Synthesis and antimicrobial evaluation of some new thiophene derivatives

Article abstract of DOI:10.1080/00397910903161652

2-(2-Cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3- carboxamide(3) was used as starting material for synthesis of 4-thiazolidinone, thiazolidine, and thiophene derivatives 6, 7a, b, and 8a, b, respectively. Thiocarbomyl derivative 5, 4-thizolidinone 9, and thioxothiazolidine 10 were obtained from reaction of 3 with thioglycolic acid and phenyl isothiocyanate/sulfur, respectively. Condensation of 3 with selected cyclic ketones and aromatic aldehydes yielded the arylidine derivatives 11a, b and 13, respectively. Refluxing of 11a, b with sulfur and morpholine yielded the thiophene derivatives 12a, b, respectively. Diazocoupling of compound 3 withp-tolyl diazonium chloride yielded the hydrazone derivative 14. The newly synthesized compounds were characterized by infrared, 1H NMR, and mass spectral studies. Representative compounds of the synthesized product were tested and evaluated as antimicrobial agents. Compound 12b gives very high antimicrobial activity against Ampicillin. Copyright

Full text of DOI:10.1080/00397910903161652

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Synthesis and Antimicrobial Evaluation
of Some New Thiophene Derivatives
A. M. Khalil a , M. A. Berghot a , Ghada E. Abd El-Ghani a & M. A.
Gouda a
a Department of Chemistry, Faculty of Science, Mansoura University,
Mansoura, Egypt
Published online: 06 May 2010.
To cite this article: A. M. Khalil , M. A. Berghot , Ghada E. Abd El-Ghani & M. A. Gouda
(2010): Synthesis and Antimicrobial Evaluation of Some New Thiophene Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:11, 1658-1669
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Synthetic Communications1, 40: 1658–1669, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903161652
SYNTHESIS AND ANTIMICROBIAL EVALUATION
OF SOME NEW THIOPHENE DERIVATIVES
A. M. Khalil, M. A. Berghot, Ghada E. Abd El-Ghani,
and M. A. Gouda
Department of Chemistry, Faculty of Science, Mansoura University,
Mansoura, Egypt
2-(2-Cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide(3) was
used as starting material for synthesis of 4-thiazolidinone, thiazolidine, and thiophene
derivatives 6, 7a, b, and 8a, b, respectively. Thiocarbomyl derivative 5, 4-thizolidinone 9,
and thioxothiazolidine 10 were obtained from reaction of 3 with thioglycolic acid and phenyl
isothiocyanate/sulfur, respectively. Condensation of 3 with selected cyclic ketones and aro-
matic aldehydes yielded the arylidine derivatives 11a, b and 13, respectively. Refluxing of
11a, b with sulfur and morpholine yielded the thiophene derivatives 12a, b, respectively.
Diazocoupling of compound 3 withp-tolyl diazonium chloride yielded the hydrazone deriva-
tive 14. The newly synthesized compounds were characterized by infrared, 1H NMR, and
mass spectral studies. Representative compounds of the synthesized product were tested
and evaluated as antimicrobial agents. Compound 12b gives very high antimicrobial activity
against Ampicillin.
Keywords: Ampicillin; antimicrobial evaluation; thiazolidine; thiazolidinone; thiophene; thiophene
derivatives
INTRODUCTION
Substituted 2-aminothiophene are important intermediates, extensively studied
because of their biological activities,[1] that have recently found application in the
syntheses of compounds such as allosteric enhancers of adenosine A1 receptor,[2]
antibacterial compounds,[3] GABAB allosteric enhancers for treating central nervous
system disorders,[4] kinase inhibitors,[5] and more recently as antitubercular drugs
against Mycobacterium tuberculosis H37RV[6] and as anti-Alzheimer drugs.[7] In
view of these findings and in continuation of our efforts to design new, potent,
selective, and antimicrobial compounds, we report here the synthesis of some new
heterocyclic systems incorporated with the thiophene moiety, starting from
2-(2-cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (3),[8]
in order to investigate their antimicrobial activity.
Received February 10, 2009.
