Chiral bidentate nitrogen ligand based on cinchona alkaloid skeleton, preparation method and application

Abstract

The invention relates to the technical field of asymmetric catalysis, and in particular to a chiral bidentate nitrogen ligand based on a cinchona alkaloid skeleton, a preparation method and an application thereof. The compound is used to catalyze an asymmetric hydrogenation reaction of a heterocyclic aromatic ketone. The metal catalytic reaction product co-modified with the chiral ligand and an achiral phosphine ligand has a high conversion rate, and the enantioselectivity can reach 99.9%. The chiral bidentate nitrogen ligand is prepared by using cinchona alkaloid as a raw material, the raw material is cheap and easy to obtain, the preparation reaction process is simple, and the compound is stable in an air environment, and the compound has a very high application value.

Description

Technical Field

[0001] The invention relates to the technical field of asymmetric catalysis, and in particular to a chiral bidentate nitrogen ligand based on a cinchona alkaloid skeleton, a preparation method and an application thereof. Background Art

[0002] In the past few decades, the preparation of chiral alcohols through asymmetric hydrogenation of ketones has made rapid progress, especially the use of various chiral ligands that can effectively improve the enantiomeric selectivity of asymmetric hydrogenation reactions. Since the chiral bidentate phosphine ligands and chiral diamine ligands developed by Noyori et al. were successfully applied to the asymmetric catalytic hydrogenation of ketones in 1995, various chiral phosphine ligands and chiral nitrogen ligands have been synthesized and applied to the asymmetric hydrogenation of ketones, such as BICP, TolBINAP, spiro diphosphines, hemisalen type ligands, ferrocene-based ligands, aminoalcohols, etc. However, the synthesis of these ligands is limited by many steps, complex reactions, and the easy oxidation of phosphine ligands. In addition, the asymmetric hydrogenation of heterocyclic aromatic ketones has always been a major difficulty in this research direction, usually with low hydrogenation activity and poor enantiomeric selectivity. Therefore, it is of great significance to directly synthesize new multidentate chiral nitrogen ligands using chiral natural products and combine them with achiral phosphine ligands to co-modify metals to catalyze the asymmetric hydrogenation of heterocyclic aromatic ketones to prepare chiral alcohols. Summary of the invention

[0003] The technical problem to be solved by the present invention is to provide a chiral bidentate nitrogen ligand based on a cinchona alkaloid skeleton, a preparation method and an application thereof.

[0004] The technical solution of the present invention to solve the above technical problems is as follows:

[0005] The present invention provides a chiral bidentate nitrogen ligand based on a cinchona alkaloid skeleton, the chemical formula of which is shown in general formula (I):

[0006]

[0007] In the general formula (I), R independently represents methyl, ethyl, C3-C7 straight-chain alkyl, C3-C7 branched alkyl or heterocyclic alkyl, R' independently represents methoxy or hydrogen, and R" independently represents ethyl or vinyl.

[0008] Furthermore, in the general formula (I), the configuration of the carbon atoms connecting the two nitrogen-containing heterocyclic rings and the amino group is R-type or S-type.

[0009] Furthermore, R is independently represented by one of methyl, propyl, pentyl, heptyl, and pyrrolidinyl; R' is independently represented by one of methoxy and hydrogen; R" is vinyl; its chemical formula is shown in general formula (II):

[0010]

[0011] Furthermore, the chiral bidentate nitrogen ligand has the structural formula:

[0012] One of them.

[0013] The present invention also provides a method for preparing the chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton as described above, firstly deriving the cinchona alkaloid compound into an amine compound, and then reacting the obtained amine compound with an aldehyde compound to generate the chiral bidentate nitrogen ligand with a spatial configuration.

