A method for synthesizing an N-aromatic phthalimide compound

Abstract

The application relates to a synthesis method of N-aromatic phthalimide compounds, characterized by the following steps: taking aromatic amine and NHPI as raw materials, adding a catalyst and 2,2'-dipyridyl as a ligand in an oxygen atmosphere, and reacting in a solvent to synthesize N-aromatic phthalimide compounds; the N-aromatic phthalimide compounds are synthesized by taking aromatic amine and NHPI as raw materials, copper salt as a catalyst and 2,2'-dipyridyl as a ligand, the preparation process is simple, the condition is easy to control, the raw material cost is low, and the synthesis is easy.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic material preparation, and particularly relates to a synthesis method of N-aromatic phthalimide compounds. BACKGROUND

[0002] N-aromatic phthalimide compounds have high value in the aspects of medicine synthesis, protein modification, optical materials, organic synthesis intermediates, and composite material preparation.

[0003] The preparation methods of N-aromatic phthalimide compounds include:

[0004] (1) Kuribara et al. (Visible-Light-Induced Metal- / Photocatalyst-Free C-H Bondlmidation of Arenes. Organic Letters, 2020, 22(6): 2235-2239) reported the reaction of phthalimide and aromatic compounds in 2020, and the method needs visible light induction, which has certain limitations for practical application.

[0005] (2) Ranadive, V. B et al. (Nucleophilic reactions of N-hydroxy-, methoxy-, 2,3-epoxy-propoxy-phthalimides. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1994, 33B(12): 1175-1177) reported the reaction of aromatic amine and N-methoxy phthalimide in 1994, and the N-methoxy phthalimide required by the method is expensive and has low economic efficiency.

[0006] (3) Esteban E et al. (Oxidative a-Functionalization of 1,2,3,4-Tetrahydroisoquinolines Catalyzed by a Magnetically Recoverable Copper Nanocatalyst. Application in the Aza-Henry Reaction and the Synthesis of 3,4-Dihydroisoquinolones. Journal of Organic Chemistry, 2022, 87(20): 13480-13493) reported N-aryl isoindole oxidation reaction in 2022, which needs to prepare silica-coated iron oxide catalyst, which is relatively cumbersome.

[0007] (4) Takakazu et al. (Copper promoted coupling reaction. I. Phenyl ation of oxygen-hydrogen and nitrogen-hydrogen compounds with C6H5X by using copper catalyst itself as the acceptor of HX released. Synthetic Communications, 1979, 9(3): 219-222) reported halobenzene and phthalimide reaction in 1979, which needs more than 200 degrees, longer reaction time and larger energy consumption.

[0008] (5) Lv, Bin (Iron(III)-catalyzed direct C-H radical amination of (hetero)arenes. Organic Chemistry Frontiers, 2021, 8(19): 5440-5445) reported NHPI and aromatic compound reaction in 2021, which needs to use trimethyl phosphite, which has greater danger.

[0009] (6)Rohith et al.(A phthalimidation protocol that follows protein defined parameters.Chemical Communications(Cambridge,United Kingdom),2015,51(3):473-476)reported the reaction of NHPI with aromatic amines in 2015, which requires precise control of the pH of the reaction system and has certain limitations on the reaction substrates.

[0010] Therefore, it is very important to seek a method for synthesizing N-aromatic phthalimide compounds with mild reaction conditions, high economic value, low equipment requirements, and environmentally friendly reagents. SUMMARY

[0011] The purpose of the present application is to overcome the shortcomings of the prior art and provide a method for synthesizing N-aromatic phthalimide compounds.

[0012] The present application adopts the following technical solutions:

[0013] A method for synthesizing N-aromatic phthalimide compounds, characterized in that: aromatic amines and NHPI are used as raw materials, a catalyst, 2,2'-bipyridine as a ligand are added, and N-aromatic phthalimide compounds are synthesized by reaction in a solvent under an oxygen atmosphere.

[0014] Further, in the structural formula of the N-aromatic phthalimide compound, R is one or more of halogen, alkoxy, alkyl, trifluoromethoxy, and trifluoromethyl.

[0015] Further, the catalyst is a copper salt, and the amount of catalyst used is 15-30% of the amount of aromatic amines in terms of molar quantity.

[0016] Further, the copper salt is one of CuI, CuCl, and CuBr.

[0017] Further, the molar quantity of NHPI is 1.0-2.0 times the molar quantity of aromatic amines.

