5.5,4.0Hz,1H),3.88(t,J=6.6Hz,2H),3.11(d,J=4.1Hz,1H),2.18-1.99(m,2H); 13 C NMR (101MHz, CDCl3) δ168.85,143.60,134.10,132.01,128.48,127.53,125.70,123.37,71.24,37.66,34.92.

[0095] Example 15

[0096]

[0097] Under an argon atmosphere, Ni(OAc)₂·4H₂O (2.5 mg, 0.01 mmol), (S,S) p5.9 mg of t-Bu-Phosferrox (0.012 mmol) and 1.0 mL of 2,2,2-trifluoroethanol were added to a Schlenk tube equipped with a magnetic stir bar. The resulting solution was stirred at room temperature for 30 minutes. A solution of 1.0 mL of 2,2,2-trifluoroethanol containing 3.8 mg of cuprous iodide (0.02 mmol), 39 mg of zinc powder (0.6 mmol), and 46 mg of isoindoline-1,3-dione (0.2 mmol) was added to the mixture. After adding 18 μL of H₂O (1 mmol), the mixture was stirred at 70 °C and monitored by TLC until 2,2,2-(2-cyclopropyl-2-oxyethyl)isoindoline-1,3-dione was completely consumed. Among them, 2-(2-cyclopropyl-2-oxoethyl)isoindoline-1,3-dione, Ni(OAc)2·4H2O, (S,S) p The molar ratio of )-t-Bu-Phosferrox, cuprous iodide, zinc powder, and H2O was 1:0.05:0.06:0.1:3:5. The residue was purified by silica gel column chromatography to obtain the desired product (R)-2-(2-cyclopropyl-2-hydroxyethyl)isoindoline-1,3-dione (15.8 mg, 43% yield, 97% ee). 1 HNMR (400MHz, CDCl3) δ7.86 (dd, J=5.4, 3.1Hz, 2H), 7.74 (dd, J=5.5, 3.1Hz, 2H), 3.92 (d, J=5.9Hz, 2H), 3.28 (dq, J= 8.2,5.6Hz,1H),2.30(d,J=4.9Hz,1H),0.94(qt,J=8.1,4.9Hz,1H),0.54(dq,J=7.9,1.5Hz,2H),0.42-0.25(m,2H); 13 C NMR (101MHz, CDCl3) δ169.02,134.24,132.05,123.54,74.56,44.13,15.56,2.51,2.19.

Claims

1. A method for preparing chiral amino alcohols from amino ketones using water as a hydrogen source and nickel metal catalysis, characterized in that, The process involves dissolving a nickel metal catalyst, zinc powder, additives, and ligands in a dry organic solvent under an inert gas atmosphere, then adding phthalimide ketone compounds and water, and reacting at 40-70°C to obtain the target product. The structural formulas of the phthalimide ketone reaction substrates are shown in Formula I or Formula II: ； Wherein: R is selected from any one of alkyl and heterocyclic; R1, R2, R3, R4, and R5 are each independently selected from any one of hydrogen, alkyl, aryl, or halogen substitution; n takes the value of 1 or 2; The additive is one or more of silver iodide, cuprous bromide, cuprous iodide and cuprous chloride; The ligand is ( S, S p )- t- Bu-Phosferrox, ( S, S p )-Bn-Phosferrox、( R, R p )-Ph-Phosferrox or ( R, R p )- i- Pr-Phosferrox.

2. The method for preparing chiral amino alcohols from amino ketones using water as a hydrogen source and catalyzed by nickel metal according to claim 1, characterized in that, The nickel metal catalyst is Ni(OAc)2·4H2O, NiBr2·DME, NiBF4·6H2O, NiCl2·DME, Ni(OTf)2, or NiNO3·6H2O.

3. The method for preparing chiral amino alcohols from amino ketones using water as a hydrogen source and catalyzed by nickel metal according to claim 1, characterized in that, The molar ratio of aminoketone compounds, nickel metal catalyst, zinc powder, water, additives and ligands is 1:0.025~0.05:3~4:5~30:0.05~0.2:0.05~0.

12.

4. The method for preparing chiral amino alcohols from amino ketones using water as a hydrogen source and catalyzed by nickel metal according to claim 1, characterized in that, The dried organic solvent is one or more of dried toluene, dried dichloroethane, dried 2,2,2-trifluoroethanol, and dried 1,4-dioxane.

5. The method for preparing chiral amino alcohols from amino ketones using water as a hydrogen source and catalyzed by nickel metal according to claim 1, characterized in that, The inert gas is nitrogen or argon.

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