A Novel and Expedient Approach to New Thiazoles, Thiazolo[3,2-a]pyridines, Dihydrothiophenes, and Hydrazones Incorporating Thieno[2,3-b]thiophene Moiety

This paper reports details about the synthesis of a series of novel functionalized symmetrical bis-heterocyclic compounds containing a thieno[2,3-b]thiophene motif. Bis-thiazole derivatives 2, 3a-c and thiazolo[3,2-a]pyridine derivatives 4a-c are achieved. The hitherto unknown dihydrothiophene derivatives 6a-d via bis-pyridimium salt 5 are obtained. Additionally, the novel hydrazonothieno[2,3-b]thiophene derivatives 10a-c are obtained via bis-tosylacetylthieno[2,3-b]thiophene derivative 9. All compounds are characterized by 1H-, 13C-NMR, GCMS, IR, and UV-vis spectrometry. These compounds represent a new class of sulfur and nitrogen containing heterocycles that should also be of interest as new materials.


Results and Discussion
Refluxing of equimolar amounts of the bis-2-bromoacetylthieno [2,3-b]thiophene derivative 1 and cyanothioacetamide in ethanol and in the presence of a catalytic amount of TEA, afforded the corresponding bis-thiazole derivative 2. The structure of the isolated cycloadduct was identified as 2,2'-(4,4'-(3,4'-dimethylthieno [2,3-b]thiophene-2,5-diyl)bis(thiazole-4,2-diyl))diacetonitrile (2) on the basis of its elemental analyses and spectral data. The IR spectrum of the reaction product exhibited absorption bands at 2259 cm −1 due to the nitrile group. The 1 H-NMR spectrum of compound 2 revealed three singlets at δ 2.21, 3.79 and 7.80 due to methyl, methelene and CH thiazol protons, respectively. The reactivity of compound 2 towards some heterocyclic aldehydes was also investigated. Thus, the treatment of compound 2 with aldehyde derivatives in ethanol and in the presence of a catalytic amount of TEA afforded bis-thiazole derivatives 3a-c. The 1 H-NMR spectrum of 3a showed three singlets at δ 2.28, 8.50 and 8.84 due to CH 3 , CH and CH thiazol protons respectively, in addition to an aromatic multiplet in the region 6.99-7.40. Compounds 3a-c were alternatively obtained by the reaction of the treatment of bis-2-bromoacetylthieno [2,3-b]thiophene derivative 1 with 2-cyano-2-arylmethylene-thioacetamide derivatives in ethanol/DMF (Scheme 1). Treatment of the bis-thiazole derivatives 3a-c with malononitrile afforded the corresponding thiazolo pyridine derivatives 4a-c (Scheme 1). Compounds 4a-c were alternatively obtained by reaction of the treatment of bis-thiazole derivative 2 with 2-cyano-2-arylmethylenethioacetamide derivatives in ethanol/DMF (Scheme 1). On the other hand, compounds 4a-c underwent a thermal intramolecular cyclization reaction via an initial Michael type adduct. The IR spectrum of compound 4b, taken as a typical example of the prepared series, revealed absorption bands at 2241, 2193, and 3383-3320 cm −1 corresponding to two nitrile and amino functions, respectively. Its 1 H-NMR spectrum showed signals at δ 2.31, 4.57, 4.72, and 9.23, due to CH 3 , CH 2 , NH 2 and CH thiazol protons respectively, in addition to an aromatic multiplet in the region 6.99-7.40. An aromatic multiplet in the region δ 7.49-7.60 was also found. Its mass spectrum revealed a molecular ion peak at m/z 789.

