Chiral nitrogen-nitrogen-phosphine compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of asymmetric catalysis, and particularly relates to a chiral nitrogen-nitrogen-phosphine compound as well as a preparation method and application thereof. The chiral nitrogen-nitrogen-phosphine-phosphine compound contains two achiral phosphine atoms and two chiral nitrogen atoms, and when the chiral nitrogen-nitrogen-phosphine-phosphine compound is adopted as a ligand to catalyze an asymmetric hydrogenation reaction of o-amino diaryl ketone, the conversion rate is high, the capability of stabilizing a catalytic active center is achieved, and the enantiomer selectivity reaches 96% or above.

Description

Technical Field

[0001] The present invention belongs to the technical field of asymmetric catalysis, and in particular relates to a chiral nitrogen-nitrogen-phosphine compound and a preparation method and application thereof. Background Art

[0002] In recent years, the asymmetric hydrogenation reaction of ketones has developed rapidly. A variety of new chiral ligands have been synthesized and applied to the asymmetric catalytic reaction of ketones. However, different substrates often require different chiral ligands to achieve high enantiomeric selectivity.

[0003] o-Aminodiarylmethanols of optical alcohols are a very important class of intermediates, and their derivatives are widely used in pharmaceuticals, pesticides, and other fields. For example, the key structure of the plant growth retardant inabenfide is (2-amino-5-chlorophenyl)-benzyl alcohol. Currently, relatively few studies have been conducted on the direct asymmetric catalytic synthesis of o-aminodiarylmethanols of optical alcohols. In 2022, Xiangping Hu et al. reported a method for synthesizing o-aminodiarylmethanols of optical alcohols by in situ modification of iridium metal with DPEN-derived NNP ligands via the asymmetric hydrogenation of o-aminodiaryl ketones. Further deacetylation was performed to prepare o-aminodiarylmethanols. Although this method yielded chiral alcohols with high enantioselectivity, the direct preparation of o-aminodiarylmethanols required a two-step reaction. In 2023, Wanbin Zhang reported the RuPHOX-Ru-catalyzed asymmetric hydrogenation of o-aminodiaryl ketones to produce optically pure o-aminodiarylmethanols, but the catalyst activity was relatively low. Therefore, the development of a highly active and highly enantioselective chiral ligand for the asymmetric hydrogenation of o-aminodiaryl ketones to directly prepare optically pure o-aminodiarylmethanols has important academic significance and practical industrial application prospects. Summary of the Invention

[0004] In view of this, the technical problem to be solved by the present invention is to provide a chiral nitrogen-nitrogen-phosphine compound for the asymmetric hydrogenation reaction of o-aminodiaryl ketone, and a preparation method and application thereof.

[0005] The technical solution of the present invention to solve the above technical problems is as follows: In the first aspect of the present invention, a chiral nitrogen-nitrogen-phosphine compound is provided, the chemical formula of which is shown in the general formula (I):

[0006] General formula (Ⅰ) Wherein, R is selected from an aryl group or a cycloalkyl group, R′ is selected from a C1-C6 alkyl group, a C1-C6 alkoxy group or hydrogen, and R″ is selected from a C1-C6 alkyl group or a C2-C6 alkenyl group.

[0007] In some embodiments, the R is selected from unsubstituted or substituted phenyl, the substituted phenyl is substituted by one or more of hydrogen, C1-C6 alkoxy or C1-C6 alkyl; the R′ is selected from methoxy or hydrogen, and the R″ is selected from C1-C3 alkyl or C2-C6 alkenyl.

[0008] In some embodiments, the R is selected from unsubstituted phenyl, or phenyl substituted with one or more substituents of methoxy or C1-C3 alkyl; the R′ is selected from methoxy or hydrogen, and the R″ is selected from ethyl or vinyl.

[0009] In some embodiments, the configuration of the carbon atom at position 9 of the general formula (I) is R or S.

[0010] In some embodiments, the chiral nitrogen-nitrogen-phosphine compound has a structural formula selected from the following structures: (1); (2); (3); (4).

[0011] The second aspect of the present invention provides a method for preparing the aforementioned chiral nitrogen-nitrogen-phosphine compound, wherein the chiral nitrogen-nitrogen-phosphine compound is prepared by a reductive amination reaction of a raw material M4' with an amine compound. The specific synthetic route is as follows: .

[0012] In some embodiments, when R connected to P is selected from a phenyl group, the raw material M4' is the following M4 structure, the amine compound is the following A1 structure, and the chiral nitrogen-nitrogen-phosphine compound is prepared by a reductive amination reaction of the M4 and the amine compound, and the specific synthesis route is as follows: .

