Synthesis, Characterization and Study of Biological Activity of Some New Schiff Bases ,1,3-Oxazepine and Tetrazole Derived from 2,2 di thiophenyl Acetic Acid

In this study new derivatives of Schiff bases 5-8 , 1,3oxazepine 9-16 and tetrazoles 1719 have been synthesized from the new starting material 1 which has synthesized the reaction of one mole of dichloro acetic acid and two moles of thiophenol , the esters 2-3 were synthesized from the reaction of compound 1 with methanol or ethanol respectively in the presence of H2SO4 as catalyst then 2,2-dithiophenylaceto Hydrazide 4 were synthesized from the reaction of 2 or 3 with hydrazine hydrate 80 % , Schiff bases 5-8 were synthesized from the reaction of 4 with appropriate aldehyde or ketone .Treatment of Schiff bases with maleic and phathalic anhydride in dry benzene to give 1,3-oxazepen derivatives 9-16 and with sodium azide in tetrahydrofuran (THF) afforded tetrazole derivatives 17-19. All these compounds have been characterized from their melting pointes, FTIR, 1HNMR and compounds 1,5 and 18 by mass spectrometry. Derivatives 6,7,11,16,17 and 18 were tested against inhibition of E. coli and. Staphylococcusaureus and were all funds to be active. Scheme (1). Keyword: Dithiophenyl, Schiff bases, 1,3-oxazepien, tetrazole.


Introduction
Heterocyclic compounds are very wide spread in the natural and in non-natural molecules, from this are the compounds which entered as an essential compound in the life, many compounds such as vitamins, essential amino acids, hormones and the synthetic drugs includes heterocyclic ring system, also they are very important in the pharmacological and synthetic fields [1].
Schiff bases are compounds have an azomethine group (-C=N-), They have important application in pharmaceutical fields and in polymer chemistry in addition of their biological activity such as antibacterial, antifungal, anticancer and another application [2] 1,3-Oxazepines have significant application in medicine and in the bioactivity such as hypnotic muscle relaxation, antagonistic, anti-inflammatory, antifungal and another uses [3] also they have been used as protective of amino group in the organic synthesis [4].
Tetrazole has five member hetroaromatic ring [5]. it is an important ring have many applications in the medicine chemistry and in materials application [6].In this work we intend to synthesize new heterocyclic compounds including tetrazole and 1,3-oxazepein derivatives beginning from the synthesis of new 2,2-dithiophenyl acetic acid starting material derived from dichloro acetic acid.

Experimental Instrument
Melting points were recorded on Gallenkamp melting device and were uncorrected , FTIR spectra were recorded on Shimadzu FTIR 8400 fourier transform infrared spectrophotometer using KBr disc , 1 HNMR spectra were recorded on Bruker 400 MhZ spectrometer using DMSO-d6 as a solvent and tetra methyl silane (TMS) as internal standard , mass spectra were recorded on Gcms QP Gas chromatography mass spectrometer agilent technology (HP) .Chemicals All the chemical reagent was used as a received, and were not purification.

-Synthesis of 2,2-dithiophenyl acetic acid [7] 1:
Thiophenol (1.7 g ,0.015 mole) was dissolved in aqueous solution of 50 ml distilled water contain a potassium hydroxide (1.1 g ,0.02 mole); then carefully dichloro acetic acid (1g ,0.007 mole) was added.The mixture of reaction was heated on the sand bath for 6 hrs.After completion, the mixture cooled to room temperature and acidified by hydrochloric acid 10 % to precipitate the acetic acid derivative, then the crude product was recrystallized from ethanol to give high yield (80 %) with melting point (60 0 C), The physical properties of this compound are shown in the table (1) 2, 2-dithiophenyl acetic acid 1 (1 g, 0.003 mole) was dissolved in ethanol or methanol (50 ml) then (1ml) of concentration sulfuric acid was added to the mixture.The mixture then refluxed for (6 hrs) and monitored by (TLC).When the reaction was completed it was cooled to room temperature and neutralized by ( NaHCO3) .The solvent was removed under reduced pressure and the crud product was diluted with water (20 ml) and extracted three times with ethyl acetate (3×40 ml).The combined organic layers were dried over magnesium sulphate and the solvent was removed under reduced pressure to afford 2 and 3 as a syrup.The nomenclature, physical properties and yield of the compounds were shown in table (1)
-Syntheses of substituted 1,3 oxazepine [11] 9-16: Compounds 5-8 (0.0006 mole) were dissolved in dry benzene (40 ml).Subsequently (0.0006 mole) of maleic anhydride or phathalic anhydride was added, then the reaction mixture was refluxed for (6-7) hrs.The reaction mixture was cooled to room temperature.The product was filtrated and recrystallized from appropriate solvent, A mixture of compounds 5-8, (0.0006 mole) and sodium azide (0.039g ,0.0006 mole) in the (THF ) (15 ml) was stirred under refluxed for (4 hrs) and monitored by (TLC).Then the reaction mixture was cooled to room temperature and filtrated.The filtrate was poured in to ice-water (20 ml). the precipitate was collected and recrystallized from appropriated solvent.