Address correspondence to M. A. Gouda, Department of Chemistry, Faculty of Science, Mansoura
University, Mansoura 35516, Egypt. E-mail: dr_mostafa_chem@yahoo.com
1658

NEW THIOPHENE DERIVATIVES
1659
RESULTS AND DISCUSSION
Chemistry
The synthetic procedures adopted to obtain the target compounds are depicted
in Schemes 1–3. The starting compound 2-(2-cyano-acetylamino)-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxamide (3)[8] was obtained by treatment of 1 with
chloroacetyl chloride[9] and subsequent treatment with potassium cyanide in
dimethylformamide (DMF). The structure of compound 3 was established by spec-
tral data. The infrared (IR) spectrum showed a characteristic absorption band at
1
2242 cmꢀ1 due to the CN group. The H NMR spectrum revealed the presence of
a singlet signal, equivalent to two protons at d 4.14 ppm, which represents the meth-
ylene protons of the cyanoacetamide group. Moreover, the mass spectrum exhibited
the molecular ion peak at m=z 263, which is in agreement with the molecular formula
C12H13N3O2S. In view of the synthetic importance of thiocarbomyl derivatives[10–20]
and the biological results of compounds that contain thiazolidinone,[20,21] thiazoli-
dine,[21,22] and thiophene[23] moieties, our attention was directed to incorporating
the benzo[b]thiophene nucleus into these ring systems. Thus, the base-catalyzed reac-
tion of compound 3 with phenyl isothiocyanate yielded the nonisolable potassium
Scheme 1.
Scheme 2.

1660
A. M. KHALIL ET AL.
Scheme 3.
salt of thiocarbamoyl derivative 3, which was then acidified with dilute hydrochloric
acid to afford the thiocarbamoyl derivative 5 (Scheme 1).
The reaction of 5 with ethyl choroacetate, chloroacetone, or phenancyl chlor-
ide in DMF under refluxing conditions afforded the corresponding thiazolidinone
and thiazolidine derivatives 6 and 7a, b, respectively. The analytical and spectral data
are in agreement with the proposed structure. Thus, the IR spectrum of compound 6
showed an absorption band at 1737 cmꢀ1 due to the carbonyl group of thiazolidin-
1
4-one nucleus, and the H NMR spectrum displayed a singlet signal, equivalent to
two protons at 4.15 ppm, which represented to C5 protons of thiazolidin-4-one
nucleus. Moreover, the IR spectrum of compounds 7a and 7b showed the presence
of an NH group in the 3448–3065 cmꢀ1 region, a cyano group in the 2179–2178 cmꢀ1
region, and two carbonyl groups in the 1669–1655 cmꢀ1 region, whereas the reaction
of 5 with chloroacetone or phenacyl chloride in DMF and in the presence of a
catalytic amount of triethylamine (TEA) yielded thiophene derivatives 8a, b. The
structures of compounds 8a and 8b were established by spectral data. The IR
spectrum of compound 8a showed the absence of the typical cyano group at the
region 2187 cmꢀ1, indicating that the cyano group was lost during the reaction.
1
The H NMR revealed three singlet signals at 1.85, 10.9, and 12 ppm due to CH3,
NHPh, and NHCO protons, respectively (Scheme 2).
On the other hand, 2-[4-oxothiazolidinone]-cyanoacetamido derivative 9 was
obtained by the reaction of 3 with thioglycolic acid through modification of the pre-
1
viously reported method for the synthesis of analogs.[24–27] The H NMR spectrum
of compound 9 revealed the presence of methylene protons of the thiazolidinone
ring at d 4.09 ppm, while its mass spectrum exhibited the molecular ion peak at
m=z 368 (Mþ), corresponding with the molecular formula C13H15N3O3S2. In
view of the growing biological importance of the 4-amino-3-phenyl-2-thioxo-2,3-
dihydrothiazole derivative,[24] we decide to synthesize novel derivatives. Thus,

NEW THIOPHENE DERIVATIVES
1661
stirring 3 with sulfur and phenyl isothiocynate in a mixture of DMF and absolute
ethanol containing a catalytic amount of triethylamine at 60 ꢁC yielded the corre-
sponding 2-[2-thioxothiazoline]-cyanoacetamido derivative 10. The mass spectrum
of 10 exhibited the molecular ion peak at m=z 430 (Mþ), corresponding to the
molecular formula C19H18N4O2S3.
2-[2-Cycloalkylidene]-cyanoacetamido derivatives 11a, b were prepared by con-
densation of compound 3 with the appropriate cyclic ketone in ethanol and sodium
acetate. Treatment of compounds 11a or 11b with elemental sulfur in absolute etha-
nol containing morpholine as catalyst under refluxing conditions yielded 12a and
12b, respectively. Compounds 12a and 12b were also obtained directly by one-pot
Gewald reaction of 3 with the same selected cyclic ketones and elemental sulfur in
ethanol containing morpholine. Mass spectrum of 12b exhibited the molecular ion
peak at m=z 375 (Mþ), corresponding to the molecular formula C18H21N3O2S2.
