Synthesis of New-1 , 3 , 4-Thiadiazoles Substituted with Oxazepine and Benzoxazepine Moieties FAEZ ABDUL-HUSSEIN ALRAMMAHI

2-amino-5-mercapto-1,3,4-thiadiazole 1 was introduced in condensation reaction with terephthaldehyde to yield bis-imine derivative 2. Compound 1 was also converted to the corresponding diazonium salt which was introduced in coupling reactions with alkaline solution of 2-hydroxybenzaldehyde and 4-hydroxybenzaldehyde as coupling reagents to give azo derivatives 4a and 4b containing aldehyde group, respectively. The resulting aldehydes 4a and 4b were then introduced in condensation reactions with 2-amino-5-mercapto-1,3,4-thiadiazole 1 to obtain the imines 5a and 5b respectively. The resulting imines 2, 5a and 5b were treated with both maleic and phthalic anhydrides, respectively, under (2+5) cycloaddition conditions afforded eight new bis-1,3,4-thiadiazoles substituted with 1,3-oxazepine and 1,3-benzoxazepine moieties (3a, 3b) and (6a-d)respectively. The new synthesized thiadiazoles have some biological, pharmaceutical and medicinal applications.


INTRODUCTION
Thiadiazoles are clear to yellowish liquids which are soluble in alcohol, ether and slightly soluble in water; they are starting material for numerous chemical compounds including sulphur drugs 1 .Thiadiazoles are easily metabolized by biochemical reactions and they are noncarcinogenic in nature 2 .Thiadiazoles and their derivatives exhibit wide range of pharmacological activities such as antimicrobial activity 3 , antidepressant, cardiotonic 4 , antibacterial activity against Klebsiella pneumonia 5 , antitubercular 6,7 , anticonvulsant 8 , antileshmanial , analgesic 9 , antiinflammtory 10 , anticancer 11 , phosphodiesterase inhibitors 12 and effect on Tyrosinase enzyme 13 .This diversity of biological activity may be due to the presence of -N=C-S moity 14,15 .There are four isomers of thiadiazole , among these four isomers 1,3,4-thiadiazole is the most thermally stable; which is only isomer doesn ´t contain any sulphur-nitrogen bond 16 .1,3,4-thiadiazole relatively stable in aqueous acid solutions but the nucleus can undergo ring cleavage by aqueous base solutions 17 .
Heterocyclic seven-membered ring constitutes the core or a key fragment of a number of bioactive compounds including isolated from natural products, oxazepine derivatives were found to exhibit a vast variety of biological activities 18 and found to be a vital moiety in many psychoactive pharmaceuticals 19 .Thus, in this article, we reported here the synthesis of 1,3,4-thiadiazole derivatives containing biologically active oxazepine and benzoxazepine moieties, which might have some biological activity.

EXPERIMENTAL General
The chemicals used were purchased from Merck & Co., BDH, Sigma Aldrich and CDH and were used without further purification.Silica TLC plates were used with an aluminum backing (0.2 mm, 60 F 254 ).The progress of reactions were monitored by TLC and visualized by development of the TLC plates with iodine vapor.Melting points were determined on an Electro thermal Stuart SMP 30 capillary melting point apparatus.Infrared spectra were recorded on SHIMADZU FTIR-8400S Infrared Spectrophotometer as potassium bromide discs. 1 H NMR spectra were collected on NMR spectrometer, Broker 2009 spectrometer at 400 MHz in DMSO-d6 as solvent and TMS as an internal standard at Kashan University, Iran.Elemental Analysis (CHNS) was carried out with Perkin Elmer 300A Elemental Analyzer at Kashan University, Iran.Azoaldehyde derivatives 4a and 4b were prepared following the method described by Acton 20 .

General procedure for the synthesis of azoimine derivatives (5a, 5b):
Azoaldehyde derivatives 4a or 4b(0.665g, 2.5 mmol) was dissolved in (30 ml) of absolute ethanol, then 2-amino-5-mercapto-1,3,4thiadiazole 1 (0.3325 g , 2.5 mmol) was added.The reaction mixtures were refluxed with stirring on a water bath at 65 o C for 10 h and monitored by TLC.The mixtures were then allowed to cool down to room temperature , the colored precipitates were filtered and recrystallized from ethanol.

