uobj_paper_2014_41318687

Introduction

Azo group is considered biological active group (Wilson and Givolds, 1982 and Pod Dick et.al., 1985).The most important method for preparing azo compounds is the coupling reaction between diazonium salts and phenols (Vogel, 1973) .

Schiff bases or imines are prepared via acid-catalysed condensation reaction of aromatic aldehydes or ketones with primary amines (Al-juboori , 2005 and Salih, 2005).Azo Schiff bases are prepared by reaction of azoaldehydes with primary amines(Jarrahpour et.al., 2004). Mechanism of Schiff base formation was well known (Al-juboori , 2005 and Salih, 2005) .Various azo Schiff bases derivatives were prepared and some of them showed biological activity such as anticancer (Desai et.al., 2001), antiviral (Wang et.al., 1990),antifungal (Singh and Dash, 1988) , antibacterial (More et.al.,2001) and anticonvulsant (Verma et.al., 2004) .Thiadiazoles have a variety of potential biological activities (Noto et.al., 1996 and Al-Ani, 2004) , therefore a large number of thiadiazole derivatives have been prepared (Noto et.al., 1996 and AlOmran et.al.,2002) .Many synthesis of 1,3,4-thiadiazoles proceed from thiosemicarbazide or substituted thiosemicarbazide (Ainsworth,1956 and Mohan et.al., 1988) . For a long time, the synthesis of 1,3- and 1,4-oxazepine rings was based on two limited classical types of reactions, the first reaction is called Valence-bond isomerization which is carried out via irradiation of polyarylpyridine N-oxides. This irradiation results in ring expansion to 1,3-oxazepine in high yield and some deoxygenation to the parent amines (Buchardt et.al., 1972) . The second reaction is called Enamines condensation which is carried out by reaction of Erythro 1,2- diphenyl-2-phenylaminoethanol with dimethylacetylene dicarboxylate in methanol at room temperature to give a mixture of the Michael adduct and tetrahydro-1,4- oxazepin-7-one (Tsuge et.al., 1982). Recently, a pericyclic reactions are used to synthesis of 1,3-oxazepine ring (Ali,2005, Al-Jamali,2008,Haiwal,2008 and Abood,2009). This type of reactions is not limited and gives various 1,3-oxazepine ring derivatives. The type of cycloaddition reaction that used to synthesis of 1,3-oxazepine ring was classified as (2+5) → 7 cycloaddition reaction in which two atoms of imine group as two-membered component was added to five-membered component such as maleic or phthalic anhydrides to give a seven-membered heterocycle (Ali,2005, AlJamali,2008,Haiwal,2008 and Abood,2009) .Some oxazepine derivatives showed biological activities against various types of bactria (Serrano et.al., 2002) and some of them act as inhibitors of some enzymes action (Smith et.al., 2006) .

Also , the 1,3-dipolar cycloaddition reaction,which was used to synthesis of tetrazole ring was classified as (2+3) cycloaddition , in which two atoms of the first component ( imine or nitrile groups as a 1,3-dipolarphiles) react with three atoms of the second component ( azide group as a 1,3-dipolar molecule ) (Miller, 1998 and Abood et.al. 2008) .Tetrazole derivatives showed fungicidal and antiviral activities (Modzelewska et.al.,2004) .

The aim of this research is synthesis of some new oxazepine and tetrazole derivatives containing the biologically active azo group and thiadiazole ring all together, as attempt for increasing the biological activity and its variety.

Experimental

General

1)The solvents and liquid reagents were purified when it was necessary; the solid materials were also dried under reduced pressure when it was necessary.

2)TLC were performed on pre-coated sheets with 0.25 mm layer of Silica Gel GF254 of the Merck company, the detection was followed by coloring with iodine or

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then the mixture was refluxed with stirring at 80 ºC for 3hrs. , T.L.C. (ethanol:benzene)(1:1) ,Rf = 0.8.The mixture was allowed to cool down to room temperature.The solvent was then removed by evaporation and the product was extracted by addition of distilled water (30mL) and ethyl acetate (2×25mL) .The organic layer was dried with anhydrous mangensium sulphate and removed by evaporation ,recrystallized from ethanol , yield 70% , M.P.225-227 ºC.

