Synthesis of novel fused tricyclic quinolones: 4a,5‐Dihydro‐1H‐[1;2,4]triazino[1,6‐a]quinoline‐2,4,6(3H)‐triones

Abstract

A versatile methodology to build the 1H-[1,2,4]triazino[1,6-a]quinoline-2,4,6(3H)-trione structure from methyl 6-fluoro4-oxo-1,4-dihydro-2-quinolinecarboxylate was developed. The method involves an N-amination followed by condensation of an aroyl isocyanate to form an alpha semicarbazidocarboxylate that readily cyclizes to the fused [1,2,4]triazino ring under ammonia/ethanol condition. Also, the reactivity of the [1,2,4]triazino ring thus obtained was studied. Among the different quinolones carboxylic families of antibacterial agents there is a series of potent tricyclic and tetracyclic compounds containing a three-or four-a t o m bridge connecting the N1-C8 vicinal positions of quinolones [1]. These series include oxolinic acid [2], tioxacin [3], flumequin [4], ofloxacin [5], and other different tricyclic quinolones, which contain a three-atom bridge connecting the C2 to either the N1 [6a-c] or the C3 [6d].So, we are interested in preparing novel fused tricyclic quinolones that are non carboxylic at the C3 position, and contain a four-atom bridge connecting the N1 with the C2

8‐Fluoro‐4‐hydroxy‐1H‐[1,2,4]triazino[4,5‐a]quinoline‐1,6(2H)‐dione: Synthesis and reactivity

“…Scheme 5 8-Fluoro-4-hydroxy-1H- [1,2,4]triazino [4,5-a]quinoline-1,6(2H)-dione Sep-Oct 2003 791 delocalised onto the oxygen atom at position-6 making it unreactive, due to conjugation of this lone pair with the π-bond of the hydrazone moiety of the tautomeric form Id (scheme 6), as described previously [3].…”

“…The nitrogen atom N2 can be selectively alkylated by a Michael addition and by a reaction with sodium hydride whereas a standard alkylation with potassium carbonate gave an N-and Oalkylated product (double alkylation). The structural modification within the triazino ring level in comparison with the 8-fluoro-1H- [1,2,4]triazino [1,6-a]quinoline-2,4,6(3H)trione I considerably alters the reactivity of the molecule toward the phosphorus oxychloride: in the case of the [1,2,4]triazino [1,6-a]quinoline-2,4,6(3H)-trione I, chlorination readily gave the dichloro compound [3], whereas for 8-fluoro-4-hydroxy-1H- [1,2,4]triazino [4,5-a]quinoline-1,6 (2H)-dione II, the chlorination occurred selectively at the more reactive carbonyl group at the 6-position. This result may be explained by extensive delocalisation of the lone pair from the nitrogen at the ring junction onto the oxygen atom in 6 position in case of compound II, which cannot occur in case of the 8-fluoro-1H- [1,2,4]triazino [1,6-a]quinoline-2,4,6(3H)-trione I because of the presence of the ring junction nitrogen atom within a hydrazino group.…”

“…The 8-fluoro-1H- [1,2,4]triazino [1,6-a]quinoline -2,4,6(3H)-trione I (Scheme 1), the first molecule of this class, was obtained from methyl 6-fluoro-4-oxo-1,4-dihydro-2-quinolinecarboxylate by an N-amination followed by a condensation of an aroyl isocyanate to form an alpha semicarbazido-carboxylate that readily cyclizes to give a fused [1,2,4] triazino ring upon treatment with ammonia/ethanol solution as described previously [3].…”