Isocyanates 3-aminocrotonates

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

A number of alternative preparations of Biginelli-type compounds and similar dihydropyrimidines have been described. A route to N-l-substituted compounds 27, which are difficult to make by the standard Biginelli reaction, involved reaction of an a-chlorobenzyl isocyanate with A-substituted aminocrotonates <06SL375>. 

Phenyluracils with alkyl groups substituted in the 5- and 6-positions, such as (L), are reported to have analgesic and antipyretic activity [376, 377]. The 1-position may also be alkylated. Such compounds are prepared by the treatment of a-alkyl-/3-aminocrotonates with phenyl isocyanate. When the 5-substituent is an isopropyl group, the resulting compound is a sodiuretic without increase in potassium excretion. 

According to Bucha et al. (1962), the synthesis of isocil is effected by reacting isopropyl isocyanate with methyl 3-aminocrotonate to form methyl 3-(3-butyIureido)crotonate, which is cyclised without isolation by heating in 6% sodium hydroxide. The uracil is then precipitated by acidification and brominated to give the end-product. 

N-l Substituted DHPMs 22 (Scheme 9) have also been obtained through a two-step regioselective cyclocondensation of a-chlorobenzyl isocyanates with ethyl N-substituted-p-aminocrotonates 21 (R = alkyl/ aryl) (06SL375, 07S835). This methodology is further extended to synthesize N1-C6 linked bicyclic DHPM derivatives (07S835). 

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