A copper complex containing an ortho-carborane Schiff base ligand and its preparation method and application

Abstract

The present invention relates to a copper complex containing an ortho-carborane Schiff base ligand, a preparation method, and an application thereof. The chemical structural formula of the copper complex is: #imgabs0#, wherein "·" represents a boron-hydrogen bond, and Ar represents any one of phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-nitrophenyl, or 2-pyridyl. The preparation method comprises the following steps: 1) dissolving ortho-carborane dicarboxaldehyde and aromatic amine in an organic solvent, reacting to obtain a mixed solvent; 2) adding CuBr2 to the mixed solvent, reacting, and separating to obtain a copper complex. The copper complex is used as a catalyst for catalytic synthesis of isoindolinone and its derivatives. Compared with the prior art, the present invention adopts a one-pot process to obtain a copper complex containing an ortho-carborane Schiff base ligand. The synthesis method has excellent selectivity and high yield. The obtained copper complex can catalyze the reaction of 2-bromobenzoic acid, terminal alkynes, and primary amines to synthesize isoindolinone derivatives at room temperature, with high reaction efficiency and environmental friendliness.

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic chemistry technology and relates to a copper complex containing an ortho-carborane Schiff base ligand, a preparation method thereof and application thereof in the synthesis of isoindolinone compounds. Background Art

[0002] Isoindolinone compounds are a class of nitrogen-containing heterocyclic compounds with extensive biological activity, attracting widespread attention from pharmaceutical researchers. Traditional synthesis methods for these compounds use o-benzoimide as a starting material via Wittig, Grignard, and Diels-Alder reactions (Tetrahedron Lett. 1969, 10, 1161; J. Org. Chem. 1989, 54, 4335; Chem. Asian J. 2009, 4, 1668). Alternatively, isoindolinone compounds can be synthesized via base-catalyzed intramolecular ring closure of o-alkynylbenzamide (J. Org. Chem. 2012, 77, 1572). However, these synthetic methods involve harsh reaction conditions, poor regioselectivity, and difficult substrate acquisition. In recent years, metal-catalyzed complex molecules have become increasingly popular. Both the Kundu and Cossy groups have developed palladium catalytic systems to synthesize isoindolinone compounds. The disadvantage is that the catalyst is expensive (Tetrahedron 2000, 56, 4777; Org. Lett. 2004, 6, 2511); in 2020, the Liu group developed a copper-catalyzed multi-component reaction to prepare isoindolinone compounds (Chin. J. Syn. Chem. 2020, 28, 188), but this method requires the participation of additives, and the reaction requires a high temperature of 130 degrees, and the reaction conditions are harsh.

[0003] Therefore, the development of new and efficient metal catalysts and new methods for the metal-catalyzed synthesis of isoindolinone compounds has important research value. Summary of the Invention

[0004] The purpose of the present invention is to provide a copper complex containing an ortho-carborane Schiff base ligand, a preparation method and application thereof, and to use the prepared copper complex to catalyze the synthesis of isoindolinone compounds to solve the problems of harsh reaction conditions and low yield in traditional methods for synthesizing isoindolinone compounds.

[0005] The purpose of the present invention can be achieved by the following technical solutions:

[0006] The first aspect of the present invention provides a copper complex containing an ortho-carborane Schiff base ligand, wherein the chemical structural formula of the copper complex is:

[0007]

[0008] Wherein, "·" represents a boron-hydrogen bond, and Ar represents any one of phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-nitrophenyl or 2-pyridyl.

[0009] The second aspect of the present invention provides a method for preparing a copper complex containing an ortho-carborane Schiff base ligand as described in the first aspect, the method comprising the following steps:

[0010] 1) dissolving ortho-carborane dicarboxaldehyde and aromatic amine in an organic solvent to react to obtain a mixed solvent;

[0011] 2) Adding CuBr2 to the above mixed solvent for reaction, and obtaining a copper complex after separation.

[0012] Furthermore, in step 1), the aromatic amine is selected from any one of aniline, 4-methoxyaniline, 4-bromoaniline, 4-nitroaniline or 2-pyridinamine.

[0013] Furthermore, the organic solvent is toluene.