Similarly, 2-[2-arylidene]cyanoacetamido derivatives 13a, b were obtained by con-
densation of 3 with the appropriate aromatic aldehyde in ethanol containing a cata-
1
lytic amount of pipridine. The H NMR spectra of 13a, b revealed signals at d 8.43
and 8.59 ppm, respectively, due to a methine proton. The mass spectrum of com-
pound 13a exhibited the molecular ion peak at m=z 385 (Mþ), corresponding to
the molecular formula C18H16N3O2SCl. Diazo coupling of compound 3 with of
p-tolyldiazonium chloride in pyridine yielded the hydrazone derivative 14. The IR
1
and the H NMR spectra of compound 14 revealed the existence of two possible
=
tautomeric forms, ꢀCH(CN)ꢀN NꢀAr and ꢀC(CN) ¼ NꢀNHꢀAr. The IR
ꢀ1
spectrum showed NH stretching absorption at 3166 cmꢀ1 and N N at 1527 cm
.
=
Also, the 1H NMR spectrum revealed NH signals at d 12.3 and 13.3 ppm (Scheme 3).
Pharmacology
Antimicrobial evaluation. Ten compounds were screened in vitro for their
antimicrobial activities against two strains of bacteria, Bacillus thuringiensis and
Klebsiella pneumoniae, and two strains of fungi, Botrytis fabae and Fusarium oxy-
sporum, by the agar diffusion technique.[28] A 0.15 mg=ml solution in dimethylsulf-
oxide (DMSO) was used. The bacteria and fungi were maintained on nutrient agar
and Czapek–Dox agar media, respectively. DMSO showed no inhibition zones.
The agar media were incubated with different microorganism cultures. After 24 h
of incubation at 30 ꢁC for bacteria and 72 h of incubation at 28 ꢁC for fungi, the
diameter of inhibition zone (mm) was measured (Table 1). Ampicillin from the
Egyptian market used in a concentration of 25 mg=ml was as reference for antibac-
terial and antifungal activities. The results for antibacterial activities are depicted
in Table 1.
The results depicted in Table 1 reveal that most of the synthesized compounds
showed good antimicrobial activity, especially compounds 10, 12b, and 13c, with
respect to the reference chemotherapeutic. It is worth mentioning that incorporation
of the thiophene or thiazole nucleus to 4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxamide nucleus produced high antimicrobial activity. In conclusion, we report
herein a simple and convenient route for the synthesis of some new heterocycles
based on 2-(2-cyano-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide
(3) for antimicrobial evaluation.

1662
A. M. KHALIL ET AL.
Table 1. Inhibition zone (mean diameter of inhibition in mm) as a criterion of antibacterial
and antifungal activities of the newly synthesized compounds
Bacteria
Fungi
Gram-positive
bacteria Bacillus
Theringiensis
Gram-negative
bacteria
K. Pneumoniae
Compound
B. Fabe
F. Oxysporum
6
20
24
20
20
18
23
22
17
25
24
17
20
19
17
15
20
19
15
22
20
14
20
17
17
13
20
20
15
23
22
12
—
13
12
11
—
18
11
20
19
7a
7b
8a
8b
9
10
12a
12b
13c
Reference drugs
Ampicillin
18
19
17
15
EXPERIMENTAL
All melting points are recorded on a Gallenkamp electric melting-point
apparatus and are uncorrected. The IR spectra n cmꢀ1 (KBr) were recorded on a
Perkin-Elmer IR spectrophotometer (model 157, Grating). The H NMR spectra
1
were obtained on a Varian spectrophotometer at 200 MHz using tetramethylsilane
(TMS) as an internal reference and DMSO-d6 as solvent. The mass spectra (EI) were
recorded at 70 eV with Kratos MS equipment and=or a Varian MAT 311 A spec-
trometer. Elemental analyses (C, H, and N) were carried out at the Microanalytical
Center of Cairo University, Giza, Egypt. The results were found to be in good agree-
ment (ꢂ0.3%) with the calculated values. Microbiology screening was carried out in
the Botany Department, Faculty of Science, Mansoura University, under the super-
vision of Prof. Dr. Yhia A. O. Ellazeik and Dr. Ehab Ali Metwally.