General procedure for the synthesis of oxazepine and benzoxazepine derivatives 6a-d:
A mixture of azoimine derivatives 5a or 5b (0.381 g, 1 mmol)and maleic or phthalic anhydride (1 mmol) in dry benzene (20 ml) was refluxed on a water bath at 70 o C for 24 h.and monitored by TLC.The mixtures were then allowed to cool down to room temperature, the colored precipitates were filtered, dried and recrystallized from ethanol.

Scheme. 2. Proposedmechani sm for the formation of oxazepinering.
The chemical structures of these newly oxazepines were confirmed by IR, 1 H NMR spectral measurements and (CHNS) elemental analysis and were in good agreement with the proposed structures.
The IR spectrum of bis-imine 2 showed the stretching absorption band of the (C=N) function at 1691 cm -1 , while the absorption bands due to (NH 2 ) group at 3336 and 3267 cm -1 have disappeared.The broad absorption band at 3194 attributed to the (N-H)str.in thione form.The stretching band of (C=S) function in thione form appeared as strong band at 1051 cm -1 .The IR spectra of compounds 3a and 3b indicated the absence of (C=N) absorption band and the appearance of (C=O)str.for oxazepine ring at 1699 and 1695 cm -1 , respectively.
The 1 H NMR spectrum of bisimine 2 showed the (HC=N) protons as a singlet at δ 8.8 ppm, the (N-H) protons of thione forms appeared as a singlet at 10.09 ppm, the (Ar-H) protons at δ 7.09 -8.17 ppm.Moreover, the spectrum showed the (SH) protons asa singlet at 13.17 ppm. 21.
The 1 H NMR spectra of oxazepine compounds 3a and 3b showed the disappearance of the (CH=N) protons at 8.8 ppm, the thioic (S-H) protons appeared as a singlet at δ 13.2 and 13.16 ppm, respectively.The (N-H) protons for thione forms as a singlet at 10.1.The signals of aromatic protons (Ar-H) and (C-H) protons of oxazepine rings appeared at δ 7.08-8.16ppm.Moreover, the olefinic (=CH) protons of the oxazepine rings in compound 3a appeared as singlet at 6.2 and 6.6 ppm.

HS NH2
1. NaNO2 , HCl , ( 1. NaNO2 , HCl , ( The structures of the compounds synthesized were deduced by IR, 1 H NMR spectral measurements and (CHNS) elemental analysis and were in good agreement with the proposed structures.
The IR spectra of azoaldehde derivatives 4a and 4b indicated the absence of the doublet band at 3336 and 3267 cm -1 for (-NH 2 )str.and appearance of broad band at 3281 and 3284 cm -1 assigned to (O-H)str., the absorption band at 1629 and 1627 cm -1 belong to the aldehydic (C=O)str., respectively.The IR spectra of imine derivatives 5a and 5b showed the disappearance of the absorption bands at 1629 and 1627 cm -1 for aldehydic (C=O)str., also disappearing the doublet band for (-NH 2 )str. in 2-amino-5-mercapto-1,3,4-thiadiazole at 3336 and 3267 cm -1 , while the absorption bands attributed to (C=N)str.appearedat 1620 and 1610 cm -1 , respectively.In the IR spectra of oxazepine , respectively, while the absorption bands due to (C=N)str.at 1620 and 1610 cm -1 have disappeared.
The 1 H NMR spectra of azoaldehyde compounds 4a and 4b showed the (S-H) proton as a singlet at δ 13.1 and 12.34 ppm 20 .the(O-H) proton appeared as a singlet at 10.7 and 8.8 ppm, the (HC=O) proton as a singlet at δ10.2 and 9.7 ppm, , the (Ar-H) protons at δ 6.90-7.81ppm.
The 1 H NMR spectra of imine compounds 5a and 5b showed the (S-H) proton as a singlet at δ 13.6 and 13.4 ppm, the (O-H) proton appeared as a singlet at 10.2 and 10.5 ppm, the (HC=N) proton as a singlet at δ 7.77 and 8.8 ppm, , the (Ar-H) protons at δ 6.90 -7.77 ppm.
The structures of the compounds synthesized were proven by IR, 1 H NMR spectral measurements and (CHNS) elemental analysis and were in good agreement with the proposed structures.