[0014] Furthermore, in step 1), the reaction temperature is 60-100° C. and the reaction time is 8-12 h.

[0015] Furthermore, in step 2), the reaction temperature is room temperature and the reaction time is 3-6 hours.

[0016] Furthermore, in step 2), in the separation, the separation process is: standing and filtering to obtain a crude product, then washing and drying the crude product, and the solution used in the washing is diethyl ether.

[0017] Furthermore, the molar ratio of the ortho-carborane dicarboxaldehyde, aromatic amine and CuBr2 is (1.0-1.2):(2.0-2.4):(1.0-1.2).

[0018] The third aspect of the present invention provides an application of a Schiff base ligand containing an ortho-carborane, wherein the copper complex is used for catalytic synthesis of isoindolinone and its derivatives.

[0019] Furthermore, the copper complex, 2-bromobenzoic acid, terminal alkyne, primary amine, and base are dissolved in an organic solvent, and the reaction is carried out at room temperature for 3-8 hours. After separation and purification, isoindolinone and its derivatives are obtained. More preferably, the reaction time is 6 hours.

[0020] Furthermore, in the separation and purification process, separation and purification are performed by column chromatography, and the eluent is petroleum ether: dichloromethane = 8:1.

[0021] Furthermore, the molar ratio of the copper complex, 2-bromobenzoic acid, terminal alkyne, primary amine and base is (0.01-0.03):(1.0-1.2):(1.0-1.2):(1.0-1.2):(1.2-1.5).

[0022] Furthermore, the terminal alkyne is selected from one of phenylacetylene, 2-methylphenylacetylene, 2-methoxyphenylacetylene, 4-methoxyphenylacetylene, 4-chlorophenylacetylene, 4-nitrophenylacetylene, and 2-pyridineacetylene.

[0023] Furthermore, the primary amine is selected from one of benzylamine, 4-methylbenzylamine and 3-fluorobenzylamine.

[0024] Furthermore, the base is selected from one of Cs2CO3, Na2CO3 or K2CO3. Further preferably, the base is Cs2CO3.

[0025] Furthermore, the organic solvent is toluene, tetrahydrofuran (THF), methanol (CH3OH), N,N-dimethylformamide (DMF) and dichloromethane (CH2Cl2). Further preferably, the organic solvent is methanol.

[0026] Compared with the prior art, the present invention has the following characteristics:

[0027] 1) The copper complex containing an ortho-carborane Schiff base ligand prepared in the present invention can efficiently catalyze the synthesis of isoindolinone and its derivatives. The catalyst has good selectivity, low dosage, and mild reaction conditions. The copper complex can catalyze the reaction of 2-bromobenzoic acid, terminal alkynes, and primary amines to synthesize isoindolinone derivatives at room temperature. The reaction rate is fast, the yield is high, and it is environmentally friendly. The substrate range is wide, and it has broad application prospects in industry.

[0028] 2) The preparation method of the copper complex containing an ortho-carborane Schiff base ligand in the present invention is simple, and the copper complex containing an ortho-carborane Schiff base ligand can be obtained in a high yield through a one-pot reaction, and can exist stably in the air. DETAILED DESCRIPTION

[0029] The present invention is described in detail below with reference to specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0030] In the following examples, unless otherwise specified, raw materials, reagents or processing techniques are all conventional commercially available products or conventional processing techniques in the art.

[0031] Example 1:

[0032] Preparation of copper complex 1 containing ortho-carborane Schiff base ligand:

[0033]

[0034] o-Carborane dicarboxaldehyde (o-C2B 10 H 10 )(CHO)2 (1.0 mmol) and aniline (2.0 mmol) were dissolved in toluene and reacted at 60°C for 12 h. After the reaction, the mixture was cooled to room temperature. Then, CuBr2 (1.0 mmol) was added to the reaction system and the reaction was continued at room temperature for 3 h. After the reaction was completed, the mixture was allowed to stand and filtered. The solvent was dried under reduced pressure. The crude product was washed with ether and dried to obtain copper complex 1 (C 16 B 10 H 22 Br2N2Cu, yield 81%).