Synthesis of 2-(2-Cyano-acetylamino)-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxamide (3)
Chloroacetylamino derivative 2 (1.09 g, 4 mmol) was dissolved in DMF
(20 cm3), and the resulting clear solution was heated to 70 ꢁC. The latter was added
cautiously and gradually to a solution of potassium cyanide (0.26 g, 4 mmol) in 5 cm3
water with stirring. Addition was controlled so that the temperature of the reaction
mixture was maintained at 70 ꢁC. After the complete addition to the cyanide sol-
ution, stirring was continued for a further 15 min, and then the reaction mixture
was cooled and added in portions to an ice-cooled solution of hydrochloric acid
(2 cm3 of conc. HCl in 100 cm3 H2O). The precipitate was filtered off and recrystal-
lized from ethanol to give compound 3: brown powder; yield 70%; mp 175 ꢁC; IR
(KBr) nmax.cmꢀ1: 3436, 3342, 3268 (NH), 2242 (CN) and 1677, 1643 (2C O);
=

NEW THIOPHENE DERIVATIVES
1663
1H NMR (DMSO-d6) d ppm: 1.75 (m, 4H, C5-2H, C6-2H), 2.51 (s, 2H, C4-2H), 2.66
(s, 2H, C7-2H), 7.38 (s, 2H, NH2), and 11.66 (s, 1H, NH); MS: m=z (%) 263 (Mþ,
40.6), 246 (78.4), 206 (100), 178 (24.5), 151 (27.4), 123 (11.9), 91 (16.4) and 68
(40.4). Anal. calcd. for C12H13N3O2S (263.32): C, 54.74; H, 4.98; N, 15.96%. Found:
C, 54.80; H, 5.13; N, 16.1%.
Synthesis of 2-(2-Cyano-2-phenylthiocarbamoyl-acetylamino)-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (5)
An equimolar mixture of cyanoacetamide derivative 3 (1.05 g, 4 mmol) and
KOH (0.22 g, 4 mmol) in dry dimethylformamide (10 cm3) was stirred for 30 min,
and then phenyl isothiocyanate (0.54 gm, 4 mmol) was added. The mixture was stir-
red at room temperature overnight, then poured into ice-cold water and acidified
with 0.1 N HCl to pH 3–4. The resulting precipitate was filtered off, dried, and crys-
tallized from aqueous ethanol to give compound 5; yellow crystals; yield 60%; mp
212 ꢁC; IR (KBr) nmax. cmꢀ1: 3384, 3324, 3197 (NH), 2187 (CN), and 1629 (br,
1
=
2C O); H NMR (DMSO-d6) d ppm; 1.71 (m, 4H, C5-2H, C6-2H), 2.52 (m, 2H,
C4-2H), 2.54 (m, 2H, C7–2H), 6.91–7.73 (m, 7H, Ar-H, CH, NH), and 13.3 (s,
1H, NH); MS: m=z (%) (246) (Mþ-C7H7SN), 222 (17.4), 206 (51.8), 179 (38.8),
151 (35.8), 135 (28.8), 93 (100), and 51 (86.6). Anal. calcd. for C19H18N4O2S2
(398.50): C, 57.27; H, 4.55; N, 14.06%. Found: C, 57.42; H, 4.74; N, 14.23%.
Synthesis of 2-[2-Cyano-2-(3-phenyl-thiazolidin-2-ylidene)-
acetylamino]-4,5,6,7-tetrahydro-benzo[b]thiophene-
3-carboxamide Derivatives (6, 7a, 7b)
Purified thiocarbamoyl derivative 5 (1.594 g, 4 mmol) was dissolved in
dimethylformamide (20 cm3), and the appropriate a-halogenated compounds
(4 mmol) were added. The reaction mixture was heated under reflux for 6 h, cooled,
and neutralized with saturated sodium carbonate solution. The resulting precipitate
was filtered off, dried, and crystallized from benzene–ethanol.
2-[2-Cyano-2-(4-oxo-3-phenyl-thiazolidin-2-ylidene)-acetylamino]-4,5,6,
7-tetrahydro-benzo[b]thiophene-3-carboxamide (6). Brown crystals; yield 70%;
mp 187 ꢁC; IR (KBr) nmax.cmꢀ1: 3384, 3324, 3197 (NH), 2187 (CN) and 1737, 1629 (br)
1
=
(3C O); H NMR (DMSO-d6) d ppm: 1.73 (m, 4H, C5-2H, C6-2H), 2.55 (m, 2H, C4-
2H), 2.64 (m, 2H, C7-2H), 4.15 (s, 2H, CH2CO), 7.10–7.49 (m, 6H, Ar-H, NH2), and
11.3 (s, 1H, NH). Anal. calcd. for C21H18N4O3S2 (438.52): C, 57.52; H, 4.14; N,
12.78%. Found: C, 57.71; H, 4.32; N, 12.68%.
