A Reexamination of the Mechanism of the Biginelli Dihydropyrimidine Synthesis. Support for an N-Acyliminium Ion Intermediate1

Abstract

The mechansim of the three-component Biginelli dihydropyrimidine synthesis was reinvestigated using ¹H and ¹³C NMR spectroscopy. Condensation of benzaldehyde, ethyl acetoacetate, and urea (or N-methylurea) in CD₃OH according to the procedure described by Biginelli produced the expected 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates. According to NMR measurements, there is no evidence that the first step in the Biginelli reaction is an acid-catalyzed aldol reaction of ethyl acetoacetate and benzaldehyde leading to a carbenium ion intermediate, as has been suggested previously. In contrast, all experimental evidence points to a mechanism involving an N-acyliminium ion as the key intermediate, formed by acid-catalyzed condensation of benzaldehyde and urea (or N-methylurea). Interception of this iminium ion by ethyl acetoacetate produces open-chain ureides which subsequently cyclize to the Biginelli dihydropyrimidines.