A One-Pot Synthesis of Pyrido[2,3-d]- and Quinolino[2,3-d]pyrimidines

Abstract

The in situ formed methylene derivatives of 1,3-dicarbonyl compounds; ethyl cyanoacetate; malononitrile and ketones; react with 6-amino1,3-dimethyluracil as activated alkenyl derivatives, affording Michael adducts. The adduts simultaneously undergo cyclization to furnish pyrido[2,3-d]or quinolino[2,3-d]pyrimidine derivatives in high yield. Uracil and its annelated substrates occupy a unique place in the field of medicinal chemistry as useful anticancer and antiviral drugs. Besides, the discoveries of many pyrido[2,3-d]pyrimidine derivatives with potential antitumor, anti-inflammatory and CNS depressant activities, have stimulated considerable interest in the synthesis of pyrido[2,3-d]pyrimidines via new and efficient routes. Many strategies have been developed for the preparation of these compounds. One of the major routes involves the reaction of 6-aminouracil with cyanolefins. An alternative route involves the condensation of 6amino-1,3-dimethyluracil-5-carboxaldehyde with active methylene compounds. Herein we wish to disclose a simple straightforward, three-component heteroannulation reaction that converts 6-aminouracil into pyrido[2,3-d]or quinolino[2,3-d]pyrimidines in high yield. The reaction of active methylene compounds with formaldehyde has been reported to afford in situ the corresponding ylidene derivatives and thus can be considered as synthetic equivalent of these intermediates. The reaction of these reactive synthons with heterocyclic enamines has not been reported. 6-Aminouracils have been reported to behave as heterocyclic enamines and undergo Michael addition with different activated olefins and acetylenes, followed by cyclization to afford annelated heterocycles. We have found that a 2: 2: 1 mixture of active methylene compounds (1a-e); formaldehyde and 6-amino-1,3-dimethyluracil (2), reacts in refluxing ethanol containing a catalytic amount of piperidine to give the annelated pyrimidine derivatives (4a-e) in 91-73 % yield. However, bis(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimid-5-yl)methane (5) was detected in a minute amount and was separated easily by fractional crystallization (lit., mp > 300 C). Moreover, the reaction tolerates cyclic active methylene compounds. Thus, the reaction of indane-1,3-dione or dimedone with formaldehyde and 2 affords the indenopyridopyrimidine derivative (6) and quinolinopyrimidine derivative (7) in 69% and 81%yields, respectively.