[0013] In some embodiments, the synthesis of the raw material M4 is carried out through the following synthetic route: .

[0014] In some embodiments, the method for preparing the chiral nitrogen-nitrogen-phosphine compound comprises the following steps: S1. Under a nitrogen atmosphere, add the raw material M4', an amine compound, and a transition metal catalyst in a molar ratio of (10-12):(10-12):1. Then, add 20 mL of anhydrous and oxygen-free dichloromethane and react at room temperature for 3.5-4.5 h. S2 was added after anhydrous oxygen-free treatment of methanol, and a reducing agent was added under ice bath conditions, the molar number of the reducing agent is 3 to 3.2 times the molar number of M4 ', returned to room temperature and reacted 1.5 to 2.5h, the reaction was quenched with water to obtain a first mixture; S3. The first mixture in S2 was extracted with dichloromethane, and the obtained organic phase was dried over anhydrous sodium sulfate and then filtered. The solvent was removed from the filtrate under reduced pressure, and the chiral nitrogen-nitrogen-phosphine compound was separated by column chromatography.

[0015] The third aspect of the present invention provides an application of the chiral nitrogen-nitrogen-phosphine compound in the asymmetric hydrogenation reaction of o-aminodiaryl ketone, wherein the chiral nitrogen-nitrogen-phosphine compound serves as a ligand, the substrate is an o-aminodiaryl ketone compound, and the asymmetric hydrogenation reaction of the substrate is in situ catalyzed by a transition metal iridium complex in an organic solvent.

[0016] The beneficial effects of the present invention compared to the prior art include: 1) The chiral nitrogen-nitrogen-phosphine compound of the present invention can be used as a chiral ligand to catalyze the asymmetric hydrogenation reaction of o-aminodiaryl ketones. The reaction has a high conversion rate and an enantiomeric selectivity of more than 96%.

[0017] 2) The starting reactants of the chiral nitrogen-nitrogen-phosphine compound of the present invention are cheap and readily available, and have extremely high application value.

[0018] 3) The chiral nitrogen-nitrogen-phosphine compound of the present invention is used for the iridium-catalyzed asymmetric hydrogenation reaction of o-aminodiaryl ketones. The substrate-to-catalyst ratio is as high as 500 / 1, and an isolation yield of more than 84% can be obtained after 2 hours of reaction. Compared with existing methods, the reaction activity is greatly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other embodiments can be obtained based on these drawings without paying any creative work.

[0020] Figure 1 Chemical formulas of chiral nitrogen-nitrogen-phosphine ligands are provided for some embodiments of the present invention. DETAILED DESCRIPTION

[0021] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the embodiments of the present invention are further described in detail below in conjunction with specific embodiments and with reference to the accompanying drawings.

[0022] It should be noted that all expressions using "first" and "second" in the embodiments of the present invention are for distinguishing two non-identical entities with the same name or non-identical parameters. It can be seen that "first" and "second" are only for the convenience of expression and should not be understood as limitations on the embodiments of the present invention. Subsequent embodiments will not explain this one by one.

[0023] The first aspect of the present invention provides a chiral nitrogen nitrogen phosphine phosphine compound, such as Figure 1 As shown, its chemical formula is shown in general formula (I):

[0024] General formula (Ⅰ) Wherein, R is selected from aryl or cycloalkyl (the aryl or cycloalkyl is substituted or unsubstituted aryl or cycloalkyl), R′ is selected from C1-C6 alkyl (the alkyl is a straight chain or branched alkyl, including but not limited to), C1-C6 alkoxy or hydrogen (the alkoxy is a straight chain or branched C1-C6 alkoxy), and R″ is selected from C1-C6 alkyl or C2-C6 alkenyl.

[0025] The chiral nitrogen-nitrogen-phosphine compound of the present invention has a novel nitrogen-nitrogen-phosphine tetradentate structure and can be used as a chiral ligand in the asymmetric hydrogenation of o-aminodiaryl ketones. The compound contains two chiral nitrogens and two achiral phosphines and can be used as a chiral ligand in the asymmetric hydrogenation of o-aminodiaryl ketones. The chiral nitrogen-nitrogen-phosphine compound of the present invention not only provides sufficient steric hindrance to fix the substrate conformation but also avoids coordination failure caused by excessive crowding. Its structure can enhance the structural rigidity of the metal center, reduce the risk of catalyst dissociation, and form more stable octahedral or tetrahedral complexes with transition metals (such as iridium and ruthenium). This can increase the number of catalytic cycles and reaction efficiency of the chiral nitrogen-nitrogen-phosphine ligand in the asymmetric hydrogenation of o-aminodiaryl ketones. Furthermore, the synergistic electronic effect of the two phosphine groups in the structure of this invention allows for flexible regulation of the electron density of the metal center (e.g., electron-donating or electron-withdrawing), optimizing the activation energy of reaction intermediates. This makes it particularly suitable for asymmetric hydrogenation reactions with high energy barriers (such as the asymmetric hydrogenation of o-aminodiaryl ketones), where sufficient steric hindrance is required to stabilize the substrate conformation while avoiding excessive crowding that could lead to coordination failure. For example, the aryl phosphine groups (e.g., phenyl) stabilize the metal complex through conjugation, enhancing catalytic activity. This ligand, when combined with an iridium catalyst, can achieve enantioselectivities of 96% or greater in the asymmetric catalytic hydrogenation of o-aminodiaryl ketones. Iridium catalysts modified with this type of ligand exhibit higher activity and enantioselectivity than other ligands.

