Fused quinoline heterocycles X. First synthesis of new four heterocyclic ring systems 10-amino-6,9-disubstituted-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-<i>c</i>]quinoline derivatives

<p>A novel, simple, and efficient synthetic methodology for the synthesis of hitherto unreported tetracyclic 10-amino-6,9-disubstituted-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-<i>c</i>]quinolines, in one step, has been developed by coupling of various active methylene compounds with diazotized heterocyclic amines. Reacting 2,4-dichloroquinoline-3-carbonitrile (<b>1</b>) with cyanoacetic acid hydrazide (<b>2</b>) in the presence of triethylamine in refluxing MeOH gave the unexpected 3-amino-4-chloro-1<i>H</i>-pyrazolo[4,3-<i>c</i>]quinoline (<b>4</b>), instead of the desired tetracyclic ring system <b>3</b> (<a href="#C0001" target="_blank">Scheme 1</a>). Refluxing <b>4</b> with excess of cyclic secondary amines <b>5a–c</b> in boiling dimethylformamide yielded the corresponding 4-amino-pyrazolo[4,3-<i>c</i>]quinolines <b>6a–c</b>. Diazotization of compounds <b>4</b> and <b>6a–c</b> with sodium nitrite and concentrated HCl at −5 °C gave the corresponding diazonium salts <b>17a–d</b>, which were then subjected to couple with different active methylene nitriles, namely, 2-cyanothioacetamide (<b>12</b>), ethyl cyanoacetate (<b>13</b>), malononitrile (<b>14</b>), 2-cyanoacetamide (<b>15</b>), and 2-cyano-<i>N</i>-phenylacetamide (<b>16</b>), in aqueous ethanol containing sodium acetate as a buffer solution. The coupling reaction of diazonium salts <b>17</b> with <b>12, 13</b>, and <b>14</b> leading to the novel perianellated tetracyclic ring system 10-amino-6,9-disubstituted-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-<i>c</i>]quinolines <b>19, 23</b>, and <b>27</b>, respectively, in one step, is described for the first time. On the other hand, coupling reaction of diazonium salt <b>17a</b> with both <b>15</b> and <b>16</b> yielded the previously unknown tetracyclic 10-amino-6-chloro-[1,2,4]triazino[4′,3′:1,5]pyrazolo[4,3-<i>c</i>]quinoline-9-carboxamides <b>28a</b> and <b>28b</b>, respectively (<a href="#C0006" target="_blank">Scheme 6</a>). No chromatographic techniques have been used for the purification of the products. The structures of all the newly synthesized compounds were unambiguously confirmed by spectroscopic and analytical techniques.