Synthesis of 2,6‐Dialkyl(aryl)purine Nucleosides by Exploiting the Reactivity of Nebularine N1‐Oxide towards Grignard Reagents

Abstract

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

Applications of Purine Ring Opening in the Synthesis of Imidazole, Pyrimidine, and New Purine Derivatives

“…This process can be accelerated with Ac 2 O/Py. [136] If peroxide is added, the ring expansion products 164 are obtained in high yields (Scheme 26). [137] 1,3-Cycloaddition between dimethyl acetylenedicarboxylate (166) and nebularine N-1-oxide 165 led to both purine ring opening (path A) and ring expansion (path B) of the pyrimidine ring, producing a mixture of products 170 and 173.…”

“…Intermediates 162 are unstable and slowly decompose to the 2,6‐disubstitued purines 163 . This process can be accelerated with Ac 2 O/Py [136] . If peroxide is added, the ring expansion products 164 are obtained in high yields (Scheme 26).…”

“…accelerated with Ac 2 O/Py. [136] If peroxide is added, the ring expansion products 164 are obtained in high yields (Scheme 26). [137] 1,3-Cycloaddition between dimethyl acetylenedicarboxylate (166) ).…”

Recent Progress in Non‐Catalytic C–H Functionalization of Heterocyclic N‐Oxides

“…As C‐nucleophiles, it is possible to use independently prepared organolithium [ 61–67 ] and organomagnesium [ 68–72 ] compounds.…”

Direct Regioselective C-H Cyanation of Purines

“…As is generally known, purine consists of an electron-deficient pyrimidine and an electron-rich imidazole partner ( Scheme 1 d). In other previous work and our own work, when purines were exposed to nucleophilic reagents such as Grignard reagents [ 17 , 18 , 19 , 20 ] and nucleophilic radical agents (Minisci reaction) [ 21 , 22 , 23 , 24 , 25 , 26 ], the regioselectivity of the reaction predominantly lay at the electron-deficient 6-position [ 12 , 13 , 14 , 15 , 16 ]. In contrast, when the electrophilic bromine was introduced, a C 8 -brominated purine derivative was obtained ( Scheme 1 c).…”