[0026] In some embodiments, the R is selected from unsubstituted or substituted phenyl, the substituted phenyl is substituted by one or more of hydrogen, C1-C6 alkoxy or C1-C6 alkyl; the R′ is selected from methoxy or hydrogen, and the R″ is selected from C1-C3 alkyl or C2-C6 alkenyl.

[0027] In some embodiments, the R is selected from unsubstituted phenyl, or phenyl substituted with one or more substituents of methoxy or C1-C3 alkyl; the R′ is selected from methoxy or hydrogen, and the R″ is selected from ethyl or vinyl.

[0028] In some embodiments, the configuration of the carbon atom at position 9 of the general formula (I) is R or S. By precisely controlling the chiral configuration of the carbon atom at position 9, the stereocompatibility between the ligand and the substrate can be directional controlled, thereby achieving precise control of the absolute configuration of the product. When used as a ligand product, the product can be one of a (9S)-nitrogen-nitrogen-phosphine compound and a (9R)-nitrogen-nitrogen-phosphine ligand.

[0029] In some embodiments, the chiral nitrogen nitrogen phosphine phosphine ligand has a structural formula selected from the following structures: (1); (2); (3); (4). The ligands of specific structural formulas (1)-(4) exhibit high enantioselectivity in the hydrogenation reaction of o-aminodiaryl ketones, and the reaction yield can reach more than 95%, which is significantly better than existing similar ligands.

[0030] The second aspect of the present invention provides a method for preparing the chiral nitrogen-nitrogen-phosphine compound according to the first aspect of the present invention. The chiral nitrogen-nitrogen-phosphine compound is prepared by a reductive amination reaction of a raw material M4' with an amine compound. The specific synthesis route is as follows: .

[0031] In some embodiments, when R connected to P is selected from a phenyl group, the raw material M4' is the following M4 structure, the amine compound is the following A1 structure, and the chiral nitrogen-nitrogen-phosphine compound is prepared by a reductive amination reaction of the M4 and the amine compound, and the specific synthesis route is as follows: The 2nd and 6th positions of the benzene ring of M4 of the present invention are occupied by substituents, resulting in enhanced rigidity of the benzene ring: the conformation of the benzene ring is fixed, the rotational freedom is reduced, and the condensation reaction of the amine and the aldehyde is more directional; and the 2nd and 6th positions of the benzene ring are occupied by substituents, which significantly increases the steric hindrance of the molecule and inhibits side reactions (such as multi-molecular condensation). At the same time, the 2nd and 6th positions of the benzene ring are occupied by substituents, and the substituents can regulate the reaction activity through electronic effects.

[0032] In some embodiments, the synthesis of the raw material M4 is carried out through the following synthetic route: The method of the present invention utilizes cheap and readily available 2,6-dibromobenzaldehyde as a raw material and is prepared through steps such as aldehyde group protection, diphenylphosphine substitution, and aldehyde group deprotection. Compared with the existing technology, the production cost can be greatly reduced, and the intermediates generated by the reaction are highly stable and suitable for industrial scale-up production.

[0033] In some embodiments, the method for preparing the chiral nitrogen-nitrogen-phosphine compound comprises the following steps: S1. Under a nitrogen atmosphere, add the raw material M4', an amine compound, and a transition metal catalyst in a molar ratio of (10-12):(10-12):1. Then, add 20 mL of anhydrous and oxygen-free dichloromethane and react at room temperature for 3.5-4.5 h. S2 was added after anhydrous oxygen-free treatment of methanol, and a reducing agent was added under ice bath conditions, the molar number of the reducing agent is 3 to 3.2 times the molar number of M4 ', returned to room temperature and reacted 1.5 to 2.5h, the reaction was quenched with water to obtain a first mixture; S3. The first mixture in S2 is extracted with dichloromethane. The resulting organic phase is dried over anhydrous sodium sulfate and filtered. The solvent is removed from the filtrate under reduced pressure, and the chiral nitrogen-nitrogen-phosphine compound is separated by column chromatography. By optimizing reaction conditions (such as reagent ratios and temperature control), the reaction time can be shortened to less than 6 hours, and the purity of the product after column chromatography separation is increased, significantly improving preparation efficiency.

