Barbituric acid ring synthesis

Wang et al. [56] developed a one-pot iodine-catalyzed synthesis of benzo[/] pyrimido[4,5-6]quinoline derivatives 29 via a three-component reaction of benzal-dehydes, naphthalen-2-amine, and barbituric acid at room temperature in aqueous media (Scheme 10.22). The reaction was carried out in water at room temperature to avoid a ring-opening reaction. It was observed that no reaction occurred without using the catalyst. Then, reaction was attempted by changing the mol% of I2. The results showed that 5 mol% at room temperature in water was sufficient to push the reaction forward. Increas loading of the catalyst did not improve the yield to a great extent. 

For many years the mainstay of the clinician s armamentarium in the area of h) pnodcs and anxiolytics were the barbiturates. These compounds are essentially derivatives of barbituric acid, with the clinically used compounds often possessing dual substitution at the 5 position of the ring. Barbituric acid (Fig. 13.10) has no biological activity itself and it was only with the synthesis of barbital (Fig. 13.10) that the hypnotic/anxiolytic activity was observed. 

The barbiturates were widely used as sedative-hypnotic drugs. Barbital was introduced as a drug in 1903. The method of synthesis for thousands of its analogs has undergone little change. Urea reacts with various derivatives of malonic acid, usually a diethyl ester of a dialkyl substituted malonic acid. This is a classic example of a nucleophilic acyl substitution. A derivative of ammonia reacts with esters to form an amide, only in this case a cyclization to a strainless six-membered ring results because of the proximity of the bifunctionality. 

Labeling of phenobarbital, a barbiturate used in the treatment of convulsions, was carried out by acylation of p-aminophenobarbital 15 by the acid chloride of cymantrene 11 (Scheme 8.8). Synthesis of 15 was performed by nitration of the benzene ring of phenobarbital [35] to give a mixture of m- andp-nitrophenobarbital 13 and 14 followed by reduction of p-nitrophenobarbital by hydrogenation in the presence of palladium on charcoal [36]. 

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