Morphan organic phosphine ligand as well as preparation method and application thereof

Abstract

The invention discloses a morpholine organic phosphine ligand and a preparation method and application thereof.The preparation method of the morpholine organic phosphine ligand comprises the steps that under the nitrogen condition, m-dibromobenzene, morpholine, inorganic alkali and a first catalyst are added into a reactor, tetrahydrofuran serves as a reaction solvent, a reaction is conducted for 5-7 h at the temperature of 45-55 DEG C, then the reaction temperature is reduced to-75 DEG C to-80 DEG C, and the morpholine organic phosphine ligand is obtained. And adding n-butyllithium, stirring, raising the reaction temperature to 0 DEG C, adding a second catalyst and a halogenated phosphine reagent, and reacting to obtain the morpholine organic phosphine ligand. According to the morpholine organic phosphine ligand as well as the preparation method and the application thereof, a method for synthesizing a novel morpholine organic phosphine ligand under a mild condition is provided, the morpholine organic phosphine ligand is successfully applied to a Pd-catalyzed C-N bond formation reaction, high efficiency and selectivity are shown, reaction conditions are simplified, and the application range is widened.

Description

Technical Field

[0001] The invention belongs to the technical field of organic phosphine ligands, and specifically relates to a morpholine organic phosphine ligand and a preparation method and application thereof. Background Art

[0002] For the cross-coupling reaction of aryl halides and amine compounds catalyzed by Pd, researchers represented by Buchwald and Hartwig have conducted in-depth and systematic research and established an effective method for synthesizing N-substituted aromatic amine compounds. This type of reaction is called the Buchwald-Hartwig cross-coupling reaction. In this reaction, monodentate or bidentate phosphine ligands with large steric hindrance and strong electron-donating ability are usually used, such as tri-tert-butylphosphine (P(t-Bu)3), tricyclohexylphosphine (PCy3), 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (t-Butyl-Xphos) and 2-dicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl (Dave Phos), etc., which can make the Pd-catalyzed CN bond formation reaction efficiently completed under mild conditions, but these ligands are usually unstable or difficult to synthesize easily, so it is necessary to explore new ligands and their synthesis methods.

[0003] Morpholine is an important class of nitrogen heterocyclic compounds, which has a wide range of application value and significance in the field of drug research and development and organic synthesis. Due to the broad application prospects of morpholine compounds, new morphine derivatives, especially morphine derivatives combined with organic phosphine ligands, have attracted the attention of chemists and pharmacologists. This type of ligand has both the electron-rich nature of organic phosphine ligands and the stereo skeleton of morpholine structure. Therefore, exploring an efficient and mild synthesis method and applying it to catalyze the construction of CN bonds is an important research direction in the field of organic synthesis. Summary of the invention

[0004] The purpose of the present invention is to provide a morpholine type organic phosphine ligand and its preparation method and application, so as to solve the problems that the organic phosphine ligand for catalyzing CN bond synthesis has poor stability and a relatively complicated synthesis method.

[0005] To achieve the above object, the first aspect of the present invention provides a morpholine organic phosphine ligand, the chemical structure of the morpholine organic phosphine ligand is as follows:

[0006]

[0007] The second aspect of the present invention provides a method for preparing a morpholine organic phosphine ligand, comprising the following steps:

[0008] Under nitrogen conditions, m-dibromobenzene, morpholine, an inorganic base and a first catalyst are added to a reactor, tetrahydrofuran is used as a reaction solvent, and the reaction is carried out at 45 to 55° C. for 5 to 7 hours, then the reaction temperature is reduced to -75 to -80° C., n-butyl lithium is added, and after stirring, the reaction temperature is increased to 0° C., a second catalyst and a halogenated phosphine reagent are added, and after the reaction, a morpholine-type organic phosphine ligand is obtained.

[0009] The chemical reaction equation of the present invention is:

[0010]

[0011] Preferably, the inorganic base is potassium carbonate and the first catalyst is cobalt acetate.

[0012] Preferably, the mass ratio of m-dibromobenzene, morpholine, inorganic base and the first catalyst is 10-25 g: 15-20 g: 32-35 g: 1.5-2 g.

[0013] Preferably, the concentration of n-butyl lithium is 1.5-1.8 M, and the amount added is 60-65 mL.