[0034] In some embodiments, the transition metal compound may be iron (III) tris(trifluoromethanesulfonate).

[0035] In some embodiments, the reducing agent is sodium borohydride (NaBH 4 ).

[0036] A third aspect of the present invention provides a use of the chiral nitrogen-nitrogen-phosphine compound described in the first aspect of the present invention in the asymmetric hydrogenation of an o-aminodiaryl ketone. The chiral nitrogen-nitrogen-phosphine compound is used as a compound, and the substrate is an o-aminodiaryl ketone compound. The asymmetric hydrogenation reaction of the substrate is in situ catalyzed by a transition metal iridium complex in an organic solvent. In some embodiments, the o-aminodiaryl ketone compound is specifically a substituted or unsubstituted diaryl ketone; the diaryl ketone having a substituent on the nitrogen atom includes acetyl, pyridyl, or methyl substituted groups.

[0037] In some embodiments, the complex of the chiral nitrogen-nitrogen phosphine ligand and transition metal iridium in an organic solvent in situ catalyzes the reaction of the o-aminodiaryl ketone.

[0038] In some embodiments, the iridium complex is an iridium-cyclooctadiene complex [Ir(COD)Cl]2.

[0039] The specific structure of the chiral nitrogen-nitrogen-phosphine ligand of the present invention has high coordination ability and spatial adjustability, is suitable for highly sterically hindered substrates (such as o-aminodiaryl ketones containing strong electron-withdrawing groups), has strong substrate universality, and is widely used in industry.

[0040] In some embodiments, the transition metal iridium complex is synthesized by coordination reaction of the chiral nitrogen-nitrogen-phosphine ligand and an iridium precursor under inert gas protection; the iridium precursor is selected from one or more of iridium (III) chloride dihydrate, iridium (III) acetylacetonate or potassium hexachloroiridate (IV).

[0041] The scheme of the present invention will be explained below in conjunction with the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the examples, conventional technical solutions in the art are used. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0042] Example 1: Synthesis of Compound M2

[0043] Synthesis steps of M2: 2,6-dibromobenzaldehyde (5 g, 19.1 mmol) and 1,2-ethylene glycol (1.78 g, 28.7 mmol) were added to a 100 mL two-necked flask, and p-toluenesulfonic acid (PTS) (0.33 g, 1.9 mmol) and 50 mL of toluene were added. The mixed solution was heated to 130°C and stirred, and the water produced during the reaction was removed through a water separator. After the reaction was carried out for 4 hours, the temperature was cooled to room temperature and the reaction solution was concentrated under vacuum. The obtained mixture was separated and purified by silica gel column chromatography to obtain M2 (5.3 g, 91% yield). White solid, 1 H NMR (600 MHz, CDCl3) δ 7.57 (d, J = 6.0 Hz, 2H),7.04-7.07 (m, 1H), 6.40 (s, 1H), 4.34-4.36 (m, 2H), 4.08-4.10 (m, 2H). 13 C NMR (150 MHz, CDCl3) δ 132.6, 131.6, 130.4, 123.9, 103.2, 64.9. Example 2: Synthesis of Compound M3

[0044] Synthesis of M3: Under nitrogen, M2 (5 g, 16.3 mmol) was added to a three-necked flask containing 30 mL of anhydrous and oxygen-free tetrahydrofuran. The temperature was lowered to -78°C, and n-butyllithium (n-BuLi) (34.2 mmol) was slowly added dropwise at this temperature. After the addition was complete, the reaction was stirred at this temperature for 2 hours. A solution of diphenylphosphine chloride (7.5 g, 34.2 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise to the reaction solution at this temperature using a constant pressure dropping funnel. After the addition was complete, the reaction was stirred at this temperature for 0.5 hours, then the temperature was raised to room temperature and stirred overnight. After the reaction was completed, distilled water (20 mL) was added, extraction was performed, and the organic phase was collected and dried over anhydrous sodium sulfate. After drying, the solution was filtered, concentrated under vacuum to remove the solvent, and recrystallized from ethanol to obtain M3 (6.4 g, 76% yield). A white solid, 1 H NMR (600MHz, CDCl3) δ 7.38-7.39 (m, 11H), 7.32-7.34 (m, 9H), 7.17-7.19 (m, 1H), 7.05-7.07 (m, 2H), 6.86-6.88 (m, 1H), 4.30-4.32 (m, 2H), 3.87-3.89 (m, 2H). 13 C NMR(150 MHz, CDCl3) δ 143.8, 137.1, 137.0, 134.7, 132.7, 132.5, 128.2, 127.4,127.3, 127.3, 101.6, 64.0. Example 3: Synthesis of Compound M4

