The Reaction of Cyanoacetic Acid Hydrazide with 2-Acetylfuran : Synthesis of Coumarin , Pyridine , Thiophene and Thiazole Derivatives with Potential Antimicrobial Activities

The hydrazide-hydrazone derivative 1 was formed through the reaction of cyanoacetic acid hydrazide with 2-acetylfuran. Compound 1 underwent a series of hetrocyclization reactions through its reaction with different chemical reagents to produce arylidene, coumarin, aryl hydrazone, pyridine, thiophene and thiazole derivatives 2–10. The MIC values for the newly synthesized products were tested against E. coli, B. cereus, B. subtilis and C. albicans compared with ampicilline and cycloheximide as reference drugs.


Results and Discussions
Cyanoacetylhydrazine reacts with 2-acetylfuran to give the hydrazide-hydrazone derivative 1.The structure of compound 1 was established on the basis of analytical and spectral data.Thus 1 H NMR spectrum showed the presence of a singlet at δ 1.01 ppm corresponding to CH 3 group, a singlet at δ 3.31 ppm for CH 2 group, a multiplet at δ 6.42-7.29 ppm for the furan protons and a singlet at δ 7.90 ppm for an NH group.Moreover, the 13 C NMR data showed the presence of δ 18.7 (CH 3 ), 27.9 (CH 2 ), 110.3, 129.6, 137.2, 143.9 (furan C), 156.9 (C=N), 168.4 (C=O).Further elucidation for the structure of 1 was obtained through studying its chemical reactivity through some chemical reagents.Thus, the reaction of 1 with aromatic aldehydes either benzaldehyde, 4-chlorobenzaldehyde or 4-methoxybenzaldehyde gave the benzalidene derivatives 2a-c, respectively.Analytical and spectral data are in agreement with the proposed structures.On the other hand, the reaction of 1 with salicylaldehyde gave the coumarin derivative 3. The reaction goes in analogy with the reported literature [16,17].The reaction of 1 with either benzenediazonium chloride, 4-chlorobenzenediazonium chloride and 4-methylbenzenediazonium chloride gave the aryl hydrazone derivatives 4a-c, respectively.
The reaction of compound 1 with cinnamonitrile derivatives was studied.Thus, the reaction of 1 with either α-cyanocinnamonitrile or ethyl α-cyanocinnamate gave the pyridine derivatives 6a and 6b, respectively.The reaction took place through the intermediate formation of 5a,b.Structures of 6a and 6b were based on analytical and spectral.Thus, the 1 H NMR spectrum of 6a showed the presence of a singlet at δ 1.05 corresponding to the CH 3 group, a singlet at δ 4.87 for an NH 2 group, a multiplet at δ 7.28-7.41phenyl and furan protons.Further confirmation for the structures of 6a and 6b were obtained through their synthesis via another reaction root.Thus, the reaction of compound 2a with either malononitrile or ethyl cyanoacetate gave the same pyridine derivatives 6a and 6b, respectively (m.p., mixed m.p. and fingerprint IR).The reaction of 1 with either malononitrile or ethyl cyanoacetate gave the pyridin-2-one derivatives 7a and 7b, respectively.Analytical and spectral data are consistent with the proposed structures.
The reaction of 1 with either malononitrile or ethyl cyanoacetate and elemental sulfur in the presence of triethyl amine gave the thiophene derivatives 8a and 8b, respectively.The reaction goes in parallel to the reported Gewald's thiophene synthesis [18].Similarly, the reaction of 1 with cyclohexanone and elemental sulfur gave the 4,5,6,7-tetrahydrobenzothiophene derivative 9. Formation of 9 took place according the similar reported reactions of cyclohexanone with methylene reagents and elemental sulfur [19].On the other hand the reaction of 1 with elemental sulfur and phenylisothiocyanate gave the thiazole derivative 10.Formation of the latter product took place in parallel to the reported Hanzesch reported reaction [20].Structures of compounds 9 and 10 were based on analytical and spectral data.According to the results shown in Table 1, only two compounds 1 and 4b are moderately active against E. coli in the concentrations tested (average MIC 12.5 μgmL -1 ), the cyanoacetyl and 4-chlorophenyl derivatives of furan moieties being responsible for such activity.However, compound 1 was the higher active compound.Compounds 2a, 6b and 7b are highly active compounds against B. Cereus.Also compound 6b showed the highest activity towards B. subtilis with respect to ampicilline.The compounds 2c, 4a, 6a and 8b shows the highest activity against C. albicans.Comparing the SAR of compounds 6a,b compound 6b with the Ethylester group showed the highest activity towards B. subtilis.On the other hand considering the hydrazone derivatives 4a-c, the phenylhydrazone Sci Pharm.2009; 77; 355-366.compound 4a showed the highest activity towards C. albicans.Substitution with 4-chloro group as in 4b showed no activity towards C. albicans.Compounds 6a,b and 7a,b (the substituted hydrazone derivatives) one can notice that the activity against B. cereus was increased due to the existence of the pyridine ring, but compounds 6b and 7b are higher active than the corresponding 6a and 7a due to the presence of the ethyl pyridine-3carboxylate moiety and hydroxy group respectively.Finally compound 6b is the only highest active against B. subtilis due to the presence of the ethyl pyridine-3-carboxylate moiety.

Synthetic methods, analytical and spectral data
Melting points were determined on an electrothermal apparatus (Buchi 535, Switzerland) in an open capillary tube and are uncorrected.Elemental analyses were determined on a Yanaco CHN Corder elemental analyzer (Japan).IR spectra expressed in (ν cm -1 ) were recorded in KBr pellets on a PA-9721 IR spectrophotometer (Shimadzu, Japan). 1 H NMR & 13 C NMR spectra were obtained on a Jeol 300 MHz (Japan) spectrometer in DMSO-d 6 as solvent, using TMS as internal reference and chemical shifts (δ) are expressed in ppm.Mass spectra were recorded on Kratos (75e-v) Ms Equipment (Germany).Synthetic pathways are presented in Schemes 1, 2 and 3. Physicochemical and spectral data for the synthesized compounds are given.The antimicrobial activities of the tested compounds are given in the table.All compounds produced in this work are novel.

Antimicrobial Activity
The in vitro antimicrobial activity of the newly heterocyclic derivatives against two strains of Gram positive bacteria (Bacillus subtilis CECT 498 and Bacillus cereus CECT 148), one