Synthesis of Oxadiazoles, Thiadiazoles and Triazoles Derived from Benzo[b]thiophene.

In this work 3-chloro-2-chlorocarbonylbenzo[b]thiophene (1) was prepared from cinnamic acid and then converted into the acid hydrazide 2. The azomethines 3a-e were prepared from the corresponding aryl aldehydes and the acid hydrazide 2. Treatment of compound 2 with formic acid gave the N-formyl acid hydrazide 4, which upon refluxing with phosphorous pentoxide or phosphorous pentasulphide in xylene yielded the corresponding 2- (3-chloro-1-benzothien-2-yl)-1,3,4-oxadiazole (5) and 2-(3-chloro-1-benzo-thien-2-yl)-1,3,4- thiadiazole (6). Reaction of 1-thiosemicarbazide 7 with NaOH leads to ring closure giving 5- (3-chloro-1-benzothien-2- yl)-4H–triazole-3-thiol (8) which is converted into a number of derivatives 9-12 Reaction of 2 with phenyl isothiocyanate and NaOH afforded 5-(3-chloro- 1-benzothien-2-yl)-4-(phenyl)-4H-1,2,4-triazole-3-thiol (14).


Introduction
Derivatives of 1,3,4-oxadiazole and 1,3,4 -thiadiazole have been found to possess a wide spectrum of pharmacological ,medical,and biological activities [1]. Schiff bases have also been widely reported to be biologically versatile compounds having antifungal, herbicidal and plant growth regulating properties [2]. Moreover derivatives of 1,2,4-triazole are known to exhibit anti-inflammatory [3], antiviral [4], analgesic [5], antimicrobial [6], anticonvulsant [7] and antidepressant activities [8]. A series of 1,2,4-triazole derivatives have been patented and extensively employed in agriculture [9]. We now report on the synthesis of compounds derived from benzo[b]thiophene containing oxadiazole, thiadiazole and triazole moieties, with the purpose of investigating in the future their possible antibacterial and antifungal activities.

Results and Discussion
The new oxadiazole and thiadiazole derivatives were prepared following the reaction sequences depicted in Scheme 1. The starting material for the synthesis of the targeted compounds is 3-chloro-2chlorocarbonyl benzo[b]thiophene (1) which was prepared by the reaction of cinnamic acid with thionyl chloride in DMF and dry pyridine according to the reported method [10]. Reaction between 1 and hydrazine hydrate afforded the acid hydrazide 2 in good yield. The IR spectra showed the N-H stretching absorption near 3140 cm -1 and the C=O stretching one at 1640 cm -1 . Condensation of the acid hydrazide 2 with aryl aldehydes in absolute ethanol gave the Schiff bases 3a-e.

NaOH
The formation of these Schiff bases was indicated by the presence in their IR spectra of the azomethine (CH=N) stretching band at 1600 cm -1 , combined with the disappearance of the NH 2 stretching band. Further, 3-chloro-2-(N-formyl acid hydrazide)benzo[b]thiophene (4) was obtained in 70% yield when the acid hydrazide 2 was allowed to react with formic acid [11,12]. The structure of compound 4 was confirmed by the presence of two amidic carbonyl stretching bands at 1720 cm -1 and 1660 cm -1 (CO-NH-NH-CHO).  Refluxing compound 4 with phosphorous pentoxide in xylene for one hour afforded 2-(3-chloro-1benzothien-2-yl)-1,3,4-oxadiazole (5), which displayed two bands at 1245 cm -1 and 1080 cm -1 for the C-O-C asymmetric and symmetric stretching, respectively [12,13], in addition to the band at 1620 cm -1 for the C=N stretch. Moreover, 2-(3-chloro-1-benzothien-2-yl)-1,3,4-thiadiazole (6) was obtained in 62-68% yield from the reaction of 4 with phosphorous pentasulphide under reflux in xylene solution. The absorption band at 1610 cm -1 in the IR spectrum of 6 is due to C=N stetching. On the other hand the reaction of 1 with powdered thiosemicarbazide in dry benzene afforded the acylthiosemicarbazide 7, which upon ring closure with NaOH gave 5-(3-chloro-1-benzothien-2-yl)-4H-1,2,4-triazole-3-thiol (8) [14] which exists in a tautomeric thiol -thione equilibrium, as indicated by the C=S stretching band at 1190 cm -1 and S-H stretch at 2600 cm -1 [15]. Alkylation of 8 gave compound 9, while treatment with secondary amines resulted in compound 10 by nucleophilic displacement of the SH group. Further, reaction of 8 with propargyl chloride led to the introduction of alkynyl functionality, thus affording compound 11, as indicated by the strong band at 2100 cm -1 for the C≡C stretch and 3300 cm -1 for the ≡C-H stretching vibration, respectively. Treatment of 11 with secondary cyclic amines, namely morpholine, piperidine or piperazine, under Mannich reaction conditions resulted into the Mannich bases 12a-c, which was indicated by the disapperance of the ≡C-H vibration band.
In another triazole preparation, condensation of acid hydrazide 2 with phenyl isothiocyanate afforded the corresponding thiosemicarbazide 13 in moderate yield. Ring closure of arylthiosemicarbazides in an alkaline medium is a well known method for the synthesis of 1,2,4-triazoles and thus 5-(3-chloro-1-benzothien-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (14) was obtained from the corresponding 13 by this method. The IR spectra of 1,4-substituted thiosemicarbazide derivative 13 display a C=O stretching band at 1680 cm -1 and C=S stretching band at 1240 cm -1 . It is worth mentioning that compounds 8 and 14 exist as thiol -thione tautomers, as indicated by their IR spectra which showed a band due to SH and another band to N-C=S .

General
Melting points were determined in open capillary tubes on a Gallenkamp mething point apparatus and are uncorrected. The IR spectra (KBr discs) were recorded with a Pye-Unicam SP-300 spectrometer. UV spectra were recorded on Hitachi-2000 spectrophotometer using absolute ethanol as solvent. 1 H-NMR on a Hitachi-Perkin-Elmer 60 MHz NMR spectrometer in DMSO-d 6 solutions and with tetramethylsilane as an internal standard. Elemental analysis were done on a 1106 Carlo -Erba instrument.

Preparation of compounds 9a-c.
To the stirred solution of compound 8 (0.001 mole) and sodium acetate (0.0024 mole) in ethanol (20 mL), alkyl/aryl halide (0.001 mole) was added. The mixture was refluxed for 3 hours. After cooling, the solution was poured onto crushed ice (30 g). The precipitate was filtered and recrystallized from acetone -water.

Preparation of compounds 10a-c.
To a stirred solution of compound 8 (0.003 mole) in dry dioxane (10 mL) was added a solution of the appropriate secondary amine (0.003 mole) in dry dioxane (5 mL). The mixture was refluxed for four hours. After cooling, the precipitate was filtered and crystallized from methanol. General procedure for preparation of compounds 12a-c.
General procedure for preparation of compound 14.