[0045] Synthesis of M4: Under nitrogen, M3 (5 g, 9.7 mmol) was added to a 50 mL mixture of water and acetone (volume ratio 1:1) that had been treated for anhydrous and oxygen-free conditions. p-Toluenesulfonic acid (172 mg, 1 mmol) was then added, and the temperature was raised to 60°C and stirred for 2 hours. After the reaction, distilled water (20 mL) was added, and the mixture was extracted with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. After drying, the solution was filtered, concentrated under reduced pressure to remove the solvent, and recrystallized from ethanol to obtain M4 (4.0 g, 86% yield). A yellow solid was obtained. 1H NMR (600 MHz, CDCl3) δ 10.87-10.89 (m,1H), 7.30-7.34 (m, 13H), 7.26-7.28 (m, 5H), 7.25 (d, J = 1.5 Hz, 3H), 6.93-6.95(m, 2H). 13 C NMR (150 MHz, CDCl3) δ 189.6, 141.7, 141.6, 139.2, 135.7, 135.7,133.0, 132.9, 131.3, 128.0, 127.6, 127.6. Example 4: Synthesis of ligand (1)

[0046] Synthesis steps of ligand (1): Under N2 atmosphere, M4 (1.00 g, 2.1 mmol), amine compound (1) (615 mg, 2.1 mmol) and tris(trifluoromethanesulfonate) iron (Fe(otf)3) (0.2 mmol, 100 mg) were added to a 100 mL reaction bottle, and finally 20 mL of anhydrous and oxygen-free dichloromethane was added. After reacting at room temperature for 4 h, 20 mL of anhydrous and oxygen-free methanol was added, and sodium borohydride (238 mg, 6.3 mmol) was added under ice bath conditions. After returning to room temperature and reacting for 2 h, water was added to quench the reaction, and the reaction system was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and the ligand (1) (725 mg, yield 46%) was obtained by column chromatography. White solid, 1 H NMR (600 MHz, CDCl3) δ 8.88 (d, J = 3.0 Hz, 1H), 8.12-8.20 (m, 2H), 7.65-7.68 (m, 2H), 7.49-7.51 (m, 2H), 7.29-7.32 (m, 6H), 7.21-7.25 (m, 9H), 7.13-7.15 (m, 3H), 7.01-7.03 (m, 2H), 6.84-6.90 (m, 2H), 5.86-5.91 (m,1H), 5.05-5.17 (m, 2H), 4.66 (d, J= 6.0 Hz, 1H), 3.82-4.07 (m, 3H), 3.10 (s, 1H), 2.74-2.77 (m, 3H), 2.22 (s, 1H), 1.42-1.53 (m, 2H), 1.15-1.29 (m, 2H), 0.72-0.88(m, 2H). 13 C NMR (150 MHz, CDCl3) δ 149.7, 147.1, 136.7, 136.6, 136.5, 134.2,132.8, 132.7, 132.7, 132.6, 132.6, 129.3, 127.5, 127.4, 127.4, 126.8, 125.0,121.9, 119.7, 61.2, 57.2, 56.9, 48.4, 48.1, 47.9, 47.7, 46.2, 28.7, 26.6,23.3. 31 P NMR (303 MHz, CDCl3) δ -14.35. HRMS (ESI) calcd. for C 50 H 48 N3P2[M+H] + :752.3323, found: 752.3325. Example 5: Synthesis of ligand (2)