[0014] Further, the reaction step of the amine compound and the aldehyde compound is:

[0015] Add the aldehyde compound and 4A molecular sieve to the amine compound, then add 1,2-dichloroethane, stir at room temperature for 24 hours, filter the 4A molecular sieve and collect the filtrate; remove 1,2-dichloroethane in the filtrate under vacuum, then add anhydrous methanol, and add sodium borohydride at 0°C; stir for 4 hours after returning to room temperature, add water to quench the reaction, extract the reaction system after quenching the reaction with dichloromethane, dry the organic phase obtained after extraction with anhydrous sodium sulfate, and then perform reduced pressure distillation after drying to remove dichloromethane; separate and purify the obtained crude product by column chromatography to obtain the chiral bidentate nitrogen ligand;

[0016] Wherein, the structure of the aldehyde compound is shown in general formula (III):

[0017]

[0018]

[0019] The reaction equation is:

[0020]

[0021] Furthermore, the molar ratio of the amine compound to the aldehyde compound is 1:1.14-3.0; the mass ratio of the amine compound to the 4A molecular sieve is 1:10; the mass ratio of the amine compound to the 1,2-dichloroethane is 1:25; the mass ratio of the amine compound to the anhydrous methanol is 1:20; and the molar ratio of the amine compound to the sodium borohydride is 1:3.

[0022] The present invention also provides an application of the chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton as described above in the asymmetric hydrogenation reaction of heterocyclic aromatic ketones, wherein the chiral bidentate nitrogen ligand and the achiral phosphine ligand are in situ catalyzed in an organic solvent under the action of a transition metal complex to perform the asymmetric hydrogenation reaction of the heterocyclic aromatic ketone.

[0023] Furthermore, the chemical formula of the achiral phosphine ligand is shown in general formula (IV):

[0024]

[0025] In the general formula (IV), R1 independently represents one of an unsubstituted phenyl group, an alkyl-substituted phenyl group and an alkoxy-substituted phenyl group.

[0026] Furthermore, the transition metal complex is [Ir(COD)OMe]2; the molar ratio of the chiral bidentate nitrogen ligand, the achiral phosphine ligand and [Ir(COD)OMe]2 is 2-8:2-8:1.

[0027] The beneficial effects of the present invention compared to the prior art include:

[0028] 1) The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention has an alkyl group as a substituent on the N connected to the C at position 9 of its chemical formula and does not contain unstable phosphorus elements, making the ligand itself more stable and easily available;

[0029] 2) The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention can be used as a chiral ligand and an achiral phosphine ligand to catalyze the asymmetric hydrogenation reaction of heterocyclic aromatic ketones, which can ensure both the stability of the ligand itself and the effectiveness of the asymmetric hydrogenation reaction; the reaction product catalyzed by the chiral ligand has a high conversion rate, and the enantioselectivity of the isomer can reach 99.9%;

[0030] 3) The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention uses cinchona alkaloid raw materials and aldehyde raw materials as reactants. The raw materials are cheap and easy to obtain, and have extremely high application value;

[0031] 4) The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention contains a cinchona alkaloid skeleton in its structure. Cinchona alkaloid is a kind of alkaloid widely existing in nature. This type of compound contains a unique chiral structure. In the process of preparing the chiral bidentate nitrogen ligand, it can be simply derived into an amine compound by the existing chemical synthesis method, and the chiral bidentate nitrogen ligand with a special spatial configuration can be prepared by using the formed chiral amine. The reaction process is simple and easy to operate;

[0032] 5) The method for preparing the chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention has lower requirements on preparation conditions and does not need to be carried out in nitrogen or other oxygen-free environments, and is more suitable for promotion and application. DETAILED DESCRIPTION

[0033] The principles and features of the present invention are described below. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0034] The chiral bidentate nitrogen ligand based on cinchona alkaloid as a skeleton of the present invention has a novel nitrogen-nitrogen multidentate structure and can be used as a chiral ligand in the asymmetric hydrogenation of heterocyclic aromatic ketones.

[0035] The compound contains two chiral nitrogen atoms in its structure and can be used as a chiral ligand in the asymmetric hydrogenation of ketones.

[0036] The compound and iridium catalyst can obtain more than 99% enantioselectivity in the asymmetric catalytic hydrogenation of various ketones. Compared with other advantageous ligands, this type of ligand is extremely simple to synthesize, low in cost, and stable in structure, which is conducive to large-scale synthesis and application.

[0037] The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention has a chemical formula as shown in general formula (I):

[0038]

[0039] In the general formula (I), R independently represents methyl, ethyl, C3-C7 straight-chain alkyl, C3-C7 branched alkyl or heterocyclic alkyl, R' independently represents methoxy or hydrogen, and R" independently represents ethyl or vinyl.