[0018] Further, the amount of 2,2'-bipyridine used is 15-30% of the amount of aromatic amines in terms of molar quantity.

[0019] Further, the ratio of aromatic amines to solvent is 1(g):8-50(ml).

[0020] Further, the reaction temperature is 60-75°C.

[0021] Further, the solvent is acetonitrile.

[0022] From the above description of the present application, compared with the prior art, the beneficial effects of the present application are: the present application uses aromatic amine and NHPI as raw materials, copper salt as catalyst, 2,2'-dipyridyl as ligand to synthesize N-aromatic phthalimide compounds, the preparation process is simple, the conditions are easy to control, and the raw material cost is low, easy to synthesize. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 Structure formula diagram of aromatic amine;

[0024] Figure 2 Structure formula diagram of NHPI;

[0025] Figure 3 Structure formula diagram of N-aromatic phthalimide compound;

[0026] Figure 4 Synthesis route diagram of the present application;

[0027] Figure 5 Synthesis route diagram of Example 1;

[0028] Figure 6 Synthesis route diagram of Example 2;

[0029] Figure 7 Synthesis route diagram of Example 3;

[0030] Figure 8 Synthesis route diagram of Example 4;

[0031] Figure 9 Synthesis route diagram of Example 5;

[0032] Figure 10 Synthesis route diagram of Example 6;

[0033] Figure 11 Synthesis route diagram of Example 7;

[0034] Figure 12 Synthesis route diagram of Example 8;

[0035] Figure 13 Synthesis route diagram of Example 9;

[0036] Figure 14 Synthesis route diagram of Example 10;

[0037] Figure 15 Synthesis route diagram of Example 11;

[0038] Figure 16 Synthesis route diagram of Example 12;

[0039] Figure 17Synthetic route map for Example 13;

[0040] Figure 18 Synthetic route map for Example 14;

[0041] Figure 19 Synthetic route map for Example 15;

[0042] Figure 20 Synthetic route map for Example 16. DETAILED DESCRIPTION

[0043] The application is further described below through a specific embodiment.

[0044] The application discloses a synthesis method of N-aromatic phthalimide compounds, which is characterized by comprising the following steps: taking aromatic amine and NHPI as raw materials, adding copper salt as a catalyst and 2,2'-dipyridyl as a ligand in a solvent, and reacting under an oxygen atmosphere to synthesize N-aromatic phthalimide compounds, wherein the reaction temperature is 60-75 DEG C.

[0045] In the formula, the structural formula of the aromatic amine refers to Figure 1 , the structural formula of NHPI refers to Figure 2 , and the structural formula of the N-aromatic phthalimide compound refers to Figure 3 , specifically, Figure 1 and Figure 3 In the formula, R is one or more of halogen, alkoxy, alkyl, trifluoromethoxy and trifluoromethyl.

[0046] Specifically, the amount of the copper salt is 15-30% of the amount of the aromatic amine in terms of molar quantity, the molar quantity of NHPI is 1.0-2.0 times of the molar quantity of the aromatic amine, and the amount of 2,2'-dipyridyl is 15-30% of the amount of the aromatic amine; further, the copper salt is one of CuI, CuCl and CuBr.

[0047] The ratio of the aromatic amine to the solvent is 1 (g) : 8-50 (ml), and further, the solvent is acetonitrile.

[0048] The catalyst and the solvent of the application have multiple choices, and the following is taken as an example: taking aniline as a substrate, the amount of aniline is 2 mmol, the amount of NHPI is 1.0 times of the amount of aniline, the amount of the solvent is 8 mL, the amounts of the copper salt and 2,2'-dipyridyl are both 0.2 times of the amount of aniline, the reaction condition is 70 DEG C, and the reaction is carried out under an oxygen atmosphere; the suitable conditions of the reaction are explored, and the specific parameters refer to Table 1.

[0049] Solvent Copper salt 4h conversion 8h conversion Ethyl acetate CuI _ 8.49 Ethanol CuI 76 86 DMF CuI 65 81 1,2-Dichloroethane CuI 5 22 Tetrahydrofuran CuI 10 18 Acetonitrile CuI 62 82 Acetonitrile CuBr 53 83 Acetonitrile Cu 66 83 Acetonitrile CuO 62 67 Acetonitrile CuCl 85 98

[0050] In summary, the synthetic route map of the application specifically refers to Figure 4 .

[0051] Example 1

[0052] The synthetic route thereof is specifically referred to Figure 5 .