[0014] Preferably, the second catalyst is cupric chloride, and the mass ratio of cupric chloride to the halogenated phosphine reagent is: 0.8-1.0 g:20-25 g.

[0015] The third aspect of the present invention provides an application of a morpholine type organophosphine ligand, and the application of the morpholine type organophosphine ligand in the cross-coupling reaction of halogenated aromatic hydrocarbons and amine compounds.

[0016] Preferably, the specific process of the cross-coupling reaction between halogenated aromatic hydrocarbons and amine compounds is:

[0017] Add p-bromotoluene, a base, a third catalyst and a morpholine-type organic phosphine ligand into a reactor, replace the gas with nitrogen three times, add toluene and aniline, seal the reactor, put the reactor into an oil bath preheated to 95-105° C., heat and stir to react, and obtain the target product 4-methyl-N-phenylaniline.

[0018] Preferably, the base is sodium tert-butoxide NaOtBu, and the third catalyst is tris(dibenzylideneacetic acid)dipalladium Pd2(dba)3.

[0019] Preferably, the molar ratio of p-bromotoluene, base, third catalyst, morpholine organic phosphine ligand and aniline is 0.8-1.2:1.2-1.6:0.01-0.015:0.04-0.08:1.0-1.4.

[0020] Therefore, the present invention adopts a morpholine organic phosphine ligand of the above structure and its preparation method and application, which have the following beneficial effects:

[0021] (1) The synthesis route of the present invention is novel. By using raw materials such as m-dibromobenzene and morpholine, a multi-step reaction is carried out under specific conditions to synthesize the target ligand, providing a novel and effective synthesis route.

[0022] (2) The reaction conditions of the present invention are mild. The temperature range used in the entire synthesis process is from room temperature to 55°C, and at low temperatures of -75°C to -80°C. These conditions are relatively mild and are conducive to reducing the occurrence of side reactions.

[0023] (3) The present invention is simple to operate. The solvents (such as tetrahydrofuran) and reagents (such as n-butyl lithium) used in the synthesis process are common chemicals and are easy to obtain. The operation steps are also relatively direct, which is convenient for large-scale production.

[0024] (4) The organic phosphine ligand prepared by the present invention can improve the catalytic efficiency. As a ligand in the Pd-catalyzed cross-coupling reaction of halogenated aromatic hydrocarbons and amine compounds, it can show better catalytic activity or selectivity than traditional phosphine ligands.

[0025] (5) The organophosphine ligand of the present invention combines the characteristics of morpholine and organophosphine. This type of ligand can not only promote the formation of CN bonds, but also may be applicable to other types of coupling reactions, thereby increasing its application flexibility.

[0026] (6) The organic phosphine ligand prepared by the present invention is used for CN bond synthesis, and the coupling reaction is carried out at a temperature of 95-105° C. The reaction conditions are mild, which is easier to control during industrial scale-up and helps to reduce costs. The CN bond synthesis reaction system of the present invention uses a simple base (such as sodium tert-butoxide) and a known catalyst (such as tris(dibenzylideneacetic acid)dipalladium), which simplifies the reaction conditions and improves the feasibility of the reaction.

[0027] The technical solution of the present invention is further described in detail below through embodiments. DETAILED DESCRIPTION

[0028] The present invention will be further described below. It should be noted that this embodiment is based on the technical solution and provides a detailed implementation method and a specific operation process, but the present invention is not limited to this embodiment.

[0029] Example 1

[0030] A method for preparing a morpholine organic phosphine ligand comprises the following steps:

[0031] Under nitrogen conditions, the reaction raw materials m-dibromobenzene 23.5g, morpholine 18.3g, potassium carbonate (34.5g) and catalyst cobalt acetate (1.7g) were added to a dry reactor, and tetrahydrofuran was used as a reaction solvent. After reacting at 50°C for 6h, the reaction temperature was lowered to -78°C, n-butyl lithium (1.6M, 62.5mL) was added, and after stirring for 1h, the reaction system was heated to 0°C and reacted with cyclohexylphosphine chloride (23.2g) reagent in the presence of copper chloride (0.99g) to prepare 4,4'-(2-(dicyclohexylphosphino)-1,3-phenylene)dimorpholine 34.6g (78%).

[0032] The following are the H-NMR and C-NMR data of the prepared product, indicating that the product has been successfully synthesized.

