The Synthesis of BicyclicN4-Amino-2′-deoxycytidine Derivatives

Abstract

Nucleosides which have ambivalent tautomeric properties have value in a variety of nucleic acid hybridization applications, and as mutagenic agents. We describe here synthetic studies directed to stable derivatives of this kind of nucleoside based on N4-aminocytosine. Treatment of the 4-(1H-1,2,4-triazol-1-yl)-5-(chloroethyl)pyrimidinone nucleoside derivative 5 with hydrazine leads to formation of the 6,6-bicyclic pyrimido-pyridazin-7-one 3, and with methylhydrazine to the corresponding fixed tautomeric 1-methyl derivative 7 (Scheme 1). If these cyclization reactions are carried out in the presence of a base, the 6-ring bicyclic derivatives undergo rearrangement to their corresponding 5-ring pyrrolo-pyrimidin-2-one analogues 8 (Scheme 2). In the reaction of the triazolyl derivative 5 with 1-[(benzyloxy)carbonyl]-1-methylhydrazine, spontaneous cyclization gives the 5-ring derivative 13 related to 8 rather than the open-chain product 12 (Scheme 4). Reaction of an acetylated analogue of triazolyl derivative 5 with 1,1-dimethylhydrazine gives rise to some of the open-chain product 9, but it too cyclizes to a product that we have assigned the structure of the 6,6-ring quaternary ammonium salt 11 (Scheme 3).