[0053] The synthetic method is specifically as follows: aniline 198 mg, NHPI 460 mg, CuI 78 mg, 2,2'-dipyridyl 63 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under the atmosphere of oxygen and at 70 DEG C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate = 4:1, and the product 352 mg is separated and obtained with a yield of 72%.

[0054] Example 2

[0055] The synthetic route thereof is specifically referred to Figure 6 .

[0056] The synthetic method is specifically as follows: p-fluoroaniline 228 mg, NHPI 446 mg, CuI 69 mg, 2,2'-dipyridyl 61 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under the atmosphere of oxygen and at 70 DEG C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate = 7:3, and the product 243 mg is separated and obtained with a yield of 74%.

[0057] Example 3

[0058] The synthetic route thereof is specifically referred to Figure 7 .

[0059] The synthetic method is specifically as follows: p-fluoroaniline 218 mg, NHPI 450 mg, CuI 69 mg, 2,2'-dipyridyl 61 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under the atmosphere of oxygen and at 70 DEG C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 7:1:2, and the product 388 mg is separated and obtained with a yield of 79%.

[0060] Example 4

[0061] The synthetic route thereof is specifically referred to Figure 8 .

[0062] The synthetic method is specifically as follows: o-fluoroaniline 220 mg, NHPI 447 mg, CuI 74 mg, 2,2'-dipyridyl 64 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under the atmosphere of oxygen and at 70 DEG C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate = 7:3, and the product 360 mg is separated and obtained with a yield of 74%.

[0063] Example 5

[0064] The synthetic route thereof is specifically referred to Figure 9 .

[0065] The synthetic method is specifically as follows: 3,5-difluoroaniline 259 mg, NHPI 442 mg, CuI 72 mg, 2,2'-bipyridine 60 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out at 70°C overnight under an oxygen atmosphere, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 426 mg of product is separated, and the yield is 82%.

[0066] Example 6

[0067] The synthetic route thereof is specifically referred to Figure 10 .

[0068] The synthetic method is specifically as follows: 3,5-difluoroaniline 259 mg, NHPI 442 mg, CuI 72 mg, 2,2'-bipyridine 60 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out at 70°C overnight under an oxygen atmosphere, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 426 mg of product is separated, and the yield is 82%.

[0069] Example 7

[0070] The synthetic route thereof is specifically referred to Figure 11 .

[0071] The synthetic method is specifically as follows: 3,5-difluoroaniline 259 mg, NHPI 442 mg, CuI 72 mg, 2,2'-bipyridine 60 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out at 70°C overnight under an oxygen atmosphere, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 426 mg of product is separated, and the yield is 82%.

[0072] Example 8

[0073] The synthetic route thereof is specifically referred to Figure 12 .

[0074] The synthesis method is as follows: 3-amino-4-methylbenzonitrile 216 mg, NHPI 448 mg, CuI 76 mg, 2,2'-bipyridine 57 mg, acetonitrile 8 mL are added into a reaction vessel, and the reaction is carried out at 70°C overnight under oxygen atmosphere, and monitored by GC. The reaction is terminated, silica gel is added into the reaction system, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 454 mg of product is separated by yield 95%.

[0075] Example 9

[0076] The synthesis route thereof is specifically referred to Figure 13 .

[0077] The synthesis method is as follows: 3-amino-4-methylbenzonitrile 216 mg, NHPI 448 mg, CuI 76 mg, 2,2'-bipyridine 57 mg, acetonitrile 8 mL are added into a reaction vessel, and the reaction is carried out at 70°C overnight under oxygen atmosphere, and monitored by GC. The reaction is terminated, silica gel is added into the reaction system, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 454 mg of product is separated by yield 95%.

[0078] Example 10

[0079] The synthesis route thereof is specifically referred to Figure 14 .

[0080] The synthesis method is as follows: 3-amino-4-methylbenzonitrile 216 mg, NHPI 448 mg, CuI 76 mg, 2,2'-bipyridine 57 mg, acetonitrile 8 mL are added into a reaction vessel, and the reaction is carried out at 70°C overnight under oxygen atmosphere, and monitored by GC. The reaction is terminated, silica gel is added into the reaction system, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 454 mg of product is separated by yield 95%.

[0081] Example 11

[0082] The synthesis route thereof is specifically referred to Figure 15 .