2-[2-Cyano-2-(4-methyl-3-phenyl-3H-thiazol-2-ylidene)-acetylamino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (7a). Brown crystals;
yield 70%; mp 253 ꢁC; IR (KBr) nmax.cmꢀ1: 3388, 3339, 3187 (NH), 2179 (CN),
1
=
1669 (br, 2C O); H NMR (DMSO-d6) d ppm; 1.71 (m, 4H, C5-2H, C6-2H), 1.85
(s, 3H, CH3), 2.58 (m, 2H, C4-2H), 2.66 (m, 2H, C7-2H), 6.98 (s, 1H, thiazolidine
C5-H), 7.51–7.59 (m, 7H, Ar-H, NH2), and 12.02 (s, 1H, NH). Anal. calcd. for
C22H20N4O2S2 (436.55): C, 60.53; H, 4.62; N, 12.83%. Found: C, 60.73; H, 4.87;
N, 12.92%.

1664
A. M. KHALIL ET AL.
2-[2-Cyano-2-(3,4-diphenyl-3H-thiazol-2-ylidene)-acetylamino]-4,5,6,7-
tetrahydro-benzo[b]thiophene-3-carboxamide (7b). Brown crystals; yield 70%;
mp 275 ꢁC; IR (KBr) nmax.cmꢀ1: 3419, 3400, 3256 (NH), 2178 (CN), 1655 (br, 2C O);
=
1H NMR (DMSO-d6) d ppm: 1.77 (m, 4H, C5-2H, C6-2H), 2.59 (m, 2H, C4-2H), 2.73
(m, 2H, C7-2H), 7.16 (s, 1H, thiazolidine C5-H), 7.23–7.55 (m, 12H, Ar-H, NH2), and
11.02 (s, 1H, NH). Anal. calcd. for C27H22N4O2S2 (498.62): C, 65.04; H, 4.45; N,
11.24%. Found: C, 65.21; H, 4.39; N, 11.50%.
Synthesis of 2-[(5-Substituted-4-amino-2-phenylamino-thiophene-
3-carbonyl)-amino]-4,5,6,7–tetrahydro-benzo[b]thiophene-
3-carboxamide (8a, b)
A mixture of compound 5 (1.594 g, 4 mmol) and a-halogenated compounds
(0.04 mmol) in dimethylformamide (20 cm3) in the presence of a catalytic amount
of triethylamine (0.2 cmꢀ3) was refluxed for 6 h. Then, the reaction mixture was
cooled, and the resulting precipitate was filtered off, dried, and crystallized from
benzene–ethanol.
2-[(5-Acetyl-4-amino-2-phenylamino-thiophene-3-carbonyl)-amino]-4,5,
6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (8a). Brown crystals; yield
70%; mp 243 ꢁC; IR (KBr) nmax.cmꢀ1: 3331, 3257, 3189 (NH), 1641, 1654, 1747
1
=
(br, 3C O); H NMR (DMSO-d6) d ppm: 1.73 (m, 4H, C5-2H, C6-2H), 1.85 (s,
3H, COCH3), 2.59 (m, 2H, C4-2H), 2.71 (m, 2H, C7-2H), 6.98–7.6 (m, 7H, Ar-H,
NH2), 10.9 (s, 1H, NH), and 12.0 (s, 1H, NH). Anal. calcd. for C22H22N4O3S2
(454.57): C, 58.13; H, 4.88; N, 12.33%. Found: C, 58.02; H, 4.82; N, 12.19%.
2-[(5-Benzoyl-4-amino-2-phenylamino-thiophene-3-carbonyl)-amino]-
4,5,6,7–tetrahydro-benzo[b]thiophene-3-carboxamide (8b). Brown crystals;
yield 70%; mp 250 ꢁC; IR (KBr) nmax.cmꢀ1: 3412, 3062 (NH), 1748, 1633 (br,
1
=
3C O); H NMR (DMSO-d6) d ppm; 1.73 (m, 4H, C5-2H, C6-2H), 2.64 (m, 2H,
C4-2H), 2.70 (m, 2H, C7-2H), 7.08–8.10 (m, 7H, Ar-H, NH2), 8.2 (br, 1H, NH)
and 12.6 (s, 1H, NH). Anal. calcd. for C27H24N4O3S2 (516.63): C, 62.77; H, 4.68;
N, 10.84%. Found: C, 62.68; H, 4.59; N, 10.72%.
