Xu Feng, Armstrong Joseph D, Zhou George X, Simmons Bryon, Hughes David, Ge Zhihong, Grabowski Edward J J
Contribution from the Departments of Process Research and Analytical Research, Merck Research Laboratory, Rahway, NJ 07065, USA.
J Am Chem Soc. 2004 Oct 13;126(40):13002-9. doi: 10.1021/ja046488b.
A practical, one-pot process for the preparation of beta-keto amides via a three-component reaction, including Meldrum's acid, an amine, and a carboxylic acid, has been developed. Key to development of an efficient, high-yielding process was an in-depth understanding of the mechanism of the multistep process. Kinetic studies were carried out via online IR monitoring and subsequent principal component analysis which provided a means of profiling the concentration of both the anionic and free acid forms of the Meldrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of beta-keto amides from acyl Meldrum's acids occurs via alpha-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated alpha-oxoketene intermediates 3 or nucleophilic addition-elimination pathways.
已开发出一种实用的一锅法，通过包括丙二酸亚异丙酯、胺和羧酸的三组分反应制备β-酮酰胺。开发高效、高产率工艺的关键是深入了解多步反应的机理。通过在线红外监测和随后的主成分分析进行动力学研究，这提供了一种实时分析丙二酸加合物6的阴离子形式和游离酸形式浓度的方法。这些在有亲核试剂和无亲核试剂情况下的研究强烈表明，由酰基丙二酸形成β-酮酰胺是通过α-氧代乙烯酮物种2发生的，并排除了文献中提出的其他可能反应途径，如通过质子化的α-氧代乙烯酮中间体3或亲核加成-消除途径。
