The aza-ene reaction of heterocyclic ketene aminals with activated carbonyl compounds: a novel and efficient synthesis of γ-lactam-fused diazaheterocycles

Abstract

Reactions of heterocyclic ketene aminals with activated carbonyl compounds are strongly influenced by the structure of the heterocycle moiety. Six-membered heterocyclic ketene aminals with or without an N-methyl group such as 3 and 4 underwent efficient addition and consecutive cyclocondensation reactions with diethyl oxomalonate 9 to produce γ-lactam-fused pyrimidine derivatives 10 and 11 in moderate to excellent yield. For the five-membered enediamines, however, those compounds without any N-substituent such as 6 underwent the same reaction slowly and no reaction at all was observed with N-methyl and N,N′-dimethyl-substituted analogs 7 and 8. Heterocyclic ketene aminals 3 also reacted with glyoxylic acid esters 17 to afford 8-aroyl-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidines 18 in good yield. No asymmetric induction was found, however, when (1R,2S,5R)-(–)-menthyl glyoxylate 17b was employed as a chiral substrate. An aza-ene reaction mechanism involving heterocyclic ketene aminals as the aza-ene component (H–N–CC) has been proposed. The effects of intramolecular hydrogen bonding and heterocyclic ring size on the reactivity are also discussed.