[0033] 1 H NMR(400MHz, CDCl3) δ6.96(t,J=15.0Hz,1H),6.07(d,J=15.0Hz,2H),3.72(t,J=9.2Hz ,8H),3.18(t,J=9.1Hz,8H),2.21-1.88(m,4H),1.68-1.50(m,6H),1.33-1.01(m,10H). 13 C NMR (100MHz, CDCl3) δ166.7,153.8,131.9,112.5,65.8,47.4,29.5,25.9,25.6,23.0.

[0034] Example 2

[0035] A method for preparing a morpholine organic phosphine ligand comprises the following steps:

[0036] Under nitrogen conditions, 23.5 g of m-dibromobenzene, 18.3 g of morpholine, alkali potassium carbonate (34.5 g) and catalyst cobalt acetate (1.7 g) were added to a dry reactor. Tetrahydrofuran was used as a reaction solvent. After reacting at 50° C. for 6 h, the reaction temperature was lowered to -78° C., n-butyl lithium (1.6 M, 62.5 mL) was added, and after stirring for 1 h, the reaction system was heated to 0° C. and reacted with phenylphosphine chloride (22.1 g) reagent in the presence of copper chloride (0.99 g) to prepare 31.5 g (73%) of 4,4'-(2-(diphenylphosphino)-1,3-phenylene)dimorpholine.

[0037] The following are the H-NMR and C-NMR data of the prepared product, indicating that the product has been successfully synthesized.

[0038] 1H NMR (400MHz, CDCl3) δ7.52-7.40(m,4H),7.40-7.25(m,6H),7.00(t,J=15.0H z, 1H), 6.08 (d, J = 14.9Hz, 2H), 3.71 (t, J = 9.2Hz, 8H), 3.17 (t, J = 9.2Hz, 8H). 13 C NMR (100MHz, CDCl3) δ156.2,138.9,134.0,132.8,129.2,128.6,123.3,115.0,65.8,47.4.

[0039] Example 3

[0040] A method for preparing a morpholine organic phosphine ligand comprises the following steps:

[0041] Under nitrogen conditions, 23.5 g of m-dibromobenzene, 18.3 g of morpholine, alkali potassium carbonate (34.5 g) and catalyst cobalt acetate (1.7 g) were added to a dry reactor. Tetrahydrofuran was used as a reaction solvent. After reacting at 50° C. for 6 h, the reaction temperature was lowered to -78° C., n-butyl lithium (1.6 M, 62.5 mL) was added, and after stirring for 1 h, the reaction system was heated to 0° C. and reacted with tert-butylphosphine chloride (23.1 g) reagent in the presence of copper chloride (0.99 g) to prepare 4,4'-(2-(di-tert-butylphosphino)-1,3-phenylene)dimorpholine.

[0042] The following are the H-NMR and C-NMR data of the prepared product, indicating that the product has been successfully synthesized.

[0043] 1 H NMR (400MHz, CDCl3) δ6.96 (s, 1H), 6.07 (d, J = 14.9Hz, 2H), 3.72 (t, J = 9.2Hz, 8H), 3.18 (t, J = 9.2Hz, 8H), 1.15 (s, 18H). 13 C NMR (100MHz, CDCl3) δ170.8,170.6,153.8,153.7,132.5,132.5,106.3,106.3,65.9,49.8,49.6,47.4,47.4,28.0,27.9.

[0044] Example 4

[0045] The morpholine organic phosphine ligands prepared in Examples 1 to 3 are applied to the CN bond synthesis process, and the specific application process is as follows:

[0046] Add p-bromotoluene (171 mg, 1 mmol), NaOtBu (135 mg, 1.4 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol) and the morpholine organic phosphine ligand (0.06 mmol) prepared in Examples 1 to 3 to a 25 ml Schlenk bottle, replace with N2 three times, add toluene (2.5 ml) and aniline (111.6 mg, 1.2 mmol). Seal the Schlenk bottle, put it in an oil bath preheated to 100°C, and heat and stir for 6 hours. After the reaction is complete, the target product 4-methyl-N-phenylaniline is obtained by post-treatment.

