Effect of substituents on the formation of isomeric isoxazolo heterocycles: rationalization by semi-empirical PM3 molecular orbital calculations

The different behavior of 4-amino- vs 4-hydroxypyridinones 7 and 8, respect ively, towards hydroxylamine is rationalized with the aid of semi-empirical PM3 molecular orbital calculations including solvent effects. Four differe nt 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 disf avored. For compound 7 a beta-carbon addition of NH2OH at C-4 of the pyridi none 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/Hartre e-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 wi th hydroxylamine at the hydroxyethylidene carbon atom [(Z)-8B] or acyl func tionality (8A) to give hydroxyaminoethylidene compound 38 (oxime 23). Subse quent cyclization of either of these intermediates leads to compound 10. Co pyright (C) 1999 John Wiley & Sons, Ltd.