吲哚合成方法

1、吲噪一词来源于印度的英文单词（India）：在十六世纪从印度进口的蓝色染 料被称作靛篮。将此染料化学降解可得到氧化的吲噪一吲噪酚和羟基吲噪。吲噪 在1866年通过在锌粉作用下蒸馏羟基吲噪第一次被制备出来。吲噪可能是自然界中分布最广的杂环化合物。色氨酸是必需的氨基酸，也是 大多数蛋白质的组成部分。它还可作为各种色胺、吲噪和2, 3 二氢吲噪的生 物合成前体。色氨酸在动物中，存在于血液中的5一羟基色胺（5HT）是中枢神经系统中非常重要的神经递质，在心血管和胃肠道中也起很大作用。结构类似的激素褪黑素被 认为能控制生理功能的昼夜节律。植物王国中色胺酸衍生物包括3一吲噪基乙酸，它是一种有效的植物生长调

2、节激素；以及大量不同结构的二级代谢产物一吲噪类生物碱，这一类化合物由于 其有效的生理活性被广泛作为药物使用。吲噪的结构单元也大量出现在许多人工合成的药物中，如具有消炎镇痛作用的环氧酶抑制剂吲噪美辛，止吐作用的5HT3受体拮抗剂昂丹司琼等。COOHCH OCH3Cl吲哚美辛昂丹司琼由于吲噪在天然产物全合成和药物合成中的重要性，有机合成领域不断有大 量关于吲噪环的全新合成方法和改进方法出现，已经形成了一个相当系统的合成 框架，以下是一些目前可行的最重要的合成方法及示例。通过醛和酮的苯腙的制备方法（1） Fischer 合成法Fischer吲哚合成法发明于1883年，利用苯腙在酸或Lewis酸催化下

3、通过重排反应，亲核关环，再消除氨而形成吲哚环nn=CH3 也牛174H PhPhH 1事实上，有时将醛或酮与苯肼在乙酸中一起加热即可发生“一锅煮”的反应 2,生成的苯腙可不经分离直接发生重排反应。甲基苯磺酸、阳离子交换树脂及 三氯化磷都可有效地催化环化反应，有时在室温或更低的温度下反应也可进行3。 苯环上的供电基能提高Fischer环化反应的速率，而吸电基则降低反应速率。但 带有硝基的苯腙在合适的酸和反应条件下也可较好地发生反应，如甲苯与多聚磷 酸的两相混合物4或三氟化硼的乙酸溶液5。多步Fischer反应的详细机理仍不能 完全确定，但有一点可以肯定的是，最重要的一步碳碳键形成的反应是与Cla

4、isen 重排类似的电环化反应。（2） Grandberg 合成法nhnh通过邻一（2 一氧代烷基）苯胺的制备方法(1) Reissert 合成法CH3 (EtO2C)2/KO EtNOEtOH/Et2O2COOEtNO22AcOHH /PdNHCOOEtLeimgruber-Batcho 合成法Leimgruber-Batcho合成法8是最广泛使用的新方法之一，其主要是利用芳环 硝基邻位或毗啶a，B位9甲基的酸性与作为“一碳单位”的烯胺缩合而引入吲 噪a -碳。该方法首先将邻硝基甲苯结构的底物与二甲基甲酰胺二甲缩醛（DMF-DMA）在DMF中加热回流（无须加碱）缩合形成烯胺中间体，然后将硝基

5、 还原，经过分子内关环形成吲噪环。据报道，三（1-派啶基）甲烷与双（二甲氨 基）-叔丁氧基甲烷是比DMF-DMA更有效的“一碳单位”试剂1。广TCH3 DMFDMA -广* aq.TiCl/NHAc-YO2 DMF,Reflux*、23V NCOOEtCOOEtCOOEt 11还原试剂通常使用金属与酸的组合，也可采用钯碳/甲酸铵(或甲酸/三乙胺)还原铁粉/醋酸/硅胶13或市售三氯化钛盐酸溶液/醋酸铵14。通过邻炔基芳胺的制备方法H3C SiMe3NH Pd(Ph P) Cl /曰 N/DMF,Reflux 32234.通过邻甲酰替苯胺的制备方法(1) Madelung 合成法ClCHq3 n-

6、BuLiNH -20 C - r.tO Ph通过a一芳氨基羰基化合物的制备方法(1) Bischler 合成法17通过毗咯的制备方法18通过邻取代硝基芳烃衍生物的制备方法(1) Bartoli 合成法HzC=CHMgBrNO THF /-40 0：BrBrNH 19HCH3CH320O2NBrPd(OAc) /Et N O2nDMFOBnH3NH 21通过N-芳基烯胺的制备方法BrPd.AcLPhgP/NaHCOg人/ CH3DMFN CH3通过N-烯丙基邻卤芳胺的制备方法C.CNj.t11 H3COCOOMe通过烯胺和对苯醍的制备方法 (1) Nenitzescu 合成法EtOOCt-BuO

7、ClNH2 CH2C|2/-70oC通过芳胺的制备方法(1) Gassman 合成法NTiCyZnDME,RefluxNH24通过邻酰基酰替苯胺的制备方法(1) Furstner 合成法通过邻异氤基苯乙烯的制备方法(1) Fukuyama 合成法+COOC%CH3CNn-Bu Sn/AIBN _ h+25通过邻氯乙酰基芳胺的制备方法(1) Sugasawa 合成法通过氮宾成环的制备方法通过芳炔成环的制备方法NaNH /NaOt-Bu- 2THF,r.t通过邻硝基苯乙烯的制备方法Pd(OAc)2/CO/PPh3/Et3N DMF/MeOHNO2N H29通过二氢吲噪的制备方法。旅alcomine

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