吲哚合成方法

1、吲噪一詞來(lái)源于印度的英文單詞（India）：在十六世紀(jì)從印度進(jìn)口的藍(lán)色染 料被稱(chēng)作靛籃。將此染料化學(xué)降解可得到氧化的吲噪一吲噪酚和羥基吲噪。吲噪 在1866年通過(guò)在鋅粉作用下蒸餾羥基吲噪第一次被制備出來(lái)。吲噪可能是自然界中分布最廣的雜環(huán)化合物。色氨酸是必需的氨基酸，也是 大多數(shù)蛋白質(zhì)的組成部分。它還可作為各種色胺、吲噪和2, 3 二氫吲噪的生 物合成前體。色氨酸在動(dòng)物中，存在于血液中的5一羥基色胺（5HT）是中樞神經(jīng)系統(tǒng)中非常重要的神經(jīng)遞質(zhì)，在心血管和胃腸道中也起很大作用。結(jié)構(gòu)類(lèi)似的激素褪黑素被 認(rèn)為能控制生理功能的晝夜節(jié)律。植物王國(guó)中色胺酸衍生物包括3一吲噪基乙酸，它是一種有效的植物生長(zhǎng)調(diào)

2、節(jié)激素；以及大量不同結(jié)構(gòu)的二級(jí)代謝產(chǎn)物一吲噪類(lèi)生物堿，這一類(lèi)化合物由于 其有效的生理活性被廣泛作為藥物使用。吲噪的結(jié)構(gòu)單元也大量出現(xiàn)在許多人工合成的藥物中，如具有消炎鎮(zhèn)痛作用的環(huán)氧酶抑制劑吲噪美辛，止吐作用的5HT3受體拮抗劑昂丹司瓊等。COOHCH OCH3Cl吲哚美辛昂丹司瓊由于吲噪在天然產(chǎn)物全合成和藥物合成中的重要性，有機(jī)合成領(lǐng)域不斷有大 量關(guān)于吲噪環(huán)的全新合成方法和改進(jìn)方法出現(xiàn)，已經(jīng)形成了一個(gè)相當(dāng)系統(tǒng)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。通過(guò)醛和酮的苯腙的制備方法（1） Fischer 合成法Fischer吲哚合成法發(fā)明于1883年，利用苯腙在酸或Lewis酸催化下

3、通過(guò)重排反應(yīng)，親核關(guān)環(huán)，再消除氨而形成吲哚環(huán)nn=CH3 也牛174H PhPhH 1事實(shí)上，有時(shí)將醛或酮與苯肼在乙酸中一起加熱即可發(fā)生“一鍋煮”的反應(yīng) 2,生成的苯腙可不經(jīng)分離直接發(fā)生重排反應(yīng)。甲基苯磺酸、陽(yáng)離子交換樹(shù)脂及 三氯化磷都可有效地催化環(huán)化反應(yīng)，有時(shí)在室溫或更低的溫度下反應(yīng)也可進(jìn)行3。 苯環(huán)上的供電基能提高Fischer環(huán)化反應(yīng)的速率，而吸電基則降低反應(yīng)速率。但 帶有硝基的苯腙在合適的酸和反應(yīng)條件下也可較好地發(fā)生反應(yīng)，如甲苯與多聚磷 酸的兩相混合物4或三氟化硼的乙酸溶液5。多步Fischer反應(yīng)的詳細(xì)機(jī)理仍不能 完全確定，但有一點(diǎn)可以肯定的是，最重要的一步碳碳鍵形成的反應(yīng)是與Cla

4、isen 重排類(lèi)似的電環(huán)化反應(yīng)。（2） Grandberg 合成法nhnh通過(guò)鄰一（2 一氧代烷基）苯胺的制備方法(1) Reissert 合成法CH3 (EtO2C)2/KO EtNOEtOH/Et2O2COOEtNO22AcOHH /PdNHCOOEtLeimgruber-Batcho 合成法Leimgruber-Batcho合成法8是最廣泛使用的新方法之一，其主要是利用芳環(huán) 硝基鄰位或毗啶a，B位9甲基的酸性與作為“一碳單位”的烯胺縮合而引入吲 噪a -碳。該方法首先將鄰硝基甲苯結(jié)構(gòu)的底物與二甲基甲酰胺二甲縮醛（DMF-DMA）在DMF中加熱回流（無(wú)須加堿）縮合形成烯胺中間體，然后將硝基

5、 還原，經(jīng)過(guò)分子內(nèi)關(guān)環(huán)形成吲噪環(huán)。據(jù)報(bào)道，三（1-派啶基）甲烷與雙（二甲氨 基）-叔丁氧基甲烷是比DMF-DMA更有效的“一碳單位”試劑1。廣TCH3 DMFDMA -廣* aq.TiCl/NHAc-YO2 DMF,Reflux*、23V NCOOEtCOOEtCOOEt 11還原試劑通常使用金屬與酸的組合，也可采用鈀碳/甲酸銨(或甲酸/三乙胺)還原鐵粉/醋酸/硅膠13或市售三氯化鈦鹽酸溶液/醋酸銨14。通過(guò)鄰炔基芳胺的制備方法H3C SiMe3NH Pd(Ph P) Cl /曰 N/DMF,Reflux 32234.通過(guò)鄰甲酰替苯胺的制備方法(1) Madelung 合成法ClCHq3 n-

6、BuLiNH -20 C - r.tO Ph通過(guò)a一芳氨基羰基化合物的制備方法(1) Bischler 合成法17通過(guò)毗咯的制備方法18通過(guò)鄰取代硝基芳烴衍生物的制備方法(1) Bartoli 合成法HzC=CHMgBrNO THF /-40 0：BrBrNH 19HCH3CH320O2NBrPd(OAc) /Et N O2nDMFOBnH3NH 21通過(guò)N-芳基烯胺的制備方法BrPd.AcLPhgP/NaHCOg人/ CH3DMFN CH3通過(guò)N-烯丙基鄰鹵芳胺的制備方法C.CNj.t11 H3COCOOMe通過(guò)烯胺和對(duì)苯醍的制備方法 (1) Nenitzescu 合成法EtOOCt-BuO

7、ClNH2 CH2C|2/-70oC通過(guò)芳胺的制備方法(1) Gassman 合成法NTiCyZnDME,RefluxNH24通過(guò)鄰?；Ｌ姹桨返闹苽浞椒?1) Furstner 合成法通過(guò)鄰異氤基苯乙烯的制備方法(1) Fukuyama 合成法+COOC%CH3CNn-Bu Sn/AIBN _ h+25通過(guò)鄰氯乙?；及返闹苽浞椒?1) Sugasawa 合成法通過(guò)氮賓成環(huán)的制備方法通過(guò)芳炔成環(huán)的制備方法NaNH /NaOt-Bu- 2THF,r.t通過(guò)鄰硝基苯乙烯的制備方法Pd(OAc)2/CO/PPh3/Et3N DMF/MeOHNO2N H29通過(guò)二氫吲噪的制備方法。旅alcomine

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