[0040] Preferably, when R" is a vinyl group, the chemical formula of the chiral bidentate nitrogen ligand is as shown in general formula (II):

[0041]

[0042] Preferably, R is independently one of methyl, propyl, pentyl, heptyl and pyrrolidinyl.

[0043] The configuration of the 9th carbon of the chiral bidentate nitrogen ligand of the present invention is S type or R type; when the compound of the present invention is used as a ligand product, the product can be one of (9S)-nitrogen-nitrogen ligands and (9R)-nitrogen-nitrogen ligands or a mixture of the two.

[0044] The compound of the present invention is firstly prepared from amino derivatives using commercial cinchona alkaloid compounds as raw materials, and then respectively prepared from amino derivatives by reductive amination reaction with aldehyde compounds. The cinchona alkaloid compounds can be cinchonine, cinchonidine, quinine, or quinidine.

[0045] The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention can be seen from the general formula (I) that the optional structures of the substituent R connected to the N of the 9th carbon do not contain phosphine, which makes the ligand of the present invention more stable.

[0046] In fact, there are many types of ligand compounds for asymmetric hydrogenation of ketones, but most of them use phosphine-containing substituents at the above positions. Although such ligand compounds have good conversion rates and high selectivity, their properties are not stable and require high preparation conditions. They are usually prepared under oxygen-free and water-free conditions to avoid oxidation. This results in such compounds having good effects in theory, but in actual use, the preparation and storage costs are high and difficult to put into large-scale use.

[0047] The chiral bidentate nitrogen ligand of the present invention, on the one hand, has undergone a disruptive change in the structure of the substituent R, so that it has good stability, greatly reduces the preparation cost and storage cost, and can be put into use in a real sense; on the other hand, the above structure of the present invention can also ensure that the ligand also has good conversion rate and high selectivity, especially for the asymmetric hydrogenation reaction of heterocyclic aromatic ketones. The present invention combines the chiral bidentate nitrogen ligand with an achiral phosphine ligand, so that it has a higher conversion rate for the asymmetric hydrogenation reaction of heterocyclic aromatic ketones, and the enantioselectivity of the isomers can reach 99.9%.

[0048] The specific preparation steps are as follows:

[0049] 1) deriving the cinchona alkaloid compound into an amine compound, which is an existing step, specifically comprising:

[0050] Under N2 environment, cinchona alkaloid compound and triphenylphosphine (PPh3) are mixed and added to tetrahydrofuran (THF) after anhydrous and oxygen-free treatment. The mixed solution is transferred to 0°C and stirred, diisopropyl azodicarboxylate (DIAD) is added at one time and stirred for 15 minutes, diphenyl phosphohydride ((PhO)2P(O)3) is added to tetrahydrofuran and mixed evenly and then slowly added to the reaction solution. After the dropwise addition is completed, the reaction is transferred to room temperature and stirred for 12 hours, the temperature is raised to 50°C and the stirring reaction is continued for 2 hours, triphenylphosphine is added and the stirring reaction is continued at 50°C for 2 hours, the reaction solution is cooled to room temperature, distilled water is added and the reaction is continued at room temperature for 18 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure and vacuum, the concentrate is extracted with dichloromethane and dilute hydrochloric acid, the aqueous phase is collected, and the aqueous phase is continuously extracted with dichloromethane three times, the organic phase is discarded, the aqueous phase is adjusted to a pH of about 9 with excess ammonia water, and is continuously extracted with dichloromethane, the organic phase is collected, dried with anhydrous sodium sulfate, and separated and purified by silica gel column chromatography to obtain amine compounds.

[0051] 2) reacting the obtained amine compound with an aldehyde compound to generate a chiral bidentate nitrogen ligand with a spatial configuration

[0052] Add formaldehyde compounds and 4A molecular sieves to the amine compounds, then add 1,2-dichloroethane, stir at room temperature for 24 hours, filter the 4A molecular sieve and collect the filtrate; remove 1,2-dichloroethane in the filtrate under vacuum conditions, add anhydrous methanol, and add sodium borohydride at 0°C, return to room temperature and stir for 4 hours, add water to quench the reaction, and the amine compounds react under the reduction effect of sodium borohydride in the environment of methanol as a solvent to generate chiral nitrogen compounds; after the reaction, The reaction system is quenched by extraction with dichloromethane, and the organic phase obtained after extraction is dried over anhydrous sodium sulfate. After drying, the organic phase is distilled under reduced pressure to remove dichloromethane and possible residual methanol solvent. The crude product is separated and purified by column chromatography to finally obtain a pure chiral bidentate nitrogen ligand. The above reaction process is a one-pot reaction, and the reaction principle is that formaldehyde compounds and amine compounds are dehydrated in 1,2-dichloromethane through molecular sieves to form imines, and the imines are reduced by sodium borohydride to obtain chiral bidentate nitrogen ligands.

