A kind of synthetic method of 3-ethyl-5-hydroxyl-1,3-diarylindolinone

Abstract

The invention discloses a 1,3-bis-(2,4,6-trimethylphenyl)-imidazole nitrogen-heterocyclic carbene catalyzed aryl ethyl ketene and N A new method for the synthesis of 3-ethyl-5-hydroxy-1,3-diarylindolone through the reaction of -aryliminoquinone. An imidazole nitrogen heterocyclic carbene catalyst is used to efficiently catalyze the [2+2] cycloaddition reaction. The resulting four-membered ring product is efficiently aromatized by a catalytic amount of Lewis acid to obtain aromatized indolinone. products. The method of the invention has the advantages of mild conditions, simple operation, green efficiency and high atom utilization rate.

Description

technical field

[0001] The invention relates to a method for synthesizing 3-ethyl-5-hydroxyl-1,3-diarylindolinone, which belongs to the field of organic chemistry.

[0002] technical background

[0003] The indolinone structure is an important pharmacophore, which is contained in many natural products or synthetic drugs with various biological activities. Therefore, how to synthesize bioactive indolinone derivatives concisely, efficiently and greenly has attracted many chemical workers to make unremitting efforts.

[0004] In the present invention, target product similar compound synthesis existing report ( Journal of Medicinal Chemistry , 2004, 47(11) :2816-2825.), the specific route is as follows:

[0005]

[0006] In this method, 4-methoxyiodobenzene and 2,6-dichloroaniline are used as starting materials, and 2-indolinone derivatives are obtained through four-step reactions. The temperature used in this synthesis method is as high as 100 o Above C, the reaction t...

Examples

Embodiment 1

[0022] Preparation of 3-ethyl-5-hydroxy-1,3-diphenylindolinone

[0023] Add nitrogen heterocyclic carbene catalyst A 1,3-bis-2,4,6-trimethylphenyl-imidazole hydrochloride (13.6 mg, 0.04 mmol) and cesium carbonate (9.8 mg, 0.03 mmol) into the Schlenk bottle , replace the nitrogen three times, add 1 mL of diethyl ether (aluminum lithium hydrogen distilled to remove water), stir at room temperature for 5-10 minutes, and N -Phenyliminoquinone (36.6 mg, 0.2 mmol) and phenyl ethyl ketene (58.0 mg, 0.4 mmol) were added to the reaction system, and reacted at room temperature for 30 minutes, monitored by TLC plate, the reaction was complete, and boron trifluoride ether was added (5.0 μL, 0.04 mmol), after continuing to react for 30 minutes, remove the solvent under reduced pressure, and separate by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 3-ethyl-5-hydroxyl-1, 3-Diphenylindolinone (64.0 mg, 97%). 1 H NMR (400 MHz, Acetone- d 6 ) δ 8.23 ​​(s, 1H), 7.63 ...

Embodiment 2

[0025] Preparation of 3-ethyl-5-hydroxy-1,3-diphenylindolinone

[0026] The nitrogen heterocyclic carbene catalyst C was used as the catalyst, and the rest of the operations were the same as in Example 1, and the product 4 was finally obtained with a yield of 54%.

Embodiment 3

[0028] Preparation of 3-ethyl-5-hydroxy-1,3-diphenylindolinone

[0029] The nitrogen heterocyclic carbene catalyst D was used as the catalyst, and the rest of the operations were the same as in Example 1, and the product 4 was finally obtained in a yield of 60%.

technical field

[0001] The invention relates to a method for synthesizing 3-ethyl-5-hydroxyl-1,3-diarylindolinone, which belongs to the field of organic chemistry.

[0002] technical background

[0003] The indolinone structure is an important pharmacophore, which is contained in many natural products or synthetic drugs with various biological activities. Therefore, how to synthesize bioactive indolinone derivatives concisely, efficiently and greenly has attracted many chemical workers to make unremitting efforts.

[0004] In the present invention, target product similar compound synthesis existing report ( Journal of Medicinal Chemistry , 2004, 47(11) :2816-2825.), the specific route is as follows:

[0005]

[0006] In this method, 4-methoxyiodobenzene and 2,6-dichloroaniline are used as starting materials, and 2-indolinone derivatives are obtained through four-step reactions. The temperature used in this synthesis method is as high as 100 o Above C, the reaction t...

Examples

Embodiment 1

[0022] Preparation of 3-ethyl-5-hydroxy-1,3-diphenylindolinone

[0023] Add nitrogen heterocyclic carbene catalyst A 1,3-bis-2,4,6-trimethylphenyl-imidazole hydrochloride (13.6 mg, 0.04 mmol) and cesium carbonate (9.8 mg, 0.03 mmol) into the Schlenk bottle , replace the nitrogen three times, add 1 mL of diethyl ether (aluminum lithium hydrogen distilled to remove water), stir at room temperature for 5-10 minutes, and N -Phenyliminoquinone (36.6 mg, 0.2 mmol) and phenyl ethyl ketene (58.0 mg, 0.4 mmol) were added to the reaction system, and reacted at room temperature for 30 minutes, monitored by TLC plate, the reaction was complete, and boron trifluoride ether was added (5.0 μL, 0.04 mmol), after continuing to react for 30 minutes, remove the solvent under reduced pressure, and separate by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 3-ethyl-5-hydroxyl-1, 3-Diphenylindolinone (64.0 mg, 97%). 1 H NMR (400 MHz, Acetone- d 6 ) δ 8.23 ​​(s, 1H), 7.63 ...

Embodiment 2

[0025] Preparation of 3-ethyl-5-hydroxy-1,3-diphenylindolinone

[0026] The nitrogen heterocyclic carbene catalyst C was used as the catalyst, and the rest of the operations were the same as in Example 1, and the product 4 was finally obtained with a yield of 54%.

Embodiment 3

[0028] Preparation of 3-ethyl-5-hydroxy-1,3-diphenylindolinone

[0029] The nitrogen heterocyclic carbene catalyst D was used as the catalyst, and the rest of the operations were the same as in Example 1, and the product 4 was finally obtained in a yield of 60%.

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