[0047] Synthesis steps of ligand (2): Under N2 atmosphere, M4 (1.00 g, 2.1 mmol), amine compound (2) (678 mg, 2.1 mmol) and tris(trifluoromethanesulfonic acid) iron (Fe(otf)3) (0.2 mmol, 100 mg) were added to a 100 mL reaction bottle, and finally 20 mL of anhydrous and oxygen-free dichloromethane was added. After reacting at room temperature for 4 h, 20 mL of anhydrous and oxygen-free methanol was added, and sodium borohydride (238 mg, 6.3 mmol) was added under ice bath conditions. After returning to room temperature and reacting for 2 h, water was added to quench the reaction, and the reaction system was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and ligand (2) (705 mg, yield 43%) was obtained by column chromatography. White solid, 1 H NMR (600 MHz, CDCl3) δ 8.73-8.74 (m, 1H), 8.02 (d, J= 3.0 Hz, 1H), 7.58-7.63 (m, 2H), 7.47-7.51 (m, 2H), 7.42-7.44 (m, 2H), 7.38 (d, J = 1.5 Hz, 1H),7.31-7.34 (m, 6H), 7.19-7.28 (m, 8H), 7.13-7.15 (m, 3H), 6.97-7.03 (m, 2H),6.87-6.88 (m, 1H), 5.88-5.94 (m, 1H), 5.09-5.18 (m, 2H), 4.54-4.57 (m, 1H), 3.96-4.02 (m, 2H), 3.80-3.87 (m, 4H), 3.64-3.70 (m, 1H), 2.99-3.03 (m, 1H),2.76-2.81 (m, 1H), 2.24 (s, 1H), 1.56 (s, 1H), 1.47 (s, 1H), 1.29-1.31 (m,1H), 1.19-1.26 (m, 2H), 0.79 (s, 1H). 13 C NMR (150 MHz, CDCl3) δ 157.4, 148.3,144.2, 137.7, 137.7, 137.6, 135.0, 133.9, 133.8, 133.7, 133.7, 133.6, 131.9,131.8, 131.6, 128.5, 128.4, 127.8, 121.2, 121.0, 100.9, 64.3, 62.2, 58.3,55.4, 49.1, 45.9, 27.5, 25.4, 24.5, 18.5, 9.0. 31 P NMR (303 MHz, CDCl3) δ -14.15. HRMS (ESI) calcd. for C 51 H 50 N3OP2[M+H] + : 782.3424, found: 782.3417. Example 6: Synthesis of ligand (3)

[0048] Synthesis steps of ligand (3): Under N2 atmosphere, M4 (1.00 g, 2.1 mmol), amine compound (3) (615 mg, 2.1 mmol) and tris(trifluoromethanesulfonate) iron (Fe(otf)3) (0.2 mmol, 100 mg) were added to a 100 mL reaction bottle, and finally 20 mL of anhydrous and oxygen-free dichloromethane was added. After reacting at room temperature for 4 h, 20 mL of anhydrous and oxygen-free methanol was added, and sodium borohydride (238 mg, 6.3 mmol) was added under ice bath conditions. After returning to room temperature and reacting for 2 h, water was added to quench the reaction, and the reaction system was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and ligand (3) (804 mg, yield 51%) was obtained by column chromatography. White solid, 1 H NMR (600 MHz, CDCl3) δ 8.90 (d, J = 1.5 Hz, 1H), 8.22 (d, J = 3.0 Hz, 1H),8.14 (d, J = 6.0 Hz, 1H), 7.65-7.67 (m, 2H), 7.49-7.52 (m, 1H), 7.29-7.33 (m,6H), 7.24 (s, 9H), 7.13 (s, 4H), 7.00-7.03 (m, 2H), 6.89 (d, J = 6.0 Hz, 2H),5.63-5.69 (m, 1H), 4.90-4.95 (m, 2H), 4.66 (d, J = 6.0 Hz, 1H), 4.09 (s, 1H), 3.81 (d, J = 6.0 Hz, 1H), 3.43 (s, 1H), 3.04-3.08 (m, 1H), 2.22 (s, 1H), 1.55(s, 2H), 1.21-1.28 (m, 5H), 0.82-0.89 (m, 2H). 13C NMR (150 MHz, CDCl3) δ150.8, 149.1, 148.1, 137.7, 137.5, 137.4, 135.2, 133.8, 133.7, 133.7, 133.7,133.6, 133.6, 130.4, 128.4, 127.9, 126.2, 122.7, 120.9, 58.2, 53.4, 48.8,41.1, 31.9, 30.2, 29.7, 27.5, 22.7, 18.4, 14.1. 31 P NMR (303 MHz, CDCl3) δ -14.49. HRMS (ESI) calcd. for C 50 H 48 N3P2[M+H] + : 752.3318, found: 752.3297. Example 7: Synthesis of ligand (4)

