4- Amino-5-imidazolecarboxylic acid synthesis

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

In an effort to find a more efficient synthesis of purine analogues, Dang et al. have explored the inverse electron demand Diels-Alder reaction between 5-aminoimidazoles 86a-c and 1,3,5-triazines 87. Reaction of 5-amino-l-benzyl-4-imidazolecarboxylic acid 86a with 87 at 80 °C in DMF led to 9-benzyl-2,6-bis(ethoxycarbonyl)purine (88a) in 83% yield. 

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