Synthesis of 2-[2-(4-Oxo-4,5-dihydro-thiazol-2-yl)-acetylamino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (9)
Thioglycolic acid (0.368 g, 4 mmol) was added to a solution of compound 3
(1.05 g, 4 mmol) in dioxane (20 cm3). The reaction mixture was heated under reflux
for 10 h and then left to cool to room temperature. The separated crystalline product
was filtered off, dried, and crystallized from benzene–ethanol to give compound 9.
Yellow crystals; yield 65%; mp 314 ꢁC; IR (KBr) nmax.cmꢀ1: 3444, 3309, 3168
1
=
(NH) and 1698, 1645 (2C O); H NMR (DMSO-d6) d ppm; 1.73 (m, 4H, C5-2H,
C6-2H), 2.62 (m, 2H, C4-2H), 2.66 (m, 2H, C7-2H), 4.12 (s, 2H, CH2 thiazolidinone),
7.40 (m, 2H, NH2), and 11.61 (s, 1H, NH); MS: m=z (%) 368 (Mþ, 17.1), 337 (34.3),
245 (22.9), 218 (25.7), 196 (82.9), 179 (100), 151 (57.1), 121 (20), 93 (37.1), and 68
(65.7). Anal. calcd. for C14H15N3O3S2 (337.42): C, 49.83; H, 4.48; N, 12.45%. Found:
C, 49.98; H, 4.62; N, 12.69%.

NEW THIOPHENE DERIVATIVES
1665
Synthesis of 4-Amino-3-phenyl-2-thioxo-2,3-dihydro-thiazole-5-
carboxylic Acid (3-Carbamoyl-4,5,6,7-tetrahydro-benzo[b]thiophen-
2-yl)-amide (10)
A mixture of compound 3 (1.05 g, 4 mmol), finely divided sulfur (0.128 g,
4.4 mmol), and triethylamine (four drops) in DMF (20 cm3) and ethanol (2:1) was
stirred at 60 ꢁC for 30 min. The phenyl isothiocyanate (0.54 g, 4 mmol) was gradually
added, and stirring was continued for 4 h. The separated crystalline product was fil-
tered off, dried, and crystallized from benzene–ethanol to yield compound 10. Pale
yellow crystals; yield 75%; mp 258 ꢁC; IR (KBr) nmax.cmꢀ1: 3451, 3396, 3324,
1
=
=
3255, 3178 (NH) 1625 (br, 2C O) and 1341 (C S); H NMR (DMSO-d6) d ppm:
1.76 (m, 4H, C5-2H, C6-2H), 2.64 (m, 2H, C4-2H), 2.75 (m, 2H, C7-2H), 7.00 (br.,
2H, NH2), 7.41–7.62 (m, 5H, Ar-H) and 12.29 (s, 1H, NH); MS: m=z (%) 430
(Mþ, 16.9), 413 (19.1), 371 (15.2), 235 (32.4) 196 (33.8), 179 (53.7), 151 (22.8), 135
(45.6), 104 (34.6), 77 (100), 51 (61.8). Anal. calcd. for C19H18N4O2S3 (430.57): C,
53.00; H, 4.21; N, 13.01%. Found: C, 53.26; H, 4.32; N, 13.17%.
Synthesis of 2-(2-Cyano-2-[cycloalkylidene]acetamido)-4,5,6,7-
tetrahydro-benzo[b]thiophene-3-carboxamide Derivatives (11a, b)
A mixture containing compound 3 (1.05 g, 4 mmol), sodium acetate (0.328 g,
4 mmol), and cycloalkanone (4 mmol) was refluxed in absolute ethanol (30 cm3)
for 6 h and left to cool at room temperature. The separated crystalline product
was filtered, washed with water, dried, and recrystallized from DMF–methanol to
give compounds 11a, b.
2-(2-Cyano-2-cyclopentylidene-acetylamino)-4,5,6,7-tetrahydro-benzo[b]
thiophene-3-carboxamide (11a). Brown crystals; yield 75%; mp 243 ꢁC; IR (KBr)
1
max.cmꢀ1: 3420, 3253, 3186, (NH), 2214 (CN) and 1668, 1631 (2C O); H NMR
=
n
(DMSO-d6) d ppm: 1.76 (m, 8H, C5-2H, C6-2H, ‘C3-2H, ‘C4-2H), 2.65 (m, 6H,
C4-2H, ‘C2-2H, ‘C5-2H,), 2.78 (m, 2H, C7-2H), 7.56 (s, 2H, NH2), and 12.79 (s,
1H, NH); MS: m=z (%): 312 (Mþ, 100), 179 (79.6), 134 (36.1), 79 (73.3). Anal. calcd.
for C17H19N3O2S (329.42): C, 61.98; H, 5.81; N, 12.76%. Found: C, 62.02; H, 5.94;
N, 12.93%.
