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The reduction of 1-methyl-, 3-methyl- and 1,3-dimethyl-5-nitrouracil (Ia-c) to the corresponding 5-aminouracils (IIa-c) is described. Diazotization of 5-amino-1-methyluracil (IIa) and 5-amino-1,3-dimethyluracil (IIc) gave 5-diazouracils which were characterized as thermally stable C6 covalent hydrates (III and XIII). Diazotization of 5-amino-3-methyluracil (IIb) gave anhydro 5-diazo-3-methyluracil (X) which underwent covalent methanolation and thermally reversible covalent hydration. Treatment of III and XIII with hot methanol resulted in solvent exchange of the C6 hydroxyl groups by a mechanism which may involve initial formation of diazoethers. Treatment of the methanolates (IV, XI and XIV) with dimethylamine resulted in coupling at the diazo group with a concomitant expulsion of the C6 methoxyl groups to give 5-(3,3-dimethyl-1-triazeno)uracils (XVa-c).

Tiopinac (1) [6, 11-dihydro-11-oxodibenzo[b,e]thiepin-3-acetic acid, (1)] has shown a high degree of antiinflammatory activity and a low incidence of side effects in animals (2). On the basis of these results, Tiopinac was chosen for human evaluation in 1978 (2a).

The thermolysis of 5-diazo-6-methoxy-1-methyl-1,6-dihydrouracil (1) has afforded methyl N-(1-methyl-1,2,3-triazol-4-oyl)carbamate (2), bis-(1-methyl-1,2,3-triazol-4-oyl)amine (3) and di-methylcarbimate (4). The reaction was shown to proceed with the initial formation of 2 followed by a subsequent disproportionation of 2 to give 3 and 4. A similar thermolysis of 5-diazo-6-ethoxy-1-methyl-1,6-dihydrouracil (9) gave ethyl N-(1-methyl-1,2,3-triazol-4-oyl)car-bamate (10) as the sole product. Double labeling experiments have indicated that a major pathway for these reactions involves an intermolecular transfer of the C-6 substituent to the C-2 position.

The structure of 5-diazouracil and several closely related derivatives have been revised on the basis of pmr spectroscopy. 5-Diazouracil, 5-diazouracil hydrate, 5-diazouracil methanol adduct, 5-diazouridine and 5-diazo-2′-deoxyuridine have been reassigned the structures 5-diazopyrimidin-2,4(3H)dione (XI), 5-diazo-6-hydroxy-1,6-dihydropyrimidin-2,4(1H,3H,6H)dione (XIII), 5-diazo-6-methoxy-1,6-dihydropyrimidin-2,4(1H,3H,6H)dione (XII), 1 -(β-D-ribofuranosyl)-O5′ -6(S)cyclo-5-diazo-1,6-dihydropyrimidin-2,4(3H,6H)dione (XVII) and 1-(2-deoxy-β-D-ribofuranosyl)-O5′ -6(S)cyclo-5-diazo-1,6-dihydropyrimidin-2,4(3H,6H)dione (XIX), respectively. Treatment of XII with dimethylamine resulted in a coupling of the 5-diazo group with dimethylamine and a concomitant rearomatization of the heterocyclic ring by expulsion of the 6-methoxy group to furnish 5-(3,3-dimethyl-1-triazeno)uracil (XIV). A similar reaction of XIX and XVII with dimethylamine furnished the corresponding 5-(3,3-dimethyl-1-triazeno)derivatives. The effect which certain resonance hybrids of the diazo moiety may exert in reactions of the above hetero-cycles and the assignment of S configuration at C-6 for the nucleoside derivatives is also discussed.