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.