[0035] The copper complex 1 prepared in this example 1 The H NMR spectrum is shown in formula (1), 1 H NMR (400 MHz, CDCl3, 25°C): δ = 8.28 (s, 2H), 7.70-7.61 (m, 6H), 7.48 (d, J = 7.5 Hz, 4H), 2.93-2.15 (br, 10H). Elemental analysis: theoretical value C 16 B 10 H 22 Br2N2Cu: C 33.49, H 3.86, N 4.88; Exp.: C 33.55, H 3.85, N 4.92.

[0036] Example 2:

[0037] Preparation of copper complex 2 containing ortho-carborane Schiff base ligand:

[0038]

[0039] o-Carborane dicarboxaldehyde (o-C2B 10 H 10 )(CHO)2 (1.0 mmol) and 4-methoxyaniline (2.2 mmol) were dissolved in toluene and reacted at 80°C for 8 h. After the reaction was completed, the mixture was cooled to room temperature. Then, CuBr2 (1.0 mmol) was added to the reaction system and the reaction was continued at room temperature for 5 h. After the reaction was completed, the mixture was allowed to stand and filtered. The solvent was dried under reduced pressure. The crude product was washed with ether and dried to obtain the target product 2 (C 18 B 10 H 26 Br2N2O2Cu, yield 79%).

[0040] The copper complex 2 prepared in this example 1 The H NMR spectrum is shown in formula (2). 1 H NMR (400 MHz, CDCl3, 25°C): δ = 8.23 ​​(s, 2H), 7.85 (d, J = 7.5 Hz, 4H), 7.55 (d, J = 7.5 Hz, 4H), 3.32 (s, 6H), 2.95-2.16 (br, 10H). Elemental analysis: theoretical value C 18 B 10 H 26 Br2N2O2Cu: C 34.11, H 4.13, N 4.42; Exp: C 34.15, H 4.11, N 4.48.

[0041] Example 3:

[0042] Preparation of copper complex 3 containing ortho-carborane Schiff base ligand:

[0043]

[0044] o-Carborane dicarboxaldehyde (o-C2B 10 H 10 )(CHO)2 (1.0 mmol) and 4-bromoaniline (2.4 mmol) were dissolved in toluene and reacted at 100°C for 9 h. After the reaction was completed, the mixture was cooled to room temperature. Then, CuBr2 (1.0 mmol) was added to the reaction system and the reaction was continued at room temperature for 4 h. After the reaction was completed, the mixture was allowed to stand and filtered. The solvent was dried under reduced pressure. The crude product was washed with ether and dried to obtain the target product 3 (C 16 B 10 H 20 Br4N2Cu, yield 80%).

[0045] The copper complex 3 prepared in this example 1 The H NMR spectrum is shown in formula (3), 1 H NMR (400 MHz, CDCl3, 25°C): δ = 8.16 (s, 2H), 7.85 (d, J = 7.0 Hz, 4H), 7.45 (d, J = 7.5 Hz, 4H), 2.93-2.18 (br, 10H). Elemental analysis: theoretical value C 16 B 10 H 20 Br4N2Cu: C 26.27, H 2.76, N 3.83; Exp: C 26.31, H 2.72, N 3.88.

[0046] Example 4:

[0047] Preparation of copper complex 4 containing ortho-carborane Schiff base ligand:

[0048]

[0049] o-Carborane dicarboxaldehyde (o-C2B 10 H 10 )(CHO)2 (1.0 mmol) and 4-nitroaniline (2.2 mmol) were dissolved in toluene and reacted at 60°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature. Then, CuBr2 (1.0 mmol) was added to the reaction system and the reaction was continued at room temperature for 6 h. After the reaction was completed, the mixture was allowed to stand and filtered. The solvent was dried under reduced pressure. The crude product was washed with ether and dried to obtain the target product 4 (C 16 B 10 H 20 Br2N4O4Cu, yield 85%).

[0050] The copper complex 4 prepared in this example 1 The H NMR spectrum is shown in formula (4), 1 H NMR (400 MHz, CDCl3, 25°C): δ = 8.30 (s, 2H), 7.90 (d, J = 7.0 Hz, 4H), 7.67 (d, J = 7.0 Hz, 4H), 2.94-2.15 (br, 10H). Elemental analysis: theoretical value C 16 B 10 H 20 Br2N4O4Cu: C 28.95, H 3.04, N 8.44; Exp.: C 28.96, H 3.06, N 8.42.

