Acid-base catalysis in the synthesis of arylmethylene and alkylmethine pyrroles
Acid-base catalysis in the synthesis of arylmethylene and alkylmethine pyrroles
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DOI：
10.1021/jo971365d
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发表时间：
1998-09-18
影响因子：
3.6
通讯作者：
Walker, DA
中科院分区：
文献类型：
--
作者：
D'Silva, C;Walker, DA
N-烷基和芳基吡咯是形成改性吡咯聚合物的重要中间体，其已发现在多种应用中的用途。1，2我们对这些材料的兴趣在于它们在分子电子学和传感器中的应用。4这些化合物的制备传统上包括在氮气下在THF溶液中用Na、K、5或n-BuLi 6或在相转移条件下用t-BuOK 7或NaOH使吡咯环的1-位去质子化，然后使吡咯的碱金属盐与等量的酰基或烷基卤反应。使用这些方法制备芳基亚甲基吡咯可能证明是有问题的，这是由于2-位的反应性5，这可能导致除了所需的1-取代产物之外，还形成未反应的2-和二取代的吡咯，从而降低产率并阻碍分离。由于使用碱性条件，上述反应本身不适于制备含有碱不稳定保护基的取代吡咯。为了克服现有方法的问题，我们最近报道了一种制备芳基亚甲基吡咯的新方法，该方法基于在刘易斯酸存在下还原N-酰基吡咯8（方案1），该方法适用于碱不稳定和一些酸不稳定的保护基团，但涉及两步反应。吡咯的另一种单步方法，Paal-Knoor方法的改进，涉及伯胺与2，5-二甲氧基四氢呋喃（DMT）2，9，10的缩合（方案2）。这种反应并不像它看起来的那样普遍，许多化合物由于重排和进一步缩合而不能产生所需的产物，其机理尚未确定。1，4-二氯-1，4-二甲氧基丁烷（DMT的反应性功能等价物）克服了这些问题中的一些，但是不易获得并且水解不稳定。使用有机金属催化剂使胺与1，3-二烯12或2-丁炔-1，4-二醇13缩合提供了制备吡咯衍生物的替代方法，但是这些方法不是普遍适用的并且产率是可变的。现有的方法的局限性转化成吡咯基团的胺基，使我们寻求一种通用的程序，这种转换在中性条件下。为了证明该方法的有效性，我们将该技术应用于几个新的N-芳基亚甲基（2c-g）和N-烷基甲川基吡咯（2 h-i）衍生物的合成，其中许多是以前无法访问。DMT的商业可用性使其成为进一步研究的首选试剂。Clanson-Kaass 14等人和Josey 15使用Na 2AcOH实现了DMT与胺的反应。Schalkhammer等人2报告了使用AcOH溶液或磷酸钾缓冲液，而鹿岛等人10使用NaOAc，但未提供实验细节。当用于制备N-芳基亚甲基吡咯衍生物时，由于副产物的形成或与使用水性缓冲液相关的溶解度问题，上述方法导致可忽略的产物产率。由于相关的烯胺型反应对酸碱催化敏感，16决定研究使用酸碱溶剂混合物作为苄胺与DMT偶联中的缓冲液，因为此类混合物已用作洗脱剂，
N-Alkyl and arylpyrroles are important intermediates in the formation of modified pyrrole polymers which have found uses in a wide variety of applications. 1, 2 Our interest in these materials is in their use in molecular electronics3 and sensors. 4 The preparation of these compounds traditionally has involved deprotonation of the 1-position of the pyrrole ring under nitrogen in a solution of THF with Na, K, 5 or n-BuLi6 or under phase transfer conditions with t-BuOK7 or NaOH followed by reaction of the alkali salt of pyrrole with an equivalent amount of acyl or alkyl halide. The preparation of arylmethylene pyrroles using these methods can prove problematic due to the reactivity of the 2-position5 which can result in the formation of unreacted 2-and disubstituted pyrroles in addition to the desired 1-substituted product, thus reducing yield and hindering isolation. The above reaction, due to the use of basic conditions, renders itself unsuitable for the preparation of substituted pyrroles containing base labile protecting groups. In an attempt to overcome the problems of existing methods we recently reported a new method to arylmethylene pyrroles based on the reduction of N-acylpyrroles8 (Scheme 1), undertaken in the presence of a Lewis acid, which is suitable for use with base labile and some acid labile protecting groups but involves a two-step reaction. An alternative single-step procedure to pyrroles, a modification of the Paal-Knoor method, involves the condensation of primary amines with 2, 5-dimethoxytetrahydrofuran (DMT) 2, 9, 10 (Scheme 2). This reaction is not as general as it appears, and many compounds fail to produce the desired product due to rearrangement and further condensations2 the mechanisms of which have not been identified. 1, 4-Dichloro-1, 4-dimethoxybutane, 11 a reactive functional equivalent of DMT, overcomes some of these problems, but is not readily available and is hydrolytically unstable. The condensation of amines with 1, 3-dienes12 or 2-butyne-1, 4-diol13 using organometallic catalysts affords an alternative approach to pyrrole derivatives, but these methods are not generally applicable and the yields are variable. The limitations of existing methods for the conversion of amine groups into pyrrole groups led us to seek a general procedure for this conversion under neutral conditions. To demonstrate the effectiveness of the method, we applied the technique to the synthesis of several new N-arylmethylene (2c-g) and N-alkylmethine pyrrole (2h-i) derivatives, many of which were previously inaccessible. 10The commercial availability of DMT made it the reagent of choice for further investigations. Clanson-Kaass14 et al. and Josey15 achieved reaction of DMT with amines using refluxing AcOH. Schalkhammer et al. 2 reported the use of AcOH solutions or potassium phosphate buffer while Kashima et al. 10 used NaOAc but provided no experimental details. When used for the preparation of N-arylmethylene pyrrole derivatives, the above procedures resulted in negligible yields of product due to byproduct formation or solubility problems associated with the use of aqueous buffers. As related enamine type reactions were susceptible to acid-base catalysis, 16 it was decided to investigate the use of acid-base solvent mixtures as buffers in the coupling of benzylamine with DMT, as such mixtures have been used as eluents and