Regioselective Synthesis of Some Pyrazole Scaffolds Attached to Benzothiazole and Benzimidazole Moieties

Condensation of 2-(benzothiazol-2-yl)acetonitrile (1) or 2-(1-methyl-1H-benzimidazol-2-yl)acetonitrile (2) with thiophene-2carbaldehyde afforded the corresponding acrylonitrile derivatives 3 or 4, respectively. The 1,3-dipolar cycloaddition reaction of the acrylonitrile 3 or 4 with nitrile-imine 6 gave novel pyrazole derivatives pendant to benzothiazole and benzimidazole. The pyrazoline derivative 7 was converted into the corresponding pyrazole derivative 11 via thermal elimination of hydrogen cyanide upon heating in sodium ethoxide solution. The structures of the synthesized products were confirmed by IR, H NMR, and mass spectral techniques.

General Procedure.To a mixture of acetonitrile 1 or 2 (10 mmol) and the thiophene 2-carbaldehyde (10 mmol) in ethanol (10 mL), piperidine (0.2 mL) was added, and the mixture was refluxed for 30 min.The formed coloured crystalline products were collected by filtration, washed with ethanol, and dried.Recrystallization from the appropriate solvent gave 3 or 4, respectively.

Synthesis of 5-Cyanopyrazole Derivatives 7 and 9
General Procedure.Equimolar quantities of the appropriate acrylonitrile 3 or 4 (5 mmol) and   -phenylbenzohydrazonoyl chloride 5 (5 mmol) were dissolved in dry benzene (20 mL).To the resulting solution, triethylamine (0.5 mL, 5 mmol) was added and the reaction mixture was stirred for 12 h, and then the solvent was distilled under reduced pressure.The oil residue was triturated with MeOH and the solid product was collected by filtration, washed with methanol, and recrystallized from the suitable solvent to afford the corresponding pyrazole derivatives 7 and 9, respectively.

Results and Discussion
The key starting materials 2-(benzothiazol-2-yl)acetonitrile (1) [30] and 2-(1-methyl-1H-benzimidazol-2-yl)acetonitrile (2) [31,32] are characterized by the presence of an active methylene as well as nitrile function which makes them active so they can be used as a precursors for the synthesis of biologically and chemically active compounds.In the present work, the synthetic potential of the acrylonitriles 3 and 4 has been explored.
Treatment of compound 3 with nitrile imine 6 (generated in situ from   -phenylbenzohydrazonoyl chloride 5 [33] by the action of triethylamine in benzene) afforded only one cycloadduct as deduced from TLC and 1 H NMR analysis of the crude reaction product (Scheme 2).The structure of the isolated cycloadduct was assigned as 5-(benzothiazol-2-yl)-1,3-diphenyl-4-(thiophen-2-yl)-4,5dihydro-1H-pyrazole-5-carbonitrile (7) based on its elemental analysis and its spectroscopic data.The distinction between the two possible regioisomeric cycloadducts 7 and 8 (Figure 1) was made on the basis of the IR and 1 H NMR spectra of the isolated product.
The structure of the product 7 was in agreement with its elemental analysis and spectroscopic data.Although compound 7 bears a nitrile function, its IR spectrum did not afford nitrile absorption band similar to the case of aliphatic nitriles activated by a nitrogen or oxygen atom in the position [34,35].This similarity of the absence of the nitrile absorption in the IR spectrum excludes the possibility of the other regioisomer 8 for the isolated product.This is because compound of type 8 is expected to exhibit strong nitrile absorption in their IR spectra [36].In analogous manner, the nitrile imine 6 added regioselectively to the carbon-carbon double bond of 2-(1-methyl-1H-benzimidazol-2-yl)-3-(thiophen-2-yl)acrylonitrile ( 4) in benzene at room temperature to afford 5-(1-methyl-1Hbenzoimidazol-2-yl)-1,3-diphenyl-4-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-5-carbonitrile (9) (Scheme 2).The structure of the latter product was assigned on the basis of its elemental analysis and spectral data.For example, its IR spectrum revealed no nitrile absorption band.Moreover, structure 9 was confirmed by 1 H NMR spectrum which revealed a sharp singlet signal at  5.66 assignable to the proton at C-4 of the pyrazoline ring.This chemical shift is very similar to those reported for the C-4 proton of 4,5-dihydro-1H-pyrazole derivatives [37].
When compound 7 was heated in ethanolic sodium ethoxide solution, it afforded the pyrazole derivative 11 in high yield (Scheme 3).The structure of the product was confirmed by 1 H NMR spectra, which revealed the disappearance of the proton signal at C-4.

Conclusion
We have successfully synthesized some pyrazole derivatives attached to benzothiazole and benzimidazole moieties of biological and pharmacological interest, via 1,3-dipolar cycloaddition reaction.