Kinetics and mechanism of the defluorination of 8-fluoropurine nucleosides in basic and acidic media

Abstract

For investigating the stability of C(8)–fluorine bond in 8-fluoropurine nucleosides some protected 8-fluoroguanosine, 8-fluoroinosine and 8-fluoroadenosine derivatives were prepared by direct fluorination of acetyl-protected purine nucleosides with elemental fluorine in solvents such as chloroform, acetonitrile and nitromethane. Fluorination reactions conducted in chloroform medium gave better yields of 8-fluoropurines. The fluorination yields were slightly lower when acetonitrile or nitromethane was used as solvent, but the product purification was found to be much easier. When the synthesized, protected fluoronucleosides were subjected to standard basic (NH 3 in methanol or 2-propanol) and acidic (HCl in methanol) deprotection conditions relevant to nucleoside chemistry, an efficient defluorination reaction took place. The kinetics of these defluorination reactions were conveniently followed, under pseudo-first-order reaction conditions, using 19F NMR spectroscopy. 1H NMR, LC–MS and mass spectroscopy identified the products of the kinetic reaction mixtures. The defluorination reaction rate constants ( k obs) in basic media depended upon the electron density at C(8) while the k obs data in acidic medium were determined by the p K a of N 7. An addition–elimination based mechanism (S NAr) has been proposed for the defluorination reactions of these 8-fluoropurine nucleosides.