[0053] The structure of the aldehyde compound is shown in general formula (III):

[0054]

[0055] The reaction equation occurring in the preparation process of the present invention is:

[0056]

[0057] Preferably, the molar ratio of the amine compound to the aldehyde compound is 1:1.14-1.5; the mass ratio of the amine compound to the 4A molecular sieve is 1:10; the mass ratio of the amine compound to 1,2-dichloroethane is 1:25; the mass ratio of the amine compound to anhydrous methanol is 1:20; and the molar ratio of the amine compound to the sodium borohydride is 1:3.

[0058] The chiral bidentate nitrogen ligand based on the cinchona alkaloid skeleton of the present invention can be applied to catalyze the asymmetric hydrogenation reaction of heterocyclic aromatic ketones.

[0059] Preferably, the asymmetric hydrogenation reaction is specifically a substituted or unsubstituted heterocyclic ketone or the like.

[0060] The catalyst of the present invention is a complex formed in situ by the chiral bidentate nitrogen ligand, the achiral phosphine ligand and the transition metal complex.

[0061] Preferably, the transition metal complex is an iridium complex.

[0062] Preferably, the iridium complex is an iridium methoxycyclooctadiene dimer complex [Ir(COD)OMe]2.

[0063] Preferably, the molar ratio of the chiral bidentate nitrogen ligand to the iridium methoxycyclooctadiene dimer complex [Ir(COD)OMe]2 is 6:1; and the molar ratio of the chiral bidentate nitrogen ligand to the achiral phosphine ligand is 3:1.

[0064] The catalyst of the present invention can catalyze an asymmetric hydrogenation reaction using hydrogen as a hydrogen source.

[0065] The following is an explanation using a specific reaction route as an example. The chiral bidentate nitrogen ligand in reaction route I is a chiral bidentate nitrogen ligand of general formula (II); reaction route I uses hydrogen as a hydrogen source, lithium hydroxide as a base, and a commercial non-chiral phosphine ligand and [Ir(COD)OMe]2 complex as a catalyst for an asymmetric hydrogenation reaction.

[0066] In reaction route I, during the reaction, [Ir(COD)OMe]2, a chiral bidentate nitrogen ligand and an achiral phosphine ligand are directly added to the reaction. This reaction route is an in-situ catalysis.

[0067] Reaction Scheme I:

[0068] In the above reaction scheme, It is represented by the structural formula of ketone. R3 and R4 can be independently represented by substituted or unsubstituted heterocyclic structure; substituted or unsubstituted straight chain or branched chain alkyl, cycloalkyl, halogenated alkyl, etc.

[0069] The present invention is described below by way of examples, but the present invention is not limited to the following examples.

[0070] The amine compounds in the following examples are all obtained by using their corresponding cinchona alkaloids as raw materials through the above reaction.

[0071] In the following examples, the chiral bidentate nitrogen ligands corresponding to the intermediates and their numbers are shown in Table 1:

[0072] Table 1

[0073] Example Amine compounds Compound Example 1 1a (1) Example 2 1a (2) Example 3 1a (3) Example 4 1a (4) Example 5 1b (5) Example 6 1c (6) Example 7 1a (7)

[0074] Example 1

[0075] Synthesis of compound (1):

[0076]

[0077] The synthesis steps of compound (1) are as follows: 1a (0.5 g, 1.7 mmol), paraformaldehyde (3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting at room temperature for 24 hours, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 hours, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (1).

[0078] The mass of the product in this example is 353 mg, and the yield is 67.5%.

