A morpholine organic phosphine ligand and its preparation method and application

Abstract

The invention discloses a morpholine organophosphine ligand and its preparation method and application. The preparation method of the morpholine organophosphine ligand comprises the following steps: under nitrogen conditions, adding m-dibromobenzene, morpholine, an inorganic base, and a first catalyst to a reactor; using tetrahydrofuran as a reaction solvent; reacting at 45 to 55° C. for 5 to 7 hours; then reducing the reaction temperature to 75 to 80° C.; adding n-butyl lithium; stirring; raising the reaction temperature to 0° C.; adding a second catalyst and a halophosphine reagent; and reacting to obtain the morpholine organophosphine ligand. The present invention adopts the above-mentioned morpholine organophosphine ligand and its preparation method and application to provide a method for synthesizing a novel morpholine organophosphine ligand under mild conditions. The morpholine organophosphine ligand is successfully applied to a Pd-catalyzed C-N bond formation reaction, showing high efficiency and selectivity, simplifying the reaction conditions, and broadening the scope of application.

Description

Technical Field

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

[0002] Researchers such as Buchwald and Hartwig have conducted in-depth and systematic studies on the Pd-catalyzed cross-coupling reaction of aryl halides with amines, establishing an efficient method for synthesizing N-substituted aromatic amines. This type of reaction is known as the Buchwald-Hartwig cross-coupling reaction. In this reaction, monodentate or bidentate phosphine ligands with high steric hindrance and strong electron-donating ability, such as tri-tert-butylphosphine (P(t-Bu)3), tricyclohexylphosphine (PCy3), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-Butyl-Xphos), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePos), are commonly used. These ligands enable efficient Pd-catalyzed C-N bond formation under mild conditions. However, these ligands are often unstable or difficult to synthesize, necessitating the exploration of new ligands and their synthesis methods.

[0003] Morpholines are an important class of nitrogen heterocyclic compounds with broad application value and significance in drug research and development and organic synthesis. Due to their broad application prospects, novel morphinol derivatives, particularly those conjugated to organophosphine ligands, have attracted the attention of chemists and pharmacologists. These ligands combine the electron-rich properties of organophosphine ligands with the steric structure of the morpholine structure. Therefore, the development of efficient, mild synthetic methods and their application in catalyzing C-N bond formation is a key research direction in organic synthesis. Summary of the Invention

[0004] The purpose of the present invention is to provide a morpholine-based 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 objectives, the first aspect of the present invention provides a morpholine-based organophosphine ligand, the general chemical structure of the morpholine-based organophosphine ligand is:

[0006]

[0007] The second aspect of the present invention provides a method for preparing a morpholine-based organophosphine 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 45-55° C. for 5-7 hours. The reaction temperature is then lowered to -75-80° C., n-butyl lithium is added, and after stirring, the reaction temperature is raised to 0° C., a second catalyst and a halogenated phosphine reagent are added, and after 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-butyllithium is 1.5-1.8 M, and the amount added is 60-65 mL.

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

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

[0016] Preferably, the specific process of the cross-coupling reaction between aryl halides and amine compounds is:

[0017] Add p-bromotoluene, a base, a third catalyst, and a morpholine-type organophosphine ligand to a reactor. After replacing the atmosphere with nitrogen three times, add toluene and aniline. The reactor is sealed and placed in an oil bath preheated to 95-105° C. The reaction is heated and stirred to 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 exhibit 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 C-N bonds, but may also be applicable to other types of coupling reactions, increasing its application flexibility.

[0026] (6) The organic phosphine ligand prepared by the present invention is used in C-N bond synthesis, and the coupling reaction is carried out at a temperature of 95-105°C. The reaction conditions are mild, which is relatively easy to control during industrial scale-up and helps to reduce costs. The C-N 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 examples. 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 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 23.5 g of m-dibromobenzene, 18.3 g of morpholine, base potassium carbonate (34.5 g) and catalyst cobalt acetate (1.7 g) were added to a dry reactor. Tetrahydrofuran was used as the 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 warmed to 0° C. and reacted with cyclohexylphosphine chloride (23.2 g) reagent in the presence of catalyst copper chloride (0.99 g) to prepare 34.6 g (78%) of 4,4'-(2-(dicyclohexylphosphino)-1,3-phenylene)dimorpholine.