Synthesis of 4,4'-(Biphenyl-4,4'-diylbis(diazene-2,1-diyl))bis(2-((E)-(5-(butylthio)- 1,3,4-thiadiazol-2-ylimino)methyl)phenol) [5]

Azo Benzaldehyde derivative [1]( 0.45g , 0.001 mole) was dissolved in (15 mL) of absolute ethanol containing a drop of glacial acetic acid ,then 5-(butylthio)- 1,3,4-thiadiazol-2-amine [3] (0.378 g ,0.002 mole ) was dissolved in (15 mL) of absolute ethanol and added dropwise . The reaction mixture was refluxed with stirring on a water bath at ( 70 oC ) for 2hrs.T.L.C. (ethanol:pet.ether)(1:1) ,Rf = 0.61.Then the mixture was allowed to cool down to room temperature , the coloured precipitate was filtered and recrystallized from ethanol ,yield 86% , M.P.245-247ºC.

Synthesis of 4,4'-(Biphenyl-4,4'-diylbis(diazene-2,1-diyl))bis(2-((E)-(5- (benzylthio)-1,3,4-thiadiazol-2-ylimino)methyl)phenol) [6]

Azo Benzaldehyde derivative [1]( 0.45g , 0.001 mole) was dissolved in (15 mL) of absolute ethanol containing a drop of glacial acetic acid ,then 5-(benzylthio)- 1,3,4-thiadiazol-2-amine[4] (0.446g,0.002 mole ) was dissolved in (15 mL) of absolute ethanol and added dropwise . The reaction mixture was refluxed with stirring on a water bath at ( 70 oC ) for 2hrs.T.L.C. (ethanol:pet.ether) (1:1) Rf = 0.69.Then the mixture was allowed to cool down to room temperature , the coloured precipitate was filtered and recrystallized from ethanol ,yield 84% , M.P. 263-265 ºC.

Synthesis of 2,2'-(5,5'-(Biphenyl-4,4'-diylbis(diazene-2,1-diyl))bis(2-hydroxy-5,1- phenylene))bis(3-(5-(butylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3-oxazepine- 4,7-dione) [7]

A mixture of imine derivative [5]( 0.1584 g, 0.0002 mole) and maleic anhydride (0.0392 g ,0.0004mole) in ( 20 mL) of dry benzene , was refluxed on a water bath at (75ºC) for 4hrs. T.L.C. (benzene:methanol ) (3:1) Rf = 0.79. , then the mixture was allowed to cool down to room temperature . The resulting solid crystals were filtered and recrystallized from dioxane, yield 71% , M.P.140-142 ºC.

Synthesis of 3,3'-(5,5'-(Biphenyl-4,4'-diylbis(diazene-2,1-diyl))bis(2-hydroxy-5,1- phenylene))bis(4-(5-(butylthio)-1,3,4-thiadiazol-2-yl)-3,4- dihydrobenzo[e][1,3]oxazepine-1,5-dione) [8]

A mixture of imine derivative [5]( 0.1584g, 0.0002mole) and phthalic anhydride ( 0.0592g ,0.0004mole) in ( 20 mL) of dry benzene , was refluxed on a water bath at (75ºC) for 4hrs. T.L.C. (benzene:methanol) (3:1) Rf = 0.77. , then the mixture was allowed to cool down to room temperature . The resulting solid crystals were filtered and recrystallized from dioxane, yield 69% , M.P.155-157ºC.

Synthesis of 4,4'-(Biphenyl-4,4'-diylbis(diazene-2,1-diyl))bis(2-(1-(5-(butylthio)- 1,3,4-thiadiazol-2-yl)-1H-tetrazol-5-yl)phenol) [9]

A mixture of imine derivative [5] ( 0.1584g, 0.0002 mole) and sodium azide (0.026 g , 0.0004mole ) in ( 20 mL) of dry dioxane was refluxed on a water bath at (75ºC) for 5hrs, T.L.C. (benzene:methanol ) (1:1) Rf = 0.58.The reaction mixture was allowed to cool to room temperature , filtered and recrystallized from ethanol , yield 60 % , M.P. 222-224 ºC.

