Dihydropyrimidinones, formation

An alternative solution to the workup issue relied on the attachment of CH-acidic compounds 64 to a soluble polymer support (PEG-4000). The approach improved the yields of the dihydropyrimidinones 66 by the use of a 2-fold excess of other components—urea and aldehyde in the microwave-assisted solvent-free cyclocondensation [118]. Another single-step approach towards 4,5-disubstituted pyrimidines was based on cyclocondensation of a variety of aromatic, heterocyclic and aliphatic ketones, formamide and HMDS as the ammonium source [119]. The high temperature (215 °C) required to effect the formation of pyrimidines was secured by microwave dielectric heating in sealed vessels (Scheme 45). 

In a typical general experimental procedure by using traditional conditions, a solution of a-dicaibonyl compound, an aldeltyde, and urea in ethanol was heated under reflux in the presence of a catalytic amount of CeCl3.7H20 (25 mol%) for a certain period of time required to complete the reaction (TLC), resulting in the formation of dihydropyrimidinone derivatives. The reaction mixture was then poured into crashed ice and the solid product separated was filtered and reciystallized. 

In the mechanism of the Biginelli synthesis [265], the rate-determining step is the acid-catalyzed formation of an acylimine 35 from aldehyde and urea. By N-protonation (or metal-N-coordination), the imine 35 is activated (as an iminium ion) and intercepted by the P-ketoester (as enol or metal enolate) to give rise to an open-chain ureide 36, which subsequently cyclizes (via the cyclic ureide 37 and its dehydration) to afford the dihydropyrimidinone 33. Biginelli compounds of type 33 have been synthesized independently in multistep sequences [266]. 

Biginelli reaction (combining ArCHO, MeCOCH2COEt, and urea) has been catalysed by a combination of a chiral bifunctional primary amine-pyridine and HCl in dioxane/CHCl3 to form dihydropyrimidines with up to 99% ee Lewis-acid-promoted formations of dihydropyrimidinones via Biginelli reactions catalysed by imidazolium-based ionic liquids have been found by NMR, ESI-MS, and theoretical studies to proceed via stabilized charged intermediates. ... 

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