Solid-Phase Synthesis of Dihydropyrimidones via N-Acyliminium Ion-Based α-Ureidoalkylations

The synthesis of 4-aryl-2-(thioxo)oxo-3,4-dihydropyrimidine-5-carboxylic acids is reported using two orthogonal solid-phase variations of the Biginelli condensation. In the first method, polymer-bound β-ketoesters are treated with aromatic aldehydes and urea under acidic conditions. The transient N-acyliminium ion that is initially formed from the aldehyde and urea precursors, is then intercepted by the resin-bound β-ketoesters. In an alternative approach, resin-bound β-ketoesters are condensed with aldehydes and O-methylisourea under basic conditions. Both orthogonal condensation procedures provide fair to excellent overall yields of the desired target structures.