一种3-取代异吲哚-1-酮及酞类化合物的合成方法

chem 1362 0

3-取代异吲哚-1-酮类化合物及酞类化合物存在于多种具有生物活性的天然产物中,也是制备多种药物的关键中间体。例如AKS-186AKS-182能够有效地抑制血栓素A2诱导产生的血管收缩;酞类化合物a,b具有多种药理活性,同时也是有机合成中的重要中间体。

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3-取代异吲哚-1-酮类化合物及酞类化合物的部分合成方法

3-取代异吲哚-1-酮类化合物

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酞类化合物

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文献解析
3-取代异吲哚-1-酮类化合物的合成,路线如下图

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底物普适性考察
a-2 to a-4
一种3-取代异吲哚-1-酮及酞类化合物的合成方法  第5张
当Ar为4-苯酚时,方法如下

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a-4 to a-5

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操作
a-1 to a-2:A mixture of a-1 (1 mmol) and amine (1 mmol) were stirred for 5 min at rt. After this time the ketone compound (1.0 mmol) and PhB(OH)2(0.1 mmol) were added, and the reaction mixture was stirred at 100oC.The progress of the reaction was checked by TLC. After completion of the reaction, the mixture was cooled at rt and the resulting crude product was purified by flash column chromatography using hexane-EA mixture as eluent, to give the pure products a-2.(参考文献doi.org/10.1016/j.tet.2018.05.086
a-2 to a-4:To a solution of a-2(1mmol) in THF-MeOH(7:3) (10 mL), was added NaBH4 (1.2 mmol) and stirred for 20 min at 0 oC.After completion of the reaction,the mixture was warmed to rt and quenched with NH4Cl solution, stirred for 5 min at rt and extracted with EA (3x 10 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SOand evaporated in vacuo to give crude product a-3.PTSA (0.2 mmol) was added to the crude product a-3 in toluene (15 mL) and stirred at 105 oC.After completion of the reaction, the mixturewas cooled to rt, the solvent was evaporated and the resulting crude product was purified by flash column chromatography using hexane-EAmixture as eluent, to give the pure products a-4.
a-4 to a-5:To a solution of the corresponding a-4(1 mmol) in CH3CN (5mL), K2CO3(1mmol) was added, stirred for 5 min at rt and then at 80 oC.After completion of the reaction, the mixture was cooled to rt then water (5mL) and EA (5 mL x 3) were added. The aqueous layer was extracted with EA (5 mLx 3) and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4and evaporated in vacuo. The resulting crude product was purified by flash column chromatography using hexane-EA mixture as eluent, to give a-5.


酞类化合物的合成,路线如下图

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底物普适性考察
b-1 to b-2

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b-2 to b-3
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操作
a-1 to b-1:A mixture of a-1 (1 mmol) and ketone (1.0 mmol) was stirred for 5 min at rt, followed by the addition of PhB(OH)2 (0.1 mmol). After this time, the reaction mixture was stirred at 135 oC for the appropriate time and the progress of the reaction was checked by TLC. After completion, the mixture was cooled at rt and the crude product was purified by flash column chromatography using hexane-EA as eluent, to give the pure products b-1(参考文献doi.org/10.1016/j.tet.2018.05.086).
b-1 to b-2: 参考a-2 to a-4 操作方法

b-2 to b-3: 参考a-4 to a-5 操作方法


参考文献
doi.org/10.1016/j.tet.2019.130838
doi.org/10.1016/j.tet.2018.05.086


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