Mechanistic Evidence for an α-Oxoketene Pathway in the Formation of β-Ketoamides/Esters via Meldrum's Acid Adducts

• Published in: Journal of the American Chemical Society 2004-10, Vol.126 (40), p.13002-13009
• Main Authors: Xu, Feng, Armstrong, Joseph D, Zhou, George X, Simmons, Bryon, Hughes, David, Ge, Zhihong, Grabowski, Edward J. J
• Format: Article
• Language: English
• Subjects: Chemistry; Exact sciences and technology; Kinetics and mechanisms; Organic chemistry; Reactivity and mechanisms
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja046488b

A practical, one-pot process for the preparation of β-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 Medrum's adduct 6 in real time. These studies, both in the presence and absence of nucleophiles, strongly suggest that formation of β-keto amides from acyl Meldrum's acids occurs via α-oxoketene species 2 and rule out other possible reaction pathways proposed in the literature, such as via protonated α-oxoketene intermediates 3 or nucleophilic addition−elimination pathways.