[0051] Example 5:

[0052] Preparation of copper complex 5 containing ortho-carborane Schiff base ligand:

[0053]

[0054] o-Carborane dicarboxaldehyde (o-C2B 10 H 10 )(CHO)2 (1.0 mmol) and 2-aminopyridine (2.1 mmol) were dissolved in toluene and reacted at 70°C for 11 h. After the reaction was completed, the mixture was cooled to room temperature. Then, CuBr2 (1.0 mmol) was added to the reaction system and the reaction was continued at room temperature for 5 h. After the reaction was completed, the mixture was allowed to stand and filtered. The solvent was dried under reduced pressure. The crude product was washed with ether and dried to obtain the target product 5 (C 14 B 10 H 20 Br2N4Cu, yield 81%).

[0055] The copper complex 5 prepared in this example 1 The H NMR spectrum is shown in formula (5), 1 H NMR (400 MHz, CDCl3, 25°C): δ = 8.38 (d, J = 7.5 Hz, 2H), 8.14 (s, 2H), 7.67-7.60 (m, 6H), 2.93-2.17 (br, 10H). Elemental analysis: theoretical value C 14 B 10 H 20 Br2N4Cu: C 29.20, H 3.50, N 9.73; Exp: C 29.16, H 3.56, N 9.72.

[0056] Example 6:

[0057] The copper complex 1-5 prepared in Example 1-5 was used to catalyze the reaction of 2-bromobenzoic acid, phenylacetylene and benzylamine to synthesize isoindolinone compounds:

[0058]

[0059] In a reaction tube, the copper complex, 2-bromobenzoic acid (1.0 mmol), phenylacetylene (1.0 mmol), benzylamine (1.0 mmol) and a base (1.2 mmol) were dissolved in 2 mL of an organic solvent and reacted at room temperature for 3-8 h. After the reaction, the reaction solution was concentrated, and the crude product was separated and purified by column chromatography with a elution ratio of petroleum ether:dichloromethane = 8:1 to obtain isoindolinone. The base includes Cs2CO3, Na2CO3 or K2CO3, and the organic solvent includes toluene, tetrahydrofuran (THF), methanol (CH3OH), N,N-dimethylformamide (DMF) and dichloromethane (CH2Cl2). The specific results are shown in Table 1.

[0060] Table 1

[0061]

[0062]

[0063] It can be seen from sequence numbers 1-4 in Table 1 that when the copper complex 1 is used as the catalyst and other conditions remain unchanged, the yield of the synthesized isoindolinone gradually increases with the extension of the reaction time, and when the reaction time is 6h and 8h, the yield can reach 92% and 93%, respectively. Therefore, 6h is the optimal reaction time; it can be seen from sequence numbers 3, 5, and 6 in Table 1 that when the copper complex 1 is used as the catalyst and other conditions remain unchanged, the amount of catalyst has almost no effect on the yield of isoindolinone; it can be seen from sequence numbers 3, 7-10 in Table 1 that when the copper complex 1 is used as the catalyst and other conditions remain unchanged, different solvents CH3OH, THF, toluene, CH2Cl2, and DMF have a greater effect on the yield of isoindolinone, which are 92%, 55%, 39%, 48%, and 66%, respectively. That is, copper The optimal organic solvent for the synthesis of isoindolinone catalyzed by complex 1 is CH3OH. As shown in sequence numbers 3, 11, and 12 in Table 1, when copper complex 1 is used as the catalyst and other conditions remain unchanged, the yields of isoindolinone after reaction with different bases Cs2CO3, Na2CO3, and K2CO3 are 92%, 73%, and 69%, respectively, indicating that the optimal base for the synthesis of isoindolinone catalyzed by copper complex 1 is Cs2CO3. As shown in sequence numbers 3 and 13-16 in Table 1, when copper complexes 1-5 are used as the catalyst and other conditions remain unchanged, the yields of isoindolinone are 92%, 93%, 92%, 90%, and 91%, respectively, indicating that the prepared copper complexes 1-5 can catalyze the reaction of 2-bromobenzoic acid, phenylacetylene, and benzylamine to synthesize isoindolinone with high yield at room temperature.

