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


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Abstract

Hydrogen atom in position 6 of 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.

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