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

Abstract

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.

Thermal Decomposition of Carbamoyl Meldrum's Acids: A Starting Point for the Preparation of 1,3‐Oxazine Derivatives

“…The formation of 3 may occur in two ways (Scheme ). First is by a direct attack of aldimine on the carbonyl carbon in the Meldrum's acid derivative 1 before the loss of acetone and CO 2 (path A) similarly to the “direct acylation pathway” proposed by Fillion for acylation with quaternized Meldrum's acid; however, this is in contrast with findings of Grabowski . The second possibility for forming 3 is the initial partial decomposition of 1 with a loss of acetone and reaction of 3‐oxo‐2‐carboxyketenes ( 4 ) with aldimine (path B).…”

Natural products as inspiration for the development of asymmetric catalysis

“…Thus, phenylacetic acid derivative 1 was converted into β-ketoamide 3 in a one pot procedure via acylation of Meldrum's acid, followed by treatment with triazole salt 2 (Figure 2). 38 Exposure to ammonium acetate converted this into β-enamino amide 4 as a single enamine isomer. Hydrogenation of 4 in the presence of 0.30 mol% of rhodium(I) and ligand 5 provided β-amino amide 7 in >95% conversion and 95% enantiomeric excess (ee).…”

Syntheses of Xanthofulvin and Vinaxanthone, Natural Products Enabling Spinal Cord Regeneration

“…Conversion of enaminone 19 to triketone 21 was achieved by treatment of 19 with 5-acetyl Meldrums acid (20) in toluene heated to reflux, yielding protected 5,6-dehydropolivione (21) in 42 % yield. [16] Simultaneous cleavage of the tertbutyl ester, pivaloyl, and methoxymethyl groups with boron trichloride in dichloromethane at 23 8C provided 5,6-dehydropolivione (6) in 96 % yield.…”