Synthesis and NMR studies of some imidazo[4,5‐d]pyridazine nucleosides

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Abstract
Unlike imidazo[4,5‐d]pyridazin‐4(5H)‐one (1a), which undergoes ribosylation at N‐6 in the Vorbruggen procedure for nucleoside synthesis, the 5‐benzyloxymethyl derivative 12 undergoes ribosylation at N‐1 and N‐3 to give a separable mixture of 14 and 15. Removal of the N‐5 blocking groups from 14 and 15 by treatment with boron trichloride at −78° affords the intermediates 16 and 17, which were debenzoylated to give the 4‐oxo nucleosides 5 and 6. Thiation of 16 and 17, followed by S‐methylation and ammonolysis leads to the 4‐amino nucleosides 2 and 3. The glycosylation sites of these nucleosides were assigned by using a combination of 1H and 13C nmr data, especially measurements of the spin‐lattice relaxation times (T1) of the base protons. Using these techniques, it is shown that a nucleoside previously reported to be 3 is in fact the N‐6 isomer.