Synthesis and Analysis of Some Bis-Heterocyclic Compounds Containing Sulphur

A facile and convenient synthesis of a series of bisheterocycles 7a,b 10, 12 and 13a,b containing a thieno[2,3-b]thiophene base unit via the versatile, hitherto unreported 3-[3,4-dimethyl-5-(3-nitrilopropanoyl)thieno[2,3-b]thiophen-2-yl]-3-oxopropanenitrile (4) is described.

Thienothiophene derivatives have been developed for different purposes in the pharmaceutical field and have been tested as potential antitumor, antiviral, antibiotic, and antiglaucoma drugs, or as inhibitors of platelet aggregation [16][17][18][19][20]. Recently Mashraqui [10] described the first application of thieno [2,3-b]thiophene in the design of a novel NLO system by incorporating this nucleus within an unsymmetrically functionalized cyclophane. On the other hand, pyrazolopyrimidine compounds have been found to be useful as pharmaceutically interesting compounds [21,22].
However, little is known in the literature about thienothiene derivatives with different features and applications, and there is no report of a generally useful synthesis of thienothiene derivatives,

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compounds which are of considerable interest as potential biological active compounds or pharmaceuticals. In light of these findings we report here the synthesis of some novel bis-heterocycles containing thieno [2,3-b]thiophene as a base unit.
Prompted by the aforementioned results, we have also investigated the reactivity of 5 and 6 towards 5-amino-3-phenyl-1H-pyrazole (8a). Thus, reaction of 5 and 6 with this compound in refluxing ethanol/DMF, in the presence of piperidine gave 6-[5-(7-cyanopyrazolo[1,5-a]pyrimidin-6-yl)-3,4dimethylthieno[2,3-b]thiophen-2-yl]-2-phenylpyrazolo[1,5-a]pyrimidine-7-carbonitrile (10) (Scheme 2). The structure of the obtained product was assigned as 10 and not the other expected derivative 9 based on spectral data. The IR spectrum of the reaction product revealed, in each case, no bands due to amino or carbonyl functions. Moreover, the 1 H NMR spectrum of compound 10, revealed two singlet signals at δ 7.79 and 8.9 due to pyrazole and pyrimidine CH protons, respectively. The formation of product 10 is assumed to take place via the addition of the exocyclic amino group in 5-amino-3phenyl-1H-pyrazole (8a) to the activated double bond in compounds 5 or 6 which then undergo intramolecular cyclization and subsequent aromatization via the loss of dimethylamine and water molecules under the reaction conditions to give 10 as depicted in Scheme 2. Further evidence for the proposed structure 10 was obtained by treatment of 5-(N,N dimethylaminomethylene)imino-3-phenyl-1H-pyrazole (8b) [23] with 4 in ethanol/DMF in the presence of a catalytic amount of piperidine to afford a product indentical in all respects with that obtained from the reaction of 5 or 6 with 5-amino-3-phenyl-1H-pyrazole (Scheme 2).
Reactions of 4 with aromatic diazonium salts were also investigated. Thus, treatment of bis-3oxopropanenitrile 4 with diazotized aromatic amines (aniline and p-chloroaniline) in cold ethanol/DMF, in the presence of sodium acetate trihydrate afforded the corresponding hydrazone derivatives 11a,b (Scheme 3).
The 1 H-NMR spectrum of 11a, for example, displayed besides an aromatic multiplet at δ 6.40-7.1 ppm, singlet signals at δ 2.22 and 9.20 ppm corresponding to methyl and hydrazone NH protons, respectively. Also, the IR spectra showed, in each case, absorption bands at 3200, 2220 and 1716 cm -1 due to NH, CN and CO groups, respectively. The latter hydrazones 11a,b underwent intramolecular cyclization upon treatment with hydrazine hydrate to give products identified as the 3-aminopyrazole derivatives 13a,b. The IR spectrum of 11a,b showed, in each case, the absence of nitrile and carbonyl bands and revealed the appearance of three bands in the 3340-3100 cm -1 region due to NH 2 and NH groups as depicted in Scheme 3.
The 13 C-NMR spectrum of 13a, for example, revealed twelve carbon types. Its 1 H-NMR spectrum displayed singlets at δ 4.21 and 12.7 ppm attributable to the NH 2 and NH protons, respectively. Compounds 13a,b were alternatively obtained by reaction of treatment of bis(aminopyrazole) derivative 12 with diazotized aromatic amines (aniline and p-chloroaniline) in cold ethanol/DMF, in the presence of sodium acetate trihydrate. Compound 12 was prepared by the reaction of 4 with hydrazine hydrate in refluxing ethanol (Scheme 3).

General
All melting points were measured on a Gallenkamp melting point apparatus. IR spectra were measured as KBr pellets on a Pye-Unicam SP 3-300 spectrophotometer. The NMR spectra were recorded on a Varian Mercury VX-300 NMR spectrometer. 1 H-NMR (300 MHz) and 13 C-NMR (75.46 MHz) were run in dimethylsulphoxide (DMSO-d 6 ). Chemical shifts were related to that of the solvent. Mass spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Elemental analysis was carried out on an Elementar Vario EL analyzer. Thieno[2,3-b]thiophene derivatives 1,2 were prepared following literature procedures [24,25].
Treatment of compounds 5 or 6 (1 mmol) with hydrazine hydrate and with phenyl hydrazine (0.1 mL) in dry ethanol (15 mL) under reflux for 5 h afforded the corresponding derivatives 7a,b, respectively. The solid products so formed was filtered off, washed with ethanol, dried and recrystallized from DMF/EtOH).   (20 mL), in the presence of piperidine (0.3 mL), was heated under reflux for 6 h. The solvent was removed by distillation under reduced pressure and the remainder was left to cool. The precipitated solid product was collected by filtration. Recrystallization from EtOH/DMF afforded a product identical in all respects (mp, mixed mp, TLC, IR, and mass spectra with 10.