H. EL FROM,, M. Péra, G. Leclerc
2003
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Heterocyclic Communications
Abstract
Synthesis and physico-chemical properties of some l-benzyl-azepane-2,3-dione 3(O-substituted oximes) with attribution of their Ζ and Ε configurations and 4(phenylhydrazono)azepane-2,3-dione 3-(0-substituted oximes) resulting of condensation with various O-aryl-hydroxylamines are described. These azepanedione-oxime compounds are prepared from the corresponding azepan-2-ones and 1-benzylazepan-2-ones. Introduction Through studies of amide or lactame derivatives highlighted the interesting pharmacological properties, in particular actions on central nervous system via stimulation of various ion channels [1], The synthesis of 3-[0-(benzyl)oximinoether] hexahydroazepin-2,3-diones previously reported [2] showed that they are capable to relax both rat trachea and human bronchus. The oximinoether or oxime derivatives exhibited marked antinociceptive and anticonvulsant activities [3], This work describes synthesis and physicochemical properties of l-benzylazepane-2,3-dione 3-(0-substituted oximes) with attribution of their Ζ and Ε configurations and 4-(phenylhydrazono)azepane-2,3-dione 3-(0-substituted oximes) resulting of condensation with various O-arylhydroxylamines from the corresponding azepan-2-ones and 1 -benzylazepan-2-ones. Synthesis and structural study Strategy for the synthesis of target compounds 8a-f and lOa-g (Scheme 1) was based on the construction of the azepane-2,3-dione skeleton 7, 9 followed by attachment of the Osubstituted hydroxylamines in presence of pyridine. The l-benzylazepan-2-one 2, starting compound for the preparation of the 1 -benzylazepane2,3-dione 7, was prepared from cyclohexanone [4], Chlorination of 2 by phosphorus pentasulphide [5] leads to the l-benzyl-3,3-dichloroazepan-2-one 4. This compound, after treatment by morpholine and acidic hydrolysis in cold hydrochloric acid led to the azepanedione 7. Vol. y, No. I. 2003 Synthesis of new azepanedione oximes Figure 1. Synthesis of azepanedione oxime compounds. Several methods can be used for the preparation of 4-(phenylhydrazono)azepane-2,3-dione 9. Initially, the 3,3-dichloroazepan-2-one 3 was prepared using phosphorous pentachloride. Treatment of 3 with morpholine [6] followed by condensation with phenyldiazonium chloride [7] leads to the azepane 9. The O-aryl-hydroxylamines used for the synthesis of the azepanedione oximes, were prepared according to Garoufalias et al. [8] and their physicochemical properties were reported in a previous work [2], l-Benzylazepane-2,3-dione 3-(0-substituted oximes) 8a-f were isolated as mixture of Zand Ε isomers (Table 1) in which the Ε isomer predominates. Ratio of isomers were assessed by NMR spectroscopy on the basis of the chemical shifts observed for protons on carbon adjacent to the oxime double bond [9], In accordance with assignments reported in literature for several oximes and alkylated oximes [10], Ζ isomers are more downfield than their Ε counterparts. The 4-(phenylhydrazono)azepane-2,3-dione 3-(0-substituted oximes) lOa-g were isolated in the form of only one isomer. Fragmentations observed and intensity of the peaks of isotopes under electronic impact in MS are in agreement with the structures suggested. Experimental Melting points were measured with a Thomas-Hoover capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on a Pye-Unicam SP3-100 (Philips) spectrometer. Wavelengths are expressed in cm". Nuclear magnetic resonance spectra were recorded on an AC 200 FT (Bruker) spectrometer 'H NMR at 200 MHz and C NMR at 50 MHz. Chemical shifts (δ) are expressed in part per million (ppm) and coupling constants (J) are given in hertz (Hz).