2-(2-Cyano-2-cyclohexylidene-acetylamino)-4,5,6,7-tetrahydro-benzo[b]
thiophene-3-carboxamide (11b). Brown crystals; yield 75%; mp > 320 ꢁC; IR (KBr)
1
max.cmꢀ1: 3430 (br, NH), 2184 (CN), and 1646 (br, 2C O); H NMR (DMSO-d6) d
=
n
ppm: 1.73–1.86 (m, 10H, C5-2H, C6-2H, ‘C3-2H, ‘C4-2H, ‘C5-2H), 2.54 (m, 6H, C4-
2H, ‘C2-2H, ‘C6-2H), 2.67 (m, 2H, C7-2H), 6.99 (s, 2H, NH2), and 13.00 (s, 1H, NH).
Anal. calcd. for C18H21N3O2S (343.44): C, 62.95; H, 6.16; N, 12.23%. Found: C, 62.85;
H, 6.07; N, 12.20%.
Synthesis of Thiophene Derivatives 12a, b
Method A. Morpholine (0.33 cm3), elemental sulfur (0.141 g, 4.4 mmol), and
cycloalkanone (4 mmol) were added to solution of compound 3 (1.05 g, 4 mmol) in
absolute ethanol (20 cm3). The reaction mixture was heated under reflux at

1666
A. M. KHALIL ET AL.
60–80 ꢁC for 3 h and left to cool to room temperature. The separated crystalline pro-
duct was filtered, dried, and recrystallized from DMF–acetone to give compounds
12a, b.
Method B. 2-Cycloalkylideneacetamido derivatives 11a (1.318 g, 4 mmol) or
11b (1.374 g, 4 mmol), morpholine (0.33 cm3), and elemental sulfur (0.141 g,
4.4 mmol) in absolute ethanol (20 cm3) were stirred at 60–80 ꢁC for 3 h. The reaction
mixture allow to cool at room temperature; the separated crystalline product was
filtered, dried, and recrystallized from the proper solvent to give compounds 12a, b.
2-[(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonyl)-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (12a). Brown crystals;
yield 75%; mp > 320 ꢁC; IR (KBr) nmax.cmꢀ1: 3395, 3194 (NH), 2204 (CN), and
1
=
1633 (br, 2C O); H NMR (DMSO-d6) d ppm; 1.72 (m, 6H, C5-2H, C6-2H, ‘C5-
2H), 2.62 (m, 4H, C4-2H, ‘C4-2H), 2.71 (m, 4H, C7-2H, ‘C6-2H), 7.06–7.93 (br,
4H, 2NH2), and 11.65 (s, 1H, NH). Anal. calcd. for C17H19N3O2S2 (361.48): C,
56.48; H, 5.30; N, 11.62%. Found: C, 56.63; H, 5.45; N, 11.81%.
2-[(2-Amino-5,6-dihydro-4H-cyclohexa[b]thiophene-3-carbonyl)-amino]-
4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxamide (12b). Brown crystals;
yield 75%; mp 243 ꢁC; IR (KBr) nmax.cmꢀ1: 3444, 3397 (NH) and 1637 (br,
1
=
2C O); H NMR (DMSO-d6) d ppm: 1.75 (m, 8H,C5-2H, ‘C5-2H, C6-2H, ‘C6-
2H), 2.63 (m, 4H, C4-2H, ‘C4-2H), 2.73 (m, 4H, C7-2H, ‘C7-2H), 7.43 (s, 2H,
NH2), and 11.73 (s, 1H, NH); MS m=z (%): 375 (Mþ, 33), 358 (37), 196 (30.8),
180 (100), 151 (20.4), 91 (17.9), 65 (11.1). Anal. calcd. for C18H21N3O2S2 (375.51):
C, 57.57; H, 5.64; N, 11.19%. Found: C, 57.64; H, 5.79; N, 11.35%.