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Table (1): Melting points , percent yields and (C.H.N. )analysis of the prepared compounds (1-12)

Results and Discussion

Benzidine was converted to the corresponding diazonium salt , via reaction with concentrated hydrochloric acid and sodium nitrite at (0 ºC) , which was directly introduced in a coupling reaction with 2-hydroxy benzaldehyde dissolved in sodium hydroxide solution at ( 0-5) ºC to give azo aldehyde derivative [1] (Vogel, 1973) ,then the two carbonyl groups in azo aldehyde derivative [1] were introduced in acid - catalysed condensation reaction with amino groups for each 5-(butylthio)-1,3,4- thiadiazol-2-amine [3] and 5-(benzylthio)-1,3,4-thiadiazol-2-amine [4] ,respectively in absolute ethanol to give new azo Schiff bases derivatives [5] and [6] , respectively (Jarrahpour et.al., 2004, Abood,2008 and Abood, 2009) .

.

A pericyclic reactions, between imine groups of Schiff bases derivatives [5] and [6], as two-membered components, and cyclic anhydrides (maleic anhydride and phthalic anhydride) as five-membered components in dry benzene, were carried out to synthesis of 1,3-oxazepine derivatives [7] , [8] and [10], [11] ] (Ali,2005, Al - Jamali,2008,Haiwal,2008 and Abood,2009).A pericyclic reaction is a concerted

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The structures of all synthesised compounds[1-12] were shown in scheme (3) and scheme (4) .The new synthesised compounds were characterized by their melting points ,(C.H.N.) elementary analysis which showed nearness between the found and calculated values for all compounds as it was shown in Table (1) and FT-IR spectra as it was shown in Table (2).

FT-IR spectrum of azoaldehyde derivative [1] showed the following characteristic absorption bands: the sharp absorption bands at 3296 cm-1 and 3200 cm-1 attributed to the υ(O-H) which were shifted to lower frequencies due to intramolecular hydrogen bonding with ortho aldehyde carbonyl group (Williams and Fleming, 1973).The three absorption bands at 3110 cm-1 and 3060 cm-1 attributed to υ(C-H) aromatic.The weak absorption bands at 2970 cm-1 ,2920 cm-1 ,2840cm-1 ,2800 cm-1 and 2740 cm-1attributed to the υ (C-H) aliphatic of aldehyde groups (-CHO) .The sharp strong absorption band at 1645 cm-1 due to the υ(C=O) of aldehyde groups which was shifted to lower frequency due to intramolecular hydrogen bonding with ortho hydrxy group(Williams and Fleming, 1973) .The three absorption bands at 1606cm-1 ,1568

cm-1 and 1492 cm-1 attributed to the υ ( C C ) aromatic of benzene ring. The weak absorption band at 1405 cm-1 attributed to the δ (O-H) in plane (Williams and Fleming, 1973) . The absorption band for azo group did not appear since it is very weak or inactive in infrared, some times seen in Raman.(Williams and Fleming, 1973) The strong absorption band at 1282 cm-1 attributed to the δ(C-H) aromatic in plane. (Williams and Fleming, 1973) . The two strong absorption bands at 1192 cm-1 and 1153 cm-1 attributed to the υ(C-O) of phenol. The two strong absorption bands at 825 cm-1and 756 cm-1 attributed to the δ(C-H) aromatic out of plane.The weak absorption band at 655cm-1 due to δ(O-H) out of plane. FT-IR spectrum of 5-Amino-1,3,4- thiadiazole-2-thiol [2] showed identical melting point with that published (Abood,2008) .FT-IR spectrum of compound [2] showed the following characteristic absorption bands: the two bands at 3392cm-1 and 3279cm-1 due to asymmetric and symmetric stretching vibrations of (-NH2) group, an absorption band at 3095cm-1 was due to the (-NH) stretching vibration (tautomeric form). The absorption bands at 2912cm-1 and 2766cm-1 attributable to the intramolecularly hydrogen bonded of (-NH) group(Gupta and Mishra, 1981). The (-SH) stretching band found as very weak shoulder at 2560cm-1. The absorbtion bands at 1597cm-1, 1533cm-1, and 1494cm-1 attributed to the streching vibrations of three different types of imine groups inside thiadiazole rings due to the tautomerism. Also, the absorption bands at (1350, 1280)cm-1 due to the presence of (=N-N-C-) cyclic grouping(Salih, 2005). Moreover, the absorption band at 1180cm-1 for the (C=S) group stretching vibration gives evidence that compound [2] can exist in two tautomeric forms, thiol form [2a] and

The strong absorption band at 1058 cm-1 due to the υ(N-N) inside thiadiazole ring .The strong absorption band at 738 cm-1 attributed to the υ(C-S).

