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

Unlike imidazo4,5-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.