[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, the reaction raw materials 23.5g of m-dibromobenzene, 18.3g of morpholine, base potassium carbonate (34.5g) and catalyst cobalt acetate (1.7g) were added to a dry reactor. Tetrahydrofuran was used as the 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 warmed to 0°C and reacted with phenylphosphine chloride (22.1g) reagent in the presence of catalyst copper chloride (0.99g) to prepare 31.5g (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, the reaction raw materials 23.5 g of m-dibromobenzene, 18.3 g of morpholine, base potassium carbonate (34.5 g) and catalyst cobalt acetate (1.7 g) were added to a dry reactor. Tetrahydrofuran was used as the 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 warmed to 0° C. and reacted with tert-butylphosphine chloride (23.1 g) reagent in the presence of catalyst 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 were applied to the CN bond synthesis process. The specific application process is as follows:

[0046] To a 25 ml Schlenk flask, 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-based organophosphine ligand (0.06 mmol) prepared in Examples 1-3. After three displacements with N2, add toluene (2.5 ml) and aniline (111.6 mg, 1.2 mmol). Seal the Schlenk flask and place it in an oil bath preheated to 100°C. Heat and stir for 6 h. After completion of the reaction, post-processing yields the desired product, 4-methyl-N-phenylaniline.

[0047] Comparative Example 1

[0048] The difference from Example 4 is that the morpholine organic phosphine ligand prepared in Example 4 is replaced with 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 with 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (Dave Phos). The chemical structure of Dave Phos is:

[0058]

[0059] The organophosphine ligands of Examples 1-3 and Comparative Examples 1-4 were placed in air at room temperature for 90 days before 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 organophosphine ligand and its preparation method and application, provides a method for synthesizing a new morpholine organophosphine ligand under mild conditions, and successfully applies it to the Pd-catalyzed C-N 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 solutions of the present invention rather than to limit the same. 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 solutions of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A morpholine organic phosphine ligand, characterized in that: The general chemical structure of morpholine-type organophosphine ligands is: 。 2. The method for preparing a morpholine organic phosphine ligand according to claim 1, wherein: 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 45-55° C. for 5-7 hours. The reaction temperature is then lowered to -75-80° C., n-butyl lithium is added, and after stirring, the reaction temperature is raised to 0° C., a second catalyst and a halogenated phosphine reagent are added, and after reaction, a morpholine-based organic phosphine ligand is obtained. The inorganic base is potassium carbonate, the first catalyst is cobalt acetate, and the second catalyst is copper chloride.

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

4. The method for preparing a morpholine organic phosphine ligand according to claim 3, characterized in that: The concentration of n-butyl lithium is 1.5~1.8M, and the amount added is 60~65mL.

5. The method for preparing a morpholine organic phosphine ligand according to claim 4, characterized in that: The mass ratio of copper chloride and halophosphine reagent is 0.8~1.0g:20~25g.

6. 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 aryl halides and amine compounds.

7. The use of a morpholine organic phosphine ligand according to claim 6, characterized in that: The specific process of the cross-coupling reaction between halogenated aromatics and amine compounds is as follows: Add p-bromotoluene, a base, a third catalyst, and a morpholine-based organophosphine ligand to the reactor. After replacing the atmosphere with nitrogen three times, add toluene and aniline. The reactor is sealed and placed in an oil bath preheated to 95-105°C. Heat and stir the reaction to obtain the target product, 4-methyl-N-phenylaniline.

8. The use of a morpholine organic phosphine ligand according to claim 7, characterized in that: The base is sodium tert-butoxide, and the third catalyst is tris(dibenzylideneacetone)dipalladium.

9. The use of a morpholine organic phosphine ligand according to claim 7, characterized in that: The molar ratio of p-bromotoluene, base, the third catalyst, the 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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