Pyrimidines Knoevenagel reaction

Less common are literature examples in which mechanochemical reaction was carried out at elevated temperature. Naimi-Jamal reported the heating of double-walled ball-mill beaker equipped with fittings for circulating water at 96°C (boiling water as circulant) [45]. One-pot solvent-free synthesis of pyrano[2,3-d]pyrimidine-2,4(lFf,3F0-diones 154 was achieved by simply ball milling a stioichiometric mixture of an aromatic aldehyde, malononitrile, and barbituric acid, without addition of solvent and catalyst (Scheme 2.53). Quantitative yields were obtained (Table 2.47) and products generally did not require purification, the solid products were just dried at 80°C in vacuum and recrystaUized, if necessary. Reaction presumably takes place by initial Knoevenagel condensation of aromatic aldehyde with malononitrile to afford the intermediate Michael acceptor, which subsequently reacts with barbituric acid. Tautomerization of Michael adduct is followed by intramolecular cyclocondensation and another tautomerization to afford pyrano[2,3-d]pyrimidine-2,4(177,37f)-diones 154. 

An efficient approach to pyrido[2,3-if pyrimidines 171 was reported by Singh et al. in 2011 [72]. The Knoevenagel condensation is catalyzed by L-proUne 170 in refluxing ethanol to give an ori/io-iminemethide intermediate, which forms the desired products by subsequent HDA reaction in moderate to good yields (46-88%) (Scheme 13.41). 

S. Samai, G. Chandra Nandi, S. Chowdhury, M. S. Singh, Tetrahedron 2011, 67, 5935-5941. L-Proline catalyzed synthesis of densely functionalized pyrido[2,3-d]pyrimidines via three-component one-pot domino Knoevenagel aza-Diels-Alder reaction. 

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