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Abstract In a multicomponent reaction (MCR), one can create multiple new bonds in a single reaction from readily available starting materials; thus, MCRs are resource-and timeeffective and therefore economically favorable processes in diversity generation. In contrast, there are MCRs where a multifunctional building block is introduced instead of an additional diversity-holding component, and these can be derivatized using very diverse reactions post-synthetically leading to novel chemotypes. The synthetic applications of Meldrum*s acid are focusing primarily on reactions where it is applied as an alternative for acyclic malonic esters. However, its highly acidic character broadened its applications and made it a very useful reagent for MCRs or more precisely in tandem or domino reactions. There are numerous examples reported for the use of the alkylidene conjugates of Meldrum*s acid as dienophiles in hetero-Diels –Alder reactions, as well as Michael acceptors. In most cases spontaneous or concomitant post-synthetic derivatization increased its synthetic utility. This minireview gives a non-exhaustive insight into MCRs involving Meldrum*s acid, describing various applications in combinatorial and diversityoriented synthesis. 1 Introduction Multicomponent Reactions (MCRs) have been a versatile tool for synthetic chemists in the preparation of structurally diverse compounds. MCRs comprise reactions with more than two reactants and the newly formed product contains atoms of each precursor [1]. In contrast, the probability that three or more molecules collide in the right direction and at the appropriate energy level is very low, most of the known MCRs could be considered more precisely as domino or tandem reactions. MCRs are resourceand time-effective, and therefore economically favorable processes; thus, a vast number of diverse compounds can be obtained in a parallel synthesis [2]. In recent years, there has been a growing interest in MCRs in the chemical and pharmaceutical industries, as MCRs not only lower production costs due to their high convergence and atom efficiency, but also reduces the environmental burden, which is the major principle of green chemistry. The enormous synthetic possibilities that MCRs offer can be further increased by post-synthesis transformations, which can be furnished by concomitant reaction of a suitably functionalized or protected MCR product. These modifications can be either spontaneous reactions with the medium, intramolecular rearrangements, or can take place upon treatment with additional reagents. Meldrum*s acid (1) described first by A. N. Meldrum [3] is a white crystalline solid that can be easily prepared by the condensation of malonic acid and acetone in acetic anhydride in the presence of a catalytic amount of concentrated sulfuric acid [4]. Meldrum*s acid shows several unique features. It has an unusually high acidity [5]; the pKa of Meldrum*s acid in DMSO is 7.325, but those of dimedone and dimethyl malonate, corresponding to the cyclic diketone and acyclic ester analogues, are 15.87 and 11.16, respectively. Furthermore, it is susceptible to electrophilic attack at C5 and nucleophilic attack at C4 and C6. Additionally, its unique ring-opening reactions make it a tremendously attractive and useful building block. The synthetic applications of Meldrum*s acid are focusing primarily on reactions where it is applied as an alternative for acyclic malonic esters, but there are numerous examples reported for the use of the alkylidene conjugates of Meldrum*s acid as dienophiles in hetero-Diels –Alder reactions. In most cases spontaneous or concomitant post-synthetic derivatization increases its synthetic utility. The MCRs involving Meldrum*s acid generally retain the unique ring-captured malonic acid moiety, which can be released by loss of acetone, when reacting with nucleophiles. This reaction is frequently accompanied with partial decarboxylation. In this way various diversity elements