Stereoselective conversion of 2H-1,4-oxazin-2-ones into 2,5,5-substituted viveridine-2-carboxamides and 2-methanamines and related octahydro-2H-pyrido[1,2-a]pyrazines, potential substance P antagonists
4-(Hetero)aryl-2-oxa-5-azabicyclo[2.2.2] octan-3-ones and 3,6-diones, formed via cycloaddition of 2H-1,4-oxazin-2-ones and ethene followed by functional group transformation, undergo lactone cleavage by reaction with amines to yield substituted 2-(hetero)aryl-5-hydroxy-2-piperidinecarboxamides. Subsequent reduction affords the corresponding 2-piperidinemethanamines. Both amide and amine compounds are of interest as potential Substance P antagonists. A detailed NMR study, supported by conformational calculations, of an octahydro-2H-pyrido[1,2-a]pyrazine analogue revealed the existence of a temperature and solvent dependent equilibrium mixture of transoid and cisoid invertomers. (C) 2001 Elsevier Science Ltd. All rights reserved.