A tandem reaction in the synthesis of new 4,8-disubstituted-pyrimido[5,4-d]pyrimidine derivatives

Abstract

Pyrimido[5,4-d]pyrimidines are biologically important compounds with diverse activity depending on the substituent groups around the heterocycle. The 3,4-dihydropyrimido[5,4-d]pyrimidines are efficiently converted to the aromatic derivatives by Dimroth rearrangement promoted by reaction with piperidine, in a very slow process. Subsequently, the aromatic derivatives are converted to new 4,8-disubstituted-pyrimido[5,4-d]pyrimidine derivatives by reaction with aldehydes in an acidic medium. The 4,8-disubstituted-pyrimido[5,4-d]pyrimidines are also obtained much more efficiently by a tandem reaction between the 3,4-dihydropyrimido[5,4-d]pyrimidines, piperidine and a variety of aldehydes. The cascade reaction approach has a broad application since phenyl, haloaryl, alkoxy-aryl, hydroxy-aryl, and heteroaryl aldehydes are compatible with the reaction conditions. The reactions were studied by 1H NMR. These studies support the reaction mechanisms proposals. The tandem approach involves the formation of ionic reactive intermediates that allows explain this approach's efficiency.