can be built into the diverse MCR products. Frequently, nucleophiles in appropriate proximity could intramolecularly attack the cyclic acetonide fragment, leading to unique ring systems, which can be used in Diversity-Oriented Synthesis (DOS) [6]. Based on the above findings, the MCRs involving Meldrum *s acid belong to those classes where it participates as a multifunctional building block in the reaction instead of one diversity-holding component, so the MCR product can be further derivatized in a large variety of reactions leading to diverse skeletons or chemotypes. Corresponding to the initial step and the primary intermediate formed involving Meldrum*s acid, the MCRs can be classified into various subgroups. In most cases, a reactive alkylidene Meldrum*s acid intermediate (a Knoevenagel adduct) participates in various secondary reactions. This two-step feature is reflected, in many cases, in the name of MCRs involving Meldrum*s acid [domino Knoevenagel –Diels –Alder, domino Wittig –Knoevenagel – Diels –Alder, modified Hantzsch reaction, Yonemitsu reaction (domino Knoevenagel –Michael reaction), etc.]. In most of the above cases Meldrum*s acid, condensed first with carbonyl moieties, could ultimately lead to a substituted propionic acid extension of the molecules. Domino Knoevenagel-isonitrile-cycloaddition represents a unique subclass, since the major product retains both carboxylic groups of the masked malonic acid moiety. Some MCRs cannot be clearly classified where, for example, Meldrum*s acid reacts with unsaturated carbonyl compounds in a Knoevenagel condensation and ring closure is followed by condensation. In other cases Meldrum *s acid acts as a Michael donor with its highly acidic methylene moiety in an aldol-type reaction. In the present minireview we follow this classification providing a general description and examples to each subclass. |
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2楼2009-03-28 20:09:26
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摘要 在一个多组分反应（MCRs） ，可以创建多个新键在单一 反应起始原料容易获得，因此， MCRs是资源和timeeffective 因此，在经济上有利的进程多样性一代。在 相反，在那里有MCRs多功能砌块而非介绍 另外多样性控股的组成部分，而这些可以用非常衍生 不同的反应后的综合导致小说chemotypes 。合成 应用梅尔德伦*县酸是主要侧重于反应凡适用 另一种为环丙二酯。但是，它的高酸性性质扩大 及其应用，并使它成为非常有用的试剂MCRs或更确切地说在串联 或多米诺骨牌反应。有许多例子汇报使用alkylidene 偶联的梅尔德伦*县酸dienophiles在杂Diels - Alder反应，以及 迈克尔受体。在大多数情况下自发的或伴随后合成衍生 增加了合成工具。这minireview让一个不完全了解MCRs 涉及梅尔德伦*县酸，描述各种应用程序的组合和diversityoriented 合成。 1简介 多组分反应（ MCRs ）是一个多才多艺 工具合成化学家在编制结构 不同的化合物。 MCRs包括反应 两个以上的反应和新成立的产品 包含每个原子的前体[ 1 ] 。与此相反，概率 这三个或更多的分子碰撞的方向是正确的 并在适当的能量水平非常低， 大多数已知的MCRs可以考虑更准确 如多米诺骨牌或串联反应。 MCRs是resourceand 时间效益，因此在经济上有利 进程;因此，有大量不同的化合物，可以 得到了平行合成[ 2 ] 。近年来， 人们越来越关心MCRs在化学 和制药业，因为MCRs不仅降低 由于生产成本高的收敛性和原子 效率，而且还降低了环境负担， 这是重大原则的绿色化学。 巨大的合成提供了可能性， MCRs 还可以进一步增加后合成的转变， 可同时提供一个适当的反应 功能或受保护的静止产品。这些修改 可以是自发反应的媒介， 分子重排，或可在 治疗时的额外试剂。 梅尔德伦*县酸（ 1 ）第一次描述了梅尔德伦[ 3 ] 是一种白色结晶固体，可以很容易地编写 缩合丙二酸和丙酮醋酸酐 在在场的情况下催化量的集中 硫酸[ 4 ] 。梅尔德伦*县酸显示几个 独特的功能。它有一个非常高的酸度[ 5 ] ;的 pKa值的梅尔德伦*县酸在DMSO是7.325 ，但那些dimedone 和二甲基丙二酸，相应的循环 二酮和环酯类似物，是15.87和 11月16日分别。 此外，它很容易受到攻击时电 碳五和亲核攻击的C4和C6 。此外，其 独特的开环反应，使它成为一个巨大的吸引力 和有益组成部分。合成应用 的梅尔德伦*县酸是主要侧重于反应 凡申请作为一种替代的环丙二 酯类，但也有许多例子报告 使用alkylidene结合的梅尔德伦*县酸 dienophiles在杂Diels - Alder反应。在大多数情况下 自发的或伴随后合成衍生 提高其综合利用率。涉及的MCRs 梅尔德伦*县酸一般保留独特的环状抓获 丙二酸成分，它可以释放损失的丙酮， 当反应，亲核试剂。这种反应往往是 伴随着部分脱。在这 各种方式的多样性要素可建成的不同 代谢清除率的产品。通常情况下，在适当的亲核试剂 近距离攻击可以intramolecularly循环安奈德 片段，导致独特的环系统，它可以 用于多样性导向合成（司） [ 6 ] 。 基于上述调查结果， MCRs涉及梅尔德伦 *县酸属于这些类别的情况下参加 一种多功能砌块的反应而不是 一个多元化控股的组成部分，因此，代谢清除率产品 还可以进一步衍生了大量的各种反应 导致不同的骨骼或chemotypes 。 相应的最初步骤和主要中间体 形成涉及梅尔德伦*县酸，可以在MCRs 分为不同的分组。在大多数情况下，无功 alkylidene梅尔德伦*县酸中间（一Knoevenagel反应 加合物）参加了各种继发反应。 这两个步骤的功能是体现在许多情况下，在 名称MCRs涉及梅尔德伦*县酸[骨牌Knoevenagel反应 -的Diels - Alder ，多米诺骨牌威蒂格- Knoevenagel反应- 的Diels - Alder ，修改Hantzsch反应， Yonemitsu反应 （多米诺骨牌Knoevenagel反应， Michael加成反应）等] 。在 上述大多数情况下梅尔德伦*县酸，浓缩第一 与羰基，可最终导致取代 丙酸延长分子。多米诺 Knoevenagel反应，异-环的一个独特 子类，因为这两个主要产品保留羧酸 组蒙面丙二酸成分。 一些MCRs不能明确划分，例如， 梅尔德伦*县酸反应不饱和羰基 化合物的Knoevenagel缩合反应和环关闭 其次是凝结。在其他情况下梅尔德伦 *县酸作为迈克尔捐助其高度酸性 美基的醛型反应。 在本minireview我们按照此分类 提供的一般说明和例子，每个子类。 |
4楼2009-03-29 04:02:44
5楼2009-03-29 04:03:09
