title: The mechanism of selective purine C-nitration revealed: NMR studies demonstrate formation and radical rearrangement of an N7-nitramine intermediate.
abstract: 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.
authors.affiliation: Van't Hoff Institute for Molecular Sciences, Universiteit van Amsterdam, Nieuwe Achtergracht 129, NL-1018 WS Amsterdam, The Netherlands.
authors.forename: Boris
authors.initials: B
authors.lastname: Rodenko
authors.forename: Melle
authors.initials: M
authors.lastname: Koch
authors.forename: Alida M
authors.initials: AM
authors.lastname: van der Burg
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wanner
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Koomen
mesh_terms: D000089:Acetic Anhydrides; D000814:Aniline Compounds / Q000737:chemistry; D005463:Fluoroacetates; D009578:Nitrobenzenes / Q000737:chemistry; D009587:Nitrogen Isotopes; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D014269:Trifluoroacetic Acid / Q000737:chemistry
chemical_list: D000089:Acetic Anhydrides; D000814:Aniline Compounds; D005463:Fluoroacetates; D009578:Nitrobenzenes; D009587:Nitrogen Isotopes; D011687:Purines; D000644:Quaternary Ammonium Compounds; C017958:trifluoroacetic anhydride; C009405:tetrabutylammonium; D014269:Trifluoroacetic Acid; C015384:nitramine