An environmentally benign and efficient method has been developed for the synthesis of a series of benzo[4,5]imidazo[1,2-a]pyrimido[4,5-d]pyrimidin-4(1H)-one derivatives in aqueous media under catalyst-free conditions by simply combining 2-aminobenzimidazole, aldehyde, and cyanoacetamide. The advantages of this method are that it is catalyst-free, has an easy workup, provides excellent yields, and uses water as the solvent which is considered to be relatively environmentally benign.