[0049] Synthesis steps of ligand (4): Under N2 atmosphere, M4 (1.00 g, 2.1 mmol), amine compound (4) (678 mg, 2.1 mmol) and tris(trifluoromethanesulfonate) iron (Fe(otf)3) (0.2 mmol, 100 mg) were added to a 100 mL reaction bottle, and finally 20 mL of anhydrous and oxygen-free dichloromethane was added. After reacting at room temperature for 4 h, 20 mL of anhydrous and oxygen-free methanol was added, and sodium borohydride (238 mg, 6.3 mmol) was added under ice bath. After returning to room temperature and reacting for 2 h, water was added to quench the reaction, and the reaction system was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and ligand (4) (787 mg, yield 48%) was obtained by column chromatography. White solid, 1 H NMR (600 MHz, CDCl3) δ 8.76 (d, J = 1.5 Hz, 1H), 8.05 (d, J = 6.0 Hz, 1H),7.53-7.61 (m, 2H), 7.44 (d, J = 1.5 Hz, 1H), 7.32-7.37 (m, 6H), 7.28 (d, J = 1.5Hz, 1H), 7.25 (d, J= 1.5 Hz, 8H), 7.18-7.20 (m, 1H), 7.12-7.14(m, 4H), 7.01-7.03 (m, 1H), 6.96 (s, 1H), 6.88-6.90 (m, 2H), 5.65-5.71 (m, 1H), 4.92-4.98(m, 2H), 4.57 (d, J = 3.0 Hz, 1H), 4.08 (d, J = 6.0 Hz, 1H), 3.99-4.03 (m, 1H), 3.88 (s, 3H), 3.83 (d, J = 6.0 Hz, 1H), 3.49 (s, 1H), 3.07-3.11 (m, 1H), 2.55(s, 1H), 2.28 (s, 1H), 1.60 (s, 3H), 1.25-1.29 (m, 1H), 0.86-0.94 (m, 2H). 13 CNMR (150 MHz, CDCl3) δ 157.6, 148.4, 146.7, 144.3, 137.6, 137.5, 135.2,134.7, 133.8, 133.8, 133.7, 133.7, 133.7, 133.6, 131.9, 129.8, 128.5, 128.0,121.0, 120.6, 101.6, 61.9, 58.4, 57.8, 55.6, 48.7, 46.1, 41.2, 40.7, 29.7,27.5, 24.9, 9.1. 31 P NMR (303 MHz, CDCl3) δ -14.38. HRMS (ESI) calcd. forC 51 H 50 N3OP2[M+H] + : 782.3429, found: 782.3433. Example 8: Application of Ligand (4) in the Asymmetric Hydrogenation of o-Aminodiaryl Ketones

[0050] [Ir(COD)Cl]2 (1.0 mg, 0.0015 mmol), ligand (4) (4.7 mg, 0.006 mmol), Ba(OH)2 (15.1 mg, 0.08 mmol), (2-aminophenyl)phenyl ketone (296 mg, 1.5 mmol) and methanol (2 ml) were added to the autoclave. The air in the autoclave was replaced with hydrogen three times, and the hydrogen pressure was adjusted to 6.0 MPa. The reaction was carried out at 30°C for 2 h. After the reaction was completed, the solvent was removed under reduced pressure, and 2-aminophenyl)phenyl ketone (295 mg, yield 99%) was obtained by column chromatography. White solid, 1 H NMR (600 MHz, CDCl3) δ 7.22-7.34 (m, 5H),7.08-7.11 (m, 1H), 6.98 (d, J = 3.0 Hz, 1H), 6.71-6.73 (m, 1H), 6.63 (d, J = 3.0Hz, 1H), 5.78 (s, 1H), 3.53 (s, 3H). 13 C NMR (150 MHz, CDCl₃) δ 143.7, 140.9, 127.9, 127.6, 127.4, 126.6, 125.5, 117.4, 116.0, 73.8. Enantioselectivity was determined by liquid chromatography (95% ee). HPLC conditions: Daicel OD-H: isopropanol / n-hexane = 10 / 90, 1.2 mL / min, UV 254 nm, tR (major) = 19.8 min, tR (minor) = 23.3 min. Example 9: Asymmetric hydrogenation of various o-aminodiaryl ketone substrates Under the following optimal conditions: [Ir(COD)Cl]2 (1.0 mg, 0.0015 mmol) as catalyst precursor, ligand (4) (4.7 mg, 0.006 mmol) as ligand, Ba(OH)2 (15.1 mg, 0.08 mmol) as base, substrate (1.5 mmol), methanol (2 ml) as solvent, hydrogen pressure of 6.0 MPa, temperature of 30 ° C, reaction time of 2 h. We tested the asymmetric hydrogenation of various o-aminodiaryl ketone substrates. Ligand (4) was applied to the asymmetric hydrogenation of o-aminodiaryl ketone substrates. The conversion rates and enantioselectivities (ee) of various chiral compounds were as follows:

[0051] As can be seen from the above, the asymmetric hydrogenation reaction of o-aminodiaryl ketone substrate catalyzed by iridium metal precursor modified with ligand (4) has ultra-high product yield and enantioselectivity (ee value).