[0079] The product is a light yellow oil. 1 H NMR(400MHz,D2O)δ8.73(d,J=2.0Hz,1H),8.10(d,J=4.0Hz,1H),7.90(d,J=6.0Hz,1H),7. 61-7.64(m,1H),7.50-7.53(m,1H),7.42(d,J=2.0Hz,1H),5.53-5.61(m,1H),5.04-5.09(m ,2H),4.51(d,J=4.0Hz,1H),3.60(d,J=4.0Hz,1H),3.37(d,J=4.0Hz,3H),3.23-3.30(m,1 H),2.58-2.64(m,1H),1.92(s,3H),1.63-1.84(m,3H),1.44(s,1H),0.81(d,J=4.0Hz,2H). 13 C{ 1 H}NMR(100MHz,D2O)δ149.9,146.6,145.5,136.7,130.5,128.5,128.0,127.8,122.7,1 18.6,116.6,61.0,55.6,48.4,45.5,35.7,31.8,25.9,22.6,22.5.HRMS(ESI)calcd.for C 20 H 26 N3[M+H] + :308.2121,found:308.2123.

[0080] Example 2

[0081] Synthesis of compound (2):

[0082]

[0083] The synthesis steps of compound (2) are as follows: 1a (0.5 g, 1.7 mmol), propionaldehyde (197 mg, 3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting for 24 h at room temperature, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 h, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (2).

[0084] The mass of the product in this example is 335 mg, and the yield is 58.8%.

[0085] The product is a light yellow oil. 1 H NMR(600MHz,CD3OD)δ8.86(s,1H),8.29-8.43(m,1H),8.08(d,J=6.0Hz,1H),7.60-7.80(m,3H),5.91(d,J=3.0Hz,1H),5.08-5.13(m,2H),2.95 -3.02(m,5H),2.30-2.43(m,2H),2.14-2.18(m,1H),1.53-1.57(m,4H) ,1.40-1.44(m,2H),1.27-1.29(m,2H),1.11(s,1H),0.80-0.82(m,3H). 13 C{ 1 H}NMR(100MHz,D2O)δ145.0,137.0,136.3,134.9,132.1,130.8,128.5,124.3,123.7,119.8, 117.0,67.8,60.5,49.0,48.3,46.3,35.7,25.8,25.0,22.9,22.2,10.5.HRMS(ESI)calcd.for C 22 H 30 N3[M+H] + :336.2434,found:336.2433.

[0086] Example 3

[0087] Synthesis of compound (3):

[0088]

[0089] The synthesis steps of compound (3) are as follows: 1a (0.5 g, 1.7 mmol), valeraldehyde (292 mg, 3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting for 24 h at room temperature, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 h, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (3).

[0090] The mass of the product in this example is 486 mg, and the yield is 78.7%.

[0091] The product is a light yellow oil. 1 H NMR(600MHz,D2O)δ9.04(d,J=3.0Hz,1H),8.45(d,J=6.0Hz,1H),8.12(d,J=3.0 Hz,2H),8.03(d,J=3.0Hz,1H),7.88-7.91(m,1H),5.48(d,J=6.0Hz,1H),4.92- 4.97(m,2H),4.19-4.23(m,1H),3.25-3.52(m,5H),2.59-2.66(m,2H),2.26(s, 1H),1.75(d,J=15.0Hz,3H),1.22-1.34(m,3H),0.86(s,6H),0.46-0.47(m,3H). 13 C{ 1 H}NMR(150MHz,D2O)δ148.2,144.6,138.5,136.0,135.8,132.0,128.6,123.5,122.3,120.8,117.1 ,59.6,54.7,49.4,47.3,46.9,35.4,27.6,26.1,25.5,23.3,21.7,21.3,12.8.HRMS(ESI)calcd.for C 24 H 34 N3[M+H] + :364.2747,found:364.2742.

[0092] Embodiment 4:

[0093] Synthesis of compound (4)

[0094]

[0095] The synthesis steps of compound (4) are as follows: 1a (0.5 g, 1.7 mmol), heptaldehyde (387 mg, 3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting for 24 h at room temperature, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 h, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (4).

[0096] The mass of the product in this example is 446 mg, and the yield is 67.0%.