[0064] Example 7:

[0065] The copper complex 1 prepared in Example 1 was used to catalyze the reaction of 2-bromobenzoic acid, terminal alkynes and primary amines to synthesize isoindolinone derivatives:

[0066]

[0067] In a reaction tube, copper complex 1 (0.01 mmol), 2-bromobenzoic acid (1.0 mmol), terminal alkyne (1.0 mmol), primary amine (1.0 mmol) and Cs2CO3 (1.2 mmol) were dissolved in 2 mL of methanol and reacted at room temperature for 6 h. After the reaction, the reaction solution was concentrated and the crude product was separated and purified by column chromatography with petroleum ether:dichloromethane = 8:1 as the eluent to obtain isoindolinone derivatives. The specific results are shown in Table 2.

[0068] Table 2

[0069]

[0070]

[0071] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A copper complex containing an ortho-carborane Schiff base ligand, characterized in that: The chemical structural formula of the copper complex is: Wherein, "·" represents a boron-hydrogen bond, and Ar represents any one of phenyl, 4-methoxyphenyl, 4-bromophenyl, 4-nitrophenyl, or 2-pyridyl.

2. A method for preparing a copper complex containing an ortho-carborane Schiff base ligand as claimed in claim 1, characterized in that: The method comprises the following steps: 1) dissolving ortho-carborane dicarboxaldehyde and aromatic amine in an organic solvent to react to obtain a mixed solvent; 2) Adding CuBr2 to the above mixed solvent for reaction, and obtaining a copper complex after separation.

3. The method for preparing a copper complex containing an ortho-carborane Schiff base ligand according to claim 2, wherein: In step 1), the aromatic amine is selected from any one of aniline, 4-methoxyaniline, 4-bromoaniline, 4-nitroaniline or 2-pyridinamine; and the organic solvent is toluene.

4. The method for preparing a copper complex containing an ortho-carborane Schiff base ligand according to claim 2, wherein: In step 1), the reaction temperature is 60-100° C. and the reaction time is 8-12 h; in step 2), the reaction temperature is room temperature and the reaction time is 3-6 h.

5. The method for preparing a copper complex containing an ortho-carborane Schiff base ligand according to claim 2, wherein: In step 2), the separation process is as follows: standing and filtering to obtain a crude product, and then washing and drying the crude product.

6. The method for preparing a copper complex containing an ortho-carborane Schiff base ligand according to claim 2, wherein: The molar ratio of the ortho-carborane dicarboxaldehyde, aromatic amine and CuBr2 is (1.0-1.2):(2.0-2.4):(1.0-1.2).

7. Use of the ortho-carborane Schiff base ligand according to any one of claims 1 to 6, characterized in that: The copper complex is used for catalytic synthesis of isoindolinone compounds.

8. The use of a copper complex containing an ortho-carborane Schiff base ligand according to claim 7, characterized in that: The catalytic synthesis process of the isoindolinone compound comprises: The copper complex, 2-bromobenzoic acid, terminal alkyne, primary amine and base are dissolved in an organic solvent, reacted at room temperature for 3-8 hours, and the isoindolinone and its derivatives are obtained after separation and purification.

9. The use of a copper complex containing an ortho-carborane Schiff base ligand according to claim 8, characterized in that: The molar ratio of the copper complex, 2-bromobenzoic acid, terminal alkyne, primary amine and base is (0.01-0.03):(1.0-1.2):(1.0-1.2):(1.0-1.2):(1.2-1.5).

10. The use of a copper complex containing an ortho-carborane Schiff base ligand according to claim 7, characterized in that: The terminal alkyne is selected from one of phenylacetylene, 2-methylphenylacetylene, 2-methoxyphenylacetylene, 4-methoxyphenylacetylene, 4-chlorophenylacetylene, 4-nitrophenylacetylene, and 2-pyridineacetylene; the primary amine is selected from one of benzylamine, 4-methylbenzylamine, and 3-fluorobenzylamine; the base is selected from one of Cs2CO3, Na2CO3, or K2CO3; and the organic solvent is toluene, tetrahydrofuran, methanol, N,N-dimethylformamide, and dichloromethane.

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