Scheme 1. Synthesis of thiazolo[3,2-a]pyridine derivatives 4a-c.
Our study was extended to include the synthesis of new bis-dihydrothiophene derivatives 6a-d. Thus, the bis-2-bromoacetylthieno [2,3-b]thiophene 1 was refluxed in a mixture of absolute ethanol, pyridine and THF for 1 h to give a single product of bis-pyridimium salt 5 as examined by TLC. Elemental analyses and mass spectrum analysis of the isolated product were completely in agreement with the molecular formula C 22 H 20 Br 2 N 2 O 2 S 2 . The structure of the product is assumed to be 5 according to the rationale outlined in Scheme 2 in 95% yield. The compound reacts with (E)-3-amino-2-benzyl-3-mercaptoacrylonitrile which is in resonating structure with (E)-2-cyano-3phenylprop-2-enethioamide in refluxing ethanol which undergoes intramolecular cyclization to give compound 6a in 86% yield. The 1 H-NMR of compound 6a was free of pyridine protons and exhibited two characteristic doublet signal at 4.40, 4.70 pmm integrated for 2H (for the C-H proton of the dihydrothiophene moiety). In addition, one broad signal at 4.19 ppm was integrated for 2H proton (for the NH 2 ). Furthermore, CN and NH absorption appeared at 2187, 3450 cm -1 , respectively, in the IR.
It is noteworthy to mention here that the bis-dihydrothiophene derivatives 6b-d with different moieties were also prepared from bis-pyridimium salt 5 and the corresponding aryl-mercaptoacrylonitrile derivatives but in very good yield, as depicted in Scheme 2.

Scheme 2. Synthesis of dihydrothiophene derivatives 6a-d.
There has been continuous interest in the synthesis of a new hydrazono system containing sulfone moiety because it holds considerable interest relative to the preparation of organic intermediates and physiologically active compounds. Thus, when the bis-2-bromoacetylthieno [2,3-b]thiophene 1 was treated with sodium 4-methylbenzenesulfinate in a mixture of absolute ethanol and DMF under reflux for 4 h, it afforded a white crystalline product, namely the bis-tosylacetylthieno [2,3-b]thiophene derivative 9 in a 97% yield, and its use as key intermediate for the synthesis of a wide variety of bis-(hydrazones) derivative 10 is shown in Scheme 3.
When bis-tosylacetylthieno [2,3-b]thiophene derivative 9 were allowed to react with benzenediazoniumchloride, which had been prepared in situ from the corresponding aniline in hydrochloric acid with aqueous sodium nitrite in dioxane at 0-5 °C, it resulted in a single product as examined by TLC. Elemental analyses and mass spectrum analysis of the isolated product were completely in agreement with the molecular formula C 40 H 32 O 6 S 4 . The structure of the product is assumed to be 10a according to the rationale outlined in Scheme 3 in a 76% yield. The structure of compound 10a was substantiated from its elemental and spectral analyses. Its IR spectrum showed the presence of an absorption band characteristic for NH as well as the presence of C=N absorption at 3217, and 1627 cm −1 , respectively. The fact that the 1 H NMR of compound 10a was free of tosylacetyl protons in the 1 H NMR spectrum strongly supported this assignment.
Finally, having now available the new bis-tosylacetylthieno [2,3-b]thiophene derivative 9 prompted us to study its synthetic utility as a key intermediate for novel symmetrical bis-(hydrazono) heterocycles 10b,c. Following the same methodology as described for 10a resulted in the formation of the bis-(hydrazone) derivatives 10b and 10c in 81% and 77% yield, respectively, and as depicted in Scheme 3. The structures of compounds 10b,c were inferred from different spectroscopic and analytical data.

Experimental Section
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-400 NMR spectrometer. 1 H-NMR and 13 C-NMR (400 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 analyses was carried out on an Elementar Vario EL analyzer. [2,3-

Method B:
To a solution of 2 (0.41 g, 1 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), aromatic aldehyde derivatives (2 mmol, 2.0 equiv) were added, the reaction mixture was then heated under reflux for 6-7 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 3a-c.

General Procedure for the Synthesis of Compounds 4a-c (GP2)
Method A: To a solution of 2 (0.41 g, 1 mmol, 1.0 equiv) in mixture of absolute ethanol (20 mL, 99.9%) and DMF (5 mL), 2-arylidenemalo nonitril derivatives (2 mmol, 2.0 equiv) were added, the reaction mixture was then heated under reflux for 4 h. The solution was allowed to cool to room temperature. The solid product was collected by filtration and recrystallized from EtOH/DMF to afford the compound 4a-c.

Conclusions
In conclusion, the present investigation describes an efficient method for access toward novel bis-heterocycles containing biologically active moieties. We believe that these new series of symmetrical bis-hetrocycles may exhibit potentially diverse useful applications in the field of medicinal chemistry.