The mechanism of selective purine C-nitration revealed: NMR studies demonstrate formation and radical rearrangement of an N7-nitramine intermediate.

Modified purine derivatives are of great importance in biomedical sciences, and substitution reactions on the purine skeleton are intensively studied. In our laboratory, an efficient and selective purine C2-nitration reaction was developed using a mixture of tetrabutylammonium nitrate and trifluoroacetic anhydride. The resulting 2-nitro moiety appeared to be a versatile handle to introduce a variety of pharmacophores onto the purine skeleton. Since the mechanism of this selective purine C2-nitration reaction has remained unclear, we now present an extensive NMR study leading to its elucidation, using N9-Boc-protected 6-chloropurine as a model compound. Direct electrophilic aromatic nitration of the highly electron-deficient C2 position was excluded, and we demonstrate that this reaction occurs in a three-step process. Electrophilic attack by trifluoroacetyl nitrate on the purine N7 position results in a nitrammonium species that is trapped by a trifluoroacetate anion furnishing N7-nitramine intermediate 11. This intermediate was characterized at -50 degrees C by (1)H, (13)C, (15)N, and (19)F NMR. At T > -40 degrees C, the N7-nitramine intermediate undergoes a nitramine rearrangement, which generates a C2-nitro species that immediately eliminates TFA to give 2-nitro-6-chloro-9-Boc purine 10. The involvement of radicals during the nitramine rearrangement was unequivocally established by (15)N-CIDNP. Moreover, the emission signal observed for the rearranged product, 2-nitropurine 10, showed that it is primarily formed in an intermolecular process. A quantitative radical trapping experiment finally disclosed that 65-70% of the nitramine rearrangement takes place intermolecularly.