Synthesis and reactivity of novel pyrrolo[2,3-d][1,2,3]triazine heterocycles and nucleosides. (1999)

Since only two derivatives of the pyrrolo[2,3-<italic>d</italic>][1,2,3]triazine ring system have been reported in the literature, we have prepared and explored the chemical reactivity of several members of this virtually unknown ring system including; the 7-benzyl-, the 7-(beta-D-ribofuranosyl)- and the 7-(2-deoxy-beta-D-ribofuranosyl)-derivatives. Our initial approach involved the N-1 substitution and ammonolysis of diethyl 2-nitropyffole-3,4dicarboxylate to give the diamide derivative. While arylmethyl and alkyl groups could be used in this two step procedure, diamide formation failed during the ammonolysis step when the N-1 of the pyrrole was unsubstituted or contained a glycosyl moiety. The N-1 unsubstituted derivative, 2-nitropyrrole-3,4-dicarboxamide, was obtained by a two step deprotection of 2-nitro-1-[2-(2-pyridyl)ethyl]pyrrole-3,4-dicarboxarnide. Glycosylation of 2-nitropyrrole-3,4-dicarboxamide, by the sodium-salt method, with 3,5-di-<italic>O</italic>-toluoyl-2deoxy-alpha-D-ribofuranosyl chloride gave good yields of the corresponding 2-deoxynucleoside as a mixture of anomers, which were separated. Reduction of the 2-nitro group of the beta-nucleoside followed by intramolecular diazo-coupling gave 1-[3,5-di-<italic>O</italic>-(<italic> p</italic>-toluoyl)-2-deoxy-beta-D-ribofuranosyllpyffolo[2,3-<italic> d</italic>][1,2,3]triazin-4-one-5-carboxamide. Conversion of this nucleoside to 4-(triazol-1-yl)-1-[3,5-di-<italic>O</italic>-(<italic>p</italic>-toluoyl)-2-deoxy-beta- D-ribofuranosyllpyrrolo[2,3-<italic>d</italic>][1,2,3]triazine-5-carbonitrile and a subsequent displacement of the 1,2,4-triazolyl group with methylhydrazine was followed by deprotection. of the acyl groups and ring closure under basic conditions to afford 3-amino-5-methyl-1-(2-deoxy-beta-D-ribofuranosyl)-1,5-dihydro-1,4,5,6,7,8 hexaazaacenapthalene. A similar glycosylation of 2-nitropyrrole-3,4-dicarboxamide with 2,3,5-tri-<italic>O</italic>-benzoyl-D-ribofuranosyI chloride gave exclusively the corresponding beta-nucleoside which was then transformed into 4-(triazol-1-yl)-1-(2,3,5-tri-<italic>O</italic>-benzoyl-beta- D-ribofuranosyl)pyrrolo[2,3-<italic>d</italic>][1,2,3]triazine-5-carbonitrile. Treatment of this nucleoside with ammonia in 1,4-dioxane resulted in a mixture of 4-amino-1-(2,3,5-tri-<italic>O</italic>-benzoyl-beta-D-ribofuranosyl)pyffolo[2,3-<italic> d</italic>][1,2,3]triazine-5-carbonitrile and 2-amino-l-(2,3,5-tri-<italic> O</italic>-benzoyl-beta-D-ribofuranosyl)pyrrole-3,4-dicarbonitrile. Treatment of the 4-aminopyrrolotriazine with KCN in methanol gave methyl-4-amino-l-(beta- D-ribofuranosyl)pyffolo[2,3-<italic>d</italic>] [1,2,3 ] triazine-5-form imidate. Functional group manipulations of the methyl imidate group gave various 5-substituted derivatives such as; the 5-carboxamide (2-azasangivamycin), the 5-carboxamidoxime, the 5-carboxamidrazone, and the 5-N-cyanoamidine. The 5-thiocarboxamide derivative (2-azathiosangivamycin) was prepared from 4-amino-1-(2,3,5-tri-<italic> O</italic>-benzoyl-beta-D-ribofuranosyl)pyrrolo[2,3-<italic> d</italic>][1,2,3]triazine-5-carbonitrile and then converted into the 5-carbonitrile derivative (2-azatoyocamycin). The 4-(triazol-1-yl) derivative was also converted into 3-amino-5-methyl-1-(beta-D-ribofuranosyl)-1,5-dihydro-1,4,5,6,7,8-hexaazaacenapthalene. Thermolysis of 4-amino-7-benzylpyrrolo[2,3-<italic>d</italic>][1,2,3]triazine-5-carbonitrile gave 2-amino-1-benzylpyrrole-3,4-dicarbonitrile. <super>15</super>N Labeling at the 4--NH<sub>2</sub> and N-3 position of 4-amino-7-benzylpyrrolo[2,3-<italic> d</italic>][1,2,3]triazine-5-carbonitrile gave a pyrrole, after thermolysis, that was consistent with a nitrogen extrusion mechanism that involved the loss of N-2 and N-3 from the pyrrolo[2,3,-<italic>d</italic>][1,2,3]triazine ring. Therefore, we have studied the synthesis and chemical reactivity of several novel N<super>1</super>-benzyl and N<super>1</super>-glycosyl derivatives of the pyrrolo[2,3-<italic>d</italic>][1,2,3]triazine and 1,4,5,6,7,8-hexaazaacenapthalene ring systems.