Straightforward synthesis of biologically valuable nonsymmetrical malonamides under mild conditions

Abstract

Nonsymmetrical malonamides are often found in pharmacologically relevant molecules. A flexible and atom-economical method is developed for efficient preparation of nonsymmetrical malonamides from commercial or readily available isocyanates and β-ketoamides. These substrates deliver a series of nonsymmetrical malonamides in good to excellent yields via a MgCl₂-mediated nucleophilic addition/deacetylation sequence in the presence of a base in an alcoholic solvent. Salient merits of this chemistry include step-economy, ease of work-up, mild conditions, broad substrate scope, functional group tolerance and scalability. The high efficiency and practicability enabled rapid access to diverse precursors of malonamides for use in pharmaceuticals.