[0083] The synthesis method is as follows: 3-amino-4-methylbenzonitrile 216 mg, NHPI 448 mg, CuI 76 mg, 2,2'-bipyridine 57 mg, acetonitrile 8 mL are added into a reaction vessel, and the reaction is carried out at 70°C overnight under oxygen atmosphere, and monitored by GC. The reaction is terminated, silica gel is added into the reaction system, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 454 mg of product is separated by yield 95%.

[0084] Example 12

[0085] The synthetic route thereof is specifically referred to Figure 16 .

[0086] The synthetic method is specifically as follows: p-tert-butylaniline 293 mg, NHPI 447 mg, CuI 70 mg, 2,2'-bipyridine 62 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under an oxygen atmosphere and at 70°C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 448 mg of product is separated and obtained, and the yield is 80%.

[0087] Example 13

[0088] The synthetic route thereof is specifically referred to Figure 17 .

[0089] The synthetic method is specifically as follows: p-bromoaniline 340 mg, NHPI 567 mg, CuI 77 mg, 2,2'-bipyridine 63 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under an oxygen atmosphere and at 70°C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 514 mg of product is separated and obtained, and the yield is 76%.

[0090] Example 14

[0091] The synthetic route thereof is specifically referred to Figure 18 .

[0092] The synthetic method is specifically as follows: aniline 1.0 g, NHPI 1.75 g, CuI 0.39 g, 2,2'-bipyridine 1.75 g, acetonitrile 43 mL are added into a reaction container, and the reaction is carried out overnight under an oxygen atmosphere and at 70°C, and GC monitoring. The reaction is terminated, the reaction liquid is filtered, water is added, and a solid is precipitated, filtered, and dried to obtain 1.9 g of product, and the yield is 80%.

[0093] Example 15

[0094] The synthetic route thereof is specifically referred to Figure 19 .

[0095] The synthetic method is specifically as follows: o-trifluoromethylaniline 323 mg, NHPI 448 g, CuI 71 mg, 2,2'-bipyridine 59 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under an oxygen atmosphere and at 70°C, and GC monitoring. The reaction is terminated, silica gel is added into the reaction system for mixing, and separation is carried out in a chromatographic column, and the eluent is petroleum ether: ethyl acetate: dichloromethane = 6.5:2:1.5, and 514 mg of product is separated and obtained, and the yield is 76%.

[0096] Example 16

[0097] The synthetic route is specifically referred to Figure 20 .

[0098] The synthetic method is specifically as follows: 2,6-difluoroaniline 254 mg, NHPI 442 g, CuI 72 mg, 2,2'-bipyridine 60 mg, acetonitrile 8 mL are added into a reaction container, and the reaction is carried out overnight under an oxygen atmosphere and heated to 70 DEG C. GC monitoring shows that the reaction is basically not carried out.

[0099] In summary, the present application uses aromatic amine and NHPI as raw materials, uses copper salt as catalyst, 2,2'-bipyridine as ligand, and reacts in a solvent to generate N-aromatic phthalimide compounds under an oxygen atmosphere. The preparation process is simple, the conditions are easy to control, and the raw material cost is low.

[0100] The above only describes the preferred embodiments of the present application, and therefore cannot limit the scope of the present application. Any equivalent changes and modifications made according to the scope of the present application and the content of the specification shall still fall within the scope of the present application.

Claims

1. A method for synthesizing an N-arylphthalimide compound, characterized by: The N-aromatic phthalimide compound is synthesized by using aromatic amine and NHPI as raw materials, adding catalyst and 2,2'-dipyridyl as ligand in oxygen atmosphere and in solvent, wherein the aromatic amine is aniline, p-fluoroaniline, o-fluoroaniline, m-trifluoromethylaniline, 3,5-difluoroaniline, p-trifluoromethoxyaniline, m-toluidine, p-chloroaniline, 3-chloro-4-fluoroaniline, p-methoxyaniline, p-tert-butylaniline or p-bromoaniline; The catalyst is copper salt, and the amount of catalyst is 15-30% of the aromatic amine in terms of molar amount; The copper salt is one of CuI, CuCl and CuBr; The molar amount of NHPI is 1.0-2.0 times of the molar amount of aromatic amine; The amount of 2,2'-dipyridyl is 15-30% of the aromatic amine in terms of molar amount; The reaction temperature is 60-75 DEG C; The solvent is acetonitrile.

2. The method for synthesizing an N-aromatic phthalimide compound according to claim 1, characterized in that: The ratio of aromatic amine to solvent is 1 (g):8-50 (ml).

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