Contrasting reactivity of fluorinated 2,6-heptanediones towards amines and ammonia, leading to cyclohexanediones or 2-oxa-6-azabicyclo[2.2.2]octanes and evaluation of their cytotoxicity

Abstract

The reactivity and synthetic utility of dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates 1 (2,6-heptanediones) as new fluorinated reagents prepared from the reaction of 1,4-dihydropyridines with Selectfluor® for the synthesis of carbocycles and heterocyclic bridged systems is described. The contrasting behaviour of fluorinated 2,6-heptanediones 1 towards the reaction with amines or ammonia has been revealed. 2,6-Heptanediones 1 with alkylamines form alkylammonium 3-acetyl-5-(alkyloxycarbonyl)-3,5-difluoro-2,6-dioxo-4-phenylcyclohexan-1-ides 2; however, with the less basic aniline, they do not react under similar conditions. 2,6-Heptanediones with aqueous ammonia give alkyl 4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octane-7-carboxylates 4. The cytotoxicity of 2,6-heptanediones 1a,c, the salts of 3-acetyl-5-(alkoxycarbonyl)-3,5-difluoro-2,6-dioxo-4-phenylcyclohexan-1-ides 2a,c–f, and 2-oxa-6-azabicyclo[2.2.2]octanes 4a–c on different cancer cell lines and “normal” cells has been evaluated, thus providing a basis for further studies concerning the potential use of these new compounds.