SYNTHESIS OF 3,4-DIHYDRO-2(1H)-PYRIMIDINONES AND MECHANISM OF BIGINELLI REACTION
SYNTHESIS OF 3,4-DIHYDRO-2(1H)-PYRIMIDINONES AND MECHANISM OF BIGINELLI REACTION
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DOI：
10.1021/ja00807a040
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发表时间：
1973-01-01
影响因子：
15
通讯作者：
FISSEKIS, JD
中科院分区：
文献类型：
--
作者：
SWEET, F;FISSEKIS, JD
本文研究了酸催化合成取代的3，4-二氢-2（1H）-嘧啶酮的反应。3-甲氧基丙烯酸酯与尿素和一甲基尿素缩合的主要产物是5-甲氧羰基-4-羧甲基-3，4-二氢-2（IH）-嘧啶酮及其N-甲基衍生物。脱羧衍生物5-甲氧羰基-4-甲基-3，4-二氢-2（1H）-嘧啶酮和5-甲氧羰基-1，4-二甲基-3，4-二氢-2（1H）-嘧啶酮是同一反应的次要产物。syw-二甲基脲生成5-甲氧羰基-3，4-二氢-1，3，4-三甲基-2（1H）-嘧啶酮和1，3-二甲基尿嘧啶，产率均较低。这些反应的一个integratedmechanism提出涉及初步的酸催化羟醛缩合和随后的反应的碳正离子形成的羟醛中间体。在5-甲氧羰基-4-羧甲基-3，4-二氢-2（1H）-嘧啶酮中，C-4取代基上的羧基与N-3基团之间可能通过氢键发生相互作用。它对相同羧基的酯的水解的影响已经被证明。2-二甲氧基甲基-3-甲氧基丙酸甲酯与脲的反应也产生5-甲氧羰基-3，4-二氢-2（IH）-嘧啶酮。这些冷凝的方向的影响因素被认为是。它的结论是，更多的亲核性的两个氮在取代的脲反应首先通过取代质子化的烷氧基，这是通过一个烯醇-烯丙基系统来自醛功能激活。通过游离的酰脲氮与醛基的反应完成环化成3，4-二氢-2（1H）-嘧啶酮。2-二甲氧基甲基-3-甲氧基-1-丙醇和2-羟甲基-1，1，3，3-四甲氧基丙烷与脲的缩合反应的结果与所提出的烯丙基中心与醛官能团相比的增强反应性和必然的碳正离子机理一致。该机理也适用于Biginelli嘧啶合成，其中限制步骤现在被认为是产生反应单元所需的原位羟醛缩合，该反应单元与脲缩合得到相应的3，4-二氢-2（IH）-嘧啶酮。这里提出的Biginelli合成的机制解释了以前被认为是“异常”的反应过程。
The acid-catalyzedsynthesis of substituted 3, 4-dihydro-2 (l//)-pyrimidinones from a variety of pre-cursors was studied. The major products of the condensation of 3-methoxyacrylate with urea and monomethyl-urea are 5-carbomethoxy-4-carboxymethyl-3, 4-dihydro-2 (l//)-pyrimidinone and its Nl methyl derivative. The decarboxylated derivatives, 5-carbomethoxy-4-methyl-3, 4-dihydro-2 (l//)-pyrimidinone and 5-carbomethoxy-l, 4-dimethyl-3, 4-dihydro-2 (1//j-pyrimidinone, are minor products of the same reaction. syw-Dimethylurea produces 5-carbomethoxy-3, 4-dihydro-l, 3, 4-trimethyl-2 (l//)-pyrimidinone and 1, 3-dimethyluracil, bothin small yield. An integratedmechanism for these reactions is proposed involving a preliminary acid-catalyzed aldol condensation and subsequent reactions of a carbonium ion formed from the aldol intermediate. An interaction, probably through hydrogen bonding, is shown to occur between the carboxylic group on the substituent at C-4 and the N-3 group in 5-carbomethoxy-4-carboxymethyl-3, 4-dihydro-2 (l//)-pyrimidinone. Its effect upon the hydrolysis of an ester of the same carboxylic group has been demonstrated. The reaction of methyl 2-dimethoxymethyl-3-methoxypropionate with ureas also produces 5-carbomethoxy-3, 4-dihydro-2 (l//)-pyrimidinones. Factors influencing the orientation of these condensations are considered. It is concluded that the more nucleophilic of the twonitrogens in a substituted urea reacts first by displacing the protonated alkoxy group, which is activated through an enol-allyl system derived from the aldehyde function. Cyclization tothe 3, 4-dihydro-2 (l//)-pyrimidinone is completed by re-action of the free ureide nitrogen with the aldehyde group. The results of the condensations of 2-dimethoxymethyl-3-methoxy-l-propanol and 2-hydroxymethyl-1, 1, 3, 3-tetramethoxypropane with ureas are consistent with the proposed enhanced reactivity of an allylic center as compared to an aldehyde function and with the corollary carbonium ion mechanism. This mechanismalso applies to the Biginelli pyrimidine synthesis in which the limiting step is now considered to be an in situ aldol condensation required to produce the reactive unit which condenses with a urea to give the corresponding3, 4-dihydro-2 (l//)-pyrimidinone. The mechanism proposed here for the Biginelli synthesis explains the course of reactions which had previously been considered “anomalous.”