[0097] The product is a light yellow oil. 1 H NMR(600MHz,D2O)δ9.16(d,J=3.0Hz,1H),8.59(d,J=3.0Hz,1H),8.22-8.25( m,2H),8.13-8.16(m,1H),8.01-8.04(m,1H),5.62-5.68(m,1H),5.09-5.13(m ,2H),4.27(s,1H),3.52-3.64(m,4H),2.72-2.76(m,2H),2.37-2.41(m,1H), 1.83-1.95(m,3H),1.34-1.44(m,4H),0.96-1.07(m,10H),0.60-0.62(m,3H). 13 C{ 1 H}NMR(150MHz,D2O)δ148.9,144.7,138.6,136.0,135.9,131.9,128.6,123.6,122.4,120.7,117.1,67.8 ,59.8,54.8,49.4,47.3,46.9,35.5,30.6,27.7,26.6,25.4,25.0,23.3,21.7,13.2.HRMS(ESI)calcd.for C 26 H 38 N3[M+H] + :392.3060, found:393.3054.

[0098] Example 5

[0099] Synthesis of compound (5):

[0100]

[0101] The synthesis steps of compound (5) are as follows: 1b (0.55 g, 1.7 mmol), valeraldehyde (292 mg, 3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting for 24 h at room temperature, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 h, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (5).

[0102] The mass of the product in this example is 385 mg, and the yield is 65.2%.

[0103] The product is a light yellow oil. 1 H NMR(600MHz,D2O)δ8.98(d,J=3.0Hz,1H),8.14-8.21(m,2H),7.77-7.80(m,1H),7.6 9(d,J=1.5Hz,1H),5.66-5.68(m,1H),5.10-5.17(m,2H),4.34(d,J=3.0Hz,1H),3.9 4-3.99(m,4H),3.59-3.69(m,3H),3.45-3.50(m,1H),2.76-2.84(m,2H),2.43-2.47 (m,1H),1.84-1.95(m,3H),1.35-1.53(m,3H),1.02-1.10(m,6H),0.61-0.62(m,3H). 13 C{ 1 H}NMR(150MHz,D2O)δ161.6,145.8,141.1,136.2,134.8,130.7,128.7,124.0,121.1,116.9,101.7,59 .8,56.9,54.9,49.4,47.2,47.0,35.1,27.7,26.1,25.2,23.2,21.8,21.3,12.9.HRMS(ESI)calcd.for C 25 H 36 N3O[M+H] + :394.2853,found:394.2846.

[0104] Example 6

[0105] Synthesis of compound (6):

[0106]

[0107] The synthesis steps of compound (6) are as follows: 1c (0.5 g, 1.7 mmol), valeraldehyde (292 mg, 3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting at room temperature for 24 hours, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 hours, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (6).

[0108] The mass of the product in this example is 336 mg, and the yield is 54.4%.

[0109] The product is a light yellow oil. 1 H NMR(400MHz,D2O)δ9.16(d,J=4.0Hz,1H),8.65(d,J=6.0Hz,1H),8.22-8.27(m,2H),8.14-8. 18(m,1H),8.02-8.05(m,1H),5.70-5.78(m,1H),5.07-5.13(m,2H),4.19-4.26(m,1H),3.77- 3.85(m,1H),3.67-3.73(m,1H),3.37-3.52(m,2H),2.68-2.78(m,2H),2.33-2.40(m,1H),1. 88-1.92(m,3H),1.58-1.74(m,2H),1.37-1.44(m,3H),0.88-1.03(m,5H),0.58-0.62(m,3H). 13 C{ 1 H}NMR(150MHz,D2O)δ148.6,144.7,138.6,136.0,135.9,132.0,128.6,123.6,122.4,120.7,117.1 ,66.0,59.8,54.8,49.4,47.3,46.9,35.5,27.7,25.6,23.3,21.9,21.3,12.9.HRMS(ESI)calcd.for C 24 H 34 N3[M+H] + :364.2747, found:364.2745.

[0110] Example 7

[0111] Synthesis of compound (7):

[0112]

[0113] The synthesis steps of compound (7) are as follows: 1c (0.5 g, 1.7 mmol), 2-formylpyrrole (337 mg, 3.4 mmol) and 4A molecular sieve (10 g) are added to a 25 mL reaction bottle, and finally 10 mL of 1,2-dichloroethane is added. After reacting at room temperature for 24 hours, the mixture is filtered and the filtrate is collected in another 25 mL reaction bottle. The solvent is removed under vacuum, 10 mL of anhydrous methanol is added, and sodium borohydride (193 mg, 5.1 mmol) is added at 0°C. After returning to room temperature, the mixture is reacted for 4 hours, water is added to quench the reaction, and the reaction system is extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and then filtered. The solvent is removed from the filtrate under reduced pressure and separated by column chromatography to obtain (7).

