Microwave-Assisted Biginelli Synthesis of Dihydropyrimidine-2-ones

Significance

An efficient two-step microwave-assisted synthesis of 5-aroyl-3,4-dihydropyrimidin-2-ones (DHPMs) is reported. A trimethylsilyl chloride mediated Biginelli reaction is followed by a Pd-catalyzed Liebeskind-Srogl ketone synthesis. The advantages of this method are the commercial availability of the building blocks, the use of Pd catalysis rather than the previously applied expensive Yb(OTf)₃, and the short reaction times owing to microwave assistance. The use of TMSCl (33 mol%) as a Lewis acid mediator allows the preparation of N1-alkyl substituted DHPMs. Previously, Zhu and co-workers (Y. Zhu, Y. S. Pan, S. Huang Synth. Commun. 2004, 34, 3167) used stoichiometric amounts of TMSCl in a similar approach to unsubstituted pyrimidinones. The Liebeskind-Srogl ketone synthesis represents a recent Pd-catalyzed carbon-carbon cross-coupling of phenyl boronic acid with thioesters under neutral conditions (L. S. Liebeskind, J. Srogl Org. Lett. 2002, 4, 979). The cross-coupling reaction is not air-sensitive and tolerates a broad range of substituents.