Synthesis of 2-[3-(Aryl)-2-cyano-acryloylamino]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxamide (13a, b)
A well-stirred solution of compound 3 (1.05 g, 4 mmol) in absolute ethanol
(20 cm3), piperidine (0.2 cm3), and appropriate aromatic aldehyde (4 mmol) were
added to the solution. The reaction mixture was stirred at 80 ꢁC for 3 h, during which
time crystals separated out. The crystalline product was filtered, washed with etha-
nol, dried, and recrystallized from ethanol–benzene to give compounds 13a, b.
2-[3-(4-Chloro-phenyl)-2-cyano-acryloylamino]-4,5,6,7-tetrahydro-benzo
[b]thiophene-3-carboxamide (13a). Yellow crystals; yield 65%; mp 285 ꢁC; IR
1
(KBr) nmax.cmꢀ1: 3430, 3289, 3270 (NH), 2213 (CN), and 1668, 1639 (2C O); H
=
NMR (DMSO-d6) d ppm: 1.78 (m, 4H, C5-2H, C6-2H), 2.52 (m, 2H, C4-2H), 2.90
=
(m, 2H, C7-2H), 7.36 (br, 2H, NH2), 7.68–8.43 (m, 5H, Ar.H, CH), and 13.16 (s,
1H, NH); MS m=z (%): 385 (Mþ, 46.5), 368 (100), 333 (30.2), 305 (14.1), 206 (15),
190 (66.8), 162 (54.1), 127 (48.3), 91 (19.9), 75 (25.2). Anal. calcd. for
C18H16N3O2SCl (385.87): C, 59.14; H, 4.18; N, 10.89%. Found: C, 59.32; H, 4.29;
N, 10.98%.
2-(2-Cyano-3-thiophen-2-yl-acryloylamino)-4,5,6,7-tetrahydro-benzo[b]
thiophene-3-carboxamide (13b). Yellow crystals; yield 65%; mp 280 ꢁC; IR (KBr)
1
max.cmꢀ1: 3432, 3317, 3253, 3190 (NH), 2208 (CN), and 1661, 1633 (2C O); H
=
n

NEW THIOPHENE DERIVATIVES
1667
NMR (DMSO-d6) d ppm: 1.74 (m, 4H, C5-2H, C6-2H), 2.52 (m, 2H, C4-2H), 2.65 (m,
=
2H, C7-2H), 7.38–8.17 (m, 6H, Ar-H, NH2), 8.59 (s, 1H, CH C), and 13.01 (s, 1H,
NH). Anal. calcd. for C17H15N3O2S2 (357.45): C, 57.12; H, 4.23; N, 11.76%. Found:
C, 57.41; H, 4.36; N, 11.92%.
2-[2-Cyano-2-(p-tolyl-hydrazono)-acetylamino]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylic Acid Amide (14)
Preparation of the diazonium salt. A solution of sodium nitrite (0.283 g,
4.1 mmol, in 2 cm3 water) was gradually added to a well-cooled solution of p-
toluidine (0.429 g, 4 mmol) in conc. hydrochloric acid [(1.5 cm3) in water (2 cm3)].
The diazonium salt solution was added dropwise with continuous stirring to a cold
solution of 3 (1.05 g, 4 mmol) in pyridine (10 cm3). The reaction mixture was stirred
at 0–5 ꢁC for 2 h and left to stand at room temperature. The solid products that
obtained were filtered off, dried, and recrystallized from ethanol to give compound
14: orange powder; yield 80%; mp 300 ꢁC; IR (KBr) nmax.cmꢀ1: 3166, 3237, 3315,
3409, 3432 (NH), 2215 (CN) 1656 (br, 2C O), and 1527 (N N); 1H NMR
=
=
(DMSO-d6) d ppm: 1.76 (m, 4H, C5-2H, C6-2H), 2.32 (s, 3H, CH3), 2.65 (m, 2H,
C4-2H), 2.76 (m, 2H, C7-2H), 7.2–7.9 (m, 6H, Ar-H, NH2), 12.26 (br, 1H, NH),
þ
=
=
12.89 (s, 1=2 H, NH N), and 13.25 (s, 1=2 H, NH N); MS: m=z (%) 381 (M ,
52.2), 331 (19.8), 179 (43.8), 91 (100). Anal. calcd. for C19H19N5O2S (381.45): C,
59.82; H, 5.02; N, 18.36%. Found: C, 59.74; H, 4.91; N, 18.16%.
ACKNOWLEDGMENTS
We express our sincere thanks to Prof. Dr. Yhia A. O. Ellazeik and Dr. Ehab
Ali Metwally, Botany Department, Faculty of Science, Mansoura University, for
microbiological screening.
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