Synthesis of 2,6-Dialkyl(aryl)purine Nucleosides by Exploiting the Reactivity of NebularineN1-Oxide towards Grignard Reagents

The synthesis of 2,6-dialkyl(aryl)purine nucleosides by appli- cation of a double addition of Grignard reagents to N1-oxide purine nucleosides is described. The synthetic protocol ex- ploits the reactivity of both the C6–N1–O– and C2–N1–O– moieties of the purine base. The overall process consists of initial Grignard reagent addition to the C6 of nebularine N1-oxide followed by aromatization to give a C6-substituted nu- cleoside. Regeneration of the N1-oxide is then followed by a second Grignard addition at C2 causing the opening of the pyrimidine ring. Cyclization of the transiently opened pyrim- idine is then driven by aromatization of the system to afford the final purine system.