Effect of the Structure of 1- and 3-Methyl-5-fluoropyrimidin-4-ones on H-D Exchange in Position 6 under Conditions of Base Catalysis

Abstract

Hydrogen atom in position 6of 5-fluoro-1-methylpyrimidin-4(1H)-one and its 2-methylsulfanyl, 2methoxy and 2-butylamino derivatives is readily replaced by deuterium in 90% methanol-d4 at ~20°C under conditions of base catalysis. The rate of H-D exchange decreases in the series H, SMe > OMe >> NHBu. Isomeric 5-fluoro-3-methylpyrimidin-4-ones, as well as their 5-unsubstituted analogs, do not undergo H–D exchange. Ready deuterium exchange in 5-fluoro-1-methylpyrimidin-4-ones is explained by synergistic effect of the zwitterionic structure and 5fluorine atom on the C6-H acidity. The gain in energy due to this effect, expressed through the enthalpy of dissociation of the C6-H bond, is ~15 kcal/mol provided that effect of the medium is absent; the contribution of the 5-fluorine atom is 5.3-6.0 kcal/mol.