[0047] Comparative Example 1

[0048] The difference from Example 4 is that the morpholine organic phosphine ligand prepared in Example 4 is replaced by tri-tert-butylphosphine (P(t-Bu)3). The chemical structure of P(t-Bu)3 is:

[0049]

[0050] Comparative Example 2

[0051] The difference from Example 4 is that the morpholine organic phosphine ligand prepared in Example 4 is replaced by tricyclohexylphosphine (PCy3). The chemical structure of PCy3 is:

[0052]

[0053] Comparative Example 3

[0054] The difference from Example 4 is that the morpholine organic phosphine ligand prepared in Example 4 is replaced by t-Butyl-Xphos. The chemical structure of t-Butyl-Xphos is:

[0055]

[0056] Comparative Example 4

[0057] The difference from Example 4 is that the morpholine organic phosphine ligand prepared in Example 4 is replaced by 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (Dave Phos). The chemical structure of Dave Phos is:

[0058]

[0059] The organic phosphine ligands of Examples 1 to 3 and Comparative Examples 1 to 4 were placed in air at room temperature for 90 days, and then the CN bond synthesis reaction for preparing 4-methyl-N-phenylaniline in Example 4 was carried out. The product yield of 4-methyl-N-phenylaniline is shown in Table 1.

[0060] Table 1

[0061]

[0062]

[0063] Therefore, the present invention adopts the above-mentioned morpholine organic phosphine ligand and its preparation method and application, provides a method for synthesizing a new morpholine organic phosphine ligand under mild conditions, and is successfully applied to the Pd-catalyzed CN bond formation reaction, showing high efficiency and selectivity, simplifying the reaction conditions and broadening the scope of application.

[0064] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A morpholine organic phosphine ligand, characterized in that: The general chemical structure of morpholine-based organophosphine ligands is:

2. The method for preparing a morpholine organic phosphine ligand according to claim 1, characterized in that: The following steps are involved: Under nitrogen conditions, m-dibromobenzene, morpholine, an inorganic base and a first catalyst are added to a reactor, tetrahydrofuran is used as a reaction solvent, and the reaction is carried out at 45 to 55° C. for 5 to 7 hours, then the reaction temperature is reduced to -75 to -80° C., n-butyl lithium is added, and after stirring, the reaction temperature is increased to 0° C., a second catalyst and a halogenated phosphine reagent are added, and after the reaction, a morpholine-type organic phosphine ligand is obtained.

3. The method for preparing a morpholine organic phosphine ligand according to claim 2, characterized in that: The inorganic base is potassium carbonate, and the first catalyst is cobalt acetate.

4. The method for preparing a morpholine organic phosphine ligand according to claim 3, characterized in that: The mass ratio of m-dibromobenzene, morpholine, inorganic base and the first catalyst is 10-25g: 15-20g: 32-35g: 1.5-2g.

5. The method for preparing a morpholine organic phosphine ligand according to claim 4, characterized in that: The concentration of n-butyl lithium is 1.5-1.8 M, and the amount added is 60-65 mL.

6. The method for preparing a morpholine organic phosphine ligand according to claim 5, characterized in that: The second catalyst is cupric chloride, and the mass ratio of cupric chloride to halogenated phosphine reagent is: 0.8-1.0 g: 20-25 g.

7. The use of a morpholine organic phosphine ligand according to claim 1, characterized in that: Application of morpholine-based organophosphine ligands in the cross-coupling reaction of halogenated aromatics and amine compounds.

8. The use of a morpholine organic phosphine ligand according to claim 7, characterized in that: The specific process of cross-coupling reaction between halogenated aromatics and amine compounds is as follows: Add p-bromotoluene, a base, a third catalyst and a morpholine-type organic phosphine ligand into a reactor, replace the gas with nitrogen three times, add toluene and aniline, seal the reactor, put the reactor into an oil bath preheated to 95-105° C., heat and stir to react, and obtain the target product 4-methyl-N-phenylaniline.

9. The use of a morpholine organic phosphine ligand according to claim 8, characterized in that: The base is sodium tert-butoxide and the third catalyst is tris(dibenzylideneacetic acid)dipalladium.

10. The use of a morpholine organic phosphine ligand according to claim 8, characterized in that: The molar ratio of p-bromotoluene, base, third catalyst, morpholine organic phosphine ligand and aniline is 0.8-1.2:1.2-1.6:0.01-0.015:0.04-0.08:1.0-1.4.

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