Synthesis and Characterization of Tetrachloro-1,3-Oxazepine Derivatives and Evaluation of their Biological Activities

6,7,8,9-Tetrachloro[1,3]oxazepine-1,5-dione derivatives 1b – 10b have been synthesized by reacting Schiff bases 1a – 10a with tetrachlorophthalic anhydride (TCPA) under (2 + 5 → 7) cycloaddition reaction conditons. All reactions had been monitored using TLC. FT IR and melting points have been used to characterize the Schiff bases; oxazepine compounds 1b – 10b were characterized using FT IR, 1 H NMR and their melting points. Biological activity for oxazepine compounds has been evaluated against bacterial types ( Staphylococcus aureus , Escherichia coli , Klebsiella spp .) and against a fungus ( Geotrichum spp. ). Variable activities have been observed against used strains of bacteria and fungi.


1. Materials
Aromatic aldehydes, amines and TCPA were supplied from Sigma-Aldrich Chemical Co. used without further purification. Solvents were supplied from Romil. Instrumentation: infrared spectra were recorded as ATR technique on Bruker-Tensor 27 spectrometer. 1 H NMR spectra were recorded on Bruker 300 MHz spectrometer using DMSO-d 6 as the solvent and TMS as the internal standard.

4. Procedure for the Synthesis of 1,3-Oxazepines-4,7-dione derivatives 1b-10b
To a 100 mL round bottomed flask containing 25 mL dry benzene and Schiff bases 1a-10a (1 mmol) equipped with condenser, was added TCPA(1 mmol) dissolved in 20 mL of dry benzene. The reaction mixture was refluxed for 5 h, then stirred overnight at room temperature. Thereafter, the solid product was collected by filtration and recrystallized from ethanol.

1. Chemistry
Target oxazepine compounds 1b-10b were synthesized according to the route presented in Scheme 1.
Imines 1a-10a have been synthesized as precursors for oxazepine compounds by condensation reaction of aromatic aldehydes and primary aromatic amines using absolute ethanol as the solvent. According to the yields obtained, it can be indicated that when the reacting compounds are substituted by electron withdrawing groups (EWG) on benzaldehyde (at the para position), greater amount of the product is obtained than was the case with other compounds, this being due to the substituents having -I effect that increase the magnitude of the positive charge (δ + ) on the carbonyl carbon atom. Hence, increasing the reactivity of benzaldehyde to the attack by amine (as a nucleophile).
Oxazepines have been synthesized by reactions of imines with TCPA, using dry benzene as the solvent, in (2 + 5 → 7) cycloaddition reaction. This reactions type is controlled by orbital symmetry. Therefore, the frontier molecular orbitals for the reactants have to be taken into consideration. Moreover, orbitals of the reactants (anhydride and imines) have to overlap in the convenient way to afford oxazepines by suprafacial manner.
Synthesis of oxazepines has taken place by overlapping of orbitals for imines and TCPA, through the formation of a four-membered ring as the transition state; increasing this overlap led to the formation of a seven -membered ring compounds, as depicted in Scheme 2.
In general, electron donating groups (EDG) increase HOMO energy levels, therefore, reduce the required energy to accomplish the oxazepine formation reaction; in this study, the reaction progress was in accord with the pericyclic mechanism where FMO of imines serve as HOMO, whereas those of TCPA as LUMO; this expectation is brought up through the notice that the yield for 5b, 8b and 9b is the highest, due to the precursor imines 5a, 8a and 9a having electron donating groups that increase the HOMO energy level for imines, giving rise to decreasing the required reaction's energy (Figure 1).

1. 1. Characterization of Prepared Compounds
Imine compounds 1a-10a were synthesized by reactions of aromatic aldehydes with amines, using absolute ethanol as the solvent. Color, melting point and R f changes (TLC analysis) indicated the formation of new compounds, FT IR spectra for compounds 1a-10a showed the disappearance of stretching vibration bands for NH 2 group for substituted aniline, and νC=O group absorption band for substituted benzaldehyde, moreover, appearance of strong vibration band at the range 1612-1623 cm -1 can be attributed to the ν C=N azomethine group, beside absorption bands at 3050-3071 cm -1 for aromatic νC-H, 3014-3032 cm -1 for ν NC-H and 1566-1609 and 1473-1566 cm -1 for aromatic rings.