[0052] Recognizing the significant value of developing new ligands, this invention provides a chiral nitrogen-nitrogen-phosphine tetradentate ligand for the asymmetric hydrogenation of o-aminodiaryl ketones. The raw materials for preparing this chiral nitrogen-nitrogen-phosphine ligand are derived from the natural product cinchona alkaloid, which is inexpensive and readily available. The ligand synthesis process is simple, and the structure contains two achiral phosphine atoms, which stabilize the catalytic active center. Compared to existing methods, the catalyst dosage can be as low as 0.2 mol% (0.2 mol% = 1 / 500, i.e., S / C = 500, or a catalyst-to-substrate ratio of 1 / 500), significantly improving both reaction activity and enantioselectivity.

[0053] The technical features of the above embodiments can be combined arbitrarily. To make the description concise, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0054] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A chiral nitrogen-nitrogen-phosphine compound, characterized in that Its chemical formula is shown in general formula (I): General formula (Ⅰ) Wherein, R is selected from an aryl group or a cycloalkyl group, R′ is selected from a C1-C6 alkyl group, a C1-C6 alkoxy group or hydrogen, and R″ is selected from a C1-C6 alkyl group or a C2-C6 alkenyl group.

2. The chiral nitrogen-nitrogen-phosphine compound according to claim 1, characterized in that The R is selected from unsubstituted or substituted phenyl, the substituted phenyl is substituted by one or more of hydrogen, C1-C6 alkoxy or C1-C6 alkyl; the R' is selected from methoxy or hydrogen, and the R" is selected from C1-C3 alkyl or C2-C6 alkenyl.

3. The chiral nitrogen-nitrogen-phosphine compound according to claim 1, characterized in that The R is selected from unsubstituted phenyl, or phenyl substituted by one or more substituents of methoxy or C1~C3 alkyl; the R' is selected from methoxy or hydrogen, and the R" is selected from ethyl or vinyl.

4. The chiral nitrogen-nitrogen-phosphine compound according to claim 1, characterized in that The configuration of the 9th carbon atom in the general formula (I) is R or S.

5. The chiral nitrogen-nitrogen-phosphine compound according to claim 1, characterized in that The structural formula of the chiral nitrogen-nitrogen-phosphine compound is selected from the following structures: （1）； （2）； （3）； （4）。 6. A method for preparing a chiral nitrogen-nitrogen-phosphine compound according to any one of claims 1 to 5, characterized in that: The chiral nitrogen-nitrogen-phosphine compound is prepared by reductive amination reaction of raw material M4' with an amine compound. The specific synthesis route is as follows: 。 7. The method for preparing a chiral nitrogen-nitrogen-phosphine compound according to claim 6, wherein: When R connected to P is selected from phenyl, the raw material M4' is the following M4 structure, the amine compound is the following A1 structure, and the chiral nitrogen-nitrogen-phosphine compound is prepared by reductive amination reaction of M4 and the amine compound. The specific synthesis route is as follows: 。 8. The method for preparing a chiral nitrogen-nitrogen-phosphine compound according to claim 7, wherein: The synthesis of the raw material M4 is carried out through the following synthetic route: 。 9. The method for preparing a chiral nitrogen-nitrogen-phosphine compound according to claim 6, wherein: The preparation method of the chiral nitrogen-nitrogen-phosphine compound comprises the following steps: S1. Under a nitrogen atmosphere, add the raw material M4', an amine compound, and a transition metal catalyst in a molar ratio of (10-12):(10-12):

1. Then, add 20 mL of anhydrous and oxygen-free dichloromethane and react at room temperature for 3.5-4.5 hours. S2 was added after anhydrous oxygen-free treatment of methanol, and a reducing agent was added under ice bath conditions, the molar number of the reducing agent is 3 to 3.2 times the molar number of M4 ', returned to room temperature and reacted 1.5 to 2.5h, the reaction was quenched with water to obtain a first mixture; S3. The first mixture in S2 was extracted with dichloromethane, and the obtained organic phase was dried over anhydrous sodium sulfate and then filtered. The solvent was removed from the filtrate under reduced pressure, and the chiral nitrogen-nitrogen-phosphine compound was separated by column chromatography.

10. Use of the chiral nitrogen-nitrogen-phosphine compound according to any one of claims 1 to 5 in the asymmetric hydrogenation of o-aminodiaryl ketone, characterized in that: The chiral nitrogen-nitrogen-phosphine compound is used as a ligand, the substrate is an o-aminodiaryl ketone compound, and the asymmetric hydrogenation reaction of the substrate is in situ catalyzed by a transition metal iridium complex in an organic solvent.

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