The different behavior of 4-amino-vs 4-hydroxypyridinones 7 and 8, respectively, towards hydroxylamine is rationalized with the aid of semi-empirical PM3 molecular orbital calculations including solvent effects. Four different mechanisms leading to either isoxazolo[4,3-c]pyridinones 9 or isoxazolo [4,5-c]pyridinones 10 are considered. Based on computed activation energies reaction of hydroxylamine via its oxygen atom as nucleophile is highly disfavored. For compound 7 a b-carbon addition of NH 2 OH at C-4 of the pyridinone accompanied by amine exchange and ring closure to 9 is by far the most feasible pathway. In contrast to 7, according to both NMR spectroscopy and molecular orbital [semi-empirical PM3 and hybrid density functional/Hartree-Fock (B3LYP/6-31G*)] calculations, 8 exists as a mixture of tautomers 8A (ca 20%) and (Z)-8B (ca 80%). Both tautomers of 8 are predicted to react with hydroxylamine at the hydroxyethylidene carbon atom [(Z)-8B] or acyl functionality (8A) to give hydroxyaminoethylidene compound 38 (oxime 23). Subsequent cyclization of either of these intermediates leads to compound 10.