Synthesis of New Cyano-Substituted bis-Benzothiazolyl Arylfurans and Arylthiophenes

The new compounds 2-[4-(6-cyanobenzothiazol-2-yl)phenyl]-5-(6-cyano- benzothiazol-2-yl)furan (6a) and 2-[4-(6-Cyanobenzothiazol-2-yl)phenyl]-5-(6-cyano- benzothiazol-2-yl)thiophene (6b) were synthesized by multi-step reactions from the corresponding 2-furan and 2-thiophene carboxaldehydes (route A), as well as from 2- furan and 2- thiophene carboxylic acids (route B). Route B involves one less step than route A, but the overall yields of the reactions are considerably lower.

On the other hand, bis-benzothiazoles and substituted bis-benzothiazoles are frequently fluorescent compounds and therefore convenient for fluorimetric measurements, which could serve as a potential method for detection of binding the biologically active compounds on DNA [15]. However, there is little data describing compounds containing two benzothiazole rings attached via a heterocyclic system, such as 2,5-benzothiazolylfuran and thiophene and its derivatives [16,17,18], as well as their vinylogues [19,20].

Results and Discussion
Cyano substituted bis-benzothiazolyl compounds 6a and 6b were synthesized starting from 2furan-and 2-thiophenecarboxaldehydes or from 2-furan-and 2-thiophenecarboxylic acids via multistep reactions by the two routes designated A and B, respectively (Scheme 1).
Benzothiazolyl compounds 3a and 3b, synthesized from the appropriate aldehydes and 4-amino-3mercaptobenzonitrile [22], according to a modified condensation method [18,23], have been converted to the corresponding chlorocarbonyl derivatives 4a and 4b. In the last step (route A), these chlorocarbonyl compounds were condensed with 4-amino-3mercaptobenzonitrile to obtain the biscyanobenzothiazolyl compounds 6a and 6b in good yields of about 75%.

General
Melting points were determined on a Koffler block apparatus and are uncorrected. IR spectra were determined with a Nicolet Magna 760 infrared spectrophotometer using KBr pellets. 1 H-NMR spectral data were determined with a Brucker Avance DPX 300 MHz NMR spectrometer with tetramethylsilane as an internal standard. Elemental analyses were carried out in the Microanalytical Laboratory at the Rugjer Boskovic Institute.
A solution of p-aminobenzoic acid (75 mmol) in water (120 mL) and concentrated HCl (40 mL) was cooled to 5 °C and diazotized with a solution of NaNO 2 (91 mmol) in H 2 O (35 mL). After 20 min a solution of 75 mmol of 2-furanaldehyde for 1a [20], 2-thiophenealdehyde for 1b [21], 2-furancarboxylic acid for 2a [20] or 2-thiophenecarboxylic acid for 2b, respectively, in acetone (50 mL) and a solution of CuCl 2 ·2H 2 O (23 mmol) in water (25 mL) were added to the stirred reaction mixture. The reaction mixture was left to stand at room temperature for two days with occasional shaking. After dilution with water (500 mL) the precipitated crystals were filtered off and washed with abundant hot water. 4-Amino-3-mercaptobenzonitrile (21 mmol) was added to a solution of the appropiate aldehyde 1a or 1b (21 mmol) in pyridine (60 mL) and the stirred reaction mixture was refluxed 4 h. The mixture was then poured into 2 M hydrochloric acid (400 mL), and after cooling overnight, the crystalline product obtained was oxidized with an ethanolic solution of FeCl 3 to obtain the benzothiazole compounds 3a and 3b, respectively.  General Procedure for the Synthesis of Chlorocarbonyl Compounds 4a, 4b, 5a and 5b.

General Procedure for the Synthesis of bis-Benzothiazolyl Compounds 6a and 6b.
A solution of monochlorocarbonyl compounds 4a or 4b (5.0 mmol, route A), or of dichlorocarbonyl compounds 5a or 5b (2.5 mmol, route B) in dry chlorobenzene (100 mL) was stirred under a stream of nitrogen. To these solutions 4-amino-3-mercaptobenzonitrile (5.1 mmol) was added. The reaction mixture was heated under reflux under the stream of nitrogen for 70 h. After cooling, a crystalline product was obtained.