Synthesis of Indoles and Benzisoxazolines from Baylis-Hillman Adducts of 2-Nitrobenzaldehydes
Synthesis of Indoles and Benzisoxazolines from Baylis-Hillman Adducts of 2-Nitrobenzaldehydes
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DOI：
10.5012/bkcs.2007.28.2.333
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发表时间：
2007
影响因子：
1.7
通讯作者：
Ka Young Lee;Hyun Seung Lee;Jae Nyoung Kim
中科院分区：
文献类型：
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作者：
Ka Young Lee;Hyun Seung Lee;Jae Nyoung Kim
近年来，许多有趣的化学转化反应都涉及到Baylis-Hillman加合物的应用。其中，2-硝基苯甲醛的Baylis-Hillman加合物已被广泛研究用于喹啉-N-氧化物、喹啉、喹诺酮、苯并异恶唑啉和吲哚的合成。虽然已经报道了许多吲哚衍生物的合成方法，但由于吲哚衍生物作为合成中间体的生物重要性和有用性，需要开发新的吲哚支架合成方法。几年前，我们报道了从SnCl 2介导的Baylis-Hillman加合物1a在醇溶剂中的还原合成3-烷氧基甲基2（1H）-喹诺酮（方案1）。在反应中，1a的硝基被还原为氨基，我们得到了3-烷氧基甲基2（1H）-喹诺酮作为主要产品。在某些情况下，我们获得苯并异恶唑啉化合物（5-10%）如3a作为副产物，其可能经由羟胺中间体形成。当时，我们还观察到在某些情况下形成痕量的吲哚衍生物，特别是当我们使用具有高沸点的醇时。受最近发表的关于从Baylis-Hillman加合物合成吲哚的文献的鼓舞，我们重新研究了SnCl 2介导的1a还原，以获得产率提高的苯并异恶唑啉或吲哚衍生物。令我们高兴的是，我们发现了形成3-取代吲哚和苯并异恶唑啉的有效条件，并希望在此报告结果（方案1）。如方案1所示，2-硝基苯甲醛和SnCl 2的Baylis-Hillman加合物1a在1，4-二氧六环中在室温下反应，以中等产率得到吲哚2a和苯并异恶唑啉3a。如上所述，苯并异恶唑啉化合物的形成已经在我们先前的论文中部分报道，并且反应机理可以被认为涉及羟胺中间体（I）和环化中间体（II），如方案2中所示。虽然在此阶段形成吲哚2a的反应机理尚不清楚，但我们可以尝试性地提出一种合理的机理，如方案2所示：（i）形成亚硝基中间体（III），（ii）迈克尔加成形成（IV），（iii）可逆逆羟醛型开环形成（V），（iv）环化形成（VI），（v）水辅助消除甲酸，得到吲哚啉衍生物（VII），（vi）脱水得到（VIII），最后异构化为吲哚2a。基于实验结果和提出的机理，在SnCl 2/二氧六环条件下，必须以可变的比例形成羟胺中间体（I）和亚硝基中间体（III）。为了选择性地形成（I）或（III），我们检查了反应条件，包括溶剂、温度、SnCl 2的当量，但都未能提高产率或选择性。硝基很容易转化为一系列不同还原程度的官能团：非常例外地转化为亚硝基，更常见的是转化为羟氨基，最常见的是转化为氨基。亚硝基化合物通常不直接获得，而是通过羟基氨基化合物的再氧化获得，其可以由硝基化合物通过SnCl 2制备。此外，
Recently a variety of interesting chemical transformations involving the use of Baylis-Hillman adducts have been reported. Among them the use of Baylis-Hillman adducts of 2-nitrobenzaldehydes have been investigated extensively for the synthesis of quinoline-N-oxides, quinolines, quinolones, benzisoxazolines, and indoles. Although there have been reported numerous methods for the synthesis of indole derivatives, a development of new synthetic method of indole scaffold is required due to their biological importance and usefulness as synthetic intermediates. A few years ago we reported the synthesis of 3-alkoxymethyl 2(1H)-quinolones from the SnCl2-mediated reduction of the Baylis-Hillman adducts 1a in alcohol solvent (Scheme 1). In the reaction, the nitro group of 1a was reduced to amino group and we obtained 3-alkoxymethyl 2(1H)-quinolones as the major products. In some cases we obtained benzisoxazoline compounds (5-10%) like 3a as the side products, which might be formed via the hydroxylamine intermediate. At that time we also observed the formation of trace amounts of indole derivatives in some cases, especially when we used alcohols having high boiling point. Encouraged by recent publications on the synthesis of indoles from Baylis-Hillman adducts, we reinvestigated the SnCl2-mediated reduction of 1a in order to obtain the benzisoxazoline or indole derivatives in improved yields. To our delight, we found an efficient condition for the formation of 3-substituted indoles and benzisoxazolines and wish to report herein the results (Scheme 1). As shown in Scheme 1, the reaction of Baylis-Hillman adduct 1a of 2-nitrobenzaldehyde and SnCl2 in 1,4-dioxane at refluxing temperature gave the indole 2a and benzisoxazoline 3a in moderate yields. As described above the formation of benzisoxazoline compound was already reported in part in our previous paper and the reaction mechanism could be regarded involving the hydroxylamine intermediate (I) and the cyclized intermediate (II) as in Scheme 2. Although the reaction mechanism for the formation of indole 2a was not clear at this stage we could tentatively propose a plausible mechanism as shown in Scheme 2: (i) formation of nitroso intermediate (III), (ii) Michael addition to form (IV), (iii) reversible retro-aldol type ring-opening to form (V), (iv) cyclization to (VI), (v) water-assisted elimination of formic acid to give indoline derivative (VII), (vi) dehydration to (VIII) and the final isomerization to indole 2a. Based on the experimental results and the proposed mechanism there must be formed hydroxylamine intermediate (I) and nitroso intermediate (III) under SnCl2/dioxane conditions in a variable ratios. In order for the selective formation of either (I) or (III), we examined the reaction conditions including solvent, temperature, the equivalents of SnCl2, but all failed to improve the yields or selectivity. The nitro group is readily converted to a series of functions of various degrees of reduction: very exceptionally to a nitroso group, more often to a hydroxylamino group and most frequently to the amino group. Nitroso compounds are usually not obtained directly but rather by reoxidation of hydroxylamino compounds, which can be prepared from nitro compounds by SnCl2. Moreover there have been few instances in