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Novel method for synthesizing benzimidazole[1,2-a]quinoline derivative

A technology of benzimidazole and 2-a, which is applied in the field of efficient synthesis of benzimidazole [1,2-a] quinoline derivatives, can solve the problems of difficulty in obtaining raw materials, cost of using toxic organic solvents, cumbersome reaction steps, etc. Achieve the effect of good substrate applicability, broad application prospects and low cost

Active Publication Date: 2019-08-20
SICHUAN UNIV
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  • Application Information

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Problems solved by technology

[0003] The present invention realizes the synthesis of benzimidazole [1,2-a] through transition metal-catalyzed aryl C-H activation / cyclization reaction using N-aryl amidines and benzisoxazole compounds as raw materials and ionic liquid as solvent The new method of quinoline derivatives solves the problems of cumbersome reaction steps, difficult to obtain raw materials, low atom utilization, use of toxic organic solvents and high cost in traditional synthetic methods

Method used

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  • Novel method for synthesizing benzimidazole[1,2-a]quinoline derivative
  • Novel method for synthesizing benzimidazole[1,2-a]quinoline derivative
  • Novel method for synthesizing benzimidazole[1,2-a]quinoline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Implementation Example 1: Synthesis of Compound 1

[0020]

[0021] (1) Add N-(4-methylphenyl)acetamidine (29.6 mg, 0.20 mmol), 5-chloro-3-phenylbenzisoxazole (55.1 mg, 0.24 mmol), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (6.2 mg, 0.01 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (0.6 mL) , and stirred in an oil bath at 140°C for 24 h after argon replacement;

[0022] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 57.6 mg of the product, a yellow solid, with a yield of 84%; 1 H NMR (400 MHz, Chloroform- d ) δ 8.57 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H),7.91 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.8, 2.4Hz, 1H), 7.63 - 7.47 (m, 5H), 7.39 (d, J = 8.4 Hz, 1H), 2.68 (s, 3H); 13 C NMR (100 MHz, Chloroform- d ) Δ 147.4, 143.3, 141.8, 137.6, 134.4, 133.2, 131.0,129.6, 129.5, 129.0, 128.8, 127.7, 126.5, 120.3, 116.9,113.9, 22.5; 22 h 1...

Embodiment 2

[0023] Implementation Example 2: Synthesis of Compound 2

[0024]

[0025] (1) In a clean reactor, add N-(4-fluorophenyl)acetamidine (26.8 mg, 0.20 mmol), 5-chloro-3-phenylbenzisoxazole (55.1 mg, 0.24 mmol ), dichloro(pentamethylcyclopentadienyl) iridium(III) dimer (8.0 mg, 0.01 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (0.6 mL), Stir in an oil bath at 140°C for 24 h after argon replacement;

[0026] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 51.2 mg of the product as a light yellow solid with a yield of 78%; 1 H NMR (400 MHz, Chloroform- d ) δ 8.58 (d, J = 8.8 Hz, 1H), 8.35 (d, J =8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J = 8.8 Hz,1H), 7.63 - 7.42 (m, 8H); 13 C NMR (100 MHz, Chloroform- d ) δ 147.7, 145.1, 142.4, 137.5, 134.4, 130.8, 129.8, 129.8, 129.5, 129.1, 128.9, 127.8, 124.9, 124.8, 123.2, 120.8, 118.8, 116. 21 h 14 ClN 2 [M+H] + ...

Embodiment 3

[0027] Implementation Example 3: Synthesis of Compound 3

[0028]

[0029] (1) In a clean reactor, add N-phenylacetamidine (30.4 mg, 0.20 mmol), 5-chloro-3-phenylbenzisoxazole (55.1 mg, 0.24 mmol), dichloro( Pentamethylcyclopentadienyl) rhodium(III) dimer (6.2 mg, 0.01 mmol), 1-butyl-3-methylimidazolium triflate (0.6 mL), after argon displacement Stir in an oil bath at 140°C for 24 h;

[0030] (2) After the reaction was completed, the product was directly separated and purified by silica gel column chromatography to obtain 62.2 mg of the product as a light yellow solid with a yield of 81%; 1 H NMR (400 MHz, Chloroform- d ) δ 8.41 (d, J = 8.8 Hz, 1H), 8.05 (d, J =7.2 Hz, 1H), 7.97 (dd, J = 8.8, 5.2 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.73(dd, J = 8.8, 2.4 Hz, 1H), 7.58 - 7.50 (m, 6H), 7.33 (td, J = 8.8, 2.4 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 160.6, 158.2, 148.3, 142.4, 141.5, 137.3, 134.1, 130.2, 129.9, 129.5, 129.1, 129.0, 128.0, 124.8, 121.4 (d, J ...

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Abstract

The invention relates to a novel method for synthesizing a benzimidazole[1,2-a]quinoline derivative. An N-arylamidine compound and a benzisoxazole compound are used as raw materials, and an N1, N3-disubstituted imidazole ionic liquid is used as a solvent. Through a C-H activation / cyclization reaction catalyzed by a transition metal, a C-C bond is formed on the aromatic ring and then the benzimidazole[1,2-a]quinoline derivative is synthesized. In comparison with a traditional method, the method of the invention has the following advantages: (1) the step is simple, the raw materials are easily available, the substrate has a wide application range, and the reaction yield is high; and (2) addition of silver salt and an acid or alkali additive is avoided through the catalytic system, the cost is low, and the method is safe and convenient and has a wide application prospect.

Description

technical field [0001] The present invention relates to a N-based 1 ,N 3 - Disubstituted imidazole-type ionic liquid as solvent, N-arylamidines and benzisoxazole compounds as raw materials, and transition metal catalyzed C-H activation / cyclization reaction to efficiently synthesize benzimidazol[1,2-a]quinoline A new approach to derivatives. Background technique [0002] Benzimidazole is similar in structure to purine, and is the main skeleton of many medicinal chemistry and biochemical reagents. Therefore, compounds with benzimidazole as the core skeleton have many activities, such as: anti-tumor 1-3 ,Antiviral 4,5 , antibacterial 6,7 ,Antifungal 8 , antihistamine 9 , antispasmodic activity 10 . The benzimidazol[1,2-a]quinoline derivatives formed by combining quinoline rings have stronger antitumor activity because they can easily interfere with the replication of DNA or RNA 11-14 . Currently, the commonly used methods for synthesizing benzimidazolo[1,2-a]quinoline...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 吴勇海俐刘艳昭聂瑞芳胡瑶
Owner SICHUAN UNIV
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