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compound [6] also showed appearance of another important characteristic absorption bands as follow : the srong absorption band at 1540 cm-1 due to υ(C=N) inside

thiadiazole ring.The strong absorption band at 1480cm-1 due to the υ ( C C) aromatic of benzene ring.The absorption band at 3269 cm-1 attributed to υ(O-H) in plane.The absorption band at 3180 cm-1 attributed to the υ(C-H) aromatic of benzene ring. The two weak absorption bands at 2920 cm-1 and 2841cm-1 due to the δ (C-H) aliphatic of (-CH2-) group. The weak absorption band at 1430 cm-1 attributed to the δ (C-H) aliphatic. The strong absorption band at 1373cm-1 attributed to the δ (O-H) in plane . The strong absorption band at 1270 cm-1 attributed to the δ(C-H) aromatic in plane. The strong absorption band at 1211 cm-1 attributed to the υ (C-O) of phenol. The weak absorption band at 1080 cm-1 attributed to the υ(N-N) inside thiadiazole ring. The broad strong absorption band at 939 cm-1and the weak absorption band at 755 cm-1 attributed to the υ(C-H) aromatic of benzene ring out of plane.The two weak absorption bands at 646cm-1 and 620cm-1 attributed to the δ(O-H) out of plane . The weak absorption band at 646 cm-1 attributed to the υ(C-S). FT-IR spectrum of oxazepine derivative [7] showed appearance of two strong absorption bands at 1786cm-1 and 1695cm-1 attributed to the υ (C=O) for lactone and lactam in oxazepine ring,respectively. The strong absorption band at 1612 cm-1 attributed to the υ(C=N)

inside thiadiazole ring .The absorption band at 1500cm-1 attributed to the υ ( C C) aromatic of benzene ring. The weak band at 1390cm-1 attributed to the δ (O-H) in plane. The two weak absorption bands at 1455 cm-1 and 1365 cm-1 due to the δ(C-H) aliphatic for butyl group. The strong absorption band at 1290 cm-1 attributed to the δ (C-H) aromatic in plane. The two absorption bands at 1163 cm-1 and 1109 cm-1 attributed to the υ(C-O) for phenol and υ(C-O) for lactone,respectively. The absorption band at 1043 cm-1 attributed to the υ(N-N) inside thiadiazole ring. The four absorption bands at 970 cm-1, 927 cm-1 ,827 cm-1 and 770 cm-1due to the δ(C-H) aromatic of benzene ring out of plane. The absorption band at 725 cm-1 attributed to the δ (O-H) out of plane. The absorption band at 615 cm-1 attributed to the υ(C-S). FT-IR spectrum of compound [7] also showed appearance of the following absorption bands: The absorption bands at 3200cm-1 , 3150cm-1and , 3105cm-1 and 3000cm-1 attributed to the υ (C-H) aromatic of benzene ring. The two absorption bands at 2976 cm-1 and 2877cm- 1 due to the υ (C-H) aliphatic of butyl group . The two sharp absorption bands at 3414 cm-1 and 3288cm-1 due to the υ(O-H) groups.

FT-IR spectrum of oxazepine derivative [8] showed appearance of strong broad band at 1712 cm-1 attributed to the υ (C=O) for lactone and lactam groups in oxazepine ring(interacted) .The strong absorption band at 1610 cm-1 attributed to the υ(C=N) inside thiadiazole ring. The strong absorption band at 1491 cm-1 attributed to

the υ ( C C) aromatic of benzene ring. The two weak absorption bands at 1450 cm-1 and 1365 cm-1 attributed to the δ (C-H) aliphatic of butyl group . The weak absorption band at 1400cm-1 attributed to the δ (O-H) in plane. The medium absorption band at 1270 cm-1 attributed to the δ (C-H) aromatic in plane. The two absorption bands at 1176 cm-1 and 1110 cm-1 attributed to the υ(C-O) of phenol and υ(C-O) for lactone,respectively. The strong absorption band at 1012 cm-1 attributed to the υ(N-N) inside thiadiazole ring. The broad strong absorption band at 829 cm-1 and the weak absorption band at 765 cm-1due to the δ(C-H) aromatic of benzene ring out of plane. The absorption band at 700 cm-1 attributed to the δ (O-H) out of plane. The absorption band at 615 cm-1 attributed to the υ(C-S). FT-IR spectrum of compound [8] also showed appearance of the following absorption bands: The two absorption bands at 2930cm-1 and 2860cm-1due to the υ (C-H) aliphatic of butyl group. The three

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