Result and Discussion
Compound 1 was synthesized from the reaction of two moles of potassium benzenethiolate salt with dichloride acetic acid under reflux as we show in scheme (1).FTIR spectrum of compound 1 showed appearance of two important bands at (3057-2565) cm -1 due to (O-H) group [13] and at (1701) cm -1 due to (C=O) group [14] which they indicated formation of this compound another FTIR bands are listed in the table (3).The mass spectrum of compound 1 figure (1) indicated the exact mass of this compound at m/z = 276.
Compounds 2-3 were synthesized from the reaction of compound 1 with methanol or ethanol respectively in the presence of Sulfuric acid as catalyst.The FTIR spectra of these compounds showed clear bands at (1732-1734 ) cm -1 due to (C=O) group of ester [15] and at the range (1253-1276) cm -1 for (C-O) with disappearance of two bands at (3057-2565) cm -1 due to  (O- H) group and at (1701) cm -1 due to (C=O) group of acid.
Hydrazide derivative 4 was synthesized from the reaction of compounds 2 or 3 with hydrazine hydrate 80% under reflux .The FTIR spectrum of 4 showed absorption bands at 3423 cm -1 and 3309 cm -1 due to asymmetric and symmetric stretching vibration of the (NH-NH2) group [16] and at (1623 -1666) cm -1 due to (C=O) amide [17] and disappearance of two bands at (1734) cm -1 and at 1253-1276 cm -1 due to (C=O) and (C-O-C) respectively .
Compounds 5-8 were synthesized from the reaction of compound 4 with different aromatic aldehyde and ketone by using glacial acetic acid as catalyst, the FTIR spectra of these compounds showed the disappearance of two absorption bands (3423) cm -1 and (3309) cm -1 of the (NHNH2) group and appearance of new band at range between (3188 -3115 ) due to NH group .Also the FTIR spectra showed another absorption bands at (1668-1627) cm -1 , (1608-1593) cm -1 , (1579-1443) cm -1 and at (1226-1203) cm -1 duo to (C=O) of amide, (C=N) of imine [18] , (C=C) of aromatic rings and (C-N) of amide respectively, all main absorbing bands of the FTIR spectra of compounds 5-8 were listed in the Table (3) .The FTIR absorption bands of compound 7 was shown in the figure (2).Mass spectrum of compound 5 figure (3) displayed the exact molecular ion.
Compounds 9-16 were synthesized from the reaction of compounds 5-8 with phathalic and malic anhydride respectively by using dry benzene as a solvent.The FTIR of these compounds showed absorption bands at the range of (1658-1705) cm -1 and (1710-1770) cm -1 which belong to (C=O) group of lactam and lactone [19] respectively due to oxazepine ring with disappearance of absorption bands of (C=N) group at the range (1608-1593) cm -1 of the compounds 5-8 , .FTIR spectrum of compound 12 is shown in the figure (7) 1 HNMR spectrum of compound 12 figure Derivatives 17-19 were synthesized from the reaction of compounds 5-8 and sodium azide in tetrahydrofuran (THF) and under reflux FTIR spectra of these compounds showed the disappearance of (C=N) group at the range (1608-1593) cm -1 of the compounds 5-8 and appearance of (N=N) absorbance group of tetrazole ring at the range (1469-1535) cm -1 [20], also the mass spectrum of compound 18 figure (10) indicated the exact mass of this compound.