[0114] The mass of the product in this example is 397 mg, and the yield is 62.1%.

[0115] The product is a light yellow oil. 1 H NMR(400MHz,D2O)δ9.11(d,J=2.0Hz,1H),8.62(d,J=4.0Hz,1H),8.12–8.24(m, 3H),7.98–8.02(m,1H),5.75–5.84(m,1H),5.19–5.23(m,2H),3.90–4.03(m,1H ),3.53–3.59(m,4H),3.36–3.44(m,1H),3.20–3.27(m,2H),2.79(d,J=2Hz,1H) ,2.53(d,J=2Hz,2H),1.85–1.96(m,8H),1.23–1.36(m,3H),1.10–1.13(m,1H). 13 CNMR(101MHz,D2O)δ157.11,143.90,137.53,136.52,135.67,131.05,128.79,124.02,121.46,119.42,116.95,6 1.29,59.89,55.55,48.94,47.07,46.33,44.88,35.73,27.24,25.80,22.78,22.51,22.30.HRMS(ESI)calcd.for C 24 H 32 N4[M+H] + :377.2705, found: 377.2712.

[0116] Example 8

[0117] In this example, compound (4) and non-chiral phosphine (o-methoxytriphenylphosphine) are used as ligands to coordinate with [Ir(COD)OMe]2, and applied to the asymmetric hydrogenation reaction of 2-acetylthiophene. The specific steps are as follows:

[0118] [Ir(COD)OMe]2 (1.42 mg, 0.0021 mmol), compound (4) (5.03 mg, 0.012 mmol), lithium hydroxide (7.2 mg, 0.3 mmol), 2-acetylthiophene (8.57 mmol, 1.018 g) and 2 ml of ethanol were added to the autoclave. The air in the autoclave was replaced three times with hydrogen, and the hydrogen pressure was adjusted to 6.0 MPa. The reaction was carried out at 35°C for 1 hour. The conversion rate and enantioselectivity of the reaction were determined by gas chromatography. Gas phase analysis conditions: chromatographic column β-DEX 120 (30m×0.25mm): temperature 115℃, column head pressure 0.06bar, injection volume 0.1μl, 2-acetylthiophene peak time 7.3min, 1-(2-thiophene)ethanol peak time t R (mi nor)=18.7mi n,t R (major) = 19.2min.

[0119] Examples 8 to 34 are about applying the complex in Example 8 to asymmetric hydrogenation reactions of various ketones.

[0120] In the reactions of Examples 8 to 34, the reaction yields and enantioselectivities of various ketones are shown in Table 2.

[0121] Table 2

[0122]

[0123]

[0124]

[0125]

[0126] In Table 2, the separation yield represents the ratio of the mass of the separated product to the theoretical mass of the product, and the yield percentage in the above experiment is rounded. The enantioselectivity ee represents the ratio of the content of one isomer in the generated product to the total amount of the product.

[0127] In addition, it should be noted that the stability of the ligand of the present invention and its easy preservation characteristics are obvious. The ligand compound containing phosphine is easily oxidized and loses its activity when exposed to air for a long time. Generally, no experiments are conducted to discuss this. If the phosphine ligand is oxidized, the reagent cannot perform the above reaction at all, so there is no need to conduct experiments specifically for stability.

[0128] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An application of a chiral bidentate nitrogen ligand based on a cinchona alkaloid skeleton in the asymmetric hydrogenation of heterocyclic aromatic ketones, characterized in that: In situ catalyzing the asymmetric hydrogenation reaction of the heterocyclic aromatic ketone in ethanol by using the chiral bidentate nitrogen ligand and the achiral phosphine ligand under the action of a transition metal complex; The structural formula of the chiral bidentate nitrogen ligand is: One of; The achiral phosphine ligand is o-methoxytriphenylphosphine; The transition metal complex is [Ir(COD)OMe]2; The molar ratio of the chiral bidentate nitrogen ligand to [Ir(COD)OMe]2 is 6:1, and the molar ratio of the chiral bidentate nitrogen ligand to the o-methoxytriphenylphosphine is 3:1; The reaction route of the asymmetric hydrogenation reaction is shown in Reaction Scheme I: Reaction Scheme I:

Images