New non-symmetrical 2,5-disubstituted 1,3,4-oxadiazoles bearing a benzo[ b ]thiophene moiety

A series of new 2,5-disubstituted-1,3,4-oxadiazoles derived from benzo[ b ]thiophene was obtained by dehydrative cyclization of the corresponding N,N’-diacylhydrazines, in presence of an excess of phosphorous oxychloride. The structures of the new synthesized compounds were confirmed by spectral analysis.


Results and Discussion
Synthesis of the 2,5-disubstituted-1,3,4-oxadiazoles required in a first step the preparation of the starting materials, namely the 3-chlorobenzo[b]thiophene-2-carboxyl chloride 1 and the acylhydrazides 2. The synthesis of 1 was described by Higa and Krusbsak 19 and consists in treatment of cinnamic acid with thionyl chloride, in chlorobenzene at reflux, in presence of pyridine.The acylhydrazides 2 were obtained from ethyl esters in reaction with 100% hydrazine hydrate in very good yields, according to the literature. 20(Scheme 1) All known compounds were characterized by NMR spectral analysis to confirm the structure.The key intermediates for the synthesis of the 2,5-disubstituted-1,3,4-oxadiazoles 4 are the N,N'-diacylhydrazines 3, which form as a result of the reaction between the acid chloride of 3chlorobenzo[b]thiophene-2-carboxylic acid 1 and acylhydrazides 2, in tetrahydrofuran, in presence of sodium bicarbonate (Scheme 2).All compounds are colorless crystals, except the compound 3f, which is yellow.The melting points are high, over 180 ºC in all cases.The compounds bearing nitro groups have the highest melting points.
The synthesis of 2,5-disubstituted-1,3,4-oxadiazoles was performed by treatment of N,N'diacylhydrazines 3 with an excess of POCl 3 in toluene at reflux. 21By this method the new compounds 4 were obtained in good yield as colorless crystals, except from the compound 4f, which is yellow, similar to the corresponding N,N'-diacylhydrazine.The new compounds were characterized by elemental analysis, IR, NMR spectroscopy and mass spectrometry.NMR structural assignments were made on the basis of chemical shifts, coupling constants and by comparison with literature data for similar compounds.The 1 H-NMR and 13 C-NMR spectra of compounds 3a-g and 4a-g show all expected signals.In both cases, the appearance and chemical shifts of the protons from the benzo[b]thiophene ring are very similar to those from unsubstituted benzo[b]thiophene.
The carbonyl groups from compounds 3a-g appear at ca. 160 ppm for the thiophene linked carbonyl and at ca. 165 ppm for the aryl linked one.However, in the case of 3b, where the aryl substituent is replaced by a benzyl moiety, the signal for the corresponding carbonyl is shifted upfield by ca. 5 ppm.This proves the lack of conjugation between the benzyl moiety and the carbonyl group.
In the 13 C-NMR spectra of compounds 4a-g, the two carbon atoms from the oxadiazole ring appear at ca. 160 ppm for the one linked to the benzo[b]thiophene moiety and at ca. 165 ppm for the one linked to the aryl group.The assignments were made by comparing with NMR data for 2,5-diphenyl-1,3,4-oxadiazole provided by Aldrich.The same chemical shifts are also observed in the case of intermediates 3a-g, proving the negligible effect of the substituents in positions 2 and 5 on the oxadiazole ring.These very high chemical shift values are due to the fact that both carbon atoms are part of a C=N double bond and a single C-O bond.Furthermore, when changing the aryl group with a benzyl moiety (compound 4b), no significant change was observed in the chemical shifts of the carbon atoms from the 1,3,4-oxadiazole ring.One may explain this phenomenon by the lack of conjugation between the oxadiazole ring and the aryl moiety and may assume that the two rings are not planar.

Experimental Section
General Procedures.All chemicals were obtained from commercial sources and used without any further purification.The melting points were determined in open capillaries using a STUART SMP3 electrical melting point apparatus and are uncorrected.The IR spectra were recorded on a Brucker Vertex 70 spectrometer, in the range 4000-400 cm -1 .The elemental analysis was performed on a COSTECH Instruments EAS32 apparatus.The NMR spectra were recorded on a Varian Gemini 300 BB instrument, operating at 300 MHz for 1 H and 75 MHz for 13 C, in DMSO-d 6 or CDCl 3 , using TMS as internal standard.Mass spectra were obtained on a Finnigan MAT 90 spectrometer using CI technique (150eV, isobutane).Thin Layer Chromatography was performed on silicagel plates (Merck) and visualization was made using UV light (λ=254 nm).The 3-chlorobenzo[b]thiophene-2-carboxyl chloride 1 19 and the acylhydrazides 2a-g 20 were prepared as described, and their purity was confirmed by means of melting points and NMR analysis.
General procedure for synthesis of N,N'-diacylhydrazines 3a-g. 10 To an aqueous suspension of 10 mmoles of acylhydrazine 2a-g in presence of stoechiometric amount of NaHCO 3 , 10 mmoles of acid chloride 1, dissolved in tetrahydrofuran, were added dropwise.The reaction mixture was stirred at reflux for 30 min, and then it was allowed to react overnight, at room temperature.The resulted precipitate was filtered, dried and recrystallized from the appropriate solvent to isolate the products 3a-g.