Pyrrolotriazines as Potential Inhibitors of Dihydrofolic Reductase

  • John R. Traynor

Student thesis: Doctoral ThesisDoctor of Philosophy


The chemistry of the known pyrrolotriazines is reviewed and the biochemical reasons for the synthesis of such systems are discussed,
The work described in this thesis is concerned with the preparation and properties of pyrrolo[1,2-a |[1,3,5] triazines and the attempted preparation of pyrrolo 2,1-f]/ 1,2,4] triazines. The synthesis of the pyrrold 1,2-a]/ 1,3,5] triazine system was approached by two main routes.
(i) From 1,3,5-triazines: The preparation and properties of various 1,3,5-triazines are discussed, together with their suitebility, as potential precursors, of the bicyclic system. Special reference is made to the high carbonyl stretching vibrational bands found in the infra-red spectra of the 1,3,5-triazin-2,4(1H,3H)- diones. The structures of 6-dicarbethoxymethyl-1,3,5-triazin- 2,4(1H,3H)-dione and 2,4,6-tris(dicarbethoxymethy1)-1,3,5- triazine are re-assigned, on the basis of spectroscopic evidence, as 6(1H)-dicarbethoxymethylene-1,3,5-triazin-2,4 (3H,5H)-dione and 2,4,6(1H,3H,5H)-tris(dicarbethoxymethylene)- 1,3,5-triazine, respectively. Reaction of 6-methyl- and 6-benzyl-1,3,5-triazin-2,4 (1H,3H)-dione with ethyl bromopyruvate gave ethyl pyrrolo [1,2-a ][1,3,5] triazin-2,4(1H,3H)-dione-7-carboxylate and ethyl 8-phenylpyrrolo[1,2-a [1,3,5] triazin-2,4(1H,3H)-dione7- carboxylate respectively. Difficulties were experienced when other a-halogeno-ketones were used in the above reaction. The potassium salt of 6-methyl-1,3,5-triazin-2,4(1H,3H)- dione and phenacyl bromide afforded 6-methyl-1,3,5-triazin- 2,4(1H,3H)-dione and 6-methyl-1,3-diphenacyl-1,3,5-triazin- 2,4(1H,3H)-dione as the major products. The latter compound, on treatment with acetic anhydride, gave 3-phenacyl-7-phenylpyrrolo[ 1,2-a ][1,3,5] triazin-2,4(11,3H)-dione. Plausible mechanisms for, and the limitations of, the above reactions are discussed. Bromination of ethyl 1,3-dimethylpyrrolof 1,2-a][1,3,5] triazin-2,4(1H,3H)-dione-7-carboxylate afforded a mixture of the 8-bromo-, and 6,8-dibromo-derivatives.
(ii) From 2-aminopyrroles
2-Aminopyrroles, containing electron-withdrawing groups in positions 3 and 4, and alkyl (or aryl) isocyanates afforded 3,7,8-trisubstitutedpyrrolo| 1,2-a]] 1,3,5] triazin- 2,4(1H,3H)-diones. A possible mechanism for, and the limitations of, the reaction are discussed and 1l-alkyl (or aryl)-3(3,4-disubstitutedpyrrol-2-yl)ureas are shown to be intermediates. The spectroscopic properties of the pyrrolo 1,2-a] [1,3,5] triazin-2,4(1H,3H)-diones are discussed.
The synthesis of the pyrrolo[ 2, 1-f] [1,2,4] triazines was attempted by an extension of the Tschitschibabin indolizine synthesis. Alkyl- and arylalkyl-1,2,4-triazines form quaternary salts with methyl iodide. Reaction of 3-amino- 5,6-dimethyl-1,2,4-triazine with ethyl bromopyruvate gave diethyl 4-methylpyrrolo{2,1-f] imidazo[1’,2’ -b][1,2,4] triazine- 2,7-dicarboxylate or the isomeric diethyl 4-methylpyrrolo [1,2-d] imidazo[1',2’-b][ 1,2,4] triazine-2,8-dicarboxylate. Both of these compounds are derivatives of previously unreported ring systems, although which isomer was present is unconfirmed.
The mass spectra of most of the compounds mentioned in the thesis are discussed and possible fragmentation patterns are suggested.
Date of Award1973
Original languageEnglish


  • Pyrrolotriazines